Inherited Disorders of Amino Acid Metabolism in Adults¶
Chapter 431 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Inherited amino acid disorders are rare but collectively affect ~1 in 4000 newborns, with most inherited as autosomal recessive traits.
- Newborn screening is critical for early diagnosis, enabling dietary management and preventing severe complications like intellectual disability or organ failure.
- Phenylketonuria (PKU) and homocystinuria are the most common disorders, requiring strict dietary restrictions and adjunct therapies like tetrahydrobiopterin or pegvaliase.
- Urea cycle defects and organic acidemias are managed with protein-restricted diets, arginine supplementation, and liver transplantation in severe cases.
- Alkaptonuria is treated with nitisinone to reduce homogentisic acid excretion, though it remains a progressive disorder with ochronosis.
1. DEFINITION & OVERVIEW¶
Amino acids are essential for protein synthesis, neurotransmitters, and metabolic pathways. Inherited disorders of amino acid metabolism involve enzyme deficiencies leading to toxic metabolite accumulation (e.g., phenylalanine, homocysteine) or impaired catabolism. These disorders are rare but collectively affect ~1 in 4000 newborns, with most inherited as autosomal recessive traits. Early diagnosis via newborn screening and targeted therapies (dietary restriction, enzyme replacement, gene therapy) are critical to prevent irreversible neurological and systemic damage.
Table 431-1 Inherited Disorders of Amino Acid Metabolism¶
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Phenylalanine | Phenylketonuria | Phenylalanine hydroxylase | Intellectual disability, microcephaly, hypopigmented skin and hairs, eczema, 'mousy' odor | AR |
| Phenylalanine | DHPR deficiency | Dihydropteridine reductase | Intellectual disability, hypotonia, spasticity, myoclonus | AR |
| Phenylalanine | PTPS deficiency | 6-Pyruvoyl-tetrahydr opterin synthase | Dystonia, neurologic deterioration, seizures, intellectual disability | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Phenylalanine | GTP cyclohydrolase 1 deficiency | GTP cyclohydrolase 1 | Intellectual disability, seizures, dystonia, temperature instability | AR |
| Phenylalanine | Carbinolamine dehydratase deficiency | Pterin-4a-carbinolam ine dehydratase | Transient hyperphen ylalaninemia (benign) | AR |
| Phenylalanine | DNAJC12 deficiency | Hydroxylase co-chaperone | Dystonia, parkinsonism, intellectual disability | AR |
| Tyrosine | Tyrosinemia type 1 (hepatorenal) | Fumarylacetoacetate hydrolase | Liver failure, cirrhosis, rickets, failure to thrive, peripheral neuropathy, 'boiled cabbage' odor | |
| Tyrosine | Tyrosinemia type 2 (oculocutaneous) | Tyrosine transaminase | Palmoplantar keratosis, painful corneal erosions with photophobia, learning disability | |
| Tyrosine | Tyrosinemia type 3 | 4-Hydroxyphenylpyr uvate dioxygenase | Hypertyrosinemia with normal liver function, occasional mental delay | AR |
| Tyrosine | Hawkinsinuria | 4-Hydroxyphenylpyr uvate dioxygenase | Transient failure to thrive, metabolic acidosis in infancy | |
| Tyrosine | Alkaptonuria | Homogentisic acid oxidase | Ochronosis, arthritis, cardiac valve involvement, coronary artery calcification | AR |
| Tyrosine | Maleylacetoacetate isomerase deficiency | Maleylacetoacetate isomerase | No clinical symptoms, elevated succinylacetone in blood and urine | AR |
| Tyrosine | Albinism (oculocutaneous) | Tyrosase | Hypopigmentation of hair, skin, and optic fundus; visual loss; photophobia | AR |
| Tyrosine | Albinism (ocular) | Different enzymes or transporters | Hypopigmentation of optic fundus, visual loss | AR, XL |
