• Clinical science

Inborn errors of metabolism


Inborn errors of metabolism are caused by genetic mutations which result in enzyme defects that impair the metabolism or transport of metabolites. A complete cure is usually not possible but disease outcomes and life expectancy can be improved with supportive treatment and appropriate diets.

α1-Antitrypsin deficiency (AAT deficiency)

A diagnosis of α1-antitrypsin deficiency should be considered in all COPD patients under the age of 50!


Mitochondrial myopathies

General considerations

In the case of mitochondrial myopathies, the production of energy in mitochondria (by oxidative phosphorylation) is impaired. Organs with a high energy requirement (e.g., brain, skeletal muscles) are particularly affected. Clinical features include external ophthalmoplegia, ptosis, and muscle weakness; , which is exacerbated by exertion. Mitochondrial myopathies are inherited only from the mother.

Immunohistochemistry; : a characteristic picture which is described as "ragged red fibers; " (subsarcolemmal and intermyofibrillar accumulation of mitochondria in muscles; the mitochondria stains red)

Special forms

Chronic progressive external ophthalmoplegia (CPEO)

  • Etiology: mitochondriopathy
  • Clinical features: progressive ophthalmoplegia
  • Diagnostics

Kearns-Sayre syndrome

MELAS (“Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes”)

MERRF (“Myoclonic Epilepsy with Ragged Red Fibers”)


Disorders of amino acid metabolism


  • Etiology: : rare, autosomal recessive disorder of tyrosine metabolism, caused by deficient activity of homogentisic acid dioxygenase
  • Pathophysiology: accumulation of the metabolite homogentisic acid → organ damage
  • Clinical features:
  • Diagnostics:
    • Urine initially appears normal but turns dark brown or black when left standing or alkalinized.
    • Confirmed with measurement of homogentisic acid in the urine


  • Definition: : a group of diseases in which the blood and urine levels of the amino acid homocysteine are elevated
  • Pathophysiology: genetic defects in enzymes involved in homocysteine metabolism (e.g., cystathionine synthase deficiency)
  • Clinical features: (the severity of the disease varies greatly)
  • Diagnostics: addition of sodium nitroprusside to urineurine changes color to an intense red
  • Treatment: 50% of patients respond to large doses of pyridoxine (vitamin B6)

Hartnup disease

Phenylketonuria (PKU)

  • Mode of inheritance: autosomal recessive
  • Pathophysiology: defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine (tyrosine becomes nutritionally essential) → accumulation of phenylalanine (in CNS, not in the liver!) → impaired brain growth in children and excretion of the metabolites of phenylalanine in urine (phenylketonuria)
  • Clinical features
    • A lag in psychomotor development after the 4th–6th postnatal month
    • 50% have seizures with cerebral foci
    • Light, pale hair, and blue eyes
    • Predisposition for eczema, “musty” odor
  • Diagnostics
    • Direct measurement of phenylalanine levels as a part of newborn screening for metabolic disorders (The screening test is done on the 2nd day after birth using blood obtained from a heel prick.)
      • An oral tetrahydrobiopterin loading test is done when increased phenylalanine levels are detected by a screening test.
    • Outdated: indirect measurement of phenylalanine levels on the 5th postnatal day (Guthrie-Test
  • Treatment: diet with decreased phenylalanine content and increased tyrosine content
  • Differential diagnosis: tetrahydrobiopterin deficiency (THBD)


  • Definition: cystine storage disorder
    • Three clinical forms (with variable age onset and severity) exist: infantile, juvenile, and ocular cystinosis.
  • Mode of inheritance: autosomal recessive
  • Epidemiology: The infantile form is the most common and the most severe form.
  • Clinical features
  • Diagnosis
    • Observation of cystine crystals in the cornea during slit lamp examination
    • Confirmed by measurement of increased leukocyte cystine content
  • Treatment
    • Directed at correcting metabolic abnormalities associated with Fanconi syndrome or renal failure
    • Specific therapy available with cysteamine


See cystinuria.


Maple syrup urine disease

Pyruvate dehydrogenase complex deficiency

Propionic aciduria

  • Mode of inheritance: autosomal recessive
  • Pathophysiology: defective alpha (13q32) or beta (3q13) subunit of propionyl-CoA carboxylase (most common defect) → impaired conversion of propionyl-CoA to methylmalonyl-CoA → buildup of propionyl-CoA and conversion into propionic acid in the circulation
  • Clinical features
    • Typically presents in the neonatal period, with organic acidosis, vomiting, failure to thrive, generalized hypotonia; , lethargy, and seizures.
  • Diagnosis
    • Urine and serum propionic acid
  • Treatment
    • Low protein diet, with an amino acid supplement that is completely devoid of methionine, threonine, isoleucine, and valine


Metabolic disorders of uric acid

Lesch-Nyhan syndrome


Disorders of fatty acid metabolism

Medium chain Acyl-CoA dehydrogenase deficiency (MCAD deficiency)

  • Pathophysiology
    • Defect in the breakdown of medium-chain fatty acids → disorder of fatty acid oxidation
    • Fat cannot function as an alternate energy source in the case of carbohydrate deficiency.
    • Symptoms usually triggered by:
      • Prolonged fasting (during weaning or off night-time feeds)
      • State of increased metabolic demand (e.g., infection, exercise)
  • Clinical features
    • Vomiting and lethargy
    • Can progress to coma, seizures, or cardiopulmonary collapse.
  • Complications
    • Encephalopathy
    • Fatty liver disease and decreased hepatic function
    • Sudden death
  • Diagnostics
  • Treatment
    • IV administration of 10% dextrose during acute decompensation
    • Avoid fasting states


Carnitine transporter deficiency

Carnitine palmitoyltransferase II deficiency (CPT II deficiency)


Urea cycle disorders

Ornithine transcarbamylase deficiency (OTC deficiency)

  • Etiology
  • Clinical features
    • Nausea, vomiting, irritability
    • Delayed growth and cognitive impairment
    • In severe cases, metabolic encephalopathy with coma and death
  • Diagnostics
  • Treatment
    • Strict low-protein diet
    • Sodium benzoate (nitrogen-scavenging)
    • Arginine supplement

Arginase deficiency

  • Pathophysiology
  • Clinical features
    • Episodic hyperammonemia
      • Often asymptomatic
      • Rarely severe (typically triggered by metabolic stress, e.g. infections, trauma, surgery)
    • In untreated cases
      • Diminishing linear growth by three years
      • Gradually progressive spasticity (especially of lower extremities), dystonia, ataxia, poor cognitive development, and loss of developmental milestones by school age
      • Seizures
      • By young adulthood: severe spasticity, inability to ambulate, complete loss of bowel and bladder control, and severe intellectual disability
      • Treatment typically renders the condition asymptomatic
  • Diagnostics
  • Treatment
    • Promptly reduce serum ammonia via:
      • Dialysis (severe cases)
      • Nitrogen scavengers such as sodium phenylacetate and sodium benzoate
      • Fluid management
    • Avoid heavily nitrogenous diets (proteins)
    • Seizure treatment


Orotic aciduria