Protein metabolism Flashcards
Intellectual disability, autism, eczema, seizure, mousy odor of urine
Phenylketonuria (PAH)
PKU treatment
PKU-restricted diet
Large neutral AA supplement
Sapropterin (BH4)
Palynziq (pegvaliaes-pqpz; phe ammonia lyase)
Enzymes that use biopterin (BH4)
Tryptophan, phenylalanine, and tyrosine hydroxylase + NO synthase, neurotransmitters
Ddx for high Phe
Benign hyperPhe (<360), PKU, DHPR deficiency (activity in RBC), disorders of BH4 synthesis (pterin metabolites in urine)
Developmental delay, hypotonia of trunk + hypertonia of extremities, tremors, conclusions, high Phe
GTP cyclohydrolase I deficiency, AR (GCH1). Low urine biopterin & neopterin, low CSF HVA, 5-HIAA. AD form normal Phe, reduced penetrance, dopa-responsive dystonia
Abnormal movements, DD, prematurity, low birth weight, high Phe. (Up to 1/3 present in infancy instead w/movement disorder)
PTPS deficiency, AR (PTS): high urine monapterin, low biopterin; CSF low HVA and 5-HIAA
Most asymptomatic, some with transient hypotonia, normalization of Phe in infancy
PCD deficiency, AR (PCBD1): normal CSF
Significant delays despite Phe restriction, brain abnormalities, prone to sudden death, high Phe
Dihydropteridine reductase deficiency, AR (QDPR): high urine biopterin, low CSF HVA and 5-HIAA, low RBC DHPR activity.
DD, inconsolable, dopa-responsive dystonia, psychiatric symptoms, normal Phe
Sepiapterin reductase deficiency, AR (SPR): normal urine pterins, CSF high sepiaterin and biopterin, low HVA and 5-HIAA
DD, dopa-responsive movement disorder, mild hyperPhe, PAH sequence normal
DNAJC12 defects (chaperone for hydroxylase enzymes)
Newborn w/poor feeding, lethargy, coma, seizures, abnormal movements, tonic spasms, mild hypoglycemia and acidosis, ketonuria, sweet smell
MSUD (branched chain ketoacid dehydrogenase deficiency BCKDH - any of 4 subunits)
Newborn with coagulopathy, hepatomegaly, hyperbilirubinemia. No hypoglycemia or acidosis.
Tyrosinemia type 1 (fumarylacetoacetate hydrolase, FAH)
Tyrosinemia stages of symptoms
Early infancy: liver disease
Late infancy: Renal tubulopathy (Fanconi) -> rickets if untreated
Adolescence: porphyria-like attacks.
Risk of cirrhosis -> HCC
Treatment of tyrosinemia type 1 (prevention of succinylacetone accumulation)
Limitation of dietary protein (Phe/Tyr)
NTBC/nitisinone (blocks upstream pathway) - prevents HCC
Newborn with lethargy, poor feeding, and hiccups –> seizures, apnea, coma
Nonketotic hyperglycinemia (GLDC most commonly, AMT, or GCSH)
Age of presentation of NKH vs outcome
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
Treatment of NKH
Reduce glycine with Na benzoate; antagonize NMDA with dextromethorphan, ketamine, felbamate; AEDs except valproate
Newborn with elevated methionine, elevated homocysteine
Homocystinuria (cystathionine beta-synthase deficiency, CBS).
Sx of untreated homocystinuria
Marfanoid habitus and eye problems, DD, neuropsychiatric symptoms, recurrent VTE
Treatment of homocystinuria
Reduce protein intake, 50% responsive to pyridoxine, betaine (converts homocysteine back to methionine) with caution as Met >1000 leads to cerebral edema
Infant with IUGR, generalized ichthyosis, microcephaly (w/lissencephaly, hypoplasia), low serine and glycine on PAA. Most stillborn/die prenatally.
