Amino Acid Metabolism Defects

1. DEFINITION AND OVERVIEW

Inborn errors of metabolism (IEM) affecting amino acids are caused by single-gene pathogenic variants resulting in enzyme or transporter defects. These lead to the accumulation of toxic substrates (intoxication type) or deficiency of essential products (deficiency type).

• Incidence: Individually rare, but collectively common. PKU is 1:14,000–1:20,000; non-PKU hyperphenylalaninemia is 1:50,000.
• Pathophysiology:
  • Intoxication: Accumulation of proximal toxic metabolites (e.g., Leucine in MSUD, Succinylacetone in Tyrosinemia).
  • Deficiency: Lack of downstream products (e.g., Melanin in Albinism, Neurotransmitters in PKU/BH4 deficiency).

2. CLASSIFICATION (By Amino Acid Group)

• Aromatic Amino Acids: Phenylketonuria (PKU), Tyrosinemia (I, II, III), Alkaptonuria, Albinism.
• Branched-Chain Amino Acids (BCAAs): Maple Syrup Urine Disease (MSUD), Isovaleric Acidemia (IVA), Propionic Acidemia (PA), Methylmalonic Acidemia (MMA).
• Sulfur-Containing Amino Acids: Homocystinuria, Cystinuria, Sulfite Oxidase Deficiency.
• Urea Cycle Disorders (UCDs): OTC deficiency, Citrullinemia, Argininosuccinic aciduria.
• Transport Defects: Hartnup disease, Cystinuria.
• Others: Non-ketotic Hyperglycinemia (NKH), Histidinemia.

3. CLINICAL PRESENTATION

Presentation varies from acute neonatal metabolic crisis to insidious late-onset neurologic decline.

A. Neonatal Acute Intoxication (The "Sepsis-Like" Presentation)

• Onset: Symptom-free interval (24–72 hours) followed by rapid deterioration.
• Symptoms: Poor feeding, vomiting, lethargy, hypotonia, seizures, coma.
• Specific Associations:
  • MSUD: Encephalopathy, "boxing/bicycling" movements, opisthotonus.
  • Organic Acidemias (MMA/PA/IVA): Severe metabolic acidosis, ketosis, hyperammonemia.
  • Urea Cycle Defects: Pure hyperammonemia (respiratory alkalosis), no ketosis.

B. Chronic/Late-Onset Presentation

• Neurological: Intellectual disability (PKU, Homocystinuria), developmental regression, ataxia, movement disorders (dystonia in Glutaric Aciduria).
• Hepatic: Liver failure, cirrhosis, hepatocellular carcinoma (Tyrosinemia Type I).
• Psychiatric: Behavioral issues, autism-like features (untreated PKU).
• Ocular/Cutaneous: Ectopia lentis (Homocystinuria), cataracts (Galactosemia - D/D), albinism.

C. Characteristic Odors (High Yield)

4. SPECIFIC PROTOTYPE DISORDERS

A. Phenylketonuria (PKU)

• Defect: Phenylalanine Hydroxylase (PAH) deficiency or cofactor Tetrahydrobiopterin (BH4) deficiency.
• Biochemistry: Phenylalanine (Phe) >20 mg/dL (>1200 µmol/L). Phe cannot convert to Tyrosine.
• Clinical Features (Untreated):
  • Severe intellectual disability (IQ <35 in 50–70%).
  • Microcephaly, seizures (25%), spasticity.
  • Pigment: Fair skin/hair, blue eyes (impoverished melanin synthesis).
  • Skin: Eczematoid/seborrheic rash.
• Diagnosis: Newborn screening (NBS). Plasma amino acids (High Phe, Low Tyr). BH4 loading test to rule out cofactor deficiency.
• Management:
  • Diet: Low Phe diet initiated immediately (maintain levels 2–6 mg/dL).
  • Drug: Sapropterin (BH4) for responsive cases; PEGylated phenylalanine ammonia-lyase for adults.
  • Maternal PKU: Strict control pre-conception to prevent fetal microcephaly and defects.

B. Tyrosinemia Type I (Hepatorenal Tyrosinemia)

• Defect: Fumarylacetoacetate Hydrolase (FAH).
• Pathophysiology: Accumulation of toxic fumarylacetoacetate and succinylacetone.
• Clinical Features:
  • Acute: Liver failure in infancy (jaundice, coagulopathy, ascites, hypoglycemia).
  • Chronic: Renal Fanconi syndrome (rickets), hepatoma (HCC), porphyria-like crises (pain, neuropathy).
• Diagnosis: Elevated Succinylacetone (blood/urine) is pathognomonic. Elevated Alpha-fetoprotein (AFP).
• Management:
  • Drug: Nitisinone (NTBC) blocks 4-HPPD (upstream), preventing toxin formation.
  • Diet: Low Phe/Tyr.
  • Liver Transplant: For HCC or non-responders.