| Tyrosine | DOPA-responsive dystonia | Tyrosine hydroxylase | Rigidity, truncal hypotonia, tremor, intellectual disability | AR |
| GABA | 4-Hydroxybutyric aciduria | Succinic semialdehyde dehydrogenase | Seizures, intellectual disability, hypotonia | AR |
| GABA | ABAT deficiency | GABA transaminase | Seizures, intellectual disability, hypotonia | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Tryptophan | Hydroxykynureninuri a | Kynureninase | Intellectual disability, spasticity | |
| Histidine | Histidinemia | Histidine-ammonia lyase | Benign | AR |
| Histidine | Urocanic aciduria | Urocanase | Occasional intellectual disability | AR |
| Histidine | Formiminoglutamic aciduria | Formiminotransferas e | Occasional intellectual disability | AR |
| Glycine | Glycine encephalopathy | Glycine cleavage (4 enzymes) | Infantile seizures, lethargy, apnea, profound intellectual disability | |
| Glycine | Sarcosinemia | Sarcosine dehydrogenase | Benign | AR |
| Hyperoxaluria type I | Alanine:glyoxylate aminotransferase | Calcium oxalate nephrolithiasis, renal failure | AR | |
| Hyperoxaluria type II | D-Glyceric acid dehy drogenase/glyoxylat e reductase | Calcium oxalate nephrolithiasis, renal failure | AR | |
| Serine | 3-PGDH deficiency | Phosphoglycerate dehydrogenase | Seizures, microcephaly, intellectual disability | AR |
| Serine | PSAT1 deficiency | Phosphoserine aminotransferase | Seizures, microcephaly, intellectual disability | AR |
| Serine | PSP deficiency | Phosphoserine phosphatase | Seizures, microcephaly, intellectual disability | AR |
| Proline | Hyperprolinemia type 1 | Proline oxidase | Benign | AR |
| Proline | Hyperprolinemia type 2 | D1-Pyrroline-5-carbo xylate dehydrogenase | Febrile seizures, intellectual disability | AR |
| Proline | Hyperhydroxyproline mia | Hydroxyproline oxidase | Benign | AR |
| Proline | Prolidase deficiency | Prolidase | Mild intellectual disability, chronic dermatitis, autoimmunity | AR |
| Proline | PYCR1 deficiency | Pyrroline-5-carboxyl ate reductase 1 | Wrinkly skin, joint laxity, typical facial features, intellectual disability, osteopenia, intrauterine growth retardation, hypotonia | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Proline | PYCR2 deficiency | Pyrroline-5-carboxyl ate reductase 2 | Microcephaly, hypomyelination, reduced cerebral white matter volume, failure to thrive, intellectual disability, movement disorders, seizures | AR |
| Proline | D1-Pyrroline-5-carbo xylate synthase deficiency | D1-Pyrroline-5-carbo xylate synthase | Hypotonia, seizures, neurodegeneration, peripheral neuropathy, joint laxity, skin hyperelasticity, subcapsular cataracts, hyperammonemia, adult spastic paraparesis (AD) | AR, AD |
| Methionine | Hypermethioninemia | Methionine adenosyltransferase | Usually benign | AR |
| Methionine | S-Adenosylhomocys teine hydrolase deficiency | S-Adenosylhomocys teine hydrolase | Hypotonia, intellectual disability, absent tendon reflexes, delayed myelination | AR |
| Methionine | Glycine N-methyltransferase deficiency | Glycine N-methyltransferase | Elevated liver transaminases | AR |
| Methionine | Adenosine kinase deficiency | Adenosine kinase | Intellectual disability, seizures, liver dysfunction | AR |
| Homocysteine | Homocystinuria | Cystathionine b-synthase | Lens dislocation, thrombotic vascular disease, intellectual disability, osteoporosis | AR |
| Homocysteine | Homocystinuria | 5,10-Methylenetetra hydrofolate reductase | Intellectual disability, gait and psychiatric abnormalities, recurrent strokes | AR |
| Homocysteine | Homocystinuria | Methionine synthase and methionine synthase reductase (cblE, G) | Intellectual disability, hypotonia, seizures, megaloblastic anemia | AR |
