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Inborn Errors of Protein (Amino Acid) Metabolism

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Overview Table (Harrison's 22E, Table 431-1)

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1. Phenylketonuria (PKU)

• Intellectual disability (if untreated) - phenylalanine is toxic to the developing brain
• Microcephaly
• Seizures (in untreated cases)
• Hypopigmentation - fair hair, pale skin, blue eyes (reduced tyrosine → reduced melanin)
• Eczema-like skin rash
• "Mousy" or musty odor of urine/sweat (phenylacetate)
• Behavioral disturbances

• Low-phenylalanine diet (started within first 7-10 days of life)
• Tyrosine supplementation (becomes conditionally essential)
• Oral tetrahydrobiopterin (BH4/sapropterin) 5-20 mg/kg/day - reduces phenylalanine levels in BH4-responsive patients
• Enzyme substitution with phenylalanine ammonia lyase (pegvaliase) for adults

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2. BH4 Deficiency Variants (Hyperphenylalaninemias)

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3. Tyrosinemias

Type I (Hepatorenal Tyrosinemia / Tyrosinosis)

• Liver failure and cirrhosis (most prominent)
• Hepatocellular carcinoma risk
• Renal tubular Fanconi syndrome (renal tubular acidosis, glycosuria, phosphaturia)
• Peripheral neuropathy (painful crises - "cabbage" odor)
• Elevated AFP (useful marker)

Type II (Oculocutaneous Tyrosinemia / Richner-Hanhart Syndrome)

• Painful palmoplantar hyperkeratosis
• Corneal erosions and dendritic ulcers, photophobia
• Mild intellectual disability in some

Type III

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4. Alkaptonuria

1. Homogentisic aciduria - urine turns dark/black on standing (oxidation of homogentisic acid); earliest sign is dark-stained diapers in infants
2. Ochronosis - blue-black pigmentation of cartilage (ear cartilage, intervertebral discs), sclera, and skin
3. Arthritis - progressive large-joint and spinal osteoarthritis

• Cardiac valve involvement (mitral/aortic stenosis)
• Coronary artery calcification
• Urinary/prostatic stones

• No curative treatment
• Dietary restriction of phenylalanine and tyrosine (slows accumulation)
• Nitisinone (experimental - blocks upstream HPPD, reduces HGA production)
• Symptomatic management: NSAIDs, joint replacement
• Ascorbic acid (vitamin C) - may slow ochronosis

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5. Albinism

• Generalized hypopigmentation: white/pale hair, pink/white skin
• Red pupils (light reflected from retinal vessels due to absent iris pigment)
• Nystagmus, photophobia
• Reduced visual acuity
• Misrouting of optic nerve fibers
• Markedly increased risk of skin cancer (UV damage)

• Sun protection (SPF 50+ sunscreen, protective clothing)
• Corrective lenses and low-vision aids
• No biochemical cure; gene therapy under investigation

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6. Homocystinuria

• Ectopia lentis (downward dislocation of lens) - distinguishes from Marfan syndrome where lens displaces upward
• Marfanoid habitus - tall, long limbs, arachnodactyly
• Intellectual disability (~50% of cases)
• Osteoporosis
• Thromboembolic events (major cause of morbidity/mortality) - affects coronary, renal, and cerebral vessels even in children
• Elevated plasma methionine and free homocysteine (total plasma Hcy usually >100 μmol/L)

• Pyridoxine (B6) 25-500 mg/day - ~50% of patients are B6-responsive (milder phenotype)
• Low-methionine diet
• Folate and vitamin B12 supplementation
• Betaine (trimethylglycine) - promotes remethylation of Hcy → methionine
• Cysteine supplementation (becomes essential amino acid)

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7. Maple Syrup Urine Disease (MSUD)

• Maple syrup / burnt sugar odor of urine, cerumen, and sweat (due to sotolone in keto acids)
• Neonatal encephalopathy (2-5 days of life): poor feeding, vomiting, lethargy
• Hypotonia progressing to hypertonia, opisthotonus
• Seizures
• Leucine toxicity is the primary neurotoxic mechanism
• Cerebral edema on MRI (T2 signal abnormalities in basal ganglia, brainstem, cerebellum)
• Without treatment: death or severe intellectual disability

• Synthetic BCAA-free formula with monitored small amounts of leucine, isoleucine, valine
• Thiamine (B1) supplementation (some patients are thiamine-responsive at 10-1000 mg/day)
• Acute decompensation: IV glucose (suppress catabolism), hemodialysis (rapidly lower leucine)
• Liver transplantation - effectively cures the metabolic defect (provides sufficient BCKD enzyme)
• Lifelong dietary management; leucine levels carefully monitored

