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Biochemical Genetics Flashcards

1
Q

biochemical genetic disorders

A

caused by enzyme deficiency

  • “inborn errors of metabolism”
  • problems are due to accumulation of substrates or lack of/deficiency product
  • often effectively targeted on NBS and treatable
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2
Q

biochemical genetics inheritance

A

most commonly autosomal recessive

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3
Q

PKU treatment

A

-restriction of protein in diet
+remove Phe, add tyrosine with formula
-BH4 supplementation (Kuvan) for some individuals with cofactor defect or with residual activity mutation

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4
Q

alkaptonuria

A

disorder of catabolism of tyrosine due to build up of substrates

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5
Q

alternative products

A

can be produced due to accumulation of substrates and failed conversion to normal product

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6
Q

PKU pathogenesis

A

-deficiency of PAH
-tyrosine fails to be produced
+catecholemines and neurotransmitters affected by loss of precursor
-get atypical production and urine secretion of phenylketones (phenylpyruvate, phenylacetate) due to accumulation of substrate
-elevated blood Phe levels buildup causes mental impairment

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7
Q

CAH

A

group of enzyme defects related to cortisol production from cholesterol

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8
Q

21-hydroxylase

A

most commonly mutated enzyme in CAH

  • normally converts 17-hydroxyprogesterone into 11-hydroxycortisol
  • excess 17-hydroxy converted to androgens
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9
Q

NBS detection of 21-hydroxylase deficiency

A

high levels of 17-hydroxyprogesterone and low levels of cortisol in the blood
-high false positive seen in babies born prematurely

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10
Q

low cortisol level effects

A
  • inability to retain sodium in kidney

- problems with fasting intolerance

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11
Q

effects of androgen build-up

A

virilization in females

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12
Q

reasoning behind recessive inheritance of IEMs

A

-most enzymes operate below full capacity & most physiological substrate concentration is below enzyme saturation
+only need about 10% enzyme function to avoid symptoms
+balance allows homeostasis to be maintained and gives enzymes chance to respond dynamically to substrate concentration changes

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13
Q

arginase deficiency/arginemia

A
  • failed step of urea cycle causes buildup of arginine and reduced ornithine and urea
  • affected individuals tend to develop lower limb spasticity
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14
Q

harmful double substrate

A

if the doubled concentration is problematic, the enzyme is inherited in a dominant fashion
*most heterozygotes unaffected

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15
Q

amino acid studies

A
  • quantitative
  • usually performed on blood, but can be done on urine
  • includes acids that are not part of the basic 20
  • slight elevations common so best performed after fasting-abnormal is 10x normal levels
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16
Q

organic acid studies

A
  • generally derivatives of AA, but others are part of carb metabolism or Krebs cycle
  • mostly performed on urine via GCMS
  • can be quantitative or qualitative
  • slight elevations can make results difficult to interpret
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17
Q

when to pursue AA and OA studies

A

usually performed by pediatricians, but can be done as confirmatory or follow-up studies to NBS or monitoring of therapy for affected child

  • unexplained DD
  • unexplained acute illnesses
  • FTT
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18
Q

acylcarnitine profile

A

-designed to be done on urine but now done on blood via tandem mass spec
-reflects the intracellular concentrations of acyl-CoA
+accumulating derivatives aren’t measurable in blood or urine
+report shows molecular weight or carbon number with the number of double bonds

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19
Q

enzyme assays

A

-can be performed on blood or biopsied samples
-measuring Vmax of activity in the tissue, not physiological activity
+makes some kinetic variants easy to miss because maximal activity can be normal, but at physiologic levels may not be
-stability of samples can make accuracy difficult

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20
Q

enzyme assay sources

A 
\+WBC
\+serum-non cell samples
\+NBS dried blood spot
\+skin fibroblasts
\+sometimes more invasive liver or muscle biopsies are necessary
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21
Q

CRM assay

A
  • checks for presence or absence of protein
  • antibody levels are raised to measure immunologically-looking for reaction
  • typically studied by western blot
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22
Q

treatment of CRM negative patients

A

can be more difficult because individuals have never been exposed to protein

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23
Q

gene sequencing for biochemical disorders

A

-preferable in some cases because most IEMs have causative loci & reduces issues that occur with enzymatic assay
+gene panels can also be helpful due to locus heterogeneity
+polymorphisms, VUSs and benign variants can also complicate interpretation

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24
Q

point mutations in IEMs

A
  • more likely to be crm+

- likely to allow for some enzymatic activity

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25
Q

deletions, nonsense or intronic variants

A
  • more likely to be crm-

- tend to eliminate enzymatic activity and may be more severe in some cases

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26
Q

reasons to use enzymatic tests

A
  • less expensive

- not dependent upon particular mutations

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27
Q

reasons not to use enzyme assays

A
  • activity may not be stable

- may not be active/present in easily accessible tissues

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28
Q

reasons to use gene sequencing

A
  • not tissue dependent and can detect mutations that only effect certain tissues
  • continuing decrease in costs for larger testing panels
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29
Q

reasons not to use gene sequencing

A
  • certain gene panels may not test all mutations

- interpretation challenges

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30
Q

locus/non-allelic heterogeneity

A

mutations in different genes can cause similar or the same phenotype

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31
Q

mucopolysaccharidoses

A

group of disorders with some phenotype similarities including:

  • skeletal dysplasia with joint stiffness
  • organomegaly (hepato, spleno)
  • often times intellectual deterioration
  • course facial features that become thickened
  • secretion of urine GAGs
  • 6 clinical phenotypes
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32
Q

MPS V/Schie

A

no longer used as its own phenotype, as it is caused by mutation of a shared enzyme, so it is categorized as part of a spectrum of the other type

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33
Q

MPS III/San Fillipo

A

-4 clinically indistinguishable subtypes, BUT 4 different enzyme/loci deficiencies (AR; 1 in 50000-1 in 280000)
-may have most severe neurological symptoms (ASD, aggression, restlessness)
+DD, behavioral problems cause presentation in early childhood (1.5-2y), plateau by 3 and death in teenage years
+other manifestations less severe

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34
Q

methylmalonic acidurias

A

-all affected newborns secrete methylmalonic acids in the urine
+ammonia also high
-acyl carnitine profile shows elevated C3 acyl carnitine
-gene sequencing may have to further differentiate the defective enzyme or cofactor type

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35
Q

methylmalonyl-CoA mutase deficiency genetics

A

-most common methylmalonic acidemia
+failure of methylmalonyl-CoA to be metabolized to succinyl CoA in Krebs cycle
-vitamin B12 derivative defects can also cause a similar phenotype

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36
Q

methylmalonyl-CoA mutase deficiency phenotype

A
  • acute acidosis in the neonatal period

- vitamin B12 derivative

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37
Q

Cobalamin defects

A

-compound is a B12 derivative that acts as a cofactor
+seven subtypes (A-G)
+not a vitamin deficiency, just failure to create cofactor
-dysfunction causes methylmalonic academia related to loss of cofactor
-each type caused by mutation of a different enzyme
+conical shape of teeth

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38
Q

pernicious anemia

A

B12 deficiency that leads to excretion of methylmalonic acid in urine

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39
Q

homocystinuria

A

-compound formed by removal of methyl from methionine
+typically free levels are low
-symptoms similar to marfan with ID and proneness to thromboembolism
-often picked up by NBS

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40
Q

homocystinuria co-factors

A

folic acid and B12

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41
Q

MTHFR mutation

A

causes possible increased risk for thrombotic events and babies with ONTDs
-can sometimes be missed on NBS

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42
Q

propionic acidemia phenotype

A

acute ketoacidosis (after 24h) and collapse in newborn
-high ammonia levels, high reaction metabolite levels
-apparent metabolic acidosis, hypoglycemia, hyperketonuria, hyperglycinemia
+vomiting, lethargy, altered mental status