| Homocysteine | Homocystinuria and methylmalonic acidemia | Vitamin B12 lysosomal efflux and metabolism (cblC, -epiC, -D, -F, -J, -X) | Intellectual disability, lethargy, failure to thrive, hypotonia, seizures, megaloblastic anemia | AR, XL |
| Cystathioninuria | b-Cystathioninase | Benign | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Cysteine | Sulfocystinuria | Sulfite oxidase or molybdenum cofactor deficiency | Seizures, intellectual disability, dislocated lenses | AR |
| Lysine | Hyperlysinemia, saccharopinuria | a-Aminoadipic semialdehyde synthase | Benign | AR |
| Lysine | Pyridoxine-depende nt seizures | L-D1-Piperideine-6-c arboxilate dehydrogenase | Seizures, intellectual disability | AR |
| Lysine | a-Ketoadipic acidemia | a-Ketoadipic acid dehydrogenase | Benign | AR |
| Lysine | Glutaric acidemia type 1 | Glutaryl-CoA dehydrogenase | Progressive severe dystonia and athetosis, motor delays | AR |
| Ornithine | Gyrate atrophy of the choroid and retina | Ornithine-D-aminotra nsferase | Myopia, night blindness, loss of peripheral vision, cataracts, chorioretinal degeneration | AR |
| Urea cycle | Carbamoylphosphat e synthase-1 deficiency | Carbamoylphosphat e synthase-1 | Lethargy progressing to coma, protein aversion, intellectual disability, hyperammonemia | AR |
| Urea cycle | N-Acetylglutamate synthase deficiency | N-Acetylglutamate synthase | Lethargy progressing to coma, protein aversion, intellectual disability, hyperammonemia | AR |
| Urea cycle | Ornithine transcarbamylase deficiency | Ornithine transcarbamylase | Lethargy progressing to coma, protein aversion, intellectual disability, hyperammonemia | XL |
| Urea cycle | Citrullinemia type 1 | Argininosuccinate synthase | Lethargy progressing to coma, protein aversion, intellectual disability, hyperammonemia, liver failure | AR |
| Urea cycle | Argininosuccinic acidemia | Argininosuccinate lyase | Lethargy progressing to coma, protein aversion, intellectual disability, hyperammonemia, trichorrhexis nodosa, liver failure | AR |
| Urea cycle | Arginase deficiency | Arginase | Spastic tetraparesis, microcephaly, intellectual disability, mild hyperammonemia | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Urea cycle | Hyperornithinemia, hyperammonemia, homocitrullinuria | Mitochondrial ornithine carrier ORNT1 | Vomiting, lethargy, failure to thrive, intellectual disability, episodic confusion, hyperammonemia, protein intolerance | AR |
| Urea cycle | Citrullinemia type 2 | Mitochondrial aspartate/glutamate carrier CTLN2 | Neonatal intrahepatic cholestasis, adult presentation with sudden behavioral changes and stupor, coma, hyperammonemia, liver failure | AR |
| Glutamine | Glutamine synthetase deficiency | Glutamine synthetase | Brain malformations, pachygyria, seizures, hypotonia, intellectual disability, dysmorphic features, low glutamine | AR |
| Glutamine | Glutaminase deficiency | Glutaminase | Epileptic encephalopathy, intellectual disability, ataxia, elevated glutamine | AR |
| Asparagine | Asparagine synthetase deficiency | Asparagine synthetase | Epileptic encephalopathy, seizures, microcephaly, simplified gyration pattern, hypotonia, tetraplegia, intellectual disability | AR |
| Valine | Isobutyryl-CoA dehydrogenase deficiency | Isobutyryl-CoA dehydrogenase | Benign | AR |
| Isoleucine, leucine, valine | Maple syrup urine disease | Branched chain ketoacid dehydrogenase (E1a, E1b, E2, E3 deficiency) | Lethargy, vomiting, encephalopathy, seizures, intellectual disability, 'maple syrup' odor, protein intolerance | AR |
| Isoleucine, leucine, valine | Hypervalinemia | Branched-chain amino acid transferase 2 (BCAT2) | Autism, headaches, intellectual disability | AR |
| Isoleucine, leucine, valine | Branched-chain amino acid deficiency | Branched chain ketoacid dehydrogenase kinase (BCHDK) | Autism, epilepsy, intellectual disability, microcephaly | AR |