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8. Urea Cycle Defects

• Hyperammonemia - the core toxicity
• Neonatal presentation (complete defects): refusal to eat, lethargy → coma → death at 1-4 days
• Partial defects: protein aversion, recurrent vomiting, migraine, behavioral changes, disorientation
• Elevated plasma glutamine (ammonia detox via perivenous hepatocytes)
• Chronic liver dysfunction

• Protein restriction (0.5-1 g/kg/day)
• Nitrogen scavengers: Sodium benzoate + sodium phenylacetate (Ammonul) - provide alternative pathways for nitrogen excretion
• Arginine and/or citrulline supplementation (become essential; also stimulate cycle flux)
• Acute hyperammonemia: IV glucose + lipids, hemodialysis for ammonia >500 μmol/L
• Liver transplantation - definitive cure for most urea cycle defects
• Gene therapy under investigation

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9. Other Notable Inborn Errors

Cystinuria (Cystine Transport Defect)

• Defect: SLC3A1 / SLC7A9 genes - defective transporter for cystine, ornithine, arginine, lysine in renal tubules and gut
• Symptoms: Recurrent urinary cystine stones (radiopaque), renal colic, obstructive uropathy
• Treatment: High fluid intake, urine alkalinization, D-penicillamine or tiopronin (chelate cystine)

Hartnup Disease (Tryptophan Transport Defect)

• Defect: SLC6A19 - neutral amino acid transporter; impaired intestinal/renal tryptophan absorption
• Pathway: Tryptophan → nicotinamide (NAD precursor) pathway impaired
• Symptoms: Pellagra-like rash (photosensitive), cerebellar ataxia, psychiatric symptoms; often intermittent
• Treatment: High-protein diet, niacinamide supplementation

Isovaleric Acidemia

• Defect: Isovaleryl-CoA dehydrogenase (leucine catabolism)
• Symptoms: "Sweaty feet" odor (isovalerate), metabolic acidosis, hyperammonemia, bone marrow suppression, encephalopathy
• Treatment: Low-leucine diet, glycine supplementation (conjugates isovaleryl-CoA), carnitine

Propionic Acidemia

• Defect: Propionyl-CoA carboxylase (biotin-dependent) - valine/isoleucine/methionine/threonine catabolism
• Symptoms: Neonatal ketoacidosis, hyperammonemia, hypotonia, cardiomyopathy
• Treatment: Low-protein diet, biotin, carnitine, liver transplantation

Methylmalonic Acidemia (MMA)

• Defect: Methylmalonyl-CoA mutase (requires adenosylcobalamin/B12) OR cobalamin metabolism enzymes
• Symptoms: Neonatal ketoacidosis, hyperammonemia, renal failure (long-term), optic atrophy, metabolic stroke
• Treatment: Low-protein diet, vitamin B12 (cobalamin-responsive forms), carnitine; liver/kidney transplantation

Nonketotic Hyperglycinemia (NKH)

• Defect: Glycine cleavage system (P-protein / H-protein / T-protein / L-protein)
• Symptoms: Neonatal seizures, profound hypotonia, burst-suppression EEG, hiccups, apnea, intellectual disability
• Treatment: Sodium benzoate (scavenges glycine), dextromethorphan (NMDA antagonist); poor prognosis

Hyperprolinemia

• Type I: Proline oxidase deficiency - generally benign
• Type II: Δ1-Pyrroline-5-carboxylate dehydrogenase deficiency - seizures, intellectual disability
• Symptoms: Elevated plasma/urine proline

Hydroxyprolinemia

• Defect: 4-Hydroxyproline dehydrogenase - benign, no clinical consequences

Sarcosinemia

• Defect: Sarcosine dehydrogenase - no clinical consequences; benign biochemical finding

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Key Diagnostic Concepts

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Summary Pathway Diagram

Phenylalanine
    ↓ [PAH + BH4] ← PKU (PAH defect)
Tyrosine
    ↓ [TAT]       ← Tyrosinemia II (TAT defect)
4-OH-phenylpyruvate
    ↓ [HPPD]      ← Tyrosinemia III (HPPD defect)
Homogentisate
    ↓ [HGD]       ← Alkaptonuria (HGD defect)
Maleylacetoacetate
    ↓
Fumarylacetoacetate
    ↓ [FAH]       ← Tyrosinemia I (FAH defect)
Fumarate + Acetoacetate

Tyrosine → [Tyrosinase] → DOPA → Melanin  ← Albinism (Tyrosinase defect)
Tyrosine → [TH + BH4] → DOPA → Catecholamines

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