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43
Q

propionic academias genetics

A

-defect of propionyl-CoA carboxylase (PCC)
+defect of either subunit gene can cause the phenotype
+ also requires working cofactor for phenotype avoidance
-inability to metabolize valine, odd chain fatty acids, methionine, isoleucine, threonine

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44
Q

biotin

A

-PCC cofactor, vitamin

+defects result in PCC dysfunction

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45
Q

biotin dysfunction on acyl carnitine

A

elevated C3 acyl carnitine levels

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46
Q

allelic heterogeneity

A

different mutations at same locus cause differences in phenotype

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47
Q

compound heterozygotes

A

two different mutations at same loci cause a homozygote phenotype

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48
Q

typical IEM symptom presentation

A
  • respiratory distress-deep breathing
  • vomiting
  • lethargy, seizures, coma
  • listlessness
  • hypotonia
  • severe blood acidosis
  • hypoglycemia
  • sometimes hepatomegaly
  • no dysmorphology
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49
Q

transient hyperammonemia

A

response to neonatal asphyxia that causes low APGARs, not genetic
-children pant with rapid, shallow breaths

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50
Q

prodrome

A

initially well, but develop symptoms over a period of days

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51
Q

IEM timing onset

A

-unremarkable term pregnancies
-no acute symptoms immediately after birth (24-48h buildup)
+good APGARs
+ fed well initially

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52
Q

typical IEM testing findings

A

-PE: clear lungs, no heart murmurs, (mostly) soft palpable abdomen with no organomegaly
-no signs of infection (no fever, clear chest X-ray)
-lab tests
+anion gap greater than 5 or bicarb very low
+low blood glucose
+sometimes lactic acidosis
+very high ammonia levels
+high ketonuria

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53
Q

diseases with vomiting, lethargy and coma

A
  • urea cycle defects
  • galactosemia
  • MSUD
  • organic acidemias (propionic, methylmalonic, isovaleric)
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54
Q

diseases with severe acidosis

A
  • organic acidemias (propionic, methylmalonic, isovaleric)
  • primary lactic acidoses (ETC/mito disorders, pyruvate dehydrogenase deficiency)
  • elevated lactic acid not as specific to IEMs
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55
Q

severe acidosis blood levels

A

-pH less than 7.1
+note: below 7 is life threatening
-bicarb less than 10

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56
Q

normal blood levels

A
  • pH ~7.4

- bicarb ~25

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57
Q

diseases with respiratory distress

A
  • urea cycle defects
  • organic acidemias
  • MSUD
  • nonketotic hyperglycinemia (hiccuping & apnea)
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58
Q

hyperpnea

A

rapid breathing

-can be seen in urea cycle defects due to increased ammonia increasing respiratory drive

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59
Q

Kussmaul

A

deep breathing

-can be seen with organic academias due to overcompensation for acidosis

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60
Q

respiratory depression

A

very slowed difficulty maintaining breathing

-seen in MSUD due to loss of full neurological function

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61
Q

diseases with hypoglycemia

A
  • can also lead to seizures
  • not all that uncommon in newborns
  • CAH
  • FAODs
  • galactosemia
  • propionic acidemia
  • gluconeogenic defects
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62
Q

diseases with hepatomegaly

A
  • galactosemia
  • tyrosinemia (later implication)
  • FAODs
  • LSDs (later implication)
  • liver glycogen storage diseases
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63
Q

diseases that cause seizures

A
  • due to brain intoxication by harmful buildup
  • nonketotic hyperglycinemia
  • urea cycle defects
  • organic acidemias
  • gluconeogenic defects
  • LSDs (later implication)
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64
Q

tend to present within the first week of life

A
  • amino acidopathies
  • disorders of carbohydrate metabolism
  • FAODs
  • CAH
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65
Q

urea cycle defects

A

-cause acute, severe hyperammonemia
+symptoms usually initiate at levels >200, but may not be brought to care until levels are at ~1000
+high levels are toxic, causing TCA disruption and glial swelling/cerebral edema
-initial signs: tachypnea, vomiting, lethargy, seizures, bleeding
+NOT acidotic-nL blood pH
-treatable, but longer without treament=worse long term prognosis-coma and death come on quickly
-signs begin after the first 24h

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66
Q

normal ammonia levels

A

30

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67
Q

urea cycle defect treatments

A

-hemodialysis to remove ammonia
-medications
-organ transplant-namely liver
+alternative pathway excretion has helped with the need for this (benzoate + phenyl acetate-ammonia scavengers-because glycine and glutamine come from ammonia)
-limitation of protein in diet to reduce nitrogen levels and urea that would need to be synthesized
-arginine or citrulline supplementation
-treatment of secondary effects, such as intracranial pressure, coagulation problems, etc

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68
Q

urea cycle defect diagnostic testing

A

-high ammonia levels
-serum amino acids
+citrulline and ornithine are meant to be transported across membrane-elevations of these or their substrates/products (arginine, argininosuccinate) indicate which enzyme is defective

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69
Q

urea cycle defect enzymes

A 
-mitochondrial 
\+carbamyl phosphotase synthase I
\+ornithine transcarbamylase (OTC)
-cytosolic
\+arginosuccinate synthase
\+arginosuccinate lyase
\+arginase
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70
Q

urea cycle defect NBS

A

only detects argininosuccinate lyase and synthase deficiencies based on elevated citrulline levels

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71
Q

OTC genetics

A

-X-linked inheritance
+males mostly affected
+females may be protein intolerant or have more problems during pregnancy and delivery
-deficiency of enzyme causes extreme ammonia elevation, both affected and carriers may have psychiatric issues

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72
Q

organic acidemia presentation

A
  • acute, severe ketoacidosis (pH <7.1) around a few days of life
  • vomiting, hyperpnea, lethargy
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73
Q

organic acidemia treatment

A

-special diets and vitamin treatments
+want to reduce accumulation of toxic substrate
-dialysis

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74
Q

organic acidemia diagnosis

A
  • urine organic acid study

- acylcarnitine profile

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75
Q

propionic acidemia diagnosis

A
  • urine organic acid studies show elevated methyl citrate, propinyl glycine and other substrates of reaction (VOMIT-CTU)
  • acylcarnitine shows elevated C3
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76
Q

methylmalonic acidemia presentation

A

-severe acute ketoacidosis, hyperketonuria after 24-48h
+metabolic acidosis, hyperammonemia
-hypoglycemia, hyperglycinemia
+vomiting, lethargy, altered mental status

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77
Q

isovaleric acidemia genetics

A

-defect of isovaleryl-CoA dehydrogenase
+comes from degradation of leucine
-follows enzyme that fails in MSUD
-requires riboflavin (B2) as a cofactor

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78
Q

acute isovaleric acidemia presentation

A
  • sweaty feet, dry vomit odor
  • severe ketoacidosis in newborn period, hyperammonemia, ketonuria
  • vomiting, lethargy
  • pancytopenia
  • note a chronic intermittent form brought on by a stressor and an asymptomatic variant also exist
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79
Q

isovaleric acidemia testing

A
  • elevated isovaleric acid in urine OAs

- elevated C5 acylcarnitine (studied by NBS too)

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80
Q

MSUD presentation

A

-initial signs are lethargy and hypotonia, respiratory distress/depression, seizures
-progression to acidotic state, vomiting, and coma
+if untreated get severe neurological damage due to cerebral edema
-urine and sweat smell sweet, like syrup
-older children can develop ataxia, slurred speech, altered mental status

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81
Q

MSUD genetics

A

-defect of branched chain ketoacid dehydrogenase
+failed second step of breakdown of leucine, isoleucine and valine
+3 subunit protein
-thiamine dependent
-1/185000 incidence
+higher in AJ (1/51000) & highest in mennonite (1/176)

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82
Q

MSUD testing

A
  • positive urine dipstick for ketones

- blood testing will show ketoacidosis, high branched chain acids on OA panel (elevated leucine picked up on NBS)

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83
Q

MSUD treatment

A

-respond well to special diet and vitamin supplementation
+Thiamine addition for some
+protein removal to reduce BCAAs
-dialysis to remove leucine
+sometimes a need for liver transplantation

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84
Q

galactosemia genetics

A
  • defect of galactosemia-I-phosphate uridyltransferase (GALT), carb metabolism failure that causes buildup of galactose in liver
  • frequency of 1/50000-1/80000 (AR, pan ethnic)
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85
Q

galactosemia presentation

A

-initial signs are non-specific: jaundice, hepatomegaly, feeding intolerance and vomiting
- leads to liver failure, hepatomegaly
+sometimes blood clotting abnormalities
+sepsis due to E. coli infections
-hypoglycemia seen shortly after eating
-even treated can still have neurological sequelae like speech difficulty, LD, ataxia or POI with hypergonadotrophic hypogonadism and primary or secondary anemia
-development of cataracts

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86
Q

galactosemia treatment

A
  • symptoms diminish in absence of feeding (IV fluids with glucose are fine in newborns)
  • responds well to diet-removal of milk from diet, sometimes certain foods must be added
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87
Q

galactosemia testing

A

-galactose in urine
-abnormal enzyme levels in blood (enzyme operates in RBC-what is measured on NBS)
+reflex testing to rule out certain variants
+heat-sensitivity can cause false positives in summer
+misses non-traditional enzyme mutations
-can measure blood galactose, but this is finicky due to level fluctuation related to intake

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88
Q

FAODs presentation

A

-sometimes seen a bit later on when children are sleeping through night (prodrome)
-develop fasting hypoglycemia
+hypoglycemia requires fasting for at least 6-12h
+note this is hypoketotic, which is different than typical cases of hypoglycemia
-long chain defects can cause liver and muscle disease including CM; can be transient in liver
-lettering indicates chain length and enzyme function
-lethargy and vomiting
+byproducts-especially in MCAD are poisonous
-associated with infant death due to failure to treat

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89
Q

FAODs treatment

A
  • often just avoidance of fasting

- can supplement with carnitine if low or with MCAs for LC defects

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90
Q

FAODs testing

A
  • urine OAs show levels of things that should not be present (MC dicoarboxylic acids)
  • acyl carnitine profile will show long chain results (C8, C14) and possible carnitine deficiency
  • absence of ketoacids in urine
  • carnitine profile where total might be low with increased esterified fraction
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91
Q

CAH genetics

A

defects in cortisol synthesis

  • 21-hydroxylase deficiency most common
  • incidence of 1/15000 infants
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92
Q

CAH presentation

A

-fasting intolerance & hypoglycemia due to inability to respond to gluconeogenic blunting
-lethargy
-poor response to metabolic stress
-salt wasting that causes circulatory collapse
+rapid heart rate and low BP
-prenatal virilization in females

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93
Q

CAH testing

A
  • cortisol deficiency
  • loss of salt in urine if aldosterone deficiency
  • low sodium and high potassium levels in blood due to aldosterone deficiency
  • elevated 17-hydroxyprogesterone at birth (NBS)
  • ACTH stimulation testing is diagnostic (normally completed by endocrinology)
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94
Q

CAH treatment

A
  • HRT, cortisol replacement
  • florinef and HCl replacement also sometimes needed if mineralocorticoids low
  • possible surgical intervention
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95
Q

eval for hepatomegaly

A
  • age at onset/recognition
  • developmental status-IEMs can lead to neuron impairment (DD, seizures, etc)
  • acute illness or any additional symptoms that might make you more suspicious of an infection
  • difficulty of waking the affected child in the morning
  • signs of hypoglycemia such as cold sweats, rapid heart rate, chills after fasting
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96
Q

PE with hepatomegaly

A
  • look for coarse facial features, skeletal anomalies
  • check to see whether spleen is enlarged
  • presence of joint stiffness or muscle weakness, pain on exercise
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97
Q

labs for GSDs

A

-looking at electrolytes for increased anion gap
+lactic acid might be especially elevated
-looking for low blood glucose/hypoglycemia, especially in fasting samples (glucagon injection studies)
-CBC-LSDs may cause anemia or low platelet count due to splenomegaly
-possible increased urine GAGs in MPSs
-skeletal survey-looking for dysostosis multiplex
-biopsies-especially bone marrow or liver with Gaucher disease
-gene panel

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98
Q

LSDs

A

-group of disorders that result in inability to degrade cellular structural components
+get accumulation in scavenger cells of the liver, spleen, neurons, etc
-mutant enzymes are specific to deficient organelle-they are degradative, produced by the golgi apparatus and imported
+mannose-phosphate tag targets their import

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99
Q

glycolipids

A

lipid-like molecules (sphingosine) with attached carbohydrates

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100
Q

Farber disease

A

failure of ceramide to be cleaved from sphingolipid

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101
Q

Gaucher disease genetics

A

-AR GBA mutations
-cause accumulation of glucocerebroside in lysosomes due to dysfunction of glucocerebrosidase
-panethnic (1/60000-1/100000)
+can see higher incidence of type I in AJ (N370S), type II & III in Asians
*close linkage of disease gene to highly mutagenic pseudogene

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102
Q

Krabbe disease genetics

A
  • accumulation of galactocerebroside in lysosomes due to galactocerebrosidase (GALC) deficiency
  • incidence of 1 in 100000
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103
Q

Tay-Sachs genetics

A

-GM2 ganglioside accumulation
-failed sphingolipid cleavage by HEXA
-later onset forms due to reduced enzymatic activity
-present in all populations, but AJ, Fr Ca, Cajun, Penn Dutch founder muts
+1 in 30 AJ carrier freq (1 in 3600)
+1 in 250-300 other

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104
Q

mucopolysaccharidoses genetics

A

-defects in GAG degradation
+dermatan, keratan, heparin and chondroitin sulfates
+important in cell membranes and cartilage, making the precursors helpful for treating joint pain
-6 clinically distinct types

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105
Q

MPS phenotype

A
  • skeletal problems and joint stiffness
  • hepatosplenomegaly
  • neurologic problems (can be progressive)
  • pulmonary complications causing breathing difficulty and lung stiffness
  • eye problems (retinal issues, corneal clouding)
  • cardiac valve dysfunction
  • hearing loss
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106
Q

MPS testing

A
  • skeletal survey
  • urine GAGs-generalized elevation
  • enzyme analysis usually completed on leukocytes, but can use fibroblasts***gold standard
  • genetic testing-full gene+del/dup especially if considering type II
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107
Q

GSDs

A

-group of disorders characterized by glycogen accumulation
+liver, heart and skeletal muscles often affected
-hepatic versions can have fasting hypoglycemia (<6h fasting)
-liver versions have liver enlargement, but no spleen involvement
-muscle weakness or pain with exercise common
*excessive glycogen in liver does not always mean one of these genetic conditions

108
Q

Gaucher disease presentation

A

-splenomegaly-often get anemia and thrombocytopenia
+can see bruising and blood clotting
+rarer b-cell malignancies and avascular necrotic pain crises
-interstitial lung disease-can cause hypoxemia and breathing problems
-skeletal issues
+pathological fractures-no trauma
+erlenmeyer flask deformity
-5% individuals can have Parkinsons/Lewy body dementia

109
Q

erlenmeyer flask x-ray deformity

A

suspicious for Gaucher disease if splenomegaly is seen

110
Q

Gaucher Type I

A

-most common type, more common in AJ pop (N370S)
-no neurologic involvement-rare LBD/PD
-tends to have adult onset, but can present with hepatospleno in childhood
+can also have some more severe phenotype overlap
+despite same level of enzyme deficiency can still see variability in manifestations within same family
-splenomegaly with anemia and thrombocytopenia always + osteopenia + pulmonary disease seen to some degree
+can also see B-cell malignancy
*major clinical heterogeneity

