• Clinical science

Inborn errors of metabolism


Inborn errors of metabolism are a group of inherited disorders characterized by enzyme defects. Clinical manifestations are usually due to the accumulation of toxic substances in the body. While in many cases the disorder cannot be cured, disease outcomes and life expectancy can be improved with supportive care and the appropriate diet.

Alpha-1 antitrypsin deficiency (AAT deficiency)

The diagnosis of alpha-1 antitrypsin deficiency should be considered in all COPD patients under the age of 50.


Mitochondrial myopathies

General considerations

Subtypes of mitochondrial myopathies [10]


Disorders of amino acid metabolism

Alkaptonuria [20][21]

  • Definition: : congenital disorder of impaired tyrosine degradation
  • Etiology: mutation in HGD gene
  • Inheritance: autosomal recessive
  • Pathophysiology
    • Deficient activity of homogentisic acid dioxygenase → impaired conversion of homogentisate to 4-maleylacetoacetate
    • Accumulation of homogentisic acid → tissue discoloration and organ damage
  • Clinical features
  • Diagnostics
    • Urine darkens when left standing or when alkalinized.
    • Homogentisic acid in urine and serum; normal tyrosine levels
  • Treatment: diet low in tyrosine and phenylalanine → reduced formation of homogentisic acid

Homocystinuria [22]

  • Definition: a group of congenital disorders characterized by impaired homocysteine metabolism
  • Etiology: mutations in CBS, MTHFR, MTR, MTRR, and MMADHC genes
    • Methionine synthase deficiency
    • Cystathione synthase deficiency
    • Impaired affinity of cystathionine synthase for pyridoxal phosphate
    • Methylenetetrahydrofolate reductase (MTHFR) deficiency
  • Inheritance: autosomal recessive
  • Pathophysiology
    • Methionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionine
    • Cystathionine synthase deficiency → impaired conversion of homocysteine into cystathionine
    • All forms result in accumulation of homocysteine.
  • Clinical features: Disease severity varies greatly.
  • Diagnostics
  • Treatment

Marfan syndrome and homocystinuria both present with marfanoid habitus. Distinguishing features include intellectual disability, which is only seen in homocystinuria, and the direction of lens dislocation (downwards in homocystinuria; upwards in Marfan syndrome).

Hartnup disease [22] [26]

  • Definition: : congenital disorder characterized by a defect in the renal and intestinal transport of neutral amino acids (e.g., tryptophan)
  • Etiology: mutation in the SLC6A19 gene
  • Inheritance: autosomal recessive
  • Pathophysiology: impaired Na+-dependent neutral amino acid transporterdecreased absorption of tryptophan from the gut and renal tubules → inability to synthesize vitamin B3 (niacin)
  • Clinical features: symptoms of vitamin B3 deficiency
  • Diagnostics: amino acids in urine (neutral aminoaciduria)
  • Treatment
    • High-protein diet
    • Niacin supplementation

Phenylketonuria (PKU) [27][28][29][30]

  • Definition: : congenital disorder characterized by accumulation of phenylalanine
  • Epidemiology: incidence ∼ 1:10,000
  • Etiology: mutations in the PAH gene
  • Inheritance: autosomal recessive
  • Pathophysiology
    • Accumulation of phenylalanine due to impaired conversion to tyrosine
      • Defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosinetyrosine becomes nutritionally essential (classical PKU)
      • Deficiency in tetrahydrobiopterin (BH4), a cofactor of phenylalanine metabolism (e.g., PAH) → decreased conversion of phenylalanine to tyrosine (malignant PKU)
        • Often due to a deficiency in dihydropteridine reductase: normally reduces dihydrobiopterin (DHB) to tetrahydrobiopterin (THB)
    • Excess of phenylalaninetransformed into other metabolites; (e.g., phenylpyruvate, phenylacetate, and phenyllactate) → excretion of metabolites in the urine
    • Tyrosine deficiency → decreased neurotransmitter, melanin, and thyroxine synthesis (see amino acid derivatives)
  • Clinical features
    • Symptoms may manifest within the first few months of life.
    • Psychomotor delay (starting as early as 4–6 months of age)
    • Seizures with cerebral foci [31]
    • Blue eyes; light, pale hair
    • Eczema
    • Musty odor
    • Maternal PKU; : in pregnant women with PKU who do not follow proper diet during pregnancy; infant is at risk of microcephaly, growth restriction, facial dysmorphisms, heart defects, intellectual disability
  • Diagnostics
    • Newborn screening: direct measurement of serum phenylalanine levels on the 2nd–3rd day after birth
    • If screening test is positive: oral tetrahydrobiopterin loading test
    • ↑ Phenylketones in urine: phenylacetate, phenyllactate, phenylpyruvate
  • Treatment
    • Low phenylalanine and high tyrosine diet
    • BH4 deficiency: supplementation of tetrahydrobiopterin

