Protein metabolism

Question 1

Intellectual disability, autism, eczema, seizure, mousy odor of urine

Answer 1

Phenylketonuria (PAH)

Question 2

PKU treatment

Answer 2

PKU-restricted diet
Large neutral AA supplement
Sapropterin (BH4)
Palynziq (pegvaliaes-pqpz; phe ammonia lyase)

Question 3

Enzymes that use biopterin (BH4)

Answer 3

Tryptophan, phenylalanine, and tyrosine hydroxylase + NO synthase, neurotransmitters

Question 4

Ddx for high Phe

Answer 4

Benign hyperPhe (<360), PKU, DHPR deficiency (activity in RBC), disorders of BH4 synthesis (pterin metabolites in urine)

Question 5

Developmental delay, hypotonia of trunk + hypertonia of extremities, tremors, conclusions, high Phe

Answer 5

GTP cyclohydrolase I deficiency, AR (GCH1). Low urine biopterin & neopterin, low CSF HVA, 5-HIAA. AD form normal Phe, reduced penetrance, dopa-responsive dystonia

Question 6

Abnormal movements, DD, prematurity, low birth weight, high Phe. (Up to 1/3 present in infancy instead w/movement disorder)

Answer 6

PTPS deficiency, AR (PTS): high urine monapterin, low biopterin; CSF low HVA and 5-HIAA

Question 7

Most asymptomatic, some with transient hypotonia, normalization of Phe in infancy

Answer 7

PCD deficiency, AR (PCBD1): normal CSF

Question 8

Significant delays despite Phe restriction, brain abnormalities, prone to sudden death, high Phe

Answer 8

Dihydropteridine reductase deficiency, AR (QDPR): high urine biopterin, low CSF HVA and 5-HIAA, low RBC DHPR activity.

Question 9

DD, inconsolable, dopa-responsive dystonia, psychiatric symptoms, normal Phe

Answer 9

Sepiapterin reductase deficiency, AR (SPR): normal urine pterins, CSF high sepiaterin and biopterin, low HVA and 5-HIAA

Question 10

DD, dopa-responsive movement disorder, mild hyperPhe, PAH sequence normal

Answer 10

DNAJC12 defects (chaperone for hydroxylase enzymes)

Question 11

Newborn w/poor feeding, lethargy, coma, seizures, abnormal movements, tonic spasms, mild hypoglycemia and acidosis, ketonuria, sweet smell

Answer 11

MSUD (branched chain ketoacid dehydrogenase deficiency BCKDH - any of 4 subunits)

Question 12

Newborn with coagulopathy, hepatomegaly, hyperbilirubinemia. No hypoglycemia or acidosis.

Answer 12

Tyrosinemia type 1 (fumarylacetoacetate hydrolase, FAH)

Question 13

Tyrosinemia stages of symptoms

Answer 13

Early infancy: liver disease
Late infancy: Renal tubulopathy (Fanconi) -> rickets if untreated
Adolescence: porphyria-like attacks.
Risk of cirrhosis -> HCC

Question 14

Treatment of tyrosinemia type 1 (prevention of succinylacetone accumulation)

Answer 14

Limitation of dietary protein (Phe/Tyr)
NTBC/nitisinone (blocks upstream pathway) - prevents HCC

Question 15

Newborn with lethargy, poor feeding, and hiccups –> seizures, apnea, coma

Answer 15

Nonketotic hyperglycinemia (GLDC most commonly, AMT, or GCSH)

Question 16

Age of presentation of NKH vs outcome

Answer 16

Neonatal: 85% severe w/o developmental progress, intractable epilepsy. >2 weeks, 50/50%, >3mo all attenuated some of whom do not have epilepsy and have some development

Question 17

Treatment of NKH

Answer 17

Reduce glycine with Na benzoate; antagonize NMDA with dextromethorphan, ketamine, felbamate; AEDs except valproate

Question 18

Newborn with elevated methionine, elevated homocysteine

Answer 18

Homocystinuria (cystathionine beta-synthase deficiency, CBS).

Question 19

Sx of untreated homocystinuria

Answer 19

Marfanoid habitus and eye problems, DD, neuropsychiatric symptoms, recurrent VTE

Question 20

Treatment of homocystinuria

Answer 20

Reduce protein intake, 50% responsive to pyridoxine, betaine (converts homocysteine back to methionine) with caution as Met >1000 leads to cerebral edema

Question 21

Infant with IUGR, generalized ichthyosis, microcephaly (w/lissencephaly, hypoplasia), low serine and glycine on PAA. Most stillborn/die prenatally.

Answer 21

Neu-Laxova; severe serine biosynthesis defects (PHGDH, PSAT1, PSPH)

Question 22

Infant with IUGR, microcephaly (atrophic brain w/hypomyelination, hypoplasia), irritability, epilepsy, spastic tetraplegia

Answer 22

Infantile serine biosynthesis defects (PHGDH, PSAT1, PSPH)

Question 23

Childhood loss of night vision d/t chorioretinal atrophy, loss of peripheral vision, elevated ornithine

Answer 23

Gyrate atrophy of choroid and retina (ornithine aminotransferase deficiency, OAT)

Question 24

Dark discoloration of sclerae and ears, arthritis

Answer 24

Alkaptonuria (dioxygenase) - homogentisic acid

Question 25

Painful, non-pruritic hyperkeratotic plaques on soles and palms, recalcitrant pseudodendritic keratitis, no liver/coagulopathy

Answer 25

Tyrosinemia type 2

Question 26

Fishy odor

Answer 26

Trimethylaminuria (FMO3)

Question 27

Benign aminoacidopathies

Answer 27

Familial hyperlysinemia (alpha-aminoadipic semialdehyde synthase), hydroxyprolinemia (hydroxyproline oxidase, can flag false+ for high leu), histidinemia (histidase)

Question 28

Organic acidemias caused by…

Answer 28

inability to break down carbon backbone of amino acids (vs inability to detox ammonia = UCD) –> toxic byproducts that shut down many cellular pathways.