111
Q

Gaucher Type II

A
  • often called infantile form

- rapid deterioration due to neurologic involvement

112
Q

Gaucher Type III

A
  • neuronopathic
  • chronic; slowly progressive neurologic deterioration
  • common L444P mutation, Swedish founder mutation
  • upward gaze disturbance
113
Q

NPD A & B genetics

A

allelic and due to sphingomyelinase deficiency

114
Q

NPD C genetics

A

-cholesterol trafficking defect that leads to lipid build-up
-AR NPC1, NPC2 defects
+four subtypes related to age of onset

115
Q

NPD general phenotype

A

-always have hepatosplenomegaly
+children can look malnourished due to enlarged belly and otherwise poor growth
-neurologic involvement
+hypotonia in childhood, difficulty with exercise or gait disturbance in adulthood
+deterioration-especially in Type C-gradual gait disturbance and ocular anomalies

116
Q

NPD A phenotype

A

-“infantile”, most severe form
+higher incidence in AJ
-often die by 3y due to neurologic deterioration

117
Q

NPD B phenotype

A
  • milder, despite being allelic with Type A

- often present later and have less or no neurological involvement

118
Q

NPD C phenotype

A
  • sometimes can see ascites prenatally, then have FTT, jaundice and growth deficiency
  • always have hepatosplenomegaly
  • usually presents in childhood with gait disturbance and ataxia, cataplexy/loss of control and muscle tone also happens
  • palsy of upward gaze occurs
  • SNHL sometimes
  • often see gradual buildup to ID, DD, psychiatric conditions, seizures
  • respiratory failure also a major issue
119
Q

skeletal implications of MPSs

A

-coarsening facial features
-joint stiffness
+claw hand deformity
+kink of spine (gibbus)
+difficulty raising arms above shoulders
+bent over posture and hip stiffness
-dysostosis multiplex on X-ray

120
Q

dysostosis multiplex

A

*seen on X-ray in individuals with MPSs, but not only specific to
-refers to involvement of many bones
+spindling of bones in hand (not tapered in middle)
+hooking of spinal vertebrae (rounded rather than square)
+broad ribs

121
Q

MPS I/Hurler-Scheie genetics

A

-two phenotypes with some patients falling in between
-due to L-alpha-iduronidase deficiency (IDUA)
+1 in 100000 incidence
+genotype-phenotype correlations

122
Q

MPS II/Hunter

A

-X-linked condition-few heterozygous females
-deficiency of IDS
+incidence of 1 in 100000
+gen-phen correlations exist, but many private mutations
-similar phenotype to Hurler without corneal clouding

123
Q

MPS IV/Morquio

A

-2 subtypes caused by two different enzymes (incidence of 1 in 75000; AR)
-no neurological involvement, but more severe skeletal abnormalities which can require many surgeries
+lax wrists** and hyper mobile joints
-severe corneal clouding

124
Q

MPS VI/Maroteaux-Lamy

A

-arylsulfatase B deficiency (AR)
-phenotype similar to Hurler, but distinguished by skeletal features, corneal clouding, and lack of neurological effects
+claw hand deformity & carpal tunnel
+limited mobility and significant pain requiring assistive mobility devices and surgeries
-large tonsils and adenoids

125
Q

MPSVII/Sly

A
  • most rare form (AR; <1 in 250000)
  • organomegaly and skeletal dysplasia more prominent
  • can also have respiratory disease, and progressive ID, DD
  • high mortality with few individuals living into 20s
  • hydrops can be seen in severe cases
126
Q

Hepatic GSDs

A
  • GSD I/von Gierke
  • GSD III/Forbes, Cori disease
  • GSD VI and higher/Hers disease
  • GSD IV/Andersen
  • GSD 0
127
Q

GSD I genetics

A

-disorder of the release of glucose from the liver causes glucose buildup and excessive synthesis
-two subtypes: a-glucose-6-phosphotase deficiency, b-transporter enzyme defect
-AR incidence of 1 in 100000
+R83C common EEJ mutation carrier freq 1.4%, prevalence 1 in 20000

128
Q

GSD Ia/von Gierke phenotype

A

*most severe GSD & most common, but no myopathy
-massive hepatomegaly even when sugar is well controlled
+mostly due to fat storage
-severe hypoglycemia after short fast
-hyperlipidemia, hyperuricemia
+can cause kidney problems and gout-like symptoms
-can have severe lactic acidemia due to inability of glucose release-not due to muscle defect
-doll-like facies

129
Q

GSD III/Forbes, Cori disease phenotype

A

-moderate hepatic involvement, but possible more prominent muscle involvement
+muscle weakness, progressive CM (HCM earlier in life)
+hepatomegaly able to be reduced because gluconeogenesis is functional
-can have severe hypoglycemia (not type I level)
-lactic acidemia
-sometimes hyperlipidemia or hyperuricemia

130
Q

GSD III genetics

A

glycogen debrancher enzyme deficiency

131
Q

GSD VI+ genetics

A

-deficiency of hepatic phosphorylase and those that activate phosphorylase
+Type IX for example is an X-linked kinase deficiency with mild hypoglycemia

132
Q

GSD IV/Andersen phenotype

A
  • liver damage, cirrhosis, hepatospleno and progressive failure
  • FTT
  • myopathy and cardiomyopathy-tends to become most severe symptom
133
Q

GSD IV genetics

A

disorder of glycogen synthesis due to deficiency of the glycogen brancher enzyme
+synthesize straight chain that liver can’t handle
+build-up of amylopectin

134
Q

GSD 0 genetics

A
  • glycogen synthase deficiency

- no glycogen present in liver or muscles

135
Q

GSD 0 phenotype

A

-very rare

136
Q

evaluation for neuromuscular IEMs

A

-age of presentation and staticness
+if later onset or regression more indicative
-ethnicity
-hyperaccusis presence
-lethargy or lack of attentiveness with potential seizures

137
Q

hyperaccusis

A

startle reflex with loud noises

138
Q

PE for neuromuscular IEMS

A

-eye functions
+abnormal movements-loss of acuity and roaming
+abnormal findings-ex: cherry red spot
-organomegaly
-muscle weakness, stiffness, exercise intolerance

139
Q

neuromuscular IEMs labs

A

-most routine lab work normal
-lactate levels-elevated lactic acids in mito
-CK levels elevated related to muscle damage
-MRI
+changes in white matter identify CNS involvement
-muscle biopsy
-enzyme and gene assays for formally pinpointing diagnosis

140
Q

neuromuscular IEM etiology

A

muscle weakness primarily due to brain involvement and CNS dysfunction, muscles are normal

  • no hepatosplenomegaly
  • often see eye involvement because its neuronal tissue
141
Q

cherry red spot

A

eye anomaly due to neuronal tissue damage, causing retinal paleness

142
Q

muscular IEMs etiology

A

defects of muscle metabolism without brain involvement

  • see DD due to muscle weakness
  • weakness and pain, stiffness with exercise
143
Q

myoglobinuria

A

serious condition that can lead to kidney failure and is a sign of muscle breakdown
-causes pink urine

144
Q

Tay-Sachs phenotype

A

-typical infantile presentation
+regression, seizures, myoclonic jerks, exaggerated startle-no organomegaly except for possible macrocephaly (cerebral gliosis) development
+retinal cherry red spot, vision deterioration to blindness
+see rapid decline of previously healthy child after 6mo
+respiratory failure, can see aspiration leading up to this
-later onset forms present with muscle weakness and gait anomalies (think SMA or ALS)
+can also see psychiatric symptoms (40%), cerebellar atrophy and abnormal eye movements

