Holocarboxylase synthetase deficiency: novel clinical and molecular findings

Abstract

Multiple carboxylase deficiency (MCD) is an autosomal recessive metabolic disorder caused by defective activity of biotinidase or holocarboxylase synthetase (HLCS) in the biotin cycle. Clinical symptoms include skin lesions and severe metabolic acidosis. Here, we reported four unrelated Thai patients with MCD, diagnosed by urine organic acid analysis. Unlike Caucasians, which biotinidase deficiency has been found to be more common, all of our four Thai patients were affected by HLCS deficiency. Instead of the generally recommended high dose of biotin, our patients were given biotin at 1.2 mg/day. This low-dose biotin significantly improved their clinical symptoms and stabilized the metabolic state on long-term follow-up. Mutation analysis by polymerase chain reaction-sequencing of the entire coding region of the HLCS gene revealed the c.1522C>T (p.R508W) mutation in six of the eight mutant alleles. This suggests it as the most common mutation in the Thai population, which paves the way for a rapid and unsophisticated diagnostic method for the ethnic Thai. Haplotype analysis revealed that the c.1522C>T was on three different haplotypes suggesting that it was recurrent, not caused by a founder effect. In addition, a novel mutation, c.1513G>C (p.G505R), was identified, expanding the mutational spectrum of this gene.

Genetics and genomics in Thailand: challenges and opportunities

“…There are three biochemical genetics laboratories located in university hospitals in Bangkok providing urine organic acid analysis and plasma amino acid analysis (Shotelersuk et al 2000). Although enzymatic assays of various enzymes were desired, sufficient financial support was not available and therefore, most inherited metabolic disorders are diagnosed by molecular testing (Champattanachai et al 2003;Shotelersuk et al 2004;Tammachote et al 2009Tammachote et al , 2010Tammachote et al , 2012Tammachote et al , 2013Amarinthnukrowh et al 2010;Prommajan et al 2011;Vatanavicharn et al 2012). If enzymatic assays are needed, they are sent out to other countries.…”

Paracentric Inversion of Chromosome 21 Leading to Disruption of the HLCS Gene in a Family with Holocarboxylase Synthetase Deficiency

“…Biotin supplementation in these patients overcomes this increased K m restoring enzymatic activity. These patients are clinically asymptomatic on the suggested dose of biotin 10-20 mg daily and require no additional therapies, such as protein restriction or carnitine supplementation with good clