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Board Studying > Biochem > Flashcards

Biochem Flashcards

1
Q

Common GBA mutations

A

AJew: N409S (formerly N370S)

Europe: L483P (formerly L444P)

  • Original nomenclature not include first 39AAs
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2
Q

increased aminoadipic acid semialdehyde (AASA), increased pipecolic acid

A

Pyridoxine Dependent Epilepsy (aminoadipic acid semialdehyde dehydrogenase)

ALDH7A1 (antiquitin)

  • High P6C complexes with pyridoxal 5 phosphate (B6)

Tx: B6, folinic acid, lysine restriction, arginine supplement

DDx; PNPO deficiency

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3
Q

Neuroimaging for GA1

A

Subarachnoid collections, Sylvian fissure enlargement, BG strokes

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4
Q

GA1 treatment

A

Limit substrate: Lysine free, reduced tryptophan; carnitine (glutaryl carnitine can be excreted), ?add arginine (compete with transporter)

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5
Q

ACP: C5DC

Low carnitine

UOA: 3-OH glutaric acid, glutaric acid

A

GA1

Clinical: Macrocephaly, encephalopathy, strokes (up to age 6, natural flux of transporter decreased as brain matures)

Gene: Glutaryl-CoA dehydrogenase (GCDH)

UOA: glutaric acid, 3-OH Glutaric acid (co-elutes with 2OH-GA) Decreased carnitine

ACP: glutarylcarnitine = C5DC LOW EXCRETERS EXIST

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6
Q

DDx for elevated glutaric acid in urine

A

gut bacteria overgrowth

ketosis

SCHAD (breaks down 3OH-glutaryl-CoA),

mitochondrial,

2OH-GA in GA2,

benign GA3 (NO C5DC),

renal disease,

maternal GA1

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7
Q

DDx for high glycine

A

NKH

VPA treatment

Ketotic (PA, MMA, IVA, B-ketothiolase deficiency)

PNPO deficiency

HIE (BBB breakdown)

prolonged fasting

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8
Q

Lipoic acid dependent pathways

A

BCKDH, PDH, 2-KGDH, 2-OADH, GCS (glycine cleavage system)

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9
Q

AA (CSF and Plasma) : Glycine elevated, Glycine CSF/Plasma ratio > .08

A

NKH

Genes: glycine decarboxylase/dehydrogenase (GLDC), aminomethyltransferase (AMT), Modified lipoic acid/dihydrolipoyl dehydrogenase (GCSH)

Elevated lactate in variant forms (lipoic acid/iron-sulfur cluster disorders)

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10
Q

NKH treatment

A

Na-Benzoate - conjugate with glycine to form hippurate which can be excreted;

dextromethrophan/ketamine for NMDA antagonism; folinic acid

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11
Q

Cherry Red Spots

A

NP-A (HSM)

GM1 gangliosidossis (HSM)

GM2 gangliosidosis (no HSM)

Sialidosis

Krabbe

Farber

Metachromatic leukodystrophy

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12
Q

Gaucher therapies

A

ERT: Imiglucerase, velaglucerase, taliglucerase

SRT: miglustat, eliglustat

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13
Q

Fabry therapies

A

ERT: agalsidase-beta, agalsidase-alpha

Chaperone: migalastat

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14
Q

Angiokeratomas

A

Fabry (a-Gal) - + renal/cardiac/stroke

Fucosidosis (a-fucosidase) - FUCA - + MPS features

B-Manosidosis (ID) - MANBA - + ID/neuropathy

Schilder (NAGA - aka a-GAL-B) - +neurodegeneration

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15
Q

Extensive mongolian spots

A

MPSI, MPSII, GM1

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16
Q

Heparan sulfate

A

Heparan = Head

MPS I, II, III, VII (Brain involvement)

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17
Q

Dermatan sulfate

A

Dermatan = bone + systemic

MPS I, II, VI, VII (Bone)

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18
Q

Keratan sulfate

A

MPS VI (Bone)

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19
Q

A-L-Iduronidase deficiency Treatment

A

MPS1 Hurler

HSCT before age 2

ERT: Iaronidase

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20
Q

Distinguishing features of MPSII vs MPSI

A

X linked

No corneal clouding

Dermal pebbling

Iduronidase 2- sulfatase

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21
Q

Iduronidase Sulfatase def. treatment

A

MPS II - Hunter

ERT: Idursulfase

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22
Q

MPSIII diagnosis

A

Urine: Heparan sulfate

Gene/enzyme:

Heparan N-Sulfatase (SGSH)

Alpha-N-acetyl-glucosaminidase (NAGLU)

aceyl-coa-glucosaminide acetyltransferase (HGSNAT)

N-acetylglucosamine-6-sulfatase (GNS)

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23
Q

MPS IV diagnosis

A

Morquio

Urine: Keratan sulfate

Normal intellect

Enzyme:

N-acetylgalactosamine-6-sulfatase (GALNS)

Beta-galactosidase (GLB1, Same enzyme as GM1 gangliosidosis)

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24
Q

Morquio treatment

A

ERT: Elosulfase Alpha for type IV A

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25
Q

arylsulfatase B

A

MPS VI - Maroteaux Lamy

Enzyme: ARSB

Clinical: Normal intellect, macrocephaly, bone involvement

ERT: Galsufase

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26
Q

Beta glucuronidase

A

MPS VII (GUSB) - Sly

Hurler like

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27
Q

a-mannosidosis

A

Gene: MAN2B1 (manosidase alpha)

Clinical: MPS like

Dx: urine oligosaccharides, GAGs NORMAL

Tx: HSCT

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28
Q

Neuraminic acid in urine, cherry red spot

A

Sialidosis

Enzyme/Gene: Acid sialidase (a-neuroaminidase NEU1) - sialic acid is BOUND to other sugars since this cleaves SA

Type 1: Cherry red spot, myoclonus, decreased vision

Type 2: progressive psychomotorsymptoms, kyphosis, dysmorphic, ataxia, deafness neonatal: congenital hydrops

Dx: urine neuraminic acid, oligosaccharides

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29
Q

Angiokeratoma, ID, neuropathy

A

B mannosidosis

MANBA gened (beta mannosidase)

Dx: urine oligosaccharides

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30
Q

Neurodegeneration, HSM, dysostosis, angiokeratomas

A

Fucosidosis

FUCA1 gene (Fucosidase)

Dx: Urine oligosaccharides

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31
Q

Schindler disease

A

a-N-acetylgalactosaminidase/a-galactosidase B (NAGA)

Clin: neurodegenration, myoclonic epilepsy

Dx: Urine oligosaccharides

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32
Q

HSM, neurodegeneration, connective tissue changes

A

Aspartylglucosaminuria Aspartylglucosaminase (AGA)

Oligosaccharidosis

Dx: Urine oligos, enzyme testing

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33
Q

UPDGlcNAc 1-P-transferase deficiency

A

Mucolipidosis II and III diagnosis (I cell disease/Pseudo Hurler)

  • Unable to phosphorylate mannose -> cannot get enzymes into lysosomes
  • MPS like + gingival hyperplasia

Dx: Elevated urine GAGs

Normal WBC (lysosomal) enzyme activity with elevated plasma enzyme activity due to improper targeting (mannose 6 P)

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34
Q

Salla disease

A

Sialic Acid Storage

Gene: SLC7A5 (#7) in picture

Biochem: Sialin deficiency -> deficient sialic acid (N-actylneuraminic) transport out of lysosome

Clin: Hypotonia, neurodevelopmental, ataxia, spasticity, epilepsy

Dx: Free sialic acid in urine (also seen in GNE)

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35
Q

Sialiduria

A

Gene: GNE (UDP Acetylglucosamine 2 epimerase)

Myopathy OR ID, HSM, seizures

Dx: Urine sialic acid

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36
Q

Cystinosis

A

Gene: CTNS (Cystinosin)

Biochem: Lysosomal cystin transportin

Clin: FTT, HSM, myopathy, corneal crystals, thyroid, pancreas, testes, renal fanconi, renal failure

Dx: cystine in leukocytes

Tx: Cysteamine and cysteamine eye drops

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37
Q

Fabry urine biomarket

A

GL3

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38
Q

Acid B-galactosidase deficiency

A

GM1

Morquio type B

galactosialidosis

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39
Q

GM1 clinical subtypes

A

Infantile: Hydrops, neurodevelopmental arrest, HSM, dysostosis multiplex, cherry red spot, vision loss, death by 2

Juvenile: ataxia, HSP

Adult: ataxia, dystonia

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40
Q

Foamy histiocytes, Vacuolated lymphocytes

Low B-galactosidase activity

+ cherry red spot, spasticity, HSM

NORMAL neuraminidase assay

A

GM1 gangiosidosis

GLB1

  • Hypotonia, DD, coarse facies, dysostosis multiplex, cherry red spot, HSM, spasticity
  • Need to do neuraminidase assay when B-Galactosidase is abnormal to rule out galactosialidosis
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41
Q

Biochem types of GM2

A

Tay Sachs - Hex A

Sandhoff - Hex B (elevated urine oligos, varuolated lymph)

GM2 activator protein (both Hex A and B levels normal)

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42
Q

What are the 3 clinical subtypes of GM2 gangliosidosis?

A

Infantile: Macrocephaly, cherry red macula, neuro issues, vision loss

Juvenile: ataxia, cognitive, vision loss, seizures, weakness

Adult: ataxia, neuromuscular, neuropsych

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43
Q

Sphingomyelinase deficiency (SMPD)

A

Niemann Pick A and B

A: HSM, cherry red manula, neurological, interstitial lung disease

B: MIlder, + hyperlipidemia, normal intellect

Dx: Foam cells in bone marrow

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44
Q

Sea blue histiocytes, abnormal cholestane-3β-5α-6β-triol, 7-ketocholesterol (oxysterols), filipin positive

A

NPC

NPC1 and NPC2 (intracellular cholesterol transporter)-> cholesterol storage

  • Neontal: Hydrops, cholestasis, liver failure, HSM, thrombocytopenia,
  • Juvenile: neurodegeneration w/ movement do, vertical supranuclear gaze palsy, cherry rest spot (50%), epilepsy, cataplexy, dystonia
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45
Q

NPC clinical symptoms

A

Supranuclear gaze palsy, HSM, cherry red spots, neuro

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46
Q

NPC treatment

A

SRT: Miglustat

HSCT

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47
Q

B-galactocerebrosidase disease

A

Krabbe

GLAC

Clinical: WM disease, extreme irritability

Adult form: vision loss, neuropsych

Dx: CSF protein up

Tx: HSCT before 1 month?

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48
Q

Metachromatic leukodystrophy

A

ARSA (Arylsulfatase A)

Clinical: CNS, peripheral neuropathy

Dx: urine sulphatides, CSF protein

Beware Pseudo Deficiency

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49
Q

Pompe associations

A

Cardiomyopathy

Short PR

Myopathy

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50
Q

Pompe treatment

A

ERT: Aglucosidase alpha

Immune modulation if CRIM negative

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51
Q

Pompe diagnosis

A

GAA (a-glucosidase)

Urine HEX4

oligosaccharides

Vacuolated lymphocytes

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52
Q

NCL symptoms

A

Seizure

vision loss

neurodegenerative

extrapyramidal

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53
Q

Buffy Coat EM for ceroid storage, vacuolated lymphocytes

A

NCL fibroblast findings

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54
Q

LSD with Adrenal calcifications

A

Wolman Disease

Gene: LIPA (lysosomal acid lipase)

Biochem: storage of cholesterol esters and TG

Clin: Adrenal calcifications, diarrhea, steatorrhea, HSM, anemia

Dx: Elevated cholesterol

Tx: Statins, ERT - sebelipase alpha

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55
Q

SRTs for Gaucher, Fabry, NPC

A

Gaucher - eliglustat, miglustat

Fabry - migalastat

NPC - miglustat

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56
Q

Features of peroxisomal disorders

A

Dysmorphic: large fontanelle, high forehead, shallow supraorbital ridge, epicanthal folds, micrognathia

Ears: ear anomalies, hearing loss

Eyes: Retinal dystrophy, cataracts

Liver: Cholestasis/Cirrhosis

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57
Q

Dx of Zellweger Spectrum

A

VLCFA up

Plasmalogen nl or low

Phytanic acid/pristanic acid/bile acids nl or high (phytanic from diet so normal in newborns)

Pipecolic acid high

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58
Q

MRi findings in ZSD

A

Zellweger: pachypolymicorgyria neonatal

ALD: WMS

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59
Q

Isolated Plasmalogen low

A

RCDP

PEX7 (phytanic acid high, pristanic acid low)

Alkylglycerone-phosphate synthase (AGPS)

Glyceronephosphate O-acyltransferase (GNPAT)

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60
Q

RCDP + Hypoplasia of distal phalanges

A

XL RCDP - males

Gene: ARSE

Hypoplasia of distal phalanges

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61
Q

XL RCDP - females

A

Conradi Hunermann

Gene: EBP - Sterol delta-8 isomerase (male lethal)

Dx: 8-dehydrocholestrol, 8(9)-cholesterol

  • Assymetric
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62
Q

DDx for chondrodysplasia punctata

A

RCDP

XL RCDP (male and female forms)

Warfarin embryopathy

Maternal SLE

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63
Q

Most common peroxisomal disorder

A

XALD

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64
Q

Forms of XALD

A

ALD, ANM, Addison’s

  • all boys with adrenal insufficiency should be checked because this can precede neurological sx
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65
Q

XALD Diagnosis

A

ABCD1 gene

ATP binding cassette transporter for saturated VLCFAs into peroxisome

Disorder of Beta-Oxidation

Biochem: elevated VLCFA (C26:0)

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66
Q

XALD treatment

A

Early HCST - will take 6-9 months for new glial to be functional -> need to transplant at neurological changes

HSC gene therapy

Lorenzo’s oil (glyceryl trioleate and trierucate 4:1)

Hormone replacement - steroids

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67
Q

XALD in females

A

20% develope late onset neurological changes, adrenal problems rare

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68
Q

XALD brain MRI

A

occipital/parietal leukodystrophy

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69
Q

Which peroxisomal disorder has normal VLCFA

A

RCDP

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70
Q

High phytanic acid, low pristanic acid

A

Adult Refsum Disease

PHYH (Phytanyl CoA hydroxylase)

Clin: RP, neuropathy, ataxia, deafness, ithchyosis, skeletal, cardiac , NORMAL intellect

Dx: high phytanic acid, low pristanic acid, high CSF protein

Tx: Phytanic acid restriction, PLEX

  • can be misdiagnosed as Usher
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71
Q

Dx: Elevated bile acids, high pristanic acid

A

a-methyl-acyl-CoA racemase deficiency

AMACR (isomerase that converst pristanic acid and bile acids to form needed for B-oxidation)

Adult neuropathy, encephalopathy, neonatal hepatopathy

Tx: bile acid substitution

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72
Q

Joint contracture, Skin nodules, Hoarse voice, neurodegeneration

  • Allelic with SMA-PME
A

Farber disease - acid-ceramidase deficiency

ASAH

Clin: joint, skin nodules, hoarseness, neuro

Tx: HSCT

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73
Q

Saposin Disorders

A

PSAP gene (Protein cleaved into 4 small molecules required for sphingolipid hydrolysis)

A: variant Krabbe (galactosylceramidase)

B: Variant MLD (arylsulfatase A)

C: Variant Gaucher (B-glucosidase)

Combined: severe neuro/HSM

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74
Q

Wolf Parkinson White + pompe like LSD

A

Danon Disease LAMP2 (X linked) - membrane protein

Pompe-like (liver, heart, muscle) + WPW sndrome

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75
Q

Gaucher Buzzwords

A

HSM

horizontal saccades (horizonal supranuclear gaze palsy)

tissue paper macrophages

erlenmeyer flask

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76
Q

Hepatic/hypoglycemia GSDs

A

0, 1

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77
Q

Muscle GSDs

A

V, VII

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78
Q

Mixed GSDs

A

III, IV, VI, IX

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79
Q

GSD1 Dx

A

Gene: G6PC (G6Phosphatase), SLC37A4 (G6P Transporter)

  • Last step of gluconeogenesis

Labs: high lactate, TG, uric acid, low glucose

glucose challenge -> fall in lactate

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80
Q

GSD1 features

A

Doll-like facies, big belly, thin extremities

Type 1B also has neutropenia/infections

Monitor: hepatic adenoma, IBD, renal function, osteopenia, anemia

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81
Q

GSD3 features

A

Cori/Forbes

Muscle and liver involvement

Milder than type 1 (debranching enzyme, so can process some glycogen)

+ Cardiomyopathy

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82
Q

Hepatic GSD

PAA: low ala, leu, ile, val

A

GSD3 - Cori

AGL (debranching enzyme)

Gluconeogenesis is funcitonal -> can use proteins for energy

Elevated LFTs, TG, lactate

Tx: same as GSD1, but add alanine (alanine -> pyruvate), fructose, and galactose

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83
Q

Polyglucosan accumulation, FTT, cirrhosis, fetal akinesia

Adult neurodegeneration

A

Andersen, GSD IV

GBE1 (branching enzyme)

  • Polyglucosan = unbranched glycogen -> can accumulate in CNS too

TFF, Hepatomegaly, cirrhosis, neuromuscular, HCM

Dx: enzyme assay

Tx: Transplant

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84
Q

Hepatic GSDs that resolved in puberty

A

GSD6: Hers Disease, PYGL (Liver phosphorylase)

GSD9: Phosphorylase Kinase subunits: PHKA (X LINKED); PHKB, PHKG2 (AR)

Clinical: Hepatic GSD, mild, hepatomegaly decreases with age

Dx: Low glu, high lactate, LFTs; glucose challenge -> Rise in lactate

Tx: maintain normoglycemia

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85
Q

GSD0

A

Glycogen synthase Clin: FTT, hypoglycemia, NORMAL liver size (cannot make glycogen)

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86
Q

Muscle GSDs

A

Type 5, Mcardles: PYGM (Phosphorylase)

Type 7, Tauri: PFKM (PFK)

X linked: PHKA1 (phosphylase kinase)

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87
Q

Fanconi-Bickel Disease

A

GSD XI

GLUT2 (SLC2A2 - glucose transporter)

Clin: FTT, renal fanconi, rickets, aminoaciduria, phosphaturia, glucosuria, malabsorption, large liver AND kidneys

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88
Q

Most common CDG

A

PMM2 (CDG1a)

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89
Q

PMM2-CDG features

A

cherubic face

inverted nipple

fat pads

oringe peel skin

neuropsych

RP

dysostosis multiple

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90
Q

Where are N linked glycans attached

A

Nitrogen of Asn in part of Asn-X-Ser consensus sequence

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91
Q

N linked glycosylation functions

A

Protein stability

complex formation

leukocyte targeting/inflammation

cell-cell recognition

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92
Q

O linked glycosylation functions

A

ABO groups

antibacterial

sperm binding

cell adhesion/migration

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93
Q

Causes of abnormal isoelectric focusing

A

CDG

Transferrin polymorphisms

HFI/Galactosemia

EtOH use

Liver Disease

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94
Q

O linked CDG features

A

Muscle-eye-brain disease

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95
Q

GPI anchor disorders cause…

A

Seizures, ID

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96
Q

CDG1b (MPI) symptoms

A

protein losing enteropathy

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97
Q

Which CDG do you treat with mannose

A

CDG1b, phosphomannose isomerase (MPI)

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98
Q

Which CDG uses fructose, xylose, and mannose

A

O-linked

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99
Q

Hex4 can be seen in

A

Pompe

CDG-MOGS (hypotonia, dysmorphic)

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100
Q

Dolichol CDG features

A

bone, skin, growth issues (cholesterol pathway)

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101
Q

CDG treated with heart transplant

A

DOLK1 CDG

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102
Q

Wilson-like CDG without KF-rings

A

MPI, TMEM199, ATP6AP1 Treat with transplant

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103
Q

Electron movement in ETC complexes

A

I - NADH -> CoQ

II - FADH2 -> CoQ

III - CoQ -> Cytochrome C

IV - Cytochrome C -> O2 (pump H+)

V - Proton flow back for ATPase

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104
Q

A3243G, tRNA-leuUUR

A

MELAS mutation

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105
Q

high ornithine, normal ammonia, vision loss

A

OAT (ornithine aminotransferase deficiency)

biochem: High ornithine, low creatinine (Orn is product of AGAT, first step of creatine synthesis)

Gyrate atrophy of retina (peripheral vision loss) + cataracts

Tx: Pyridoxine, arginine restriction (after neonatal period)

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106
Q

PAA: high proline

UOA: high proline, OH proline, normal P5C

A

Hyperprolinemia type 1

PRODH (proline oxidase)

Asymptomatic, risk for schizophrenia

Heterozygotes also have high proline

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107
Q

PAA: high proline

UOA: high proline, OH proline, P5C

A

Hypreprolinemia type 2

ALDH4A1 (P5C dehydrogenase)

Epilepsy, ID, pyridoxine deficiency (P5C binds pyridoxine)

Tx: may respond to pyridoxine

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108
Q

High OH proline + XLE

A

hydroxyprolinuria

OHproline oxidase deficiency (takes place in extracellular matrix)

non-disease, but false positive for MSUD because it looks the same as Leu, Ile, and AlloIle on Mass Spec

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109
Q

ID, Ulcers, infections

A

Prolidase Deficiency

PEPD (peptidase- degrade dipeptides with N terminal Prolines)

Dx: UAA - iminodipeptides elevated

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110
Q

PAA: low proline, ornithine, arginine, citrulline

A

Hypoprolinemia

P5CS (P5C synthase deficiency)

Cataract, ID, joint laxity, hyperammonemia

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111
Q

P5C reductase deficiency

A

PYCR1 and 2

1: cutix laxa, osteopenia
2: leukodystrophy

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112
Q

PAA and CSF: Low Serine

A

PGDH, PSAT, PSPH (dehydrogenase, aminotransferase, and phosphotase)

Biochem: Serine synthesized from 3-P-glycerate (glycolysis)

May have low glycine and CSF MTHF

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113
Q

Clinical features of serine deficiency

A

Clinical:

Neu-Laxova syndrome (IUGR, severe dysmorphic features and malformations including CNS)

Infantile form: CNS/cataracts, ichthyosis

Tx: Serine supplementation

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114
Q

Low ASN

A

Asparagine synthase deficiency (ASNS)

Biochem: converts ASP -> ASN

Clinical: severe CNS, hyperekplexia

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115
Q

Isolated CSF Serine deficiency

A

SLC1A4 – ASCT1 neutral amino acid transporter

CNS Serine transporter

Hypomyelination, atrophy, spasticity

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116
Q

Low glutamine, normal glutamate

A

Glutamine synthetase deficiency (GLUL)

Hyperammonemia Severe CNS, limb defects

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117
Q

High glutamine, normal glutamate

A

Glutaminase deficiency (GLS)

Can be caused by 5’UTR expansion

DD, spasticity, seizures, cerebellar atrophy

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118
Q

Low glutamine, high glutamate (UAA, MRS)

A

Glutaminase hyperactivity (GLS)

NORMAL Glu/Gln in plasma and CSF

DD, regression, cataracts, subcutaneous nodules

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119
Q

Low GAA (Guanidinoacetic acid), Creatine, Creatinine; decreased Creatine/Cr

A

AGAT (Arginine-Glycine amidinotransferase)

GATM gene

Biochem: Arg + Glycine -> Ornithine + GAA

Clinical: ID

Tx: Creatine supplement

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120
Q

High GAA, low Creatine, decreased Creatine/Cr

A

GAMT (Guanidinoacetate methyltransferase)

Biochem: GAA + SAM -> Creatine

Clinical: ID, epilepsy, movement do

Tx. Creatine, arginine, ornithine supplement, Na Benzoate

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121
Q

High Creatine/Cr ratio; low Creatine in MRS

A

Creatine transporter

SLC6A8

X linked

ID (up to 2% of all boys with ID), epilepsy

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122
Q

Urine: 3-methylcrotonylglycine, 3-OH-IVA

ACP: C5OH

A

3MCC

Gene: MCCA, MCCB

Likely aysmptomatic, may decompensate + secondary carnitine deficiency

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123
Q

Homogentisic acid in urine

A

Alkaptonuria

HGD gene

Arthritis, ochronosis, dark coloration of urine with exposure, thyroid dysfunction, aortic stenosis, prostate stone

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124
Q

CAVA

A

Carbonic anhydrase

Biochem: water + CO2 -> bicarb (needed for CPS1, TCA cycle)

Clinical: hyperammonemia + hypoglycemia

Lab: high ammonia, lactate, ketone, glutamine, maybe carboxylate metabolites

Tx: Like UCD (carbaglu)

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125
Q

Urine: Elevated Cystine + Arg, Lys, Orn + nitroprusside test

A

Cystinuria

SLC3A1 (AR), SLC7A9 (AD)

Nephrolithiasis, may be part of deletion syndrome on 2p

Tx: hydration, urine alkinization with K-Citrate, diet, Thiols/captopril to reduce cystine in to cysteine

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126
Q

Treatment of Pterin defects

A

L-Dopa

5Oh Tryptophan (serotonin precursor)

Kuvan (tetrahydroBiopterin)

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127
Q

Pterin pathway

A

GTP -(GTPCH)-> (PTPS) -> (SR) -> BH4 -(PCD) -> BH2 -(DHPR)-> BH4

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128
Q

Normal Phe, Low Neopterin, Low Biopterin

A

GTPCH (GTP Cyclohydrolase)

GCH1 gene

Dopa Responsive Dystonia

  • Homozygotes can have high phe
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129
Q

Normal Phe, Normal Neopterin, High Sepiapterin

A

SR (Sepiapterin Reductase)

SPR gene

Dopa Responsive Dystonia

  • CSF neopterin can be high or normal
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130
Q

High Phe, High Neopterin, Low Biopterin

A

PTPS (6-pyruvyl tetrahydropterin syntase)

PTS gene

DD, hypotonia, epilepsy, dystonia

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131
Q

High Phe, High Neopterin, Low/Normal Biopterin, Primapterin (Urine)

A

PCD (Pterin Carbanoamine Dehydratase)

PCBD1 gene

Motor symptoms Allelic with hypomag and MODY

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132
Q

High Phe, normal neopterin, high biopterin

A

DHPR (Quinoid dihydropteridine reductase)

QDPR gene

severe CNS

Tx: Dopa, 5OH-Try, Folinic acid (secondary cerebral deficiency)

Do NOT give Kuvan (tetrahydrobiopterin)

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133
Q

Clinical subtypes of porphyria

A

Hepatic/neurovisceral

Cutaneous Blistering (normal urine PBG)

Cutaneous non-blistering (High protoporphyrin)

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134
Q

Hepatic Porphyria: High urine aminolevulinic acid, normal porphobilinogen

A

ALAD (PGB synthase)

AR - Aminolevulinic acid dehydratase prophyria

Hepatic

DDX for high ALA: tyrosinemia, lead poisoning

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135
Q

Hepatic Porphyria: High porphobilinogen,; no fecal findings

A

Acute intermittent prophyria (HMBS)

AD

Hepatic

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136
Q

Treatment of hepatic/neurovisceral porphyrias

A

1) Hemin (feedback inhibition)
2) carb load (inhibit ALAS - first step)
3) Givosiran (siRNA for ALAS)

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137
Q

Hepatic Porphyria: High PGB, High fecal coproporphyrin

A

Heriditary coprophorphyria (CPOX)

AD

Biochem -> coprophorphyrin oxidase

Hepatic and blistering

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138
Q

Hepatic porphyria: High PGB, high fecal copro and proto porphyrin

A

Porphyria Variegata (PPOX)

AD

Biochem: protoporphyrin oxidase

Hepatic and blistering

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139
Q

Cutaneous Blistering: high PGB, fecal coproporphyrin

A

Coproporphyrinogen oxidase

CPOX

Hepatic and blistering porphyria

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140
Q

Cutaneous Blistering: high PGB, fecal copro and protoporphyrin

A

propoporphyrinogen oxiddase

PPOX

Hepatic and blistering porphyria

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141
Q

Porphyria Cutanea Tarda Tx

A

Hydroxychloroquine and phlebotomy

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142
Q

Biomarker for porphyrias

A

Hepatic: ALA high during episodes, high urine PBG (except for ALAD)

Blistering: normal uring PBG

Non blistering: RBC protoporphyrin

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143
Q

Cutaneous Blistering: normal PGB, coproporphyrin > uro/carboxylated porphyrins

A

Congenital erythorpoietic porphyria (UROS)

URO synthetase

Severe skin + corneal ulceration + teeth discoloration + red urine + hemolytic anemia

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144
Q

Cutaneous Blistering: normal PGB, uro/carboxylated porphyrins > coproporphyrin

A

Porphyria Cutanea Tarda (AD)

(UROD) - dehydrogenase

Adult onset, most common porphyria (can be secondary)

Hepatoerythropoetic porphyria (AR) - Homozygotes have severe infantile presentation of skin, teeth + hemolytic anemia just like UROS (previous enzyme in pathway)

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145
Q

Non-blistering porphyria: high protoporphyrin (RBC, fecal), RBC zinc < 15%

A

erythropoetic protoporphyria FECH (ferrochelolase)

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146
Q

Non-blistering porphyria: high protoporphyrin (RBC, fecal), RBC zine 15-50%

A

X-linked protoporphyria ALAS (ALA synthase) hyperactivity

  • Deficiency - X linked siderloblastic anemia
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147
Q

Haem Metabolism pathway

A

Glycine + succinyl CoA -(ALAS)-> :Non-blistering

ALA -(ALAD)-> :Hepatic

Porphobilinogen -(HMBS)-> :Hepatic

Hydroxymethylbilane -(UROS)-> :Blistering + hemolytic

Urophyrinogen -(UROD)-> :Blistering

Coproporphyrinogen -(CPOX)-> :Hepatic/Blistering

Protoporphyrinogen -(PPOX)-> :Hepatic/Blistering

Protoporphyrin -(FECH) -> :Non-blistering Haem

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148
Q

What are the protoporphyrias

A

non-blistering cutaneous porphyrias (Sun -> Pain)

ALAS hyperactivity (first step of pathway)

FECH (Ferrochetolase - Last step of haem synthesis)

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149
Q

Name the 2 ALA - synthase diseases

A

X linked protoporhyria (Hyperactivity)

X linked sideroblasatic anemia (deficiency)

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150
Q

Which porphyrias are both hepatic and blistering

A

Hereditary Coproporphyria (CPOX) and Variegate porphyria (PPOX)

  • Both caused by oxidase deficiencies
  • Final 2 steps of pathway before ferrochetolase
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151
Q

What are the main products of Trytophan degradation?