145
Q

Tay-Sachs testing

A

-carrier screening began in 1970s
-enzyme activity assay on blood serum or leukocytes
+serum not accurate for women on OCPs or pregnant
+beware pseudo deficiency (35% non-AJ & 2% AJ not true carriers)
-gene testing
+targeted panels with varying sensitivity
+full gene sequencing 99% sensitive

146
Q

Krabbe phenotype

A

infantile onset of muscle stiffness, less weakness

  • opisthotonic posturing with leg scissoring common
  • irritability and crying without cause
  • startle reaction/hypersensitivity
  • absence of organomegaly or eye problems
  • can develop vomiting and seizures, until plateau transitions to burn out when nerves are too damaged, then kids have blindness, decerebration and absence of voluntary movement
  • typically see death within 18mo
147
Q

opisthotonic posturing

A

common in Krabbe where children throw head back with an arched back or arched shoulders due to stiffness

148
Q

Krabbe disease treatment and screening

A

-enzyme testing on some NBS tests (0-5% GALC activity diagnostic)
-GT should be sequencing and del/dup
+30kb del accounts for 45% of mutant alleles in infantile form
+c.857G>A seen in late onset
-BMT only possible treatment, but see poor results after symptoms begin

149
Q

GSD II/Pompe genetics

A

LSD causes muscle lysosome accumulation of glycogen due to deficiency of alpha-glucosidase/maltase

  • incidence of infantile 1 in 138000, incidence of LO 1 in 57000
  • pseudodeficiency allele common in some populations
150
Q

GSD II/Pompe phenotype

A 
Infantile-typically death within 1y
-hypotonia shortly after birth
-cardiomegaly, ECG anomalies
\+short PR interval
-muscle breakdown
\+high blood CK
-progressively fatal heart (CARDIOMEGALY) and respiratory failure
-no hypoglycemia or hepatomegaly
-can see some later onset forms with progressive weakness, respiratory failure and later onset myopathy
151
Q

GSD II diagnosis and treatment

A

-sometimes people may need heart transplants
-ERT available using M-6-P tag
+most success seen if provided prior to ventilation-but doesn’t mean certain survival
+crm- patients can create antibodies that cause recurrence
-sequencing more diagnostic? due to pseudodeficiency

152
Q

GSD V/McArdle genetics

A

muscle (myo)phosphorylase deficiency

153
Q

GSD V/McArdle phenotype

A

-mostly normal but signs of muscle breakdown (rhabdomyolysis)
+exercise intolerance with pain and cramping, myoglobinuria and high CK
+no hepatomegaly, but kidney disease due to myoglobin levels
-recommend reduced exercise and sometimes high carb diet

154
Q

VLCAD phenotype

A
  • present with muscle weakness and cardiomegaly/cardiomyopathy
  • can sometimes begin in newborn period
  • may also have fasting intolerance
  • develop secondary renal disease
155
Q

VLCAD labs

A

-lipid myopathy seen on muscle biopsy
-acylcarnitine and blood carnitine levels abnormal
+purpose of carnitine is to transport these, so levels can be high due to deficiency

156
Q

VLCAD treatment

A

can sometimes see improvement with medium chain triglyceride supplementation

157
Q

genetic hypoglycemia

A
  • GSDs-inability to release produced glucose
  • FAODs-dont have supplies to create energy
  • disorders of gluconeogenesis-units of energy cannot be made or transported
  • CAH-cortisol deficiency causes decreased ability to put resources towards glucose transport
158
Q

evaluation for fasting intolerance

A
  • prodrome
  • time length of fast that caused symptoms
  • presence of lethargy or vomiting
  • PE for hepatomegaly or muscle weakness
159
Q

fasting intolerance IEMs signs

A
  • onset after newborn period
  • lethargy and possible vomiting due to fasting and byproduct buildup
  • can see hepatomegaly due to products buildup, namely fats
  • lactic acidemia (esp GSDs and gluconeogenesis disorders)
  • hypoketosis (FAOD defects reduce blood and urine ketones)
160
Q

fasting intolerance IEMs labs

A 
-anion gap measurement
\+lactic acidosis can increase difference
-lactic acid level measurement
-additional blood chemistries
\+can see high uric acid and triglycerides
-blood and urine ketones
\+low if FAOD
-urine OAs
-acylcarnitine and carnitine profiles
161
Q

FAODs genetics

A

-acetyl-CoA produced by this cycle which is an energy source needed to produce glucose during periods of fasting

162
Q

gluconeogenesis disorder genetics

A
  • failure of glucose to be produced from amino acid skeletons due to deficiency of F-6-BPase or 1,6BPase and pyruvate carboxylase
  • rarely diagnosed
163
Q

gluconeogenesis disorder presentation

A
  • association with severe lactic academia because acid can’t be recycled
  • severe hypoglycemia post-fast
  • sometimes hepatomegaly due to fat buildup
  • no OA abnormalities
164
Q

GSD I management

A

-frequent feedings with cornstarch supplementation q6h
+can need overnight N-G or G-tube feedings
-behavior problems due to challenges with eating schedule
-late onset problems such as liver adenomas or hepatomas that can become cancerous, glomerulosclerosis, IBS due to neutropenia in type B

165
Q

GSD VI+ presentation

A
  • hepatomegaly
  • fasting hypoglycemia
  • mild lactic academia and/or hyperlipidemia
166
Q

MCAD presentation

A

-most common FAOD, often picked up by NBS
+previously thought to be associated with SIDS (18% death is first symptom)
-normal except when fasting-have hypoketotic hypoglycemia
+can require hospitalization during illness, as coma can occur
-hyperammonemia that leads to liver disease
-lethargy, coma and hypotonia due to neurologic problems

167
Q

VLCAD presentation

A

-long chain fatty acid disorder
-may have muscle and cardiac involvement due to loss of fuel source
+CM
-can have exercise intolerance and skeletal muscle involvement
-hypoketotic hypoglycemia

168
Q

LCHAD presentation

A
  • “trifunctional enzyme deficiency”
  • hypoketotic hypoglycemia-but can develop without fasting
  • cardiomyopathy or cardiac malfunction
  • retinal findings or retinopathy
  • female heterozygotes (carrying affected pregnancy) can develop HELLP and have fatty liver during pregnancy
169
Q

NBS rationale

A

test all infants for treatable conditions and provide treatments to the symptoms before they become harmful and irreversible

170
Q

NBS goal

A

improving outcomes of treatment and prevention

171
Q

NBS principles

A

-reliable
-inexpensive
-reasonable confirmatory testing
-tests for treatable disorder
-early treatment improves outcome beyond waiting for symptom development
-reasonable disease frequency
+higher PPV of test

172
Q

hypothyroidism

A

-incidence of 1 in 3000
-most common condition picked up by NBS, but not an IEM
+see elevated TSH that requires follow-up by endo to determine specific issue
-mostly due to hypo- or aplasia of thyroid, though can be due to pituitary insufficiency
-symptoms can cause lethargy, poor feeding and growth, DD, hoarse cry
-treat with growth hormone

173
Q

PKU NBS

A

-originally Guthrie bacterial assay measured serum phenylalanine levels-now replaced by chemical methods
-measures Phe levels (>4mg% called positive)
+only 5% of positives are true positives

174
Q

classical PKU genetics

A

-incidence of 1/32000, 1/12000 Caucasians
+milder variants half as common-still need treatment
-levels of Phe >10mg% need treatment, classic type is >20mg%
-PAH deficiency
+greater than 200 known mutations
-tetrahydrobiopterin (BH4) cofactor

175
Q

problems with assay NBS

A

-measures substrate or protein in blood, which may be age or diet dependent
+ex: Hb ratios, amount of Phe
-not all conditions have enzyme or substrates measurable by this technique
-not a diagnostic test
+risk for false positives