Patients with PKU should be advised to avoid aspartame, an artificial sweetener that contains phenylalanine!


  • Definition: A congenital disorder characterized by impaired cystine storage.
  • Etiology: autosomal recessive inheritance
  • Epidemiology: Incidence of the most common form (infantile cystinosis): 1:100,000-200,000
  • Pathology:
    • Defective transport of cystine out of lysosomesaccumulation of cystine within lysosomes
    • Three clinical forms with variable age onset and severity → infantile form is the most severe form (infantile > juvenile > ocular (adult) cystinosis)
  • Clinical features
    • Failure to thrive
    • Vomiting, weakness, dehydration
    • Polyuria and polydipsia
    • Progressive renal failure
    • Photophobia due to corneal crystal formation
    • Additional organ involvement (e.g., hepatomegaly)
  • Diagnosis
  • Treatment

Cystinuria [35]

  • Definition: : congenital disorder characterized by hereditary defect in the amino acid transporter on the proximal convoluted tubule of the kidneys and in the intestine
  • Epidemiology: incidence ∼ 1:7,000
  • Inheritance: autosomal recessive
  • Pathophysiology: impaired renal resorption of cystine, ornithine, lysin, arginine → accumulation of cystine in the urine → precipitation of cystine stones
  • Clinical features: recurrent nephrolithiasis, starting as early as childhood (see also cystine stones)
  • Diagnostics: urine microscopy shows hexagonal cystine stones; urinary cyanide nitroprusside test positive
  • Treatment: urinary alkalinization, chelating agents, hydration


  • Definition: A rare, benign congenital disorder characterized by an impaired histidine metabolism which leads to an elevation in histidine.
  • Epidemiology: 1:11,500 [36]
  • Etiology: autosomal recessive inheritance
  • Pathology: histidase deficiency → impaired histidine breakdown → histidine accumulates
  • Clinical symptoms
    • Mostly asymptomatic
    • Complications during or after birth (e.g., temporary lack of oxygen) → possible risk factor for the development of intellectual disability
  • Diagnostics
    • Histidine in serum
    • Histidine and imidazole metabolites in urine
  • Treatment: not required [36][37]

Maple syrup urine disease [22][38][39][40]

  • Definition: : congenital disorder characterized by the impaired break down of branched-chain amino acids
  • Etiology: mutations in BCKDHA, BCKDHB, and DBT genes
  • Inheritance: autosomal recessive
  • Pathophysiology: absent or deficient branched-chain alpha-ketoacid dehydrogenase → impaired degradation of branched-chain amino acids (valine, leucine, isoleucine) → elevated α-ketoacid formation
  • Clinical features
    • Symptom onset: early neonatal period
    • Vomiting, lethargy, poor feeding
    • Dystonia
    • Intellectual disability
    • Sweet-smelling urine (maple syrup odor)
    • Death may occur without appropriate treatment.
  • Diagnostics
    • Part of newborn screening
    • Serum: increased alpha-ketoacids; increased levels of leucine, isoleucine, and valine
    • Urine: presence of abnormal branched-chain hydroxy acids and ketoacids
    • Hypoglycemia
  • Treatment

Mnemonic for amino acids involved in maple syrup urine disease: I Love Vermont maple syrup from maple trees (with branches) → I = Isoleucine, Love = Leucine, Vermont = Valine, branches = branched-chain amino-acids

Pyruvate dehydrogenase complex deficiency [22][41]

Propionic acidemia [42][43]