| Leucine | Isovaleric acidemia | Isovaleryl-CoA dehydrogenase | Acidosis, ketosis, vomiting, coma, hyperammonemia, 'sweaty feet' odor, protein intolerance | AR |
| AMINO ACID(S) | CONDITION | ENZYME DEFECT | CLINICAL FINDINGS | INHERITANCE |
|---|---|---|---|---|
| Leucine | 3-Methylcrotonyl glycinuria | 3-Methylcrotonyl-Co A carboxylase | Stress-induced metabolic acidosis, hypotonia, hypoglycemia, 'cat's urine' odor | AR |
| Leucine | 3-Methylglutaconic aciduria type I | 3-Methylglutaconyl- CoA hydratase deficiency | Stress-induced acidosis, leukodystrophy, hypotonia, hepatomegaly | AR |
| Leucine | 3-Hydroxy-3-methylg lutaric aciduria | 3-Hydroxy-3-methylg lutaryl-CoA lyase | Stress-induced hypoketotic hypoglycemia and acidosis, encephalopathy, hyperamNone |
1.1 Amino Acid Metabolism Overview¶
Amino acids serve as precursors for neurotransmitters (e.g., serotonin, dopamine), hormones, and coenzymes. Disorders arise from enzyme deficiencies in catabolic pathways, leading to toxic metabolite accumulation (e.g., phenylalanine, homocysteine) or impaired metabolic 'runoff'. Biochemical and genetic heterogeneity is common, with six forms of hyperphenylalaninemia and nine forms of homocystinuria recognized.
2. EPIDEMIOLOGY¶
Inherited amino acid disorders are individually rare, with incidences ranging from 1:10,000 (cystinuria, PKU) to 1:200,000 (homocystinuria, alkaptonuria). Collectively, they affect ~1 in 4000 newborns. Most are autosomal recessive, except ornithine transcarbamylase deficiency (X-linked). Newborn screening programs identify several disorders, enabling early intervention. Risk factors include consanguinity, family history, and certain ethnic backgrounds (e.g., galactosemia in Ashkenazi Jews).
2.1 Demographics¶
Most disorders are autosomal recessive, with exceptions like ornithine transcarbamylase deficiency (X-linked). Incidence varies by disorder: PKU (1:16,500), homocystinuria (1:450,000), alkaptonuria (1:250,000). Ethnicity influences prevalence (e.g., galactosemia in Ashkenazi Jews).
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Defects in amino acid catabolism or transport lead to toxic metabolite accumulation (e.g., phenylalanine, homocysteine) or impaired metabolic pathways. Enzyme deficiencies disrupt pathways, causing neurotoxicity, organ dysfunction, or systemic complications. For example, PKU results from phenylalanine hydroxylase deficiency, while homocystinuria stems from cystathionine β -synthase deficiency. Biochemical heterogeneity is common, with multiple subtypes of hyperphenylalaninemia and homocystinuria.
3.1 Metabolic Pathways¶
Amino acids undergo catabolic pathways involving enzymes like phenylalanine hydroxylase (PKU), cystathionine β -synthase (homocystinuria), and ornithine transcarbamylase (urea cycle). Defects in these enzymes lead to toxic metabolite accumulation (e.g., phenylalanine, homocysteine) or impaired metabolic 'runoff'.
4. CLINICAL FEATURES¶
Clinical manifestations vary widely, from benign conditions (e.g., sarcosinemia) to severe disorders (e.g., ornithine transcarbamylase deficiency). Common features include intellectual disability, seizures, metabolic acidosis, hyperammonemia, and organ-specific complications (e.g., liver failure in tyrosinemia, ochronosis in alkaptonuria). Neurological symptoms (e.g., dystonia, ataxia) and systemic complications (e.g., arthritis, renal stones) are prevalent in many disorders.
4.1 Neurological Manifestations¶
Intellectual disability, seizures, dystonia, ataxia, and developmental delays are common. DOPA-responsive dystonia and 4-hydroxybutyric aciduria are examples of disorders with distinct neurological profiles.