176
Q

DNA-based NBS

A

-allows for detection of a wider range of conditions
+does not require specific enzyme or substrate analysis from sample
-diagnostic for tested mutations
+but this is expensive
+misses mutations not targeted
-now often a reflex to abnormal results-stepwise
+ex: look for elevated trypsinogen related to CF, then test for common mutations

177
Q

DNA-based CF NBS

A

-5 mutation test identifies 85% of mutant genes
+varies by ethnic group
+of affected 72% patients homozygotes, 26% heterozygotes, 2% completely missed by this method
-have either a large number of false positives or false negatives
-should be followed up by diagnostic sweat chloride

178
Q

recommended core NBS panel

A 
-34 conditions
\+9 organic acidemias
\+5 FAODs
\+6 AAopathies
\+2 endocrine conditions
\+3 Hb-opathies
\+9 others-hearing SCID, CF
179
Q

classic PKU phenotype

A

-asymptomatic until a few months of life
-strange odor, can also see fair pigmentation
-non-reversible (sometimes mitigated) ID, DD, seizures, aggressive behavior if untreated
+treatment should begin in first week of life

180
Q

tetrahydrobiopterin deficiencies

A
  • much rarer than PKU, but cause similar defects
  • require supplementation, rather than just special diet
  • identified by low levels in urine
181
Q

maternal PKU effects

A

high phenylalanine can be vertically transmitted and is teratogenic

  • microcephaly, ID
  • CHDs
  • skeletal anomalies
  • levels should be well controlled prior to conception and during pregnancy due to level and outcome correlation
182
Q

Duarte galactosemia variant

A

-mutation of GALT/GalPut locus that causes low enzymatic activity
+N314D allele
-5% population frequency
+picked up by NBS, but does not require diet

183
Q

MCAD genetics

A
  • incidence of 1/6500-1/17000
  • defective medium chain acyl-CoA dehydrogenase
  • A985G (K304E) variant accounts for >90% cases of affected Caucasian individuals
184
Q

MCAD testing

A

-acylcarnitine profile shows elevated C8 acylcarnitine regardless of diet or fasting status
-urine OAs
+suberic and sebacic MC dicarboxylic acids and hexanoglycine are elevated
-can sometimes get positive NBS for low activity variants, so need to due further investigation

185
Q

modes of IEM therapy

A
  • provide deficient product
  • block toxic effects
  • activate enzymatic activity with cofactor supplementation
  • dietary substrate restriction
  • alternative pathway therapy
  • transplantation
  • enzyme and gene RT
186
Q

tyrosinemia type 1 treatment

A

-orfadin to block metabolism of this product, accumulation of toxic substance
+if this not used would require liver transplant
-limit protein in diet
+reduce phenylalanine and tyrosine

187
Q

tyrosinemia type 1 genetics

A

-deficiency in breakdown of tyrosine
-fumerylacetoacetate hyrdrolase (FAH) fails to cleave product into 2 and causes buildup of maleylacetoacetate
+succinylaccetone buildup causes toxicity

188
Q

tyrosinemia type 1 phenotype

A
  • liver failure
  • hepatocellular carcinoma
  • renal Fanconi’s-failed reabsorption
  • porphyria-like neurological crises
  • can have rotten-egg smell
189
Q

vitamin and cofactor therapy

A

-can activate residual activity
+sometimes poor cofactor binding occurs
-may overcome activation defects

190
Q

methylmalonic acidemia treatment

A

-B12 supplementation
+especially useful with cobalamin defects
-liver and kidney transplant

191
Q

alternative pathway treatment

A

-uses existing pathways to augment excretion of toxic metabolites as non-toxic compounds
+may use endogenous compounds or exogenous drugs

192
Q

hyperphe

A
  • residual PAH activity results in AA level above normal
  • can have a variable phenotype with variable levels and can require anywhere from new treatment, to slight diet restriction to full blown formula supplementation
193
Q

homocystinuria treatment

A
  • dietary restriction of methionine
  • addition of B6 and B12 to diet
  • prescribe betaine/cystadane to force excretion of product as methionine
194
Q

hyperhomocysteinemia

A
  • mild elevation of homocysteine with unclear cause
  • predisposition to CAD
  • recommended monitoring and treatment with folate, B6, B12
195
Q

tyrosinemia type 2 genetics

A

deficiency of tyrosine aminotransferase deficiency

196
Q

tyrosinemia type 2 phenotype

A

corneal, palmar, solar lesions/crystallizations

197
Q

chronic intermittent MMA and PA

A

may present later with acute encephalopathy, episodic ketoacidosis, DD, recurrent vomiting and FTT

198
Q

long term untreated PA

A
  • severe ID
  • hypotonia
  • recurrent life-threatening metabolic decompensation
  • end organ failure (especially fatal if cardiomyopathy occurs)
199
Q

long term untreated MMA

A
  • normal intellect to mild ID
  • recurrent metabolic decompensation
  • end organ failure
200
Q

PA and MMA treatment

A
  • low protein diet with substrate restriction
  • antibiotics to reduce gut bacterial PA production
  • biotin or hydroxy B12 cofactor supplementation
  • elimination of toxic buildup via carnitine
  • provide bicitra for acid-base stabilization
201
Q

Cbl C disease

A
  • methylmalonic acidemia+homocystinuria

- causes ID, seizures, nystagmus, cardiac abnormalities, abnormal dentition

202
Q

isovaleric acidemia treatment

A
  • low protein diet restricting leucine intake
  • excretion of harmful substrates via carnitine and glycine pathways
  • provide bicitra for acid-base stabilization
203
Q

3-MCC

A

-most common OA, but mostly asymptomatic
+possible deterioration from illnesses
-part of leucine catabolism pathway
-symptomatic individuals may have ketoacidosis, vomiting, hypoglycemia
-treatment includes protein restriction, biotin supplementation and excretion via carnitine

204
Q

hyperammonemic encephalopathy

A

usually occurs in urea cycle defects despite therapy

-intercurrent infection, fasting, protein loads and surgery can all be triggers

205
Q

arginosuccinate lyase deficiency

A

affected individuals tend to have coarse hair and cirrhotic changes

206
Q

heparan sulfate

A

GAG present in all cells

-if degradation affected in MPS can see cognitive effects

207
Q

keratan sulfate

A

GAG in corneal and collagenous tissues

208
Q

dermatan sulfate

A

GAG in skin and blood vessels

209
Q

MPS treatment

A

-some have available ERTs-can help with hepatosplenomegaly
-BMT-risky and must be completed in early infancy
+only way to treat cognitive symptoms
-surgeries, PT, OT to treat manifestations
-continued research as well

210
Q

Hurler phenotype

A

-normal at birth, then rapid progression within first 2y life
+coarsening of facial features including thick, coarse hair growth, lip thickening, enlargement of tongue and adenoids and nasal bridge flattening
-hepatosplenomegaly, cardiac disease
-skeletal anomalies-kyphosis, hip dysplasia, thickened ribs
-hydrocelphalus, corneal clouding
-DD by 18mo, then plateau and decline occur
-death by age 8-10y

211
Q

Hurler-Scheie

A

-normal at birth with symptom onset between 3-10y
+symptom progression variable and can sometimes shorten lifespan-less coarse features, varying hepatospleno, mostly normal intellect
-corneal clouding, cardiac involvement, hearing loss common
-can also often see hernias and severe skeletal anomalies

212
Q

MPS IX/Natowicz

A
  • AR, 1 known case in world, hyaluronidase deficiency
  • short stature
  • soft tissue masses that swell with fever
  • mildly dysmorphic features
213
Q

2 null HEXA alleles

A

gives infantile Tay Sachs (ex: c.1274_1277dupTATC, c.1421+1G>C, c.1073+1G>A)

214
Q

1 null + 1 late onset HEXA allele

A

causes late onset Tay Sachs

215
Q

2 late onset HEXA alleles

A

causes late onset Tay Sachs (ex: p.G269S, p. G250D)