C. Maple Syrup Urine Disease (MSUD)

• Defect: Branched-chain $\alpha$-ketoacid dehydrogenase (BCKDH) complex.
• Biochemistry: Accumulation of Leucine (neurotoxic), Isoleucine, Valine.
• Clinical Features:
  • Classic: Neonatal encephalopathy, poor feeding, apnea, cerebral edema ("Leucinosis").
  • Intermittent/Intermediate: Ataxia/lethargy during stress/infection.
• Diagnosis:
  • Pathognomonic: Presence of Alloisoleucine in plasma.
  • Urine DNPH test: Positive (Yellow precipitate).
• Management:
  • Acute: Hemodialysis (most effective for leucine removal), high-calorie anabolism.
  • Chronic: BCAA-restricted diet. Liver transplant is curative (enzyme abundant in liver).

D. Homocystinuria (Classic)

• Defect: Cystathionine $\beta$-synthase (CBS).
• Clinical Features (Marfanoid Habitus):
  • Eye: Ectopia lentis (Lens dislocates downward and inward; vs Marfan upward).
  • Skeletal: Tall stature, arachnodactyly, scoliosis, osteoporosis.
  • Vascular: Thromboembolism (major cause of mortality).
  • CNS: Intellectual disability, psychiatric issues.
• Diagnosis: Elevated Methionine and Homocysteine in plasma. Positive Cyanide-Nitroprusside test.
• Management:
  • Pyridoxine (Vitamin B6): 40% are responsive (high dose).
  • Betaine: Remethylates homocysteine to methionine.
  • Diet: Methionine restriction.

E. Urea Cycle Disorders (UCDs)

• Hallmark: Hyperammonemia + Respiratory Alkalosis (unique among metabolic comas).
• Types:
  • OTC Deficiency (X-linked): High Orotic acid in urine. Most common.
  • Citrullinemia (ASS deficiency): Extremely high Citrulline.
  • Argininosuccinic Aciduria (ASL deficiency): Trichorrhexis nodosa (brittle hair), hepatomegaly.
• Management: Ammonia scavengers (Sodium Benzoate, Phenylbutyrate), Arginine supplementation (except in Argininemia), Dialysis for acute crisis.

5. DIAGNOSTIC APPROACH (The Metabolic Workup)

A. First-Line Investigations (The "Metabolic Screen")

1. Blood Glucose: Hypoglycemia (MSUD, Tyrosinemia) vs Normal.
2. Arterial Blood Gas (ABG): Metabolic Acidosis (Organic acidemias) vs Respiratory Alkalosis (UCD).
3. Plasma Ammonia: Critical to rule out UCD.
4. Urine Ketones: Present in OAs/MSUD; Absent in Fatty Acid Oxidation Defects.
5. Lactate: To rule out mitochondrial disorders.

B. Confirmatory Tests

1. High Performance Liquid Chromatography (HPLC) for Plasma Amino Acids: The gold standard for AA disorders.
2. Urine Organic Acids (GC-MS): Essential for Organic Acidemias (methylmalonic, propionic).
3. Tandem Mass Spectrometry (TMS): Used in Newborn Screening (dried blood spots).
4. Molecular Genetics: Panel testing or Exome sequencing for definitive diagnosis.

6. GENERAL MANAGEMENT PRINCIPLES

A. Acute Decompensation (Emergency)

• Stop Protein Intake: Immediately halt exogenous protein.
• Reverse Catabolism: High calorie infusion (Glucose 10% + Lipids) to suppress protein breakdown.
• Detoxification:
  • Hemodialysis (Ammonia >500 µmol/L or severe leucine).
  • Scavengers (Benzoate/Phenylacetate) for hyperammonemia.
• Cofactors: Trial of Vit B12 (MMA), Biotin (MCD), Thiamine (MSUD), B6 (Homocystinuria).

B. Long-Term Management

• Dietary: Lifelong restriction of the offending amino acid (e.g., Phe-free formula). Supplementation of essential products (e.g., Tyrosine in PKU).
• Monitoring: Growth, neurodevelopment, and nutritional levels (Albumin, Zinc, Selenium).
• Transplantation: Liver transplant (MSUD, Tyrosinemia, UCDs) or Kidney (MMA).