Knowledge on rare diseases and orphan drugs

The exact prevalence of holocarboxylase synthertase deficiency (HCSD) is unknown, but the condition is one of the rarest inborn errors of metabolism. Prevalence at birth is estimated to be less than 1/200,000.

Clinical onset is usually within hours, days or weeks of birth, although it may occur during infancy or early childhood. Individuals with the disorder usually exhibit poor appetite, vomiting, lethargy, irritability, hypotonia and exfoliative dermatitis. Metabolically, they have ketolactic acidosis, organic acidemia (-uria) and hyperammonemia. Without treatment, affected infants may progress to intractable seizures, cerebral edema and coma. These children often develop growth and developmental delays.

HCSD is caused by mutations in the HLCS gene (21q22.1) resulting in reduced holocarboxylase synthetase (HCS) activity. This enzyme is important in covalent binding of biotin to the various biotin-dependent carboxylases that require the vitamin for activity. Failure to attach the biotin results in multiple carboxylase deficiency and accumulation of various, specific abnormal organic acids.

Some affected individuals are identified through newborn screening by demonstration of abnormal organic acids, consistent with multiple carboxyalse deficiency. Diagnosis is based on clinical signs and typical organic acid abnormalities. Diagnosis can be confirmed by enzyme activity assays in leukocytes or fibroblast extracts, or by mutation analysis.

Based on organic acids, conditions to be considered in the differential diagnosis include biotinidase deficiency and isolated carboxylase deficiencies. Other conditions to be consider include urea cycle defects (based on presence of hyperammonemia) and sepsis and other inborn errors of metabolism (based on neurological compromise and seizures in the neonatal period).

Prenatal diagnosis can be performed by organic acid analysis by stable isotope dilution techniques in amniotic fluid, enzymatic determination of HCS activity in amniocytes, or mutation analysis on DNA from chorionic villus biopsy or amniocentesis.

Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy.

The primary treatment for HCSD is free biotin supplementation which can improve the clinical status of symptomatic individuals with the enzyme deficiency and prevent some or all symptoms from developing in asymptomatic individuals with the disorder. Treatment should be started as soon as possible after diagnosis and must be continued lifelong. Affected individuals should be monitored for later-onset complications and for compliance with therapy. Timely and ongoing treatment makes it possible to reduce symptoms considerably, although some patients develop complications despite appropriate treatment often requiring higher doses of biotin.

In the absence of early diagnosis and treatment, mortality is high. Morbidity in surviving affected individuals depends on the time of diagnosis and on the degree of damage related to metabolic crises.

Last update: September 2020 - Expert reviewer(s): Dr Barry WOLF