  • Definition: : congenital disorder characterized by impaired metabolism of fats and proteins
  • Epidemiology: incidence ∼ 1:100,000
  • Etiology: mutations in the PCCA and PCCB genes
  • Inheritance: autosomal recessive
  • Pathophysiology: propionyl-CoA carboxylase deficiency → impaired conversion of propionyl-CoA to methylmalonyl-CoA → buildup of propionyl-CoA → conversion into propionic acid, which accumulates in serum and urine
  • Clinical features
  • Diagnostics: ↑ propionic acid in urine and serum (organic acidosis)
  • Treatment
    • Low protein diet (e.g., avoidance of methionine, threonine, isoleucine, or valine)
    • Amino acid supplementation

References: [21][25][23][24][26][34][37][38][40][41][42][43]

Purine salvage deficiencies

Lesch-Nyhan syndrome [44][22][45]

To remember the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), which is involved in Lesch-Nyhan syndrome: He's Got Purine Recovery Troubles

Adenosine deaminase deficiency [46]


Disorders of fatty acid metabolism

Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) [47][48]

References:[49] [48]

Primary carnitine deficiency [48][22]

Carnitine palmitoyltransferase II deficiency (CPT II deficiency) [50][51][52]

Urea cycle disorders


Ornithine transcarbamylase deficiency (OTC deficiency) [53][54][55]

  • Definition: congenital disorder characterized by the inability to excrete ammonia
  • Epidemiology: most common urea cycle defect
  • Inheritance: X-linked recessive
  • Pathophysiology:
    • Defect in the enzyme ornithine transcarbamylase → impaired conversion of carbamoyl phosphate and ornithine to citrulline (and phosphate) → ammonia cannot be eliminated and accumulates
    • Accumulation of carbamoyl phosphate → conversion to orotic acid
  • Clinical features
    • Symptoms commonly manifest in the first days of life but can develop at any age.
    • Nausea, vomiting, irritability, poor feeding
    • Delayed growth and cognitive impairment
    • In severe cases, metabolic encephalopathy with coma and death
    • Does not cause megaloblastic anemia (as opposed to orotic aciduria)
  • Diagnostics
    • Hyperammonemia (usually > 100 μmol/L)
    • Orotic acid in urine and blood, BUN
    • Carbamoyl phosphate and ↓ citrulline in the serum
    • Enzyme analysis of OTC activity
  • Treatment
    • Strict low-protein diet
    • Reduce serum ammonia
      • Nitrogen scavengers such as sodium benzoate
      • Fluid management
      • Dialysis (in severe cases)
    • Arginine supplementation → promotes urea formation

Arginase deficiency [53][56]

  • Definition: congenital disorder characterized by impaired arginase activity, resulting in the accumulation of nitrogen (in the form of ammonia)
  • Inheritance: autosomal recessive
  • Pathophysiology: absent or nonfunctional arginase enzyme → impaired conversion of arginine to ornithine → accumulation of ammonia and arginine in the serum
  • Clinical features
    • Acute: episodic hyperammonemia
      • Often asymptomatic
      • Triggered by metabolic stress (e.g., infections, trauma, surgery)
    • Chronic
      • Delayed growth (usually present by three years of age)
      • Progressive spasticity (especially of lower extremities), dystonia, ataxia, poor cognitive development, and missed developmental milestones
      • Seizures
      • By young adulthood: severe spasticity, inability to ambulate, complete loss of bowel and bladder control, severe intellectual disability
  • Diagnostics
  • Treatment
    • Reduce serum ammonia
      • Dialysis (severe cases)
      • Nitrogen scavengers such as sodium phenylacetate and sodium benzoate
      • Fluid management
    • Low-protein diet

References:[57][54][56] [53]

Orotic aciduria

  • Definition: a rare, hereditary condition that is characterized by an elevation of orotic acid in the serum and urine due to defective UMP synthase
  • Inheritance: autosomal recessive [58]
  • Pathophysiology
  • Clinical features
    • Manifests in early childhood
    • Failure to thrive
    • Delayed physical and mental development
    • Megaloblastic anemia, which does not respond to folate and vitamin B12 supplementation
    • Orotic acid crystalluria
  • Diagnostics [58]
    • Serum: hemoglobin, ↑ mean corpuscular volume, orotic acid, normal ammonia levels, normal BUN
    • Urine: orotic acid
  • Treatment: uridine monophosphate substitution [58]

Orotic aciduria can be distinguished from ornithine transcarbamylase deficiency by the presence of megaloblastic anemia and absence of hyperammonemia!