• Clinical science

Inborn errors of metabolism

Abstract

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!

References:[1][2][3][4][5][6][7]

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”)

References:[8][9][10][11][12][13][14]

Disorders of amino acid metabolism

Alkaptonuria

  • 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

Homocystinuria

  • 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)

Cystinosis

  • 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

Cystinuria

See cystinuria.

Histidinemia

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

References:[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]

Metabolic disorders of uric acid

Lesch-Nyhan syndrome

References:[18][30]

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

References:[16]

Carnitine transporter deficiency

Carnitine palmitoyltransferase II deficiency (CPT II deficiency)

References:[31][32][33][34][35]

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

References:[36][37][38]

Orotic aciduria