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At a glance

It is an inborn error of metabolism present in the neonatal period and characterized by tachypnea or Kussmaul breathing, hypotonia, and seizures. It is characterized by severe metabolic acidosis with ketosis and hyperammonemia. If present during infancy and childhood, the clinical symptoms include lethargy, muscle hypotonia, seizures, ataxia; apnea/hyperventilation, and frequent stridor. The prognosis is good (both forms), if biotin therapy is introduced early and continued throughout life. Delayed therapy can result in irreversible neurological damage, coma, and death. The recommended dose to treat profound biotinidase deficiency is usually sufficient with 10 mg/day or less; however, it must be assessed individually. Doses up to 100 mg/day of biotin may be necessary.

Synonyms

Biotinidase Deficiency; Holocarboxylase Synthetase Deficiency; Multiple Carboxylase Deficiency; Biotinidase Deficiency (BTD) Syndrome.

History

It was first described in 1971 by Wolf et al. It was immediately observed that biotin administration was curative.

Classification

There are two forms of the disease based on the onset of the symptoms. They consist of:

  • Neonatal Form: Holocarboxylase Synthetase Deficiency. Characterized by the inability to metabolize biotin effectively. Clinically, the symptoms when untreated include dysphagia, failure to thrive, hypotonia, metabolic acidosis, hyperammonemia, foul urine smell, erythematous rash, seizure, and alopecia.

  • Late-Onset Form: Biotinidase Deficiency. Characterized by a problem of absorption of biotin leading to deficiency. Clinically, the symptoms include seizures, muscle hypotonia, limbs weakness, ataxia, paresis, hearing loss, optic nerve atrophy seborrheic dermatitis, psoriasis, and alopecia. When untreated, it causes rapidly coma and death. It is inherited as an autosomal recessive trait.

Incidence

1:112,000 to 129,000 live births (biotinidase deficiency).

Genetic inheritance

Autosomal recessive; more than 40 different mutations have been described. The identified gene loci are on chromosome 3p25 (biotinidase) or 21q22.1 (holocarboxylase).

Pathophysiology

Biotinidase is essential for generation of free biotin from endogenous recycling or protein-bound biotin found in diet. Holocarboxylase synthetase is required to catalyze binding of biotin to carboxylases. Biotin is required as a cofactor for carboxylases within the body, which are involved in the metabolic pathways for a number of amino acids, gluconeogenesis, and fatty acid synthesis. Defects in either enzyme lead to organic acidosis.

Diagnosis

Clinical features, particularly skin rash and alopecia, but variability of symptoms according to importance of deficiency and amount of free biotin intake. Organic aciduria. Deficiency of specific enzyme measured in plasma. Included in neonatal screening programs in many countries.

Clinical aspects

  • Deficiency of Holocarboxylase Synthetase: Presents in more than 50% of cases in the neonatal period with tachypnea or Kussmaul breathing, hypotonia, and seizures. The presence of severe metabolic acidosis with ketosis and hyperammonemia is a characteristic of this disorder. Untreated patients will ...

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