Question 29

Severe neonatal hyperammonemia, low orotic acid

Answer 29

NAGS or CPS1 deficiency: NAGS makes N-acetylglutamate, which combines with 1st ammonia using CPS1 to make carbamyl phosphate, which combines with citrulline to start cycle. Low orotic acid as this is a metabolite of carbamyl phosphate.

Question 30

Treatment of NAGS vs CPS1 deficiency

Answer 30

NAGS: Carbaglu (provides missing metabolite, N-acetylglutamate)
CPS1: more traditional UCD management w/protein restriction, NH3 scavenger

Question 31

Hyperammonemia with increased orotic acid, low citrulline.
Disease & severity?

Answer 31

Ornithine transcarbamylase (OTC) deficiency
Very brittle, 15%+ female carriers affected

Question 32

Hyperammonemia with increased orotic acid, very high citrulline.
Disease & severity?

Answer 32

Citrullinemia type 1 (ASS1); treat with arginine, not citrulline
Can have severe hyperammonemia, but generally easily treatable, some without hyperammonemic crises.

Question 33

Neonatal hyperammonemia with increased orotic acid, high arginosuccinate –> cirrhosis, fragile hair, DD.
Disease & severity?

Answer 33

Argininosuccinic acuduria (ASL deficiency); supplement with arginine
More stable as both ammonias cleared, byproducts excreted in urine; may be able to forgo scavenger.

Question 34

Some w/hyperammonemia, most with progressive spastic diplegia, tremor/ataxia, epilepsy.
Disease & severity?

Answer 34

Arginase deficiency/hyperargininemia (ARG1)
Most ability to clear ammonia; no supplementation works. Neuro disease due to high arginine in brain.

Question 35

8% with neonatal hyperammonemia, most with DD, ataxia/spasticity, seizures, with encephalopathy crises and liver dysfunction. High orotic acid.
Disease & severity?

Answer 35

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome (SLC25A15/ORNT1) - transport of ornithine into mitochondria.
Variable onset, mostly neurological but quite variable. Treat with citrulline supplement & protein restriction.

Question 36

Newborn with poor feeding, progressive encephalopathy –> seizure, coma. AGMA, lactic & ketotic, hypoglycemia, hyperammonemia.

Answer 36

Neonatal onset propionic acidemia (PCCA or B)

Question 37

Episodic vomiting/acidosis + failure to thrive, hypotonia, DD, movement disorders, recurrent pancreatitis, pancytopenia, renal and gut dysfunction, dilated cardiomyopathy. Can also have isolated CM.

Answer 37

Late-onset propionic acidemia (PCCA or B), or later manifestations of neonatal onset.

Question 38

Toxic fuels in organic acidemias

Answer 38

Branched-chain amino acids “VOMIT” Val Met Ile Thr, odd chain FA, cholesterol side chains

Question 39

Treatment of PA

Answer 39

Protein-limited diet and avoidance of BCAA, carnitine, carbaglu; liver transplant helps hyperammonemia but not deposition in other tissues.

Question 40

Newborn with lethargy, hypothermia, vomiting, respiratory distress, encephalopathy, hyperammonemia, acidosis.

Answer 40

Methylmalonic acidemia, mut0 form of MMUT (complete deficiency) or cblB/MMAB deficiency

Question 41

Infant with feeding problems/FTT, hypotonia, DD, with episodic metabolic decompensation (hyperammonemia, acidosis) –> renal failure, dilated cardiomyopathy, BM failure, metabolic stroke, pancreatitis

Answer 41

Methylmalonic acidemia, B-12 responsive.
MMUT partial deficiency (mut-)
CblA, B, or D (MMAA, MMAB, MMADHC respectively).

Question 42

Variable, from asymptomatic to severe metabolic acidosis. Ataxia, dysarthria, hypotonia, spasticity, seizures.

Answer 42

Methylmalonic acidemia, due to methylmalonyl-CoA epimerase (MCEE) deficiency.

Question 43

Neonatal acidosis, seizures, pancytopenia; sweaty feet odor.

Answer 43

Isovaleric acidemia (isovaleryl-CoA dehydrogenase, IVD; mitochondrial) - defect in leucine metabolism

Question 44

Treatment of Isovaleric acidemia

Answer 44

Supplement glycine, carnitine, Carbaglu, leucine-free diet

Question 45

Severe movement disorder, spasticity macrocephaly w/batwing temporal lobe, acute encephalopathic crises without significant acidosis often triggered by fever.

Answer 45

Glutaric acidemia type 1 (GCDH)

Question 46

NBS elevated C5

Answer 46

Isovaleric acidemia

Question 47

NBS elevated C5-DC

Answer 47

Glutaric acidemia type 1; f/u with 3-OH-glutaric acid on UOA