216
Q

NPD A and B genetics

A 
-due to acid sphingomyelinase deficiency (SMPD1)
\+A: neuronopathic
\+B: non-neuronopathic
-incidence: 1 in 250000
\+AJ and NA founder mutations
217
Q

NPD A phenotype

A
  • hepatosplenomegaly by 3mo
  • developmental plateau 9-12mo age before regression and progressive hypotonia
  • interstitial lung disease
  • cherry red spot
  • death by age 3y
218
Q

NPD B phenotype

A

similar features to A without neurological decline

219
Q

NPD C

A
  • due to improper transport of cholesterol into lysosome

- can range in severity and cause white matter disease, which can lead to death in teens

220
Q

NPD A and B testing

A

-enzymatic analysis
+ <10% ASM enzymatic activity by blood serum or leukocytes diagnostic
-GT
+90% sensitivity for founder panel (90% A cases are from 3 AJ muts, 90% B cases from Mahgreb NA-in these populations)

221
Q

metachromatic leukodystrophy genetics

A
  • incidence of 1 in 40000-160000
  • AR caused by mutation of ARSA
  • common alleles responsible for majority of mutations where some gene-phen corr exists with age of onset
222
Q

late infantile MLD phenotype

A
  • onset between 1-2y
  • early development is normal, though children are “clumsy”
  • nerves atrophy and cognitive decline begins
  • speech difficulties develop and hypotonia transforms into increased muscle tone
  • seizures, vision & hearing loss can also occur
  • death usually by age 4-most kids surviving better with care
223
Q

infantile MLD testing

A

-enzyme analysis
+<10% ARSA activity (note: pseudo deficiency can artificially lower activity so requires multi-step workup)
-urine analysis shows high levels of sulfatides
-genetic testing via targeted panels & gene sequencing

224
Q

long term GSD Ia complications

A
  • liver adenocarcinoma progress from adenomas
  • renal disease
  • osteopenia/bone thinning
  • delayed puberty
  • short stature
225
Q

GSD Ib phenotype

A

-similar to type A with doll like facies and high levels of cholesterol, lactic acid, uric acid and associated complications
-more prone to infections and inflammation
+IBD, low WBC/neutropenia with bacterial infections

226
Q

hereditary fructosuria

A
  • frucaldolase B deficiency
  • causes severe hypoglycemia and vomiting with fructose intake
  • removing fructose from diet reverses liver disease and liver failure that can cause death
227
Q

F-1,6-BPase deficiency

A
  • causes severe lactic acidosis with hypoglycemia and ketosis
  • can be rapidly lethal
  • defect of gluconeogenesis
228
Q

carb deficient glycoproteinoses genetics

A

-incorrect synthesis of oligosaccharides in glycoproteins and glycolipids
-100 types classified
+N (more common) and O types defined by attachment

229
Q

carb deficient glycoproteinoses phenotype

A
  • present in infancy with some types being lethal
  • neurological abnormalities (hyporeflexia, nystagmus, seizures) and DD
  • multiorgan dysfunction-heart disease, liver and/or kidney problems, protein losing enteropathy of GI
  • hypoglycemia
  • skin abnormalities (peau d’orange)
  • with 1a get dysmorphism
230
Q

SCAD genetics and phenotype

A
  • common NBS referral due to asymptomatic variant but common AJ (319C>T) and non (625G>A) exists
  • muscular symptoms-myopathy, CM
  • DD
231
Q

carnitine disorders

A
  • 4 types that cause failure of LCFAs to be transported across mitochondrial membrane
  • present with hypoglycemia and muscle weakness with rhabdomyolysis that lead to CM and exercise intolerance
  • treated with levocarnitine, and avoidance of fasting with a low fat diet
232
Q

Zellweger syndrome phenotype

A
  • severe infantile presentation that causes death within the first year-sz and ID if survive past this
  • severe neonatal hypotonia and GR
  • dysmorphic features: tall boxy forehead due to skull abnormalities with large anterior fontanelle, profile hypoplasia
  • shallow orbits, down slanting and narrow PFs
  • brain development defects-“dumpy” neurons
  • congenital cataracts
  • hepatomegaly and cirrhosis with cystic kidneys
  • contractures and epiphyseal stippling on X-ray
233
Q

Zellweger genetics and diagnosis

A

-causes absence of peroxisomes leading to impaired plasmologen synthesis
+mutations of PEX genes
-elevated VLCFAs in fasting plasma is main indicator
-incidence of 1 in 25000-1 in 100000

234
Q

X-linked ALD genetics and diagnosis

A

*most common peroxisomal disorder
-due to defects in ABCD1, peroxisomal ALDP transporter membrane protein
-elevated VLCFAs in all tissues (C26, C24)
+low cortisol, high ACTH with AIS
-7 subtypes
-part of NBS by biochemical measurements
+4.1-19% de novo rate skewed by NBS
-ABCD1 gene sequencing
+if VUS or negative, send plasmologen

235
Q

XLALD phenotype

A

-variation occurs even within one family creating counseling and prognostic prediction challenges
-mean onset age at 7y with behavioral difficulties, emotional lability and school difficulties, can also see dementia, cerebellar ataxia, deafness, paralysis in cerebral type (4-8y) and spastic paresis, sensory ataxia, impotence, sphincter dysfunction and hair loss in myeloneuropathic type (20s, middle age)
-can see white matter changes on MRI that move from back to front and inflammation of lymphocytes
+progression becomes fatal within 2y of this manifestation
-development of PAD can cause fatigue, extreme weight loss, abdominal pain and hyper pigmentation (bronzing)
-80% carriers with neurologic symptoms by 60y and not <20y, can see mild myeloneuropathic features and very rare adrenal insufficiency

236
Q

XLALD treatment and monitoring

A

-BMT by autologous retroviral method
-gene therapy trials-cosyntropin
-neurology screening to look for white matter changes and suggest timing of BMT (Loes score >3)
-serum ACTH & cortisol level measurements-challenging in infants due to irregular circadian rhythm
+hydrocortisone injections if AI
-monitoring growth, especially if being prescribed hydrocortisone & for iatrogenic Cushing (DM, HTN)

237
Q

Refsum disease

A

-AR deficiency of phytanoyl-coenzyme A hydroxylase deficiency
-typical onset in early adulthood
-features: RP, peripheral neuropathy with demyelination, cerebellar ataxia, deafness, skin changes, shortened 4th toe
+infantile presents like Zellweger
-treatment: low phytanic acid/phytol diet (limit dairy, lamb, veal, beef) and plasmapheresis

238
Q

rhizomelic chondrodysplasia punctata

A
  • failed import of some peroxisomal proteins

- causes abnormal facies, skin lesions and severe proximal limb shortening

239
Q

neonatal ALD

A
  • presents like Zellweger
  • adrenal disease without renal disease
  • AR
240
Q

Gaucher diagnosis and treatment

A
  • measure leukocyte GBA (beta-glucosidase) activity (up to 15% activity)
  • be aware of pseudogene detection (0% activity) this way
  • genetic testing to help clarify if real diagnosis and geno-pheno correlation
  • responds well to ERT, can also give Miglustat (SRT)
  • monitoring of blood counts, coagulation, iron and lipids, growth, spinal and bone density, MRI of liver, spleen, bones, biomarker analysis
241
Q

Fabry genetics

A

-X-linked alpha-gal-A (A-GAL) mutations
+private mutations common
-accumulation of GL-3 (ceramide trihexidase) leads to organ dysfunction
-18% females with a severe manifestation/adverse event

242
Q

Fabry phenotype

A

-acroparasthesia (severe distal pain in hands and feet)
-abdominal pain, diarrhea after eating that can lead to nausea vomiting and weight loss or malnutrition
-eye anomalies that do not impair vision: corneal whorls/rays, corneal and lenticular opacities
-heat sensitivity and hypohidrosis
-abdominal, inguinal and mucosal angiokeratomas that worsen over time
-cardiomegaly, CMs, conduction anomalies and valve anomalies with systolic dysfunction
-kidney disease
+ESRD can shorten lifespan
-risk for early stroke