4.2 Systemic Complications¶
Organ-specific issues include liver failure (tyrosinemia), renal stones (hyperoxaluria), ochronosis (alkaptonuria), and cardiovascular complications (homocystinuria). Metabolic acidosis and hyperammonemia are frequent in urea cycle defects.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include other metabolic disorders (e.g., organic acidemias, fatty acid oxidation defects), neurological conditions (e.g., mitochondrial disorders), and genetic syndromes. Key differentiators include specific amino acid or organic acid elevations, family history, and response to dietary interventions.
5.1 Organic Acidemias¶
Conditions like methylmalonic acidemia and propionic acidemia must be differentiated from amino acid disorders via urine organic acid analysis and plasma acylcarnitine profiling.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis relies on plasma amino acid analysis (ion-exchange chromatography, LC-MS/MS), urine organic acid analysis (GC-MS), and acylcarnitine profiling. Enzyme assays and DNA testing confirm genetic defects. Newborn screening programs use tandem mass spectrometry to detect several disorders early.
6.1 Diagnostic Tests¶
Plasma amino acid analysis identifies elevated amino acids (e.g., phenylalanine in PKU). Urine organic acid analysis detects organic aciduria (e.g., homocysteine in homocystinuria). Acylcarnitine profiling helps distinguish urea cycle defects from fatty acid oxidation disorders.
7. MANAGEMENT & TREATMENT¶
Management includes dietary restriction of specific amino acids, supplementation with cofactors (e.g., tetrahydrobiopterin), and enzyme replacement therapy (e.g., pegvaliase for PKU). Liver transplantation may be required for severe urea cycle defects. Nitisinone reduces homogentisic acid excretion in alkaptonuria. Early intervention is critical to prevent irreversible damage.
7.1 Dietary Management¶
Phenylketonuria requires a low-phenylalanine diet with tyrosine supplementation. Urea cycle defects benefit from protein-restricted diets and arginine supplementation. Hyperhomocysteinemia is managed with folate, vitamin B12, and betaine.
7.2 Pharmacologic Therapies¶
Tetrahydrobiopterin (5–20 mg/kg/day) aids PKU management. Pegvaliase (PEGylated phenylalanine ammonia lyase) lowers phenylalanine levels. Nitisinone (10 mg/day) reduces homogentisic acid excretion in alkaptonuria.
8. PROGNOSIS & COMPLICATIONS¶
Early diagnosis and treatment significantly improve outcomes, with many patients surviving into adulthood. Untreated disorders often lead to severe complications: intellectual disability, organ failure, and early mortality. Long-term complications include cardiovascular disease, renal failure, and neurological decline. Prognosis varies by disorder, with some (e.g., sarcosinemia) being benign.
8.1 Long-Term Outcomes¶
Proper management prevents intellectual disability and organ failure in most disorders. However, complications like cardiovascular disease, renal stones, and neurological decline may persist. Urea cycle defects without treatment are often fatal in infancy.
9. SPECIAL CONSIDERATIONS¶
Pregnancy in women with PKU requires strict phenylalanine restriction to prevent congenital defects. Neonatal screening is critical for early detection. In adults, adherence to dietary restrictions is challenging, necessitating pharmacologic adjuncts. Genetic counseling is essential for families with affected children.
9.1 Pregnancy and Neonatal Screening¶
Women with PKU must maintain phenylalanine levels <120 µ mol/L before and during pregnancy to prevent fetal malformations. Newborn screening identifies disorders early, enabling prompt intervention.
10. KEY POINTS & CLINICAL PEARLS¶
- Newborn screening is critical for early diagnosis of amino acid disorders. 2. Dietary restriction of specific amino acids (e.g., phenylalanine, methionine) is the cornerstone of management. 3. Pharmacologic adjuncts like tetrahydrobiopterin and pegvaliase improve outcomes in PKU. 4. Urea cycle defects require lifelong protein restriction and arginine supplementation. 5. Alkaptonuria is managed with nitisinone to reduce homogentisic acid excretion.