Inherited Disorders of Amino Acid Metabolism in Adults¶
Chapter 431 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 431
Key Clinical Points¶
- Newborn screening has improved survival rates and early diagnosis for many amino acid metabolism disorders.
- Disorders are classified as aminoacidopathies (parent amino acid excess) and organic acidemias (catabolic pathway products accumulate).
- Phenylketonuria (PKU) requires lifelong dietary phenylalanine restriction; maternal PKU requires strict control before conception to prevent congenital defects.
- Classic homocystinuria presents with lens dislocation, osteoporosis, and thrombotic vascular disease; treated with pyridoxine, folate, and betaine.
- Alkaptonuria presents with dark urine (ochronosis), arthritis, and coronary artery calcification; treated with nitisinone (10 mg/d).
- Urea cycle defects present with hyperammonemia, lethargy, and coma; management involves stopping catabolism (calories) and nitrogen removal (phenylacetate/benzoate).
- Homocystinuria is associated with increased risk of coronary, cerebrovascular, and peripheral arterial disease.
- Pegvaliase is a pegylated phenylalanine ammonia lyase used to reduce phenylalanine levels in PKU.
- Nitisinone reduces urinary homogentisic acid excretion in alkaptonuria.
- Many metabolic disorders may remain asymptomatic until adulthood, presenting only during fasting or severe stress.
DEFINITION & OVERVIEW¶
• Amino Acid Function: Building blocks of proteins; serve as neurotransmitters (glycine, glutamate, γ-aminobutyric acid) or precursors for hormones, coenzymes, pigments, purines, and pyrimidines. • Essential Amino Acids: Eight amino acids are essential (histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) and must be obtained from dietary sources. • Classification Systems: • Aminoacidopathies: Parent amino acid is found in excess. • Organic Acidemias: Products in the catabolic pathway accumulate. • Heterogeneity: High biochemical and genetic diversity (e.g., 6 forms of hyperphenylalaninemia, 9 forms of homocystinuria). • Clinical Spectrum: Ranges from asymptomatic (sarcosinemia) to lethal in neonates (complete deficiency of ornithine transcarbamylase). • Diagnostic Methodology: Analysis of plasma amino acids (ion-exchange chromatography or LC/MS), urine organic acids (GC/MS), and plasma acylcarnitine profile (LC/MS). Confirmation via enzyme assay or DNA testing.
EPIDEMIOLOGY¶
• Incidence Rates: • Cystinuria/Phenylketonuria: 1 in 10,000. • Homocystinuria/Alkaptonuria: 1 in 200,000. • Collective Incidence: Approximately 1 in 4,000 newborns. • Inheritance Patterns: • Predominantly autosomal recessive (AR). • Exceptions: Ornithine transcarbamylase deficiency (X-linked) and some homocystinuria forms (AR, XL).
ETIOLOGY & PATHOPHYSIOLOGY¶
• General Mechanism: Accumulation depends on the site of enzymatic block, reversibility of proximal reactions, and availability of alternative metabolic pathways. • Phenylalanine Metabolism: • Phenylketonuria (PKU): Result of reduced activity of phenylalanine hydroxylase (frequency 1:16,500). • Pathophysiology: • Inhibits transport of other amino acids for protein/neurotransmitter synthesis. • Reduces myelin synthesis and increases degradation. • Inadequate formation of norepinephrine and serotonin. • Tyrosinase inhibition → hypopigmentation of hair and skin. • Clinical Presentation: Microcephaly, 'mousy' odor (phenylacetate), eczema, and intellectual disability. • Homocystinuria Metabolism Pathways: • Cystathioninuria: Reduced activity of cystathionine β-synthase (B6-dependent). → Results in elevated homocysteine and cystathionine. • Remethylation Defects: Defective methionine synthase or reduced cofactors (5-methyltetrahydrofolate, methylcobalamin). → Results in elevated homocysteine with low plasma methionine. • Alternative Pathways: Homocysteine can be remethylated by betaine-homocysteine methyltransferase (requires Betaine) to form dimethylglycine. • Alkaptonuria: Homogentisic acid oxidase deficiency → accumulation of oxidized homogentisic acid in connective tissues (ochronosis). • Urea Cycle Defects: • Mechanism: Impaired conversion of ammonia to urea; defects in enzymes or mitochondrial transporters. • Key Components: Includes CPS-1, OTC, Citrin (SLC25A13), and ORNT1 (SLC25A15). • Clinical Impact: Hyperammonemia, lethargy, and coma in infants (1–4 days of life).