Neu-Laxova; severe serine biosynthesis defects (PHGDH, PSAT1, PSPH)
Infant with IUGR, microcephaly (atrophic brain w/hypomyelination, hypoplasia), irritability, epilepsy, spastic tetraplegia
Infantile serine biosynthesis defects (PHGDH, PSAT1, PSPH)
Childhood loss of night vision d/t chorioretinal atrophy, loss of peripheral vision, elevated ornithine
Gyrate atrophy of choroid and retina (ornithine aminotransferase deficiency, OAT)
Dark discoloration of sclerae and ears, arthritis
Alkaptonuria (dioxygenase) - homogentisic acid
Painful, non-pruritic hyperkeratotic plaques on soles and palms, recalcitrant pseudodendritic keratitis, no liver/coagulopathy
Tyrosinemia type 2
Fishy odor
Trimethylaminuria (FMO3)
Benign aminoacidopathies
Familial hyperlysinemia (alpha-aminoadipic semialdehyde synthase), hydroxyprolinemia (hydroxyproline oxidase, can flag false+ for high leu), histidinemia (histidase)
Organic acidemias caused by…
inability to break down carbon backbone of amino acids (vs inability to detox ammonia = UCD) –> toxic byproducts that shut down many cellular pathways.
Severe neonatal hyperammonemia, low orotic acid
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.
Treatment of NAGS vs CPS1 deficiency
NAGS: Carbaglu (provides missing metabolite, N-acetylglutamate)
CPS1: more traditional UCD management w/protein restriction, NH3 scavenger
Hyperammonemia with increased orotic acid, low citrulline.
Disease & severity?
Ornithine transcarbamylase (OTC) deficiency
Very brittle, 15%+ female carriers affected
Hyperammonemia with increased orotic acid, very high citrulline.
Disease & severity?
Citrullinemia type 1 (ASS1); treat with arginine, not citrulline
Can have severe hyperammonemia, but generally easily treatable, some without hyperammonemic crises.
Neonatal hyperammonemia with increased orotic acid, high arginosuccinate –> cirrhosis, fragile hair, DD.
Disease & severity?
Argininosuccinic acuduria (ASL deficiency); supplement with arginine
More stable as both ammonias cleared, byproducts excreted in urine; may be able to forgo scavenger.
Some w/hyperammonemia, most with progressive spastic diplegia, tremor/ataxia, epilepsy.
Disease & severity?
Arginase deficiency/hyperargininemia (ARG1)
Most ability to clear ammonia; no supplementation works. Neuro disease due to high arginine in brain.
8% with neonatal hyperammonemia, most with DD, ataxia/spasticity, seizures, with encephalopathy crises and liver dysfunction. High orotic acid.
Disease & severity?
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.
Newborn with poor feeding, progressive encephalopathy –> seizure, coma. AGMA, lactic & ketotic, hypoglycemia, hyperammonemia.
Neonatal onset propionic acidemia (PCCA or B)
Episodic vomiting/acidosis + failure to thrive, hypotonia, DD, movement disorders, recurrent pancreatitis, pancytopenia, renal and gut dysfunction, dilated cardiomyopathy. Can also have isolated CM.
Late-onset propionic acidemia (PCCA or B), or later manifestations of neonatal onset.
Toxic fuels in organic acidemias
Branched-chain amino acids “VOMIT” Val Met Ile Thr, odd chain FA, cholesterol side chains
Treatment of PA
Protein-limited diet and avoidance of BCAA, carnitine, carbaglu; liver transplant helps hyperammonemia but not deposition in other tissues.
Newborn with lethargy, hypothermia, vomiting, respiratory distress, encephalopathy, hyperammonemia, acidosis.
Methylmalonic acidemia, mut0 form of MMUT (complete deficiency) or cblB/MMAB deficiency
Infant with feeding problems/FTT, hypotonia, DD, with episodic metabolic decompensation (hyperammonemia, acidosis) –> renal failure, dilated cardiomyopathy, BM failure, metabolic stroke, pancreatitis
Methylmalonic acidemia, B-12 responsive.
MMUT partial deficiency (mut-)
CblA, B, or D (MMAA, MMAB, MMADHC respectively).
Variable, from asymptomatic to severe metabolic acidosis. Ataxia, dysarthria, hypotonia, spasticity, seizures.
Methylmalonic acidemia, due to methylmalonyl-CoA epimerase (MCEE) deficiency.
Neonatal acidosis, seizures, pancytopenia; sweaty feet odor.
Isovaleric acidemia (isovaleryl-CoA dehydrogenase, IVD; mitochondrial) - defect in leucine metabolism
Treatment of Isovaleric acidemia
Supplement glycine, carnitine, Carbaglu, leucine-free diet
Severe movement disorder, spasticity macrocephaly w/batwing temporal lobe, acute encephalopathic crises without significant acidosis often triggered by fever.
Glutaric acidemia type 1 (GCDH)
NBS elevated C5
Isovaleric acidemia
NBS elevated C5-DC
Glutaric acidemia type 1; f/u with 3-OH-glutaric acid on UOA