A

Niacin (B3), Melatonin, Serotonin

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152
Q

UAA: High Ala, Ser, Thr, His

PAA: Low Ala, Ser, Thr, His

A

Hartnup SLC6A19 (B0AT1 protein)

Neutral AA transporter

Dermatitis, Diarrhea, Dementia (Pellagra like) + Cerebellar Most asymptomatic (dietary niacin?)

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153
Q

How to tell apart Hartnup from Fanconi or generalized aminoaciduria on UAA?

A

Gly, proline, Met are normal in Hartnup

high in Fanconi/aminoaciduria

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154
Q

Trp transporter defect

A

Blue diaper syndrome

Bacterial convert trp to indole –> blue eye

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155
Q

UOA: Xanthurenic acid

A

Kynureninase and HAAO deficiency

Biochem: Trp -X-> niacin VACTERL-like,

hyperphalangism (extra bone in prox. middle phalanges)

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156
Q

Hypertryptophanemia

A

Tryptophan Dioxygenase Deficiency (TDO)

non-disease

Tx: nicotinic acid (niacin) supplement

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157
Q

Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deficiency

A

Leber congenital amaurosis

Congenital coloboma, optic atrophy NAD biosynthesis defect

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158
Q

ACP: Elevated C10:2

A

Dienoyl-Coa reductase (DECR)

NADK2

Defect in NAD phosphorylation to NADH

CNS: Movement do, seizure, hypotonia, optic atrophy

PAA: high lysine

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159
Q

Hydrated NAD (NADHX) repair defects

A

NAXD (dehydrogenase) and NAXE (epimerase)

Febrile triggered - neurodegeneration, blistering skin lesions, cardiac

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160
Q

2 causes of elevated Histidine

A

Histidinemia - HAL gene, imidazolepyruvic acid in urine

Urocanic aciduria (UROC1 gene)

Both non-disease

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161
Q

What 3 AA make up glutathione

A

Glutamate, Cysteine, Glycine

AKA: gamma-glytamylcysteinylglycine

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162
Q

Low glutathione, hyperaminoaciduria, normal 5-oxoproline

A

Gamma-glutamylcysteine synthetase deficiency

Part of glutathione synthesis

Hemolytic anemia + ?neurodegeneration

Tx: Avoid triggers (like G6PD), Vit C + E

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163
Q

High urine and plasma glutathione

A

gamma-glutamyl transpeptidase deficiency (First step of glutathione degradation)

GGT1 gene

ID, psychosis

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164
Q

High cystinylglycine

A

Dipeptidase deficiency

Biochem: Glutathione breakdown pathway

Glutathione levels normal

CNS, neuropathy, deafness

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165
Q

Low glutathione, high 5-oxoproline

A

Glutathione synthetase deficiency

GSS gene Hemolytic anemia + neurodegeneration

Tx: Vit E, N-acetylcystine, avoid G6PD triggers

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166
Q

DDx for high 5-oxoproline

A

Glutathione synthetase deficiency (Hemolysis + CNS)

5-oxoprolinase deficiency (OPAH gene, non disease?)

Acute metabolic decompensation (mito, PA, urea cycle)

SJS

medications

prematurity

Nutritional

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167
Q

Rotting fish odor

A

Trimethylaminuria (FMO3 or DMGDH)

Biochem: Choline degradation pathway

Dx: Choline loading protocol (measure TMA and TMA-oxide in urine before and after)

Tx; Dietary restriction (milk, choline, lecithin, seafood)

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168
Q

DDx Elevated sarcosine (PAA)

A

Sarcosinemia (SARDH) -> causes false elevation in Creatinine measurements -> false positive for renal failure (BUN normal)

GA2

Folate deficiency

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169
Q

Choline breakdown products

A

1) Choline -> Betaine -> Dimethylglycine -> Sarcosine -> Glycine
2) Choline -> Trimethylamine -> TMA-oxiide

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170
Q

Treatment for GSD 1

A

Glycosade (modifined cornstarch) or uncooked cornstarch Liver/kidney transplant

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171
Q

GSD V vs GSD VII distinguishing characteristic

A

GSD V -> second wind

GSD VII -> Out of wind (F6P inhibition of FAO), golyglucosan storage (high G6P activates glycogen synthase, mild erythrocytosis and hemolysis (gluconeogenesis defect affecting RBCs)

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172
Q

5 Coenzymes for PDH complex

A

1 - Thiamine (TPP)

2 - Flavin (FAD)

3 - Lipoic acid

4 - CoA

5 - Nicotinamide (niacin)

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173
Q

3 steps of pyrimidine catabolism

A

Uracil/Thymine —> B-alanine/B-aminoisobutyric acid

1) dihydropyrimidine dehydrogenase
2) dihydropyrimidase
3) B-ureidopropionase

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174
Q

Hight urine thiamine and uracil

A

Dihydropyrimidine dehydrogenase deficiency

Gene: DPYD

  • asymptomatic vs seizures and ID
  • 5FU toxicity
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175
Q

UOA: high dihydrouracil/dihydrothymine, uracil, thymine

A

dihydropyrimidinase deficiency

Gene: DPYS

  • asymptomatic vs seizures and DD -

5FU toxicity

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176
Q

high ureidopropionate, B-alanine, and ureidoisobutyrate (normal-high dihydrouracil, dihydrothymine, uracil, thymine)

A

B-ureidopropinase deficiency (B-alanine synthase deficiency)

gene: UPB1
- Asymptomatic vs dystonia
- 5FU toxicity

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177
Q

CSF AA: high GABA, B-alanine, homocarnosine

A

GABA transaminase Deficiency gene ABAT

Biochem: GABA -> succinate semialdehyde

Clin: epileptic encephalopathy, macrosomia; increased growth

Avoid vigabatrin

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178
Q

UOA: 4-hydroxybutyric acid (Gamma hydroxy-butyrate)

A

Succinic Semialdehyde Dehydrogenase

SSADH gene: ALDH5A1

Clin: Slowly progressive neuropsych, movement do, seizures

MRI: BG/WM disease

  • Avoid VPA
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179
Q

High carnosine

A

Carnosinase deficiency - incidental finding - ?homocarnosinosis

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180
Q

Creatine synthesis pathway

A

Arg + Glycine - (AGAT) -> ornithine + Guanadinoacetate - (GAMT) -> creatine -(SLC6A8 transporter)-> creatinine

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181
Q

CSF: High 3OMD, low 5-HIAA, low HVA, low MHPG, low VMA

A

AADC

DDC gene

biochem -> converts 5-OHT and DOPA into serotonin and Dopamine

  • urine profile may be opposite of CSF
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182
Q

Treatment for AADC

A

Pyridoxine (B6),

MAOi, agonists

  • Do NOT give DOPA or 5-OHT
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183
Q

CSF: Low HVA, low MHPD, low VMA, low 3OMD; normal 5-HIAA

A

Tyrosine hydroxylase (TH)

Biochem: tyrosine -> DOPA

  • Movement DO, encephalopathy
  • Dopa responsive
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184
Q

CSF: Low MHPG, low VMA

A

Dopamine B- hydroxylase (DBH)

Biochem: Dopamine -> Norepi

  • Dysautonomia

Tx - droxidopa

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185
Q

CSF: Low MHPG, VMA, 5HIAA, and HVA; normal 3OMD

A

MAO deficiency

MAOA (X linked), MAOB

Clin: Serotonin + carcinoid features; atonic episodes,

Dx - Elevated urine/CSF neurotransmitters (serotonin, tyramine, normetanephrine, etc)

Tx: Diet

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186
Q

What neurotransmitter produces the following metabolites? 1) HVA 2) 5HIAA 3) MHPG 4) VMA 5) 3OMD

A

1) Dopamine
2) Serotonin
3) Norepi
4) Epinephrine
5) L DOPA

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187
Q

CSF: High HVA (isolated)

A

Dopamine Transporter (presynaptic uptake defect) SLC6A3

Clinical: Movement do

HVA/5HIAA ratio >5

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188
Q

CSF: normal

Urine: high HVA and 5HIAA, low dopamine and norepinephrine

A

VMAT2 (SLC18A2)

Biochem: defective vesicular loading

Clin: Movement do

Tx: Dopamine receptor agonist (pramipexole) -

WORSE with L DOPA (dopamine does not make it into vesicle)

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189
Q

GSDs by ascending number

A

0 - Glycogen synthase (Hepatic, No HSM)

I - G6P Phosphotase (Hepatic)

II - Acid Maltase (Muscle) - cardiac involvement

III - Debranching (Mixed) - cardiac involvement

IV - Branching (Mixed) - cardiac involvement

V - Myophosphorylase (Muscle) - 2nd wind

VI - Liver Phosphorylase (Mixed) - mild

VII - Muscle PFT (Muscle) - no wind

IX - Liver Phosphorylase Kinase (Mixed) - mild

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190
Q

Hurler-like MPS and their enzymes

A

“-Ronidase”

MPS I - a L iduronidase

MPS II - Idurotnate sulfatase (X linked)

MPS VII - B-Glucoronidase

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191
Q

Primary CNS MPS + enzymes

A

“Heparan and -glucosaminde”

MPS III

A: Hepran sulfatase (SGSH)

B: N acetylglucosamidase (NAGLU)

C: acetyl-Coa glucosaminide acyltransferase (HGSNAT)

D: N-acetylglucosamine 6 sulfafase (GNS)

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192
Q

Primary Bone MSP and enzymes

A

“galacto-“

MPS IV and VI

IV A - galactose - 6- sulfatase (GALNS)

IV B - B- Galactosidase

VI - N-acetylgalactosamine 4 sulfatase (arylsulfatase B)

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193
Q

PAA: Low cit, high gln

Urine: low orotic acid

A

CPS1 or NAGS

CPS1 = rate limiting step

Severe neonatal UCD

N gets funneled into glutamine synthesis

  • NAGS can be replaced by carbamylglutamate (Carboglu)
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194
Q

PAA: High Gln, Low Cit/Arg

Urine: Orotic acid high

A

OTC

X linked - 2/3 inherited, 1/3 de novo

Zinc-required for function

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195
Q

PAA: High gln, High cit, low Arg

Urine: high orotic acid

A

Citrullinemia type I

ASS

Arginosuccinate synthase

Milder UCD

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196
Q

PAA: High Arginosuccinic acid, high Cit, low Arg

Urine: high orotic acid, high arginosuccinic acid

A

Arginosuccinic aciduria

ASL (Lyase)

+ Trichorexis Nodosa

Urine arginosuccinic acid is more sensitive than plasma

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197
Q

PAA: high Arg

Urine: high orotic acid

A

Arginase Deficiency

ARG1 gene

Mild hyperammonemia, chronic sx

High Arg -> high GAA (creatine synthesis) -> ID, seizures, neuropathy in 2nd decade

  • May be ornithine deficient
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198
Q

PAA: High Citrulline, may be high Thr/ Met/ Tyr

A

Citrin Deficiency (Citrullinemia type 2)

Aspartate transporter (SLC25A13)

Neonate: cholestatis, hepatomegaly

Juvenile/Adult: hyperammonemia, dyslipidemia, FTT

Tx: REPLACE ASP with high protein/high fat/low carb diet

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199
Q

PAA: High ornithine, normal Cit/Arg, high glutamine (ammonia)

UOA: high ornitine, homocitrulline

A

HHH (Hyperammonemia, Hyperornithinemia, Homocitrulline)

SLC25A15 - ornithine transporter

Ammonia > Gln levels

  • Can cause coagulopathy

Tx: ammonia scavengers, cit supplement, protein restriction

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200
Q

DDx for hyperornithine

A

OAT (gyrate atrophy/eye changes) - treat with pyridoxine, arginine restriction after infancy

HHH (Ornithine transporter) - treat with citrulline supplement, protein restriction, ammonia scavengers

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201
Q

How are UCDs IDed on NBS

A

Not all identifiable

High Cit, Arg, or Arginosuccinic acid

202
Q

What are ammonia scavengers

A

Na Benzoate (Conjugates with Gly)

Phenylacetate (conjugates with Gln)

203
Q

UOA: Succinylacetone

A

Tyrosinemia type 1

FAH (Fumarylacetoacetase)

PAA: n-high Tyr

SUAC inibits ALAD -> ALA, porphyrins up

Clin: Hepatorenal, hypoglycemia, neuropathy

Tx NTBC, diet

Monitor: Hepatcellular Carcinoma w/ AFPs

204
Q

PAA: Very high Tyr, Phe

UOA: 4OH phenylpyruvate/lactate/acetate

A

Tyrosinemia type II

Tyrosine aminotransferase (TAT)

Clinical: cornea lesions, hyperkeratosis

Tx: diet

205
Q

PAA: High Tyr

A

Tyrosinemia type III

4OHpyruvate dioxigenase deficiency (HPD)

? neuro involvement

Diet

Heterozygotes = hawkinsonuria (?FTT, acidosis)

206
Q

UOA: homogentisic acid

A

Alkaptonuria

Homogentisate dioxygenase (HGD)

Clin: dark urine when alkalinized, arthritis, cardiac valve disease, skin discoloration (onchronosis)

Tx: Diet, NTBC?

