Rare metabolic diseases

Inherited Metabolic Disorders

Inherited Metabolic Disorders have their origin in specific enzymatic deficiencies, which affect a given metabolic pathway, leading to the accumulation of substrates - often toxic - and to reduced (or zero) production of a biologically important product. The enzyme deficit is the consequence of mutations in one or more genes coding for the respective metabolic step.
In short, when there is a metabolic error, some reactions at the enzymatic level do not occur with the proper efficiency. This way, the compounds before the reaction accumulate and the later ones are not synthesized correctly.
The Inherited Metabolic Disorders covered in our site are diagnosed through the neonatal heel prick or Guthrie test.

Our presentation (pdf):


Aminoacidopathies (and organic acidurias) include inherited diseases of the metabolism of amino acids in different metabolic steps. These pathologies are characterized by signs and symptoms of acute and progressive intoxication due to accumulation of toxic metabolites upstream the enzyme block. Long-term treatment consists essentially at removing the toxic product from the diet, which in practice translates into a protein restricted diet (hypoproteic diet).
Why are amino acid formulas restricted in a given amino acid (or groups of amino acids) essential in these pathologies? Because these formulas guarantee an appropriate formation of proteins, indispensable for growth, and that otherwise would not be obtained naturally, due to the toxicity associated with the respective pathology.

  • Phenylketonuria (PKU)
  • Leucinosis or Maple Syrup Urine Disease (MSUD)
  • Homocystinuria (HCU)
  • Tyrosinemia (TYR)

Organic Acidurias

Organic acidurias are characterized by the accumulation in blood and urine of compounds derived from intermediate metabolism, which have a markedly acidic pH. These acids undergo conjugation in vivo with carnitine, either for later metabolization or to facilitate their excretion (via urine), giving rise to the respective acylcarnitins.

  • Propionic (AP) and Methylmalonic (AMM) acidurias
  • Isovaleric Aciduria (AIV)
  • Glutaric Aciduria Type I (AGI)

Urea Cycle Diseases (DCU)

Urea Cycle Diseases (DCU) are caused by an enzyme deficit in one of the six enzymes normally involved in the metabolic cycle of protein nitrogen excretion, which results in an elevated concentration of ammonia in the blood (hyperammonaemia) - toxic compound, especially at the neurological level. If treatment is not carried out on time and at long term, patients with DCU may suffer from variable encephalopathy (including psychiatric manifestations) and liver dysfunction. Dietary treatment involves a hypoprotein diet, supplemented in a mixture of essential amino acids, as well as in arginine.

Primary Bile Acid Synthesis Disorders

Primary bile acid synthesis disorders (BASD) are genetic autosomal recessive diseases. There are usually present as cholestatic jaundice and/or liver failure. The two most frequent ones responsible for chronic liver disease are 3β-HSD deficiency and Δ4-3-oxoR deficiency. They correspond to a lack of one of the two enzymes, 3β-HSD or Δ4-3-oxoR, which are involved in the transformation of cholesterol into primary bile acids in liver cells. When they are missing, cholesterol transformation is incomplete which leads to the absence of production of primary bile acids and accumulation of toxic intermediates in the liver causing its deterioration. Early diagnosis of these disorders is essential.

Sources: Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 2008;5:456-68. Protocole national de diagnostic et de soins : Déficits de synthèse des acides biliaires primaires. Centre de Référence Coordonnateur de l’Atrésie des Voies Biliaires et des Cholestases Génétiques; 2019.


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