243
Q

Fabry diagnosis and treatment or management

A
  • enzyme activity at least between 2-5% used to be gold standard, now mostly jump to GT
  • slit-lamp exam to look for eye abnormalities
  • cardiology and nephrology evaluations
  • ERT, SDT in works, EET for residual activity mutations in Europe
244
Q

biotinidase deficiency genetics and diagnosis

A 
-AR biotinidase enzyme dysfunction
\+serum and plasma show <10% activity
\+incidence of 1 in 60000
-GT reveals balletic BTD mutations
-mild to moderate urine ammonia, ketones, OAs
-high blood acyl carnitines
245
Q

biotinidase deficiency symptoms

A
  • lethargy, hypotonia, seizures
  • psychomotor deficits causing DD, ataxia
  • alopecia, skin rashes
  • vision problems
  • metabolic ketoacidosis, organic aciduria, hyperammonemia
  • SNHL
  • increased immunological dysfunction risk
  • partial deficiency (10-30%) causes symptoms only if triggered
246
Q

biotinidase deficiency treatment

A

-exogenous biotin daily and avoidance of raw eggs
-annual hearing and vision evals plus genetics or metabolic consult
+may require DD intervention

247
Q

Wilson’s disease genetics

A

-AR mutation of ATP7B and potential PRNP modifier cause copper buildup in body
+incidence of 1/30000
+Sardinian, Asian and European incidence as high as 1/10000 (1/90 carrier freq)

248
Q

Wilson’s disease diagnosis and testing

A 
-low serum ceruloplasmin, high serum copper because its not bound and the copper and free radicals are in blood
\+sometimes need liver biopsy
-high urine copper (bile copper absence)
-brain MRI
-slit-lamp exam 
-ATP7B gene sequencing
249
Q

Wilson’s disease phenotype

A
  • liver disease with acute hepatitis and cirrhosis, jaundice
  • neurological manifestations cause movement disorders of basal ganglia and dementia, ID or psychiatric disorder related to neuronal toxicity in cerebral cortex
  • Kayser-Flescher ring development later
  • renal disease, CM and hemolytic anemia are rarer
250
Q

Wilson’s disease treatment and management

A
  • copper chelating agents and/or zinc and copper diet limitations (chocolate, mushrooms, shellfish, nuts, liver)
  • biannual serum copper, ceruplasmin, liver biochemistries, INR, CBC, urinalysis, PE and neurological evals
  • annual 24h urinary copper excretion
251
Q

Menke’s disease genetics and diagnosis

A

-low serum copper and ceruloplasmin
-pili torti microscopically visualized
-XLR ATP7A gene mutations (1/100000)
+cause harmful copper to buildup in small intestine and kidney
+reduced enzymatic activity and transport to other tissues
*less severe version of condition is occipital horn syndrome

252
Q

Menke’s disease phenotype

A
  • onset between 6-8w and most with death by 3y
  • FTT, hypotonia
  • seizures, regression, DD
  • brittle wooly-hair, sagging facial features
  • low body temperature
  • subdural hematomas
  • bladder diverticula
  • osteoporosis and fracturing
  • Kayser-Fleischer rings
253
Q

Menke’s disease management

A
  • no cure
  • pain and seizure meds
  • feeding tubes and bladder surgeries
  • PT/OT, orthotics
254
Q

Antley-Bixler genetics and diagnosis

A

-low uE3 prenatally, high maternal urine steroids, may also see radiologic anomalies on ultrasound
-elevated 1-hydroxylase progesterone in serum
-urine steroid profile shows elevated pregnenediol, pregnanediol
-RARE AR mutation deficiency of cytochrome P450 Oxidoreductase (POR)-potentially under diagnosed
+GT can’t confirm 5.5% cases molecularly, sometimes only one mutation identified too

255
Q

Antley-Bixler phenotype

A

-skeletal anomalies
+brachycephaly or trapezoidocephaly due to coronal and lambdoidal craniosynostosis-DD?
+radiohumeral synostosis and joint contractures, thigh bone bowing
+arachnodactly
-dysmorphic features-frontal bossing and midface hypoplasia, low-set ears
-GU anomalies
+ambiguous genitalia and external anomalies
+sometimes infertility, PCOS
-choanal atresia or stenosis cause breathing problems
-maternal visualization with affected pregnancies increases acne, hirsutism and causes nose and lip enlargement with voice deepening

256
Q

Antley-Bixler treatment and management

A
  • steroid replacement therapy for cortisol deficiencies, possible DHT or testosterone replacement for males and estrogen replacement for females
  • genitalia, craniosynostosis, nasal surgeries
  • PT, OT, EI
  • very severe types may result in still birth
257
Q

spectrum of POR deficiency

A
  • milder phenotype can cause male and female infertility, primary amenorrhea, PCOS
  • moderate causes ambiguous genitalia, infertility
  • Antley-Bixler phenotype is most severe
258
Q

Antley-Bixler Syndrome without steroidal deficiency

A
  • caused by FGFR2 mutation

- only skeletal symptoms present

259
Q

SLOS phenotype

A
  • onset in newborn period but can see oligo, kidney agenesis and IUGR prenatally
  • dysmorphic features: narrow forehead, epicanthal folds, ptosis, anteverted nares with short nose, low set ears, palatal clefting and short mandible
  • microcephaly-ID and autism, behavioral problems, seizures
  • bilateral 2-3 toe syndactyly
  • poor feeding, FTT, hypotonia
  • kidney, lung, GI and heart anomalies
  • GU anomalies (hypospadias)
  • sometimes cataracts
260
Q

SLOS genetics and diagnosis

A
  • high serum 7-DHC concentration
  • low enzyme function
  • AR so GT shows biallelic (often compound hets) DHRC7 mutation
  • incidence of 1/20000-1/60000, higher incidence in central European populations (Czechoslovakia), rare in African and Asian pops
261
Q

SLOS treatment and management

A
  • supplementation with exogenous cholesterol
  • limitation of psychotropic meds and sun exposure
  • surgical repair of physical anomalies
  • multidisciplinary care team (neuro, optho, cardio, nephro, gastroentro, ENT)
262
Q

Lesch Nyhan phenotype

A

-neurological and behavioral abnormalities
+development of self-injurious behaviors
+dystonia, chorea and ballismus/limb flailing
+wheelchair bound with little head and body control
+DD, hypotonia
-uric acid accumulation
+orange urine crystals, sometimes see kidney and bladder stones later
+gouty arthritis in joints-can be seen in carriers too
-MRI anomalies

263
Q

Lesch Nyhan genetics and diagnosis

A

-XLR mutation of HPRT1 (<1.5% enzyme activity)
+causes failed purine recycling leading to high levels of uric acid
+incidence of 1/380000
-high uric acid levels in blood and urine
-low levels of dopamine in brain

264
Q

Lesch Nyhan management

A

-ST, PT, OT, EI
-allopurinol for uric acid levels
-urology and psychiatry referrals
+monitor for stones
+sometimes need protective equipment, restraints, or teeth removal to protect from self-injury
-neuro eval and meds to help control spasticity

265
Q

Kelley-Seegmiller syndrome

A

production of <8% HPRT1 enzyme

266
Q

AIP

A
  • AD mutation of HBMS
  • look for elevation of urine PBG and sometimes ALA; urine MUST be protected from light for accurate reading
  • many affected patients show no symptoms, but more likely in women, as hormonal changes, diet changes, etc can trigger
  • symptoms can include: abdominal pain, constipation, tachycardia, peripheral neuropathy, seizures and behavioral changes
  • intravenous hematin helps control symptoms during attacks

ABGC (34 decks)

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