207
Q

Maternal PKU treatment goal

A

< 360umol/l (<6mg/dL)

208
Q

PKU treatment options

A

Diet - treat if >600; do NOT treat if <360

Tyr supplement

Kuvan (sapropterin) if not null alleles

Palinziq (enzyme replacement) if > age 18 and for less strict diet

Goal <360 in pregnancy (ID and CHD)

209
Q

PAA: Low Lys, Arg, Orn

UAA: High Lys, Arg, Orn

A

Lyrinuria Protein Intolerance

Dibasic AA transporter -> reabsorption defect

High Lys, Arg, Orn in urine

Citrulline may be low

Clinical: FTT, diarrhea, osteoporosis, renal failure, hemolysis, hyperammonemia, HLH (high LDH, ferritin)

Tx: Protein restriction, citrulline replacement

210
Q

Clinical differences between PA and MMA

A

PA: cardiomyopathy, long QT, autism

MMA: renal disease, metabolic strokes

211
Q

UOA: 3OH Propionic acid, methylcitric acid, propionylglycine, tiglylglycine

ACP: high propionylcarnitine (C3)

PAA: high Gly, Ala

A

Propinonic aciduria

Propionyl-CoA carboxylase (PCCA, PCCB)

Biotin dependent enzyme

Clin: ID, movement do, osteoporosis, pancreatitis, cardiac

  • PA inhibits urea cycle, krebs cycle -> hyperammonemia and hypoglycemia
212
Q

What is C-VOMIT

A

Propiongenic substances:

Cholesterol

Valine

Odd Chain FA (other: thymine, uracil)

Methionine

Isoleucine

Threonin

213
Q

Treatment of PA

A

Tx: Diet (limit C-VOMIT - threonine, methionine, valine, isoleucine), Carnitine, Abx to decreased GI bacteria

214
Q

UOA: methylmalonic acid, 3OH propionic acid, methylcitric acid

ACP: C3, C4DC

A

MMA

Methylmalonyl-CoA mutase (mut)

  • residual function = B12 responsive, nonresponsive = mut0

PAA - high glycine, alanine

Tx: hydroxocolbalamin, carnitine, limited C-VOMIT

215
Q

3 colbalamin pathways

A

Adenocbl (MMA) -> A, B, D-MMA

MethylCbl (homocysteine) - E, G, D-HC

Common - C, F, J

216
Q

High MMA, high Homocysteine, low cobalamin

A

Colbalamin Absorption defect

Intrinsic factor, intestinal receptors (cubilin CUBN, amnionless AMN), transcobolamin I or II

Neuro + megaloblastic anemia + FTT

Tx: Hydroxocolbalamin

217
Q

High MMA, high Hcy, normal cobalamin levels

A

Cbc C (MMACHC), Cbl F (LMBRD1), CblJ (ABCD4)

Tx: OH colbalamin, betaine, folate

FTT, neuro, anemia,

218
Q

High MMA, normal Hcy, normal Cbl

A

Cbl A (MMAA), Cbl B (MMAB), Cbl D-mma (MMADHC)

Phenocopy of MMA

Tx: Hydroxocolbalamin, diet, carnitine

219
Q

High HCy, normal MMA, normal cbl

A

Cbl E, Cbl G, Cbl D-HC

Tx: Hydroxocolbalamin, Betaine

FTT, neuro, anemia

  • DDx also include MTHFR, Folate deficiency, Homocystinuria
220
Q

High MMA, High Hcy

Bulls eye maculopathy, Hemolytic uremic syndrome

A

CblC

Tx: Hydroxocobalamin and betaine

  • Do NOT restrict protein (need methionine)
221
Q

high MMA, high malonic acid

A

Combined malonic acid and methylmalonic aciduria

ACSF3 (MMA-coa and MA-coa synthetase)

Asymptomatic - neuropsych, FTT

CMAMMA: MMA > MA

(in Malonyl-Coa Dehydrogenase deficiency MA> MMA)

222
Q

Causes of isolated MMA elevation

A

MMA (mut)

Cbl A, B, D

Transcbl receptor - benign

MM Epimerase (MCEE) - acidosis, neuro

CMAMMA (ACSF3) - asympatomatic - neuropsych

Mito encephalopathy w/ MMA (SUCLA2, SUCLG1) - encephalopathy w/ mtDNA depletion

223
Q

UOA: Isovalerylglycine, 3OH-IVA

ACP: Isovalerylcarnitine

A

Isovaleric aciduria

Isovaleryl-CoA dehydrogenase (IVD)

FAD dependent

Clinical: similar to PA/MMA

Tx: Diet, carnitine, glycine supplement

224
Q

Sweaty feet/cheesy odor, C5 carnitine

A

Isovaleric Aciduria

UOA: Isovalerylglycine, 3OH IVA

ACP: isovalerylcarnitine (C5)

Tx: carnitine, glycine, diet

225
Q

UOA: 2 methylbutyric acid

A

SBCAD

(ABCADSB) - 2 methylbutryl-coa dehydrogenase

  • C5 on NBS
  • Hmong population

non-disease

226
Q

UOA: 3-methylglutaconic acid, 3OH isovaleric acid

A

3-methylglutaconyl-CoA Hydratase deficiency

AUG gene

  • Leukoencephalopathy in adults
227
Q

Ddx for 3-methylglutaconic aciduria

A

3 methylglutaconyl-coA hydratase (+3OH-isovaleric acid)

Mitocondrial Membrane Lipid disorders - also involve cardiac manifestations, neurological problems, +/- lactic acidosis:

Barth syndrome (X linked, Taz)

SERAC1 (MEGDHEL)

AGK (Senger)

Costeff (OPA3)

DCMA syndrome (DNAJC19)

TMEM70

228
Q

UOA: 3 methrylcrotonylglycine, 3OH-Isovaleric acid

A

3-methylcrotonyluria

3-methylcrotonyl-CoA Carboxylase (MCCC1)

Non disease

  • Carnitine may be low
229
Q

UOA: 2,3-dihydroxy-2 methylbutyrate

A

Crotonase Deficiency (Short chain enoyl-CoA Hydratase)

ECHS1 gene

Leigh like disease

230
Q

UOA: 2 methyl-3 hydroxybutyric acid, tiglylglycine

ACP: normal

A

HSD10 disease (X linked)

2-methyl-3 hydroxybutyryl-Coa Dehydrogenase

Neurodegenerative in males only

cardiomyopathy

231
Q

UOA: isobutyrylglycine

ACP: C4

A

Isobutyryl-CoA Dehydrogenase deficiency

ACAD8

Mostly asymptomatic, some DD/hypotonia

232
Q

ACP: C4OH

A

3-hydroxyisobutyryl-CoA Hydrolyse (AKA deacylase)

HIBCH

C4OH - 3OH isobutyryl-carnitine

Leigh like, FTT

233
Q

UOA: 2-oxoisocaproic acid

(2-oxo or 3 keto acids)

A

MSUD

BCKDH (E1), could also be E2, or E3

PAA: High Leu, Ile, Val (normally Ile>Leu>Val) + Alloisoleucine

Should have ketones in acute state (alpha-keto acids elevated)

Clin: Chronic and acute encephalopathy; opisthotonus

Tx Diet

234
Q

Normal branch chain ratio

A

Lle: Leu: Val

1:2:3

235
Q

XLE on NBS

A

MSDU (alloisoleucine)

Hydroxyprolinuria (benign)

236
Q

PAA: high methionine

A

Mudd’s Disease

Methionine S-adenosyltransferase (MATI/MATIII)

Half benign (most common cause of high Met)

Half dystonia + demyelination (met > 800umol/L)

Cabbage-like breath

Carriers can have high Met with no symptoms

237
Q

Treatment for Mudd’s disease

A

MATI/III def

Met restricted diet if met > 800umol/L -> goal 500-600

Supplement SAM if symptomatic on treatment

238
Q

PAA: high Met, high S-adenosylMet (SAM), low S-adenosylHomocy (SAH)

A

Glycine N-methyltransferase Def

GNMT (MT in picture)

Benign

239
Q

High Met, High S-adenosylMet (SAM), high S-AdenosylHcy (SAH)

A

S-adenosylhomocysteine hydrolase (SAHH) deficiency

AHCY gene

Myopathy (high CK), demyelination, ID

Tx: Met restriction

240
Q

High homocysteine, low methionine

A

Methionine Synthase (MS/CblG)

Megaloblastic anemia + neurological

MTR gene

DDx: CblE, MTHFR

241
Q

High Met, High SAM, high SAH,

+high adenosine

A

Adenosine Kinase Deficiency

ADK

Neurological like SAHH + frontal bossing

242
Q

High Met, high homocysteine (high SAM, high SAH)

Low cysteine

A

Homocystinuria

Cystathinone Beta Synthase deficiency

  • common in Qatar

Marfanoid (cysteine residues in fibrillin)

ID

lens dislocation

myopia

thromboembolism

243
Q

Treatment for homocystinuria

A

Goal homocysteine <30umol/L

FIrst: asses B6 (pyridoxine) responsiveness

  • must be given with folate
  • If <50umol/L = responsive
  • if >20% reduction = partial response

If NON-responsive:

  • met restricted diet
  • betaine
  • hydroxocolbalamin
244
Q

Cystathione in urine

A

Cystathioninuria

Cystathion gamma lyase (CGL)

benign

DDX: liver disease, mito disease, anything that elevated homocysteine

245
Q

High taurine, high sulfocysteine, low Cys, low Homocys

Urine sulfite

A

Sulphite oxidase deficiency

SUOX

Cystic brain changes + epilepsy + Lens dyslocation

246
Q

High sulfocysteine, sulfite +, high xanthine, high hypoxanthine

low Uric acid

A

Molybdenum Cofactor Deficiency

MOCS1 and MOC2

Cystic brain changes + Epilepsy + Lens dyslocation

Cofactor for SUOX and Xanthine breakdown (purine breakdown pathway)

Tx: Cyclic Pyranopterin Monophosphate (cPMP) - Fosdenopterin for MOCS1

247
Q

Urine: high hypoxanthine, high xanthine

low uric acid

A

Xanthinuria

Xanthine oxidase def

May be benign vs renal failure + stones, arthropathy, myopathy

Tx: Purine restricted diet

248
Q

ACP: C4, C5

UOA: ethylmalonic acid, methylsuccinic acid

Lactic acidosis

A

Ethylmalonic encephalopathy

Mitochondrial sulfur dioxygenase deficiency

Clin: Neurodevelopmental, motor signs, Petechiae, Acrocyanosis, diarrhea

Tx: Metronidazole, N-acetylcysteine (neutralized H2S), transplant

249
Q

Acrocyanosis, petichiae, diarrhea, encephalopathy

A

Ethylmalonic encephalopathy

ETHE (Sulfur Dioxygenase)

Tx: N-acetylcysteine, metronidazole, transplant

250
Q

DDx for ethylmalonic acid

A

Ethylmalonic encephalopathy (ETHE)

Jamaican Vomiting sickness (unripe ackee fruit)

Lychee encephalopathy

SCAD (high butrylcarnitine and butyrlglycine) - benign

MADD (GA2 + glutaric acid)

251
Q

List the enzymes for:

Fabry

GM1-gangiosidosis

Krabbe

Gaucher

Pompe

A

Fabry: Alpha-galactosidase

GM1: Beta-galactosidase

Krabbe: Galactocerebrosidase

Gaucher: Glucocerebrosidase

Pompe: Alpha-Glucosidase

252
Q

What are the 3 functions of trifunctional protein

A

1) Hydratase (Add water -> hydroxy acyl)
2) OH-acylt coA Dehydrogenase (remove OH -> keto-acyl)
3) ketoThiolase (remove acetyl-CoA -> shorten chain)

253
Q

FAOD with Hyperinsulinism

A

HADH (3 Hydroxyl CoA- Dehydrogenase)

Equivalent of SCHAD (LCHAT for short chains)

Also hypoglycemia/liver disfunction

254
Q

FAOD with retinopathy and neuropathy

A

LCHAD and TFP

255
Q

Pregnant female with fatty liver of pregnancy and HELLP syndrome

A

Carrier for LCHAD/MTP

256
Q

ACP: C14, C14:1, C14:2, C16, C:18

A

VLCAD

ACADVL gene

Variable presentation

Hypoglycemia, hepatopathy, rhabdo, myopathy, cardiomyopathy

257
Q

ACP: C16OH, C16:1OH, C18OH

A

LCHAD

Hypoglycemia, Liver, muscle, cardiomyopathy

+ Retinopathy, neuropathy

+ Maternal fatty liver/HELLP syndrome

258
Q

Urine hexanoylglycine

A

MCAD

ACADM gene

  • Hypoglycemia (No muscle involvement)
  • Reye like severe liver failure

ACP: C8

259
Q

ACP: C4

Urine: Ethylmalonic acid

A

SCAD

ACADS gene

Non-disease

DDX for ethylmalonic encephalopathy

260
Q

ACP: C4OH

A

SCHAD

Hyperinsulinism (lack of GDH inhibition in pancreatic islet cells)

261
Q

Ichthyosis + spastic tetraplegia + short stature

+ Leukotriene B4 in urine

A

Sjogren Larsson Syndrome

ALDH3A2 (fatty alcohol dehydrogenase)

+ hyperkeratosis

+ “Glistening dots” in retina

+ ID/epilepsy

Skin, CNS, Bone, Eye

Tx: LTB4 antagonist

262
Q

Metabolic disease with Renal cysts (3)

A

GA2

Zellweger

CDG-PMM2

263
Q

What is the electron acceptor for acyl-coa dehydrogenases?