CLINICAL FEATURES¶
• Phenylketonuria (PKU): • Neurological: Intellectual disability, microcephaly, seizures, hypopigmentation. • Physical: 'Mousy' odor of skin/hair/urine; eczema. • Homocystinuria: • Cystathioninuria: Lens dislocation (3-5 years), marfanoid habitus, osteoporosis, and life-threatening vascular complications (coronary, renal, cerebral). • Remethylation Defects: Intellectual disability, hypotonia, seizures, megaloblastic anemia. • Alkaptonuria: • Connective Tissue: Ochronosis (pigmentation), arthritis, cardiac valve involvement, coronary artery calcification. • Urea Cycle Defects: • Acute Presentation: Lethargy progressing to coma; protein aversion; hyperammonemia. • Chronic Features: CNS dysfunction (delays, seizures) in >50% of cases. • Other Notable Conditions: • Tyrosinemia Type 1: Liver failure, cirrhosis, rickets, 'boiled cabbage' odor. • Tyrosinemia Type 2: Palmoplantar keratosis, painful corneal erosions. • Glycine Encephalopathy: Infantile seizures, lethargy, apnea, profound intellectual disability.
DIAGNOSTIC APPROACH¶
- Screening: Identification via newborn screening programs.
- Metabolic Profiling: • Plasma Amino Acids: Analysis by ion-exchange chromatography or LC/MS. • Urine Organic Acids: Analysis by GC/MS. • Plasma Acylcarnitine Profile: Analysis by LC/MS.
- Confirmation: • Enzyme Assay: Performed on cells or tissues from the patient. • Genetic Testing: DNA analysis to confirm specific mutations.
MANAGEMENT & TREATMENT¶
- Phenylketonuria (PKU): • Dietary: Lifelong restriction of phenylalanine. • Pharmacotherapy: Pegvaliase (pegylated phenylalanine ammonia lyase) to reduce phenylalanine levels.
- Homocystinuria: • Supplementation: Pyridoxine, folate, and betaine.
- Alkaptonuria: • Pharmacotherapy: Nitisinone at low dose (10 mg/d) to reduce urinary homogentisic acid excretion.
- Urea Cycle Defects: • Initial Management: Stop catabolism by providing adequate calories. • Nitrogen Removal: Administration of phenylacetate and benzoate.
PROGNOSIS & COMPLICATIONS¶
• General Prognosis: Improved survival rates due to early diagnosis; many children now reach adulthood. • Urea Cycle Defects: CNS dysfunction (delays, seizures, behavioral issues) in >50% of cases. Hyperammonemia is a life-threatening condition. • Homocystinuria: Life-threatening vascular complications (coronary, renal, cerebral) during the first decade of life.
SPECIAL CONSIDERATIONS¶
• Pregnancy: Maternal PKU requires strict control before conception to prevent congenital defects in offspring. • Adult Presentation: Some disorders (e.g., certain homocystinurias) may remain asymptomatic until adulthood, presenting only during fasting or severe stress.
KEY PEARLS & CLINICAL TRAPS¶
• Maternal PKU: Critical to control phenylalanine levels before conception. • Nitisinone Dose: 10 mg/d for Alkaptonuria. • Homocystinuria Differentiation: • Cystathioninuria → High cystathionine; high homocysteine. • Remethylation defects → Low methionine; high homocysteine. • Urea Cycle Defects: Most are AR, except Ornithine Transcarbamylase (OTC) deficiency which is X-linked.