A

Electron Transfer Flavoprotein (GA2)

264
Q

ACP - Elevations in all chain lengths

A

MADD (GA2)

UOA: Lactate, ethalmalonic acid, 2OH glutaric acid

Clinical: Myopathy, cardiomyopathy, renal cysts, CNS, acidosis, hypoglycemia

265
Q

UOA: Ethylmalonic acid, adipid acid, 2OH glutaric acid

A

GA2

  • Cystic kidneys, hypoglycemia, acidosis, CNS, myopathy

ACP: multiple chain length elevations

266
Q

Low F/T carnitines

ACP: all carnitines low

A

Carnitine transporter/uptake deficiency

SLC22A5

Clin: Weakness, Cardiomyopathy, hypoglycemia/hepatic

Tx: EKG, carnitine supplement

267
Q

How to tell apart CACT from CPTII

A

CACT: renal malformations, always severe

CPTII: most commonly adult myopathic form

268
Q

ACP: Low C16, C18, C18:1

High C0

A

CPT1 def

  • Inuits (alaska)

Liver, RTA, cardiomyopathy, hypoglycemia

269
Q

Low free and total carnitine

ACP: high C16, C18, C18:1

C18/C2 ratio high

+ Renal malformation

A

CACT (Carnitine translocase/SLC25A20)

  • bound to long chain but cannot get into mito
  • Cardiac, Liver, hypoglycemia, weakness
  • Most die by 3 months
270
Q

Low free and total carnitine

ACP: high C16, C18, C18:1

C18/C2 ratio high

Adult w/ weakness

A

CPTII

  • Cannot releast long chain - carnitine

Most common form = adult w/ myopathy

271
Q

Low free and total carnitine

ACP: high C16, C18, C18:1

C18/C2 ratio high

A

CPTII or CACT (translocase)

carnitine stuck on long chains

CACT has renal malformations, always severe presentation

CPTII can be severe, but usuall late onset myopathy

272
Q

Trimethyllysine high in urine and plasma

A

Trimethyllysine dioxygenase

gene: TMLHE (hydratase-epsilon)

X linked

Carnitine synthesis pathway

Trimethyllysine elevated in urine/plasma

  • Autism risk gene that can be treated w/ carnitine supplement
273
Q

normal GGT

Diarrhea, jaundice, hepatopathy, rickets

A

Bile acid synthesis disorders

3Bhydroxysterol dehydrogenase (HSD3B7)

3oxysterol 5B reductase (AKR1D1)

Oxysterol 7a hydroxylase (CYP7B1)

  • low cholesterol, high bili

Tx: Bile acid replacement

274
Q

High Cholestanol

cataracts, diarrhea, xanthoma, ataxia

A

Cerebrotendinous Xanthomatosis

Sterol 27-hydroxylase def

CYP27A1

Tx: statins + Chenodeoxycholic acid (Chenodal)

275
Q

Why is there high ammonia in PA and MMA

A

Secondary inhibition of NAG synthase

276
Q

High Hydroxybutyrate even when fed

High urine ketones

Normal ACP

A

SuccinylCoA-3-oxoacid CoA Tranferase (SCOT) deficiency

  • Episodic acidosis (ketoacids), tachypnea, hypotonia, encephalopathy
277
Q

High hydroxybutyrate

ACP: tiglycarnitine, 2-methyl-3OH butrylcarnitine

UOA: tiglyglycine, 2-methyl-3OH butryic acid, 2 methyl-acetylacetic acid

A

Beta-ketothiolase (3-oxothiolase)

Both Ketolysis and ILE breakdown

  • nauses + emesis -> encephalopathy
  • hypoglycemia (cannot use ketones for energy), metabolic acidosis, hypoerammonemia (NAGS inhibition)
278
Q

Fasting: 4 hydroxy - 6- methyl- 2 pyrone (related to acetylacetone)

Hypoketotic hypoglycemia

A

HMG-CoA Synthase

Presents like FAOD

UOA: high dicarboxylic acids (adipic, malonic, glutraic, succinic acid)

Tx: avoid fasting

279
Q

UOA: 3-hydroxy-3 methylglutaconic acid, 3 Oh isovaleric acid, 3 methylglutaric acid, 3 methylglutaconic acid

ACP: C5OH, C6DC

A

HMG-CoA Lyase deficiancy

  • FAOD and organic aciduria (final step in Leu breakdown and ketone breakdown)

Hypoketotic hypoglycemia (severe)

Hyperammonemia (secondary NAGS inhibition)

Acidosis

Tx: Carbohydrates, carnitine

280
Q

Name the Valine breakdown intermediates

A

Isobutyryl-CoA -> Dehydration (IBD)

Metharylyl-Coa -> Hydration (Crotonase/ short chain enyol-CoA hydratase)

3OH Isobutyryl-CoA -> Dehydration (HIBCH/deacylase)

3OH Isobutyrate

MMA Semialdehyde -> Thiolysis (MMSDH)

PA

MMA

SuccinylCoA

281
Q

Name the ILE breakdown Intermediates

A

2 methylbutyryl CoA -> Dehydration (2MB Dehydrogenase)

Tiglyl-CoA -> Hydration (Crotonase/Short chain enyol-CoA hydratase)

2 Methyl-2OH Butyryl CoA -> dehydration (HSD10, MHBD)

2 methylaceoacetyl CoA -> thiolysis (Beta ketothiolase)

PA + Acetyl CoA

MMA

Succinyl CoA

282
Q

Name the Leu Breakdown intermediates

A

Isovaleryl CoA -> Dehydration (IVD)

3 MethylCrotonyl CoA (3MCC)

3 methylglutaconyl CoA -> Hydration (hydratase)

3Oh 3 mehtylgluarylCoA -> Thiolysis (HMG-CoA Lyase)

AcetylCoA + Acetoacetate

283
Q

Name the main intermediates and products in Leu, Ile, and Val metabolism

A

Leu: Isovaleric, Methylcortonyl, Methylglutaryl -> Acetyl CoA + acetylacetate

ILE: Methylbutyryl, Tiglyl -> PA + acetyl CoA

Val: Isobutyryl -> MMA semialdehyde -> PA

284
Q

What AA is the precursor to endogenous Carnitine synthesis?

A

Lysine (Trimethyllysine)

285
Q

Sleeping through night -> hypoglycemia + high LFTs

A

MCAD or GSD1 (elevated TG, uric acid)

286
Q

Rhabodomyolysis with CK > 10,000 at baseline. Most common cause of rhabdo in children after FAODs (10%)

A

LPIN1 deficiency

Phosphatidic acid phosphohydrolase (PAP)

BIochem: PA -> Diacylglycerol

  • Role in PPAR activation and regulation of ETC expression

LPIN2 deficiency -> inflammatory signlating -> recurrent osteo

287
Q

Jordan’s anomaly (empty vacuoles in PMN cells that stain red), myopathy

A

Neutral lipid storage disorder

Biochem: inability to break down TG in lipid droplet (Jordan’s anomaly = lipids in macrophages)

AGTL (adipocyte TG lipase deficiency)

CGI 58 (chanarin Dorfman) + ichthyosis

288
Q

Disorders of triglyceride synthesis that cause lipodystrophy

A

AGPAT, Seipin/BSCL2 (s), HSL, PLIN-1

289
Q

3-methylglutaconic acid, positive filipin stain

SNHL, Hepatopathy, encephalopathy, dystonia

A

MEGDHEL

SERAC1 deficiency (mito membrane lipid remodeling)

3-MethylGlutaconic Acid

Deafness

Hepaopathy

Encephlopathy

Leigh syndrome

290
Q

3 methylglutaconic acid; high LysoCL:CL ratio

Dilated cardiomyopathy, Neutropenia

A

Barth syndrome

TAZ (XL)

Dilated CM, neutropenia, lactic acidosis, GI, growth, developmental issues

Tx: Elamipretide (stabalize cardiolipin)

291
Q

Neuropathy, hearing loss, ataxia, RP, Cataracts

Normal phytanic acid

A

PHARC syndrome

(ABDH12)

Polyneuropathy, Hearing loss, Ataxia, RP, Cataracts

Resembles refsum disaese, but NORMAL phytanic acid

292
Q

Dense congenital cataracts, Hypotonia, ID, renal fanconi (RTA 4)

A

Lowe syndrome (Oculocerebrorenal syndrome)

OCRL XL

Phosphoinositide phosphorylase

Eye: catracts, glaucoma

Cerebro: ID, hypotonia

Renal: tubular dysfunction

293
Q

X linked metabolic conditions

A

OTC

Glycerokinase

XALD

Fabry

G6PD

Lysch Nyhan

Creatine Transporter

Menkes

294
Q

Pseudotriglyceridemia

A

Glycerol Kinase deficiency

Biochem: Gllycerol + ATP -> glycerol-3-phosphate + ADP

Standard TG assay cleaves Acyl groups from TG and measures glycerol levels… Plasma will be clear instead of cloudy (no lipemia)

  • Also F-1,6-bisphosphatase deficiency (secondary buildup of glycerol)
295
Q

Ketotic hypoglycemia, DD, emesis, high TG

A

Glycerol Kinase Deficiency

XL

  • high urine glycerol, pseudotriglyceride
  • can be part of deletion syndrome with adrenal hypoplasia congenita and duchennes muscular dystrophy
  • false positive TG (since glycerol backbone is elevated) with normal lipid levels

Tx: Fat restricted diet

  • Daiper cream also can cause false glycerol elevation
296
Q

What is the first cyclic molecule in cholesterol synthesis pathway?

A

Lanosterol

(oxidosqualine cyclase = lanosterol synthase)

297
Q

UOA: high mevalonic acid, high mevalonoacetone, high IgD

A

Mevalonic aciduria, or hyper IgD (mild)

Mevalonic kinase

Inflammatory syndrome: Fever, rash, HSM, diarrhea, may have neuro + retinal findings

Mild form = hyper igD

Tx: Steroids, IL1 receptor antagonist (anakinra), replace uniquinone

298
Q

MVK, PMVK, MVD, FDPS

A

Porkeratosis

Mevalonate kinase, phophomevalonate kinase, dehydrogenase, famesyl-diphosphate synthase

AD diosrders of keratinization -> raised hyperkeratotis plaques with evident borders

Pre-squalene cholesterol disorders

299
Q

High desmosterol

A

Desmosterolosis

3OH oxysterol/Desmosterol reductase (DHCR24)

  • Ambiguous genetalia (sex hormones = sterols)
  • Dysmorphic, Short limbs, CNS abnormalities, arthrogryposis, ID
300
Q

High lanosterol, dihydrolanosterol

A

Antley Bixler

POR (Cyp450 oxidoreductase)

Craniosynostosis, limb defects, ambiguous genetalia, dysmorphic

301
Q

Cholesta-8,14-dien-3B-ol

Skeletal dysplasia

A

Greenberg dysplasia

3-hydroxysterol Delta-14 reductase (right below antley-bixler in pathway)

LBR gene

+ Pelger Huet anomaly

302
Q

Microcephaly, congenital cataracts, psoriaform dermatitis

SC4MOL

A

Sterol-C4-methyl oxidase

High 4-methylsterols

303
Q

Female: Unilateral ichthyosis with sharp demarcation and stippled epiphysis

Males: ID, pachygyria, dysmorphic

A

3 hydroxysterol -4 demeythylase

NDSHL (XL)

Females: CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects)

Males: Syndromic ID

  • High 4-methylsterols

Tx: Cholestrol Supplementation

304
Q

Assymetric RCDP + ichthyosis, alopecia, cataracts

A

Conradi-Hunermann

X-linked CDP

Sterol-7,8-isomerase (EBP) - Male lethal

Lab: high 8 dehydrocholestrol, 8(9)cholestrol

305
Q

High lathosterol

A

Lathosterolosis

Sterol-delta5-deatruase

SLOS-like: ID, microcephaly, catarats, micrognathia, polydactyly, liver disease

306
Q

Low maternal estriol

High 7 dehydrocholesterol and 8 dehydrocholestrol

A

SLOS

Sterol-7-reductase (DHCR7)

2/3 toe syndactyly, FTT

Dysmorphic: ptosis, anteverted nares, low set ears

  • AV canal defects (like DS)
  • GU abnormalities (cannot synthesize hormones)
307
Q

Name the syndrome for following sterol pathway enzymes:

1) sterol-14-desaturase
2) sterol 8,7 isomerase
3) sterol 5 desaturase
4) Sterol 24 reducatase
5) sterol 7 reductase

A

1) sterol-14-desaturase - Greenberg dysplasia
2) sterol 8,7 isomerase - XL-RCDP
3) sterol 5 desaturase - Lathosterolosis (SLO like)
4) Sterol 24 reducatase - desmosterolosis (CNS + other malformations)
5) sterol 7 reductase (SLOS)

308
Q

2 disorders with high 4-methylsterols

A

Sterol-C4-methyloxidase - SC4MOL- psoriaform dermatitis, cataracts, microcephaly

Sterol-4-demethylase - CHILD syndrome - hemiichthyosis + assymetric rhizomelic condrodysplasia

  • Cholesterol supplement may help with skin findings
309
Q

Most common genes for Zellwegere spectrum

A

PEX1 (60%)

PEX6 (15%)

Others rare

310
Q

Stippling of epiphysis -> Flaring epiphysis, irregular metaphysis, cataracts, rhizomelia, ID

A

RCPD

PEX7, GNPAT, AGPS

DDx: ARSE, sterol8,9isomerase, warfarin embryopathy, maternal SLE

311
Q

What is the NBS marker for XALD?

A

C26:0 lyso phosphotidylcholine

312
Q

Ddx for high phytanic acid

A

Alpha-oxidation pathway

  • Refsum disease (pristanic low)
  • Zellweger spectrum (pristanic low, VLCFA high)
  • RCPD 1 (pristanic low)
  • a-methyl-ethyl-coa Racemase (pristanic high)
313
Q

Main pathways that require riboflavin

A

FAD - electron carrier, helps with dehydrogenases

BCAA - IVD, SBCAD, IBD

FAD: SCAD, MCAD, LCAD, VLCAD, ACAD

  • Choline metabolism

ETC - complex II, GA2 like presentation when deficient -> myopathy, neuro phenotypes

314
Q

Presentation and biochemical profile of riboflavin transport/metabolism defects

A

SLC52A1/A2/A3, FLAD1 (synthase), SLC25A32 (mito transporter)

  • FAD needed for FAO dehydrogenases, BCAA dehydrogases, and ETC (complex II)

Clinical: weakness, hypotonia, neuropathy, myopathy

BIochem: GA2 like -> multiple acyl-carnitine elevations, organic acid elevations

315
Q

What are the NBS analytes for MSUD

A

Ratio Leu or Ile to Ala or Phe

316
Q

What is the standard lab technique for UOA, ACP?

A

UOA: GC/MS

ACP: MS/MS

317
Q

NBS: C5OH, healthy baby

A

Most likely 3MCC or maternal 3MCC

318
Q

What AA coelutes with homocitrulline in urine?

A

Methionine

(false elevation in Met on OAA in HHH)

319
Q

What molecule does carbamoyl phosphate and lysine form?

A

homocitrulline

320
Q

Hyperammonemia, high met on UAA

A

HHH

(homocitrulline co-elutes with methionine in urine)

321
Q

High tyrosine and methionine

A

Tyroseinemia type I

Methionine is sign of liver injury

322
Q

High methylmalonic acid, high malonic acid

ACP: C3DC

A

Malonic aciduria

MLYCD (Malonyl-Coa Decarboxylase)

MA > MMA (Opposiite in CMAMMA)

ID, emesis, epilepsy

Tx: High carb diet, carnitine

323
Q

Hypoglycemia, High free fatty acids, low ketones

A

FAOD

FFA high = Acitve liposis

if ketones are normal or low, then you have a disorder of FAO

324
Q

Hypoglycemia, low Free fatty acids, low ketones

A

Hyperinsulinism - lipolysis is being inhibited

325
Q

hyperglycemia with high ketones

A

Disorders of ketolysis

GSD 0 (glycogen synthase) - no stored glycogen -> more FAO

GSD 3 (Debranching) - glycogen unavailable -> more FAO

Organic acidurias

326
Q

hypoglycemia + high lactate + hepatomegaly

A

GSDs, gluconeogenesis disorders

327
Q

Hypoglycemia + Hepatopathy

A

HFI, tyrosinemia type I, FAOD (longer chain), mitochondrial

328
Q

Hearing loss, weakness (upper limb > lower limb), neuropathy, few facial symptoms, responsive to riboflavin

A

Brown-Vialetto-Van Laere syndrome

SLC52A2 - CNS riboflavin transporter

  • GA2 like metabolic profile
329
Q

What tissue does not have mitochondria? What does it use for ATP

A

RBC, penthose phosphate pathway

330
Q

Which polymerase replicates the mitochonidral genome?

A

Gamma -> PolG

331
Q

Which complex in ETC is completely encoded for by nuclear genes?

A

Complex II (it is part of the TCA cycle)

332
Q

Which amino acid reflects long-term lactate elevation?

333
Q

What is the treatment for MELAS?

A

IV arginine for acute stroke like episodes

PO citrulline (Arg precursor) or taurine (modifies mtLeu tRNA) may also help

334
Q

high plasma/urine levels of Thymidine and deoxyuridine

+ Psuedo obstruction

A

MNGIE (mito-neuro-gastro-intestinal encephalopathy)

Thymidine phosphorylase deficiency

  • Disruptions DNA replication system by limiting availability of T -> accumulation of mutations

+neuropathy, myopathy, ophthalmoplegia, leukoencephalopathy

335
Q

Mitochondrial encephalopathy with cortex > BG involvement

+ Liver dysfunction

A

Alpers syndrome

POLG, C10ORF2

336
Q

What are 3 markers for mitochondrial disease in blood?

A

Lactate

Alanine

GDF15

  • TCA intermediates in urine
337
Q

Normal complex II activity but decreased complexes I, III, and IV

A

Mitochondrial depletion syndrome

  • reflced abnormal mito DNA replication -> complex II is fully nuclear encoded
  • SUCLA2 (Leigh like + deafness) - high MMA and C3/C4DC on NBS
338
Q

mt3243A>G

A

MELAS

tRNA Leu

339
Q

Mt1, 4, and 6 - homoplasmic mutations

Occurs in males > females

340
Q

Progressive external ophthalmoplegia, Retinitis pigmentosa, onset <20 + ataxia/conduction block/CSF protein elevation

A

Kearns-Sayre

Large mDNA deletions/duplications

341
Q

Mt 8344G>A

Epilepsy, multiple symmetric lipomatosis

A

MERRF

tRNA Lys

342
Q

Cataract, cardiomyopathy, myopathy, lactic acidosis

A

Sengers syndrome

AGK

343
Q

Long philtrum, thin vermillion, upturned nose

Leigh-like, neuropathy

+ high lactate, alanine, and pyruvate

low-nl Lactate/pyruvate ratio

A

Pyruvate dehydrogenase deficiency

Most common PDHA1 (XL, females can be affected)

Converts pyruvate to acetyl-CoA

  • Brain malformation: ventriculomegaly, agenesis of CC
  • Fetal alcohol like facial features (EtOh -> acetaldehyde -> inhibits PDH)

Tx: Ketogenic diet (generates acetyl-CoA), thiamine

344
Q

High lactate, alanine, and pyruvate, low-nl Lactate/pyruvate ratio

Elevated Leu, Ile, Val

high a-keto-glutarate

A

E3 (Dihydrolipoamide Dehydrogenase deficiency)

  • Shared by a-KG dehydrogenase, pyruvate dehydrogenase, and Branched chain alpha-ketoacid dehydrogenase

Leigh syndrome + liver failure

345
Q

In the ETC how many ATPs are generated per each NADH and FADH?

A

NADH: 3

FADH: 2

*really closer to 2.5 and 1.5 due to leakiness of inner membrane

346
Q

PAA: High Cit, Thr, Met, Tyr

Cholestasis, fatty liver, hypoglycemia

A

Citrin deficiency

SLC25A13 - Asp, Glu carrier

Common in Japan

  • Liver disease in neonates
  • encephalopathy in adults + aversion to carbs

Tx: Galactose free diet, Ammonia scavengers, Arginine, Liver Transplant

347
Q

UOA: high D-2-hydroxyglutaric acid

Hypotonia, DD, cardiomyopathy

A

D-2-hydroxyglutaric acidruia type 2

(IDH2 Gain of function)

Type 1 is due to D2HG Dehydrogenase (no cardiomyopathy, lower extretion ~1000 instead of 2000)

348
Q

UOA: High a-ketoglutaric acid

A

E3 deficiency (a-ketoglutarate dehydrogenase + high BCAA, lactate) -leigh syndrome + liver failure

TPK - leigh syndrome

SLC19A2 (thiamine transporter) - Biotin responsive BG Disease

SLC25A19 (thiamine transporter) - Amign lethal microcephaly

349
Q

Leigh syndrome + deafness

UOA: MMA elevation

A

Succinyl-CoA synthetase (ligase)

SUCLG1, SUCLA2

  • C3 and C4DC on NBS
350
Q

Which TCA disorder presents as an Oxphos phenotype?

A

Succniate dehydrogenase

  • Part of complex II
  • Succinate + FAD -> FADH2 (used by complex II for oxphos) + fumarate

High lactate, pyruvate, and TCA intermediates (Fumarate, malate)

  • Parents at risk for malignancy (paraganglioma + pheo)
351
Q

AD: paragangliomas and pheochromocytomas

A

Succinate Dehydrogenase deficiency B-D subunits

SDHB, C, D

  • HIF regulation -> angiogenesis and inhibition of apoptosis
352
Q

ISCU (Iron-sulfur cluster protein)

A

Combined SDH and aconitase deficiency

(both enzymes need Fe-S clusters)

Swedish type mitochondrial myopathy

353
Q

Hereditary leiomyomatosis and renal cell carcinoma

A

HLRCC

Fumarase - FH heterozygotes (AD)

  • Cutaneous and uterine leiomyomas
  • Renal cell carcinoma
354
Q

UOA: high fumarate

Polymicrogyria, atrophy, open opernacula

Hypotonia, DD, seizures

Frontal bossing, hypertelorism, depressed nasal bridge

A

Fumarase deficiency

“Polygamist Down Syndrome” - common in polygamous towns in Colorado City, AZ and HIldate, Utah

355
Q

UOA: high D-2-hydroxyglutaric acid

A

D-2 hydroxyglutaric aciduria

Both: DD, hypotonia, seizures

Type 1: D2HG Dehydrogenase deficiency (no cardiomyopathy) - D2HG -> aKG

Type 2: IDH2 GOF (also has cardiomyopathy) - Isocitrate -> [aKG] -> D2HG

356
Q

UOA: high L-2-hydroxyglutaric acid

CSF AA - high lysine

A

L-2-Hydroxyglutaric aciduria

L2HG Dehydrogenase

Converst L2HG -> aKG

DD, epilepsy, leukodystrophy + brain tumor predisposition

357
Q

Mito Glutamate Carrier

A

SLC25A22

neonatal myoclonic epilepsy

358
Q

Mito ADP/ATP carrier

A

SLC25A4

AD progressive external opthalmoplegia + exercise intolerance

359
Q

Mito Phosphate Carrier

A

SLC25A3

Hypotonia, cardiomyopathy, lactate acidosis

360
Q

Steroid resistant nephrotic syndrome, hearing loss, myopathy, encephalopathy/ataxia

Lactic acidosis

A

CoQ10 biosynthesis defect

CoQ2, CoQ9, PDSS1, PDSS2, ADCK3

Complex I, II, or III activity in isolation = normal

Complex I+III or Complex II+III activity = decreased

Tx; ubiquinol

361
Q

What food should patients with multiple carboxylase deficiency avoid?

A

Avoid raw eggs (Avidin binds biotin and sequesters it)

MCD = Holocarboxylase or biotinidase

362
Q

Neurological symptoms, Hair loss, eczema, metabolic acidosis

C5OH on NBS

A

Multiple carboxylase deficiency

biotinidase or holocarboxylase

Neuro + derm + acidosis

UOA: 3MCC (3OH-IVA, 3-methylcrotonylglycine) + PCC (Methylcitrate, 3OH propionate, tiglylglycine, propionylglycine, + PC (lactate)

363
Q

PAA - high alanine

ACP - low carnitine

UOA: 3OH IVA, methylcrononylglycine, methylcitric acid, tiglylglycine

A

Multiple Carboxylase deficiency

Biotinidase or holocarboxylase (distinguish with biotinidase or holocarboxylase synthatase enzyme assay)

NBS: C5OH

Neuro + derm + acidosis

elevations due to affected 3MCC (3OH IVA, methylcrotonylglycine); PCC (methylcitrate, 3Oh propionate, propionylglycine, tiglylglycine)

PC; (lactate, alanine)

364
Q

Neurological regression with high succinate on MRS

A

Succinate dehydrogenase deficiency

Part of complex II

Succinate + FAD -> FADH2 (used immediately) + fumarate

Urine may excrete succinic acid, fumarate, or malate (TCA intermediates due to oxphos backup)

365
Q

Which GSD is X linked

A

GSD9

4 subunites:

PHKA1, PHKA2 are XL

PHKB and pHKG2 are AR

366
Q

What common factors can interfere with biotinidase assay?

A

Ampicillin

Hemoglobin (in test tube)

Liver dysfunction (low albumin or high bilirubin)

Prematurity

367
Q

X linked GSD

A

GSD 9 (Hers)

PHK - A2, B, G2, A1 (2 are X linked, 2 are AR)

Liver GSD, tends to be milder but can be severe in males

368
Q

What stain is used for glycogen?

A

PAS - periodic acid schiff

Less branched glycogen = polygucosan

369
Q

Hyperuricemia, Lactic acidosis, High alanine, high TG, low BG

370
Q

What are differences between GSD1 and GSD3?

A

GSD3 more mild and can use proteins (gluconeogenesis NOT affected)

  • Thus ala/BCAA low; add alanine for treatment
371
Q

TFF, fasting hypoglycemia, postprandial hyperglycemia

A

GSD0

  • cannot put glucose into glycogen, thus hyperglycemia after meals.

(Postprandial hyperglycemia also seen in GLUT2 (GSD XI) due to abnormal glucose transporter into and out of liver)

372
Q

Hypotonia, hepatomegaly, cardiomyopathy + WPW syndrome

A

Danon disease (LAMP2)

  • Pompe like + WPW

X-Linked

373
Q

GSD V vs GSD VII (tauri)

A

GSD V (myophosphorylase): Muscle only, Second wind (use glucose from blood or FAO)

GSD VII (Muscle PFK): Muscle and hemolysis with erythrocytosis (RBC use glycolysis for energy, but synthesis upregulated by lack of F1,6BP); out of wind because glycolysis does not work; + polyglucosan (glycogen synthase upregulated, branching enzyme activity does not match)

374
Q

What are the common clinical features of disorders of glycolysis?

A

Hemolysis (RBCs do not have mitochondria and need this for energy)

Myopathy (Think GSD VII - PFK)

375
Q

Myopathy + rhabdo with low LDH

A

LDH deficiency

  • Myopathy/cramps/rhabdo
  • Some have rash

+ high CK but LOW LDH

376
Q

Hemolysis + myopathy + severe neurological disease

A

Trisephosphate isomerase deficiency

DHAP needs to be converted into G2P, otherwise buildup -> toxic metabolite

377
Q

X linked glycolysis disorder

A

Phosphoglycerate Kinase

  • Clinically similar to PFK (tauri)
  • Anemia, muscle, CNS
378
Q

Hemolysis with erythrocytosis, out of wind phenomenon,

A

GSD VII (Tauri)

PFK is glycolysis enzyme -> RBC need this for energy

Decreased product -> upregulate marrow erythrocytosis

+ out of wind phenomenon

+ polyglucosan (high glycogen synthase activity, normal branching enzyme)

379
Q

What is the mechanism of hemolysis in G6PD?

A

Decreased NADPH -> cofactor for glutathione reductase -> necessary for ROS removal

X-Linked, first step in pentose phosphate shunt

380
Q

MRS and urine polyols: high ribitol, D-arabitol

A

Ribose-5-P isomerase deficiency

(RPIA gene)

Leukoencephalopathy, ataxia, neuropathy

381
Q

Urine polyol: High ribitol, D-arabitol, erythritol, sedoheptulose

A

Transaldolase Deficiency

Gene: TALDO1

  • Most common pentose phosphate disorder
  • Liver disease + HSM, hemolytic anemia, renal failure, cutis laxa, hepatocellular carcinoma
382
Q

Severe liver disease, CHD, HSM, hemolytic anemia, RTA, cutis laxa

A

Transaldolase deficieny

TALDO1

+hepatocellular carcinoma

Urine polyols: high Ribitol, D-arabitol, erythritol, sedoheptulose

383
Q

UOA: L-xylulose, xylose, arabinose

A

Essential pentosuria

L-xylulose reductise deficiency (DCXR)

  • Non disease
384
Q

Hyperammonemia

high: Cit, Ala, Lys, Pro

Low: Asp, Glutamate

A

Pyruvate Carboxylase Deficiency

  • Defect in glycolysis and gluconeogenesis

Lactic acidosis, Neurological, liver failure, cystic periventricular leukomalacia

Low OAA -> Low aspartate -> ASS cannot work; thus secondary UCD with high Cit;

Lys requires aKG to degrate

Proline oxidase inhibited by lactate

  • high L/P ratio; Low 3OH-butyrate/acetoacetate ratio
  • ketones
  • Low TCA intermediates (2oxoglutarate/aKG, Malate, fumarate, etc)
385
Q

high L/P ratio; Low 3OH-butyrate/acetoacetate ratio

A

Pyruvate Carboxylase Deficiency

Defect in glycolysis and gluconeogenesis

Lactic acidosis, Neurological, liver failure, cystic periventricular leukomalacia

  • Low asparatate -> Malate/Asp shuttle cannot transfer NADH from cytoplasm into mitochondria -> high NADH in cytoplasm (L/P) and low NADH in mitochondiral (HB/Acetoacetate)
  • Postprandial ketosis (glucose -> Acetoacetate instead of TCA)
  • Low TCA intermediates (low OAA)
  • Hyperammonemia (secondary ASS deficiency since Asp + Cit = Arginosuccinate
  • High Lys, Pro, Cit
386
Q

Postprandial ketosis, liver failure, encephalopathy, lactic acidosis

A

Pyruvate Carboxylase Deficiency

Defect in glycolysis and gluconeogenesis

glucose -> Acetoacetate -> ketones instead of TCA

high L/P ratio; Low 3OH-butyrate/acetoacetate ratio (Low asparatate -> Malate/Asp shuttle cannot transfer NADH from cytoplasm into mitochondria -> high NADH in cytoplasm (L/P) and low NADH in mitochondiral (HB/Acetoacetate))

  • Low TCA intermediates (low OAA)
  • Hyperammonemia (secondary ASS deficiency since Asp + Cit = Arginosuccinate
  • High Lys, Proline, Cit
387
Q

Lactate acidosis, liver failure, hypoglycemia

  • High TCA intermediates
A

Phosphoenolpyruvate Carboxykinase Deficiency

PEPCK

  • OAA is high -> high TCA intermediates
  • Impaired gluconeogenesis
388
Q

CSF/Blood glucose ratio <0.45, low lactate/alanine

A

GLUT1

SLC2A1 (AD)

CNS glucose transporter

EIEE, epilepsy, exercise induced movement disorder

Tx- Ketogenic diet

389
Q

Fasting hypoglycemia, postprandial hyperglycemia, hepatomegaly, nephropathy

NBS positive for galactosemia

UAA: multiple amino acids (including gly, met, pro) elevated

A

Fanconi Beckle (GSD IX)

GLUT2 - SLC2A2 gene

Renal/liver glucose transporter

  • Abnormal glucose import into liver -> postprandial hyperglycemia
  • Abnormal glucose export -> glucogen buildup
  • Abnormal glucose reabsorption -> renal fanconi: animoaciduria, phosphaturia, glucosuria, rickets
  • abnormal enterocyte absorption = glucose/galactose intolerance w/ diarrhea
390
Q

Amish

Diarrhea, glucosuria

A

Glucose-Galactose malabsoprption

SGLT1 deficiency (SLC5A1)

glucose/galactose transporter

  • abnormal absoprtion -> diarrhea
  • abnormal renal reabsoprtion -> glucosuria

Tx: Fructose based diet

391
Q

Hereditary Renal Glucosuria

A

SGLT2 (SLC5A2)

Glucose transporter

  • abnormal renal reabsoprtion -> glucosuria

Benign (SGLT1 can do most of the work)

392
Q

High Galactose, High Gal-1-P, high galactitol, urine reducing substances

A

Galactosemia (GALT) or Epimerase (GALE)

  • Distinsuish with GALT activity assay
393
Q

What are the short and long term symptoms of galactosemia?