Reference Tables¶
TABLE 431-1 Inherited Disorders of Amino Acid Metabolism¶
Harrison's 22e, p.3368
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Phenylalanine | Phenylketonuria | Phenylalanine hydroxylase | Intellectual disability, microcephaly, hypopigmented skin and hairs, eczema, “mousy” odor |
AR |
| DHPR deficiency | Dihydropteridine reductase | Intellectual disability, hypotonia, spasticity, myoclonus | AR | |
| PTPS deficiency | 6-Pyruvoyl-tetrahydropterin synthase | Dystonia, neurologic deterioration, seizures, intellectual disability |
AR | |
| GTP cyclohydrolase 1 deficiency |
GTP cyclohydrolase 1 | Intellectual disability, seizures, dystonia, temperature instability |
AR | |
| Carbinolamine dehydratase deficiency |
Pterin-4α-carbinolamine dehydratase | Transient hyperphenylalaninemia (benign) | AR | |
| DNAJC12 deficiency | Hydroxylase co-chaperone | Dystonia, parkinsonism, intellectual disability | AR | |
| Tyrosinemia type 1 (hepatorenal) |
Fumarylacetoacetate hydrolase | Liver failure, cirrhosis, rickets, failure to thrive, peripheral neuropathy, “boiled cabbage” odor |
||
| Tyrosinemia type 2 (oculocutaneous) |
Tyrosine transaminase | Palmoplantar keratosis, painful corneal erosions with photophobia, learning disability |
||
| Tyrosinemia type 3 | 4-Hydroxyphenylpyruvate dioxygenase | Hypertyrosinemia with normal liver function, occasional mental delay |
||
| Hawkinsinuria | 4-Hydroxyphenylpyruvate dioxygenase | Transient failure to thrive, metabolic acidosis in infancy | ||
| Alkaptonuria | Homogentisic acid oxidase | Ochronosis, arthritis, cardiac valve involvement, coronary artery calcification |
||
| Maleylacetoacetate isomerase deficiency |
Maleylacetoacetate isomerase | No clinical symptoms, elevated succinylacetone in blood and urine |
||
| Albinism (oculocutaneous) | Tyrosinase | Hypopigmentation of hair, skin, and optic fundus; visual loss; photophobia |
||
| Albinism (ocular) | Different enzymes or transporters | Hypopigmentation of optic fundus, visual loss | ||
| DOPA-responsive dystonia | Tyrosine hydroxylase | Rigidity, truncal hypotonia, tremor, intellectual disability | ||
| GABA | 4-Hydroxybutyric aciduria | Succinic semialdehyde dehydrogenase | Seizures, intellectual disability, hypotonia | AR |
| ABAT deficiency | GABA transaminase | Seizures, intellectual disability, hypotonia | AR | |
| Hydroxykynureninuria | Kynureninase | Intellectual disability, spasticity | ||
| Histidine | Histidinemia | Histidine-ammonia lyase | Benign | AR |
| Urocanic aciduria | Urocanase | Occasional intellectual disability | AR | |
| Formiminoglutamic aciduria |
Formiminotransferase | Occasional intellectual disability | AR | |
| Glycine encephalopathy | Glycine cleavage (4 enzymes) | Infantile seizures, lethargy, apnea, profound intellectual disability |
||
| Sarcosinemia | Sarcosine dehydrogenase | Benign | ||
| Hyperoxaluria type I | Alanine:glyoxylate aminotransferase | Calcium oxalate nephrolithiasis, renal failure | ||
| Hyperoxaluria type II | D-Glyceric acid dehydrogenase/ glyoxylate reductase |
Calcium oxalate nephrolithiasis, renal failure | ||
| Serine | 3-PGDH deficiency | Phosphoglycerate dehydrogenase | Seizures, microcephaly, intellectual disability | AR |
| PSAT1 deficiency | Phosphoserine aminotransferase | Seizures, microcephaly, intellectual disability | AR | |
| PSP deficiency | Phosphoserine phosphatase | Seizures, microcephaly, intellectual disability | AR | |
| Hyperprolinemia type 1 | Proline oxidase | Benign | ||
| Hyperprolinemia type 2 | Δ1-Pyrroline-5-carboxylate dehydrogenase |
Febrile seizures, intellectual disability | ||
| Hyperhydroxyprolinemia | Hydroxyproline oxidase | Benign | ||
| Prolidase deficiency | Prolidase | Mild intellectual disability, chronic dermatitis, autoimmunity | ||
| PYCR1 deficiency | Pyrroline-5-carboxylate reductase 1 | Wrinkly skin, joint laxity, typical facial features, intellectual disability, osteopenia, intrauterine growth retardation, hypotonia |
||
| PYCR2 deficiency | Pyrroline-5-carboxylate reductase 2 | Microcephaly, hypomyelination, and reduced cerebral white matter volume, failure to thrive, intellectual disability, movement disorders, seizures |
||
| Proline (ornithine, arginine, citrulline) |
Δ1-Pyrroline-5-carboxylate synthase deficiency |
Δ1-Pyrroline-5-carboxylate synthase | Hypotonia, seizures, neurodegeneration, peripheral neuropathy, joint laxity, skin hyperelasticity, subcapsular cataracts, hyperammonemia, adult spastic paraparesis (AD) |
AR, AD |
| Hypermethioninemia | Methionine adenosyltransferase | Usually benign | ||
| S-Adenosylhomocysteine hydrolase deficiency |
S-Adenosylhomocysteine hydrolase | Hypotonia, intellectual disability, absent tendon reflexes, delayed myelination |
||
| Glycine N-methyltransferase deficiency |
Glycine N-methyltransferase | Elevated liver transaminases | ||
| Adenosine kinase deficiency |
Adenosine kinase | Intellectual disability, seizures, liver dysfunction |