A

Early: Liver failure, Infection “E.Coli sepsis”, cataracts, encephalopathy

Late: Primary ovarian insufficiency, ID

394
Q

High Galactose, High Gal-1-P, normal GALT activity

A

GALE (epimerase)

Presents similar to classic galactosemia

  • MIlder biochemical variants exist
  • High galactitol, + reducing substances

Tx: Low lactose/Galactose diet

395
Q

High Galactose, low Gal-1-P

A

Galactokinase deficiency (GALK)

  • Cataracts
  • May have hgh calactitol and glucose (Urine)
396
Q

GALT N314D

A

Duarte Galactosemia

~50% activity (25% when compound het with classic variant)

  • Benign
397
Q

GALT S135L (c.404C>T)

A

Variant galactosemia

  • Common in African Americans
  • Same neonatal presentation (Liver faliure +/- encephalopathy, infection)
  • Less long term ID/ovarian insufficiency
398
Q

High urine fructose after meals, no symptoms

A

Essential fructosuria

Fructokinase (Ketokexokinase) - KHK gene

Fructose -> F-1-P

Benign

399
Q

Liver failure at 4-6 months + hypoglycemia, renal tubular dysfunction, encephalopathy

A

Hereditary Fructose intolerance

Aldolase B deficiency

+ Urine reducing substances, Hyperuricemia, Hypermagnesemia

+ Abnormal Transferrin isoelectic focusing and olisosaccharidosis enzymes (AGA, B annosidase) - sugars unavailable to attach

Tx: fructose restricted diet

400
Q

Abnormal transferring isoelectic focusing + adult with no dental carries

A

Hereditary Fructose intolerance

Aldolase B deficiency

+ Urine reducing substances, Hyperuricemia, Hypermagnesemia

+ Abnormal Transferrin isoelectic focusing and olisosaccharidosis enzymes (AGA, B annosidase) - sugars unavailable to attach

Tx: fructose restricted diet

401
Q

Abnormal transferrin isoelectic focusing + liver failure at 6 months

A

Hereditary Fructose intolerance

Aldolase B deficiency

+ renal tubular dysfunction, fructose aversion

+ Urine reducing substances, Hyperuricemia, Hypermagnesemia

+ Abnormal Transferrin isoelectic focusing and olisosaccharidosis enzymes (AGA, B annosidase) - sugars unavailable to attach

Tx: fructose restricted diet

402
Q

Ketoacidosis + Lactic acidosis + hepatomegaly

UOA: high glycerol, G-3-P

Plasma TG high

A

Fructose - 1,6-bisphosphatase deficiency

Gluconeogensis defect

+ hypoglycemia

+ Pseudotriglyceridemia due to glycerol elevation

Can have ketoacidosis without hypoglycemia (ddx for ketolytic disorders)

  • acutely responds to treatment with glucose
403
Q

Ketosis AND lactic acidosis

A

Think about gluconeogensis defects - unable to turn pyruvate into glycose duirng fasting -> lactate and acetoacetate buildup

404
Q

Glycogen storage in liver, high triglycerides

A

Liver GSD OR F1,6BPase deficiency

  • F1P, F1,6BP, and G3P intermediates inhibit glycogen phosphorylase -> secondary GSD VI
  • Pseudotriglyceridemia (2/2 high glycerol) resolves between acute episodes
405
Q

What is the prognosis/management for F1,6BPase deficiency

A
  • Some fructose can be tolerated (unlike HFI)
  • Glucose infusion during acute epidoes
  • improve with age as glycogen stores buildup -> less need for gluconeogenesis
406
Q

GALT Q188R, K285N

A

Classic galactosemia variants

Q188R - Caucasian

K285N - Central europe

407
Q

Hyperphosphatsia with ID

A

Mabry disease

Feature of GPI (glycosylphosphatidulinositol) anchor disorders

408
Q

What organ systems are commonly affected in O-glycosylation disorders?

A

Muscle, eye, brain (congenital muscular dystrophies) and LGMD

  • Alpha dystroglycan needs to be glycosylated
409
Q

Dev Delay, cerebellar hypoplasia, happy disposition, strabismus, inverted nipples, suprapubic/buttock fat pads

A

PMM2-CDG

  • Most common CDG

+ liver failure, can be hyper AND hypocoagulatble, nephrotic syndrome

+ cherubic facies, orange peel skin, esotropia, downslanting palpebral fissures

  • Type I pattern on transferring isoelectric focusing
410
Q

CDG with liver fibrosis, diarrhea, hypoglycemia, coagulopathy, NORMAL intellect

A

MPI-CDG

  • Treat with mannose

Type 1 pattern on transferring isoelectic focusing

411
Q

Transferrin isoelectic focusing: Elevations in 2 and 0 sialofransferring

A

Type 1 pattern -> PMM2 or MPI

  • represent early steps when coupled sialic acids are added
412
Q

What is a type 2 pattern in transferring isoelectic focusing?

A

high 3, 2, 1, and 0 sialotransferrin

  • represent defects in processing (later steps)
413
Q

Nephropathy w/ renal fanconi, short stature (hypophosphatemic rickets), myopathy, conreal crystals

A

Cystinosis

CTNS (lysosomal cystin transporter)

Tx - cysteamine PO and eye drops

414
Q

High N-acetylneuraminic acid (Sialic acid) in urine

Finiish, Hypotonia, ataxia, MR, growth retardation, epilepsy

A

Salla disease

SLC17A5

Lysosomal sialic acid transporter (7 in figure)

415
Q

High N-acetylneuraminic acid (Sialic acid) in urine

Infant with coarse facial features, HSM, severe dev delay

A

Infantile free sialic acid storage disease (ISSD)

SLC17A5 (lysosomal sialic acid transporter)

  • Severe form of salla disease
416
Q

High N-acetylneuraminic acid (Sialic acid) in urine

ID, dysostosis multiplex, HSM

A

Sialiuria

UDP-GlcNac-2-epimerase (GNE) mutation in allosteric side

  • Too much sialic acid synthesis due to lack of allosteric inhibition
  • Sialic acid builup in cytoplasm instead of lysosome
  • # 1 in figure
417
Q

Decreased muscle N-acetylneuraminic acid (Sialic acid) staining

Myopathy

A

GNE myopathy

UDP-GlcNac-2-epimerase (GNE) LOF

  • Unable to produce enough sialic acid -> terminal o-linked sugar in alpha-dystroglycan

Tx: IVIG contains some sialic acid

Can also give mannose-6-P (Product of GNE)

  • # 1 in figure
418
Q

GBA N448H

A

Type 3 Gaucher (chronic neuronopathic form) - neurological + systemic (osteoporosis, HSM, cytopenia) w/ Cardiac valve calficiations

419
Q

Cornea Verticillata, Angiokeratoma, high lysoGB3

A

Fabry

GLA - alpha galactosidase

  • Renal, Cardiac, Stroke

+ Cornea verticillata = whorling

+ hypohydrosis

420
Q

a-galactosidase B (a-N-acetylgalactosaminidase)

A

Schindler disease

NAGA gene

  • Neurodegeneration, angiokeratoma, neuropathy, myoclonic epilepsy
421
Q

What is the reproductive complication for men with cystinosis?

A

Testicle fibrosis -> low testosterone and azoospermia

  • Fibrosis also seen in thyroid, pancreas, and other endocrine glands
  • Females normal fertility (take off cysteiamine duirng pregnancy -> teratogen in mice)
422
Q

What is the difference in mechanism between cystinosis and cystinuria

A

Cystinosis = lysosomal transport defect

Cystinuria = plasma membrane transport defect

423
Q

What type of Gaucher Disease can ichthyosis be seen in?

424
Q

Which populations are at increased risk for Tay-Sachs?

A

Ashkenazi Jews (1:3600)

French-Canadians

Cajuns

425
Q

When working up Gm2 gangliosidosis, when should you not check HexA activity in serum?

A
  • often inconclusive in pregnancy women or women on contraceptives -> Check in leukocytes instead
  • When looking for GM2AP deficiency
  • In Juvenile forms when B1 variant (R178H) is present it may be fale negative
426
Q

High TG, High Cholesterol

LIPA deficiency

Vacuolated WBCs, foamy histiocytes in bone marrow

A

Lysosomal acid lipase deficiency

Infantile: Wolman disease - HSM, FTT, malabsorption, adrenal calcifications

Adult: Cholesterol Ester Storage disease = HSM, cirrhosis, atherosclerosis

Tx: Sebelipase Alfa (ERT), statins, steroids for adrenal dysfunction

427
Q

Cherry red spot, + oxysterols, elevated lyso-sphigomyelin 509

A

Acid-sphingomyelinase deficiency

Niemann Pick A - Cherry red spot, FTT, hypotonia, HSM, neurodegeneration

NP- B - splenomegaly, Interstitial lung disease, hypercholesterolemia

428
Q

What is the difference between Niemann PIck A and Niemann PIck B?

A

Both have HSM and poor growth

A is severe infantile form w/ neurodegeneration

B is later onset with normal intellect. + Intertitial lung disese

429
Q

Abnormal EMG, elevated CSF protein, high urine sulfatides

A

Metachromatic leukodystrophy

ARSA, or Saposin B

  • Tigroid leukodystrophy on MRI

INfantile: 1-2yo spasticity, gait changes, regression + optic atrophy/neuropathy -> death by age 6

Juvenile/Adult - childhood cognitive + gait + ataxia

Tx: HSCT for juveile cases

430
Q

Tigroid leukodystrophy on MRI + Hurler like presentation + ichthyosis

A

Multiple Sulfatase Deficiency

SUMF1 gene - formylglycine generating enzyme -> neessary in postranslational acivation of sulfatases including ARSA and many MPS enzymes

  • Test other sulfatases if cononical genes are negative for these disorders
431
Q

Extreme irritability, neuropathy, opisthotonis, hyperpyrexia

+ multinucleated macrophages

A

Krabbe Disease, AKA globoid leukodystrophy

Galactocerebrosidase/Galactosylceramidase (GALC) or saposin A

Multinucleated macrophage = globoid cell

Late onset form = ataxia, HSP, vision loss

Tx: early HSCT

432
Q

High N-acetylaspartic acid in urine and CNS

A

Canavan disease

ASPA - N-acetylaspartic aciduria/aspartoacylase deficiency

NAA is normally marker of brain health and LOW in leukodystrophies, NAA is HIGH in canavan

  • Macrocephaly, hypotonia + leukodystrophy
  • Death by 10
433
Q

Name disease with MRI pattern:

1) Posterior white matter hyperintensity
2) TIgroid with sparing of u fibers
3) Anterior leukodystrophy that moves posteriorly

A

1) Posterior white matter hyperintensity - XALD
2) TIgroid with sparing of u fibers - Metachromatic
3) Anterior leukodystrophy that moves posteriorly - Alexander

434
Q

Heparan-N-Sulfatase

A

MPSIIIA - Sanfilippo

SGSH

435
Q

N-acetylglucosaminidase

A

MPSIIIB - Sanfilippo

NAGLU

436
Q

Acetyl-CoA Glucosamine N-Acetyltrasnferase

A

MPS IIIC - Sanfilippo

HGSNAT

437
Q

N-Acetyl-glucosamine-6-sulfatase

A

MPSIIID

GNS

438
Q

N-Acteylgalactosamine-6-sulfate sulfatase

A

MPS IVA - Morquio A

GALNS

ERT: Elosulfase Alfa

439
Q

B-Galactosidase

A

MPSIVB -Morquio B (or GM1)

GLB1

440
Q

Arylsulfatase B def

A

MPS VI - Maroteaux-Lamy

ARSB

  • Dermatan and Chondrotin sulfate
  • Systemic MPS

ERT: Galsulfase

441
Q

B-Glucuronidase

A

MPS VII - Sly

GUS

Systemic MPS

Dermatan, Heparan, Chondrotin Sulfate

Tx estronidase Alfa

442
Q

In which MPS are chondrotin sulfate elevated?

A

VI (Maroteaux lamy) and VII (Sly)

443
Q

Name the MPS that goes with each ERT:

Vestronidase

Elosulfase Alfa

Idursulfase Beta

Laronidase

Idursulfase

Galsulfase

A

Vestronidase - VII - B-glucoronidase

Elosulfase Alfa - IVA - N-acetylgalactosamine-6-Sulfate sulfatase

Idursulfase Beta - II - Iduronte-2-sulfatase

Laronidase - I - A-L-Iduronidase

Idursulfase - II -Iduronte-2-sulfatase

Galsulfase - VI - Arylsulfatase B

444
Q

Joint hyperlaxity, tilted radial epiphysis, dysostosis multifplex

A

MPSIV -> morquio

B-galactosidase def or N-acetylgalactosamine-6-sulfate-sulfatase

ERT: elosulfase alfa for MPS4A

445
Q

Cathepsin A deficiency

A

Galactosialidosis

  • Responsible for stablization of enzyme complex including both neuraminidase AND B-galactosidase
  • MPS like disorder
446
Q

Elevated Gastrin, Low HCl in gastric fluid, lysosomal inclusions

A

Mucolipin 1 deficiency (Mupolipidosis IV)

  • abnormal trafficking of proteins and lipids into lysosome
  • Corneal clouding, retinal dystrophy, pyschomotor delay
447
Q

High oxalate and glycolate

Kidney stones

A

Primary Hyperoxaluria type 1

AGTX gene

Arginine-glycosylate aminotransferase deficiency - inability to process glyoxylate in proxisome -> glyoxylate converted into oxalate in cytoplasm -> deposition

+ renal failure

  • 1/3rd of cases B6 responsive (co factor for aminotransferase)
  • tx = transplant
448
Q

High oxalate and L-glycerate

kidney stones

A

Primary Hyperoxaluria type 2

Glyoxalate reductase deficiency

  • 20% get renal failure
449
Q

High oxalate and hydroxyoxoglutarate

renal stones

A

Primary Hyperoxaluria type 3

Hydroxyoxotluratrate Aldolase 1 deficiency

  • hypercalciuria
  • renal railure rare
450
Q

Neuropathy, hearing loss, ID, optic atrophy

Low Uric acid

Undetectable hypoxanthine

A

Phosphoribosylphyrophosphate synthetase deficiency

PRPS (XL)

First step of purine synthesis

451
Q

High uric acid (serum and urine), high hypoxanthine

Adults: Uric acid urolithiasis, Gout

Children: SNHL, ataxia, hypotonia

A

Phosphoribosyl pyrophosphate synthease superactivity

PRPS (XL)

Tx: allopurinol

452
Q

Psychomotor retardation, seizures, autism, ataxia, growth retardation

High succinyladenosine, high SAICA Riboside

A

Adenylosuccinate lyase deficiency

ADSL

  • Abnormal AMP biosynthesis
453
Q

Epilepsy, ID, congenital blindness, cutaneous dimples on extensor surfaces

high AICA riboside

A

5-Amino-4- imidazolecarboxamide Ribosiduria (AICAR-uria)

ATIC gene - AICAR formyltransferase

454
Q

Myoadenylate deaminase deficiency

A

AMPD1 gene

  • High CK, myopathy
  • Normal ammonia in forearm ischemia test (cannot cleave ammonia in muscle)
  • part of purine nucleotide cycle that creates fumarate (TCA intermediate) as byproduct

Tx: Ribose

455
Q

High adenosine, deoxyadenosine, lymphopenia, hypogammaglobulinemia

A

SCID

Adenosine deaminase deficiency (ADA)

Tx; BMT, ERT, gene therapy

456
Q

Low uric acid, high inosine, guanosine

ID, spasticity

A

Purine nucleoside phosphorylate deficiency (NP)

PNP gene

SCID + Neurological symptoms

Tx BMT

457
Q

Low uric acid, high xanthine and hypoxanthine

Myopathy, arthropathy, nephrolithiasis, renal failure, hematuira

A

Xanthine Oxidase deficiency

XDH (dehydrogenase and oxidase same complex)

No neurological findings (seen in molybdenum cofactor deficiency)

Tx: purine redtricted diet, fluids

458
Q

Uromodulin, Rennin

Hyperuricemia, low renal uric acid excretion

A

Familial juvenile hyperuricemic nephropathy (HNFJ)

Causes gout and renal failure

  • Problem with uric acid excretion
459
Q

High uric acid, hypoxanthine, and xanthine

movement disorder, epilepsy, hypotonia

A

Lesch Nyhan

Hypoxanthine:guanine phosphoribosyltransferase deficiency (XL)

+ self mutilation, gout, uric acid stones

Tx: allopurinol, purine restriction

460
Q

High adenine, 2,8-dihydroxyadenine

A

Adenine phosphoribosyltransferase deficiency

APRT

  • Renal stones -> renal failure

Tx: Purine restriction, allopurinol

461
Q

High orotic acid

Megaloblastic anemia (unresponsive to B12 and folic acid)

A

Hereditary Orotic aciduria

Uridine-monophosphate synthase deficiency (UMPS)

  • Megaloblastic anemia + FTT, ID

Tx: uridine supplementation

462
Q

Uridine Monophosphate Hydrolase Deficiency

A

Pyrimidine-5’ nucleotidase deficiency

UMPH enzyme; NT5C gene

  • chronic hemolytic anemia w/ basophilic stippling
  • Lead toxicity inhibits UMPH
463
Q

High lactate, glyoxalate

Megaloblastic anemia, Diabetes, hearing loss

A

Rogers syndrome

Thiamine transporter 1

SLC19A2

464
Q

high lactate, glyoxalate

Fever -> leigh like illness, basal ganglia lesions

A

Thiamine/biotin responsive BG disease

Thiamine transporter 2, SLC19A2

  • Biotin upregulates transporter expression
465
Q

Amish

High lacate, glyoxalate, 2-ketoglutarate

Sever microcephaly, progressive neuropathy and BG injury

A

Mito Thiamine transporter deficiency

466
Q

High lacatate, glyoxalate, low thiamine pyrophosphate

A

TPK deficiency

Thiamine pyrophosphokinase

Leigh like duirng illness + neurodegeneration

467
Q

Epilepsy

High 3OMD, Low NT metabolites

high Ala, Thr, Gly, ornithine

A

Pyridoxiamine 5’ phophate oxidase (PNPO) deficiency

Pyridoxial phosphate-responsive epilepsy

  • idential to B6 responsive epilepsy, but may also have hypotonia, prematurity, liver disease
468
Q

movement disorder, liver disease, polycythemia

high Manganese levels

A

SLC30A10

Manganese exporter deficiency

  • manganese accumulate within cells, including liver
  • Cannot be excreted in bile

Tx: chelation (EDTA)

469
Q

Movement disorder

High manganese

A

SLC39A14

Divalent metal transporter (Mn, Zn, Fe, Mag)

  • No liver injury (not absorbed by hepatocyte)

Tx: Chelation (EDTA), Fe supplement

470
Q

hypotonia, ID, cerebllar atrophy

Hutterite founder

Type 2 isoelectric focusing pattern

Low prolidase activity

High urine manganese

A

SLC39A8 Defciency

Manganese transporter

  • Low serum and high urine Manganese
  • Decreased reabsoprtion in kidneys
  • Mn is cofactor for a glycosylation enzyme and prolidase
471
Q

Rash in fingertips/toes, FTT, diarrhea at 4-6 months

  • Low Zinc, low Alk Phos activity, high ammonia
A

Acrodermatitis Enteropathica

ZIP4 - SLC39A4

  • Zinc transporter -> moves zinc into the cytoplasm
  • Zinc is cofactor for OTC and Alk Phos (ddx for UCD and hypophosphatasia)
  • presents after weening breastmilk

Tx: Zinc supplement -> monitor Cu levels since Zn chelates copper

472
Q

Rash in fingertips/toes, diarrhea while on breastmilk

  • Low Zinc, low Alk Phos activity, high ammonia
A

Transient neonatal zinc deficiency

maternal zinc transporter deficiency

  • SLC30A2 (ZnT2) -> transports Zn into secretory vesciles in breasts
  • Zinc is co factor for OTC and Alk Phos

- No zinc in breastmilk -> Deficient baby -> acrodermatitis enteropathica phenotype while breastfed

473
Q

Low ceruloplasmin, high urine Cu, high liver Cu

A

Wilson’s

ATP7B

  • Decreased biliary Cu excretion, decreased incorporation of Cu into ceruloplasmin (stable form in blood)
  • Blood Cu levels not useful in Dx; usually low

Tx: Chelation (Penacillamin, Trientine, Zinc)

474
Q

Subdural hematoma, easy bruising, fractures, hair changes, CNS changes

  • Low serum copper and ceruloplasmin
A

Menke’s

ATP7A

  • Unable to absorb Cu from enterocytes -> deficiency
  • Labs may be normal before 3 months of age
  • Adult variant = occipital horn disease and motor neuropathy

- May mimic child abuse (SDH, fractures, bruising)

Tx: Copper-Histidine injection

475
Q

Low T3 with high T4, high TSH

SNHL, DD, myopathy

Low selenium

A

Selenocysteine synthesis disorder

SBP2 protein (SECISBP2)

  • necessary for itodothyorine deiodeinase (converts T4 to T3)
  • Selenocysteine is synthesized from serine (OH changed for SeH on tRNA)
476
Q

Progressive cerebello-cerebral atrophy

  • low selenium
A

Disorder of selenocysteine synthesis

SEPSECS

  • Selenium is coded for by UGA stop codon + downstream secondary structure element
477
Q

HSM, cirrhosis, hepatocellular carcinoma, arthropathy, cardiomyopathy, hypogonadism, DM, hyperpigmentation

C282Y

A

Classic HFE

  • reculator of cellular iron uptake vis transferrin receptor 1
  • May be compound het with H63D
478
Q

HFE G320V

Severe Iron overload before age 30, cardiomyopathy, abd pain, cirrhosis, hypogonadism, arthropathy

A

Juvenile hemachromotosis

  • May also be HAMP (Hepcidin mutation) or HJV (Hemojuvelin)
479
Q

High ferritin, normal transferrin

liver fibrosis, microcytic anemia

A

Hemochromatosis type 4

SLC11A3

  • Iron accumulation in liver and spleen due to transporter defect

Tx: Phlebotomy, deferoxamine (same as classic hemochromatosis)

480
Q

Low ceruloplasmin, Low copper, Low Iron

Diabetes, retina degenration, dementia, parkinsonism

A

Aceruloplasminemia

CP gene

  • Deficient cerupomasmin (ferroxidase)

Tx: IV ceruloplasmin

481
Q

Which 2 disorders of BH4 metabolism have NORMAL phe

A

AD GTP Cyclohyrdrolase and Sepiapterin Reductase

482
Q

Musty Odor

483
Q

Liver failure, high AFP, High ferritin, low transferrin in neonate

A

Neonatal Hemochromatosis

- Autoimmune disease

  • May present as hydrops
484
Q

Hypoglycorrhachia

A

GLUT1 deficiency

SLC2A1 (AD)

CNS glucose transporter

Hypoglycorrhachia = low CSF glucose

CSF/Blood glucose ratio <0.45, low lactate/alanine

  • Seizures/Kinesiogenic movement disorder that respond to ketogenic diet
485
Q

Sleep disturbance + behavior changes + coarse facies

A

MPSIII San Filippo

486
Q

ACSF3

High MMA

A

CMAMMA

  • Acyl-CoA Synthetase
  • Deficiency leads inability to conjugate to carnitine -> thus ACP will be normal
487
Q

What test can help find low excreter GA1?

A

urine acylcarnitines (C5DC), molecular testing

488
Q

BCAA Ratio in MSUD and normal

A

Normal: Val:Leu:Ile 4:2:1

MSUD: Leu:Val:Ile

489
Q

Which AA synthesis disorders result in:

Cutis Laxa

Neu Laxova

Hyperammonemia with low glutamine

Hyperkeplexia

A

Cutis Laxa - Proline synthesis

Neu Laxova - Serine synthesis

Hyperammonemia with low glutamine - Glutamine synthesis

Hyperkeplexia - Aspargine synthesis

490
Q

Acetoacetic acid and 3-OH butyric acid

A

These are the most common ketones founds in urine

elevation = ketone elevation

491
Q

When do you need leukocyte sample to test for Tay Sachs

A

Pregnant women and women on oral contraceptives

  • Serum enzyme activity often inconclusive
492
Q

high cholesterol, high phytosterols, high sitosterols

A

Sitosterolaemia

Twinnned sterol transporter deficiency (ABCG5, ABCG8)

  • Increased absorption/decreased biliary excretion of plant/fish sterols
  • Dietary treatment
493
Q

Triglycerides > 500mg/dl

A

Familial chylomicronemia

Lipoprotein lipase (LPL) or ApoCII (APOC2) - both AR

Unable to break down chylomicrons/VLDL

  • Tx: low fat diet, aphoresis, can supplement ApoC2 in FFP
494
Q

High TG and cholesterol

A

Familial dysbetalipoproteinemia

APOE -> deficient IDL/remnant uptake in liver

  • treat like metabolic syndrome
495
Q

Low HDL, low ApoA1, normal TG/cholesterol

Atheroscleoriss, xanthomas, corneal clouding

A

Apolipoprotein A1 deficiency

APOA1 (AD)

  • Risk factor for atherosclerosis
496
Q

Low HDL, low ApoA1, high TG, normal/low cholesterol

Neuropathy, HSM, corneal clouding, CAD

A

Tangier disease

ABCA1 - distubed intracellular transpot of cholesterol esters in macrophages

+ Faom cells, orange tonsils

497
Q

low HDL, low ApoA1, high TG, free/total cholesterol >0.7

nephropathy, anemia, “fish eye disease”

A

Lecithin Cholesterol acyltransferase deficiency

LCAT (AR)

  • Fish eye = isolated corneal clouding
498
Q

Name 3 disorder with low HDL and ApoA1

A

Apolipoprotein A1 deficiency - deficient APOA1 - normal TG and cholesterol

Tangier Disease (hypoalphalipoproteinemia) - ABCA1 (intracellular cholesterol ester transporter) - high TG, low cholesterol + Orange Tonsils

Lecithin Cholesterol acyltransferase deficiency - LCAT - high TG, free/total cholesterol <0.7 - nephropathy, anemia, “fish eye”

499
Q

Low cholesterol and TG, no/low ApoB, acnthocytes

neuropathy, ataxia, retinopathy, myopathy, diarrhea

A

Familial abetalipoproteinemia

  • Microsomal TG transfer protein (MTTP) - AR
  • ApoB deficiency (familial hypobetalipoproteinemia) is milder and semidominant
  • Deficient TG transporter into ER -> deficient ApoB containing lipoproteint -> cannot transport fat-soluble vitamines/erythrocyte dyfunction
  • Fat malabsorption, VitE deficiency (neuropathy, ataxia, retinopathy, myopathy)
  • Tx - low fat diet, Vit E supplement
500
Q

Low cholesterol and TG, low ApoB and ApoA1

Fat droplets in enterocytes

A

Chylomicron retention disease

SAR1B -> intracellular chylomicron trafficking in enterocytes

  • Fat malabsportion, FTT, vitamin deficiency
501
Q

Name 3 diseases with low TG and cholesterol

FTT, malabsorption, and vitamin deficiency

A

Famillal abetalipoproteinemia - Micorsomal TG transfer protein (MTTP, AR) -> deficient apoB lipoprotein production -> low apoB, acanthocytosis

Familial hypobetalipoproteinemia - ApoB gene (semi Dominant) -> deficient ApoB production -> low ApoB, acanthocytosis - Milder than MTTP

Chylomicron Retention disease - SAR1B -> intracellular chylomicron trafficking in enterocytes - low apoB and apoA1; fat droplets in enterocytes

502
Q

sterol 27 hydroxylase

A

CTX

sterol27 hydroxylase

high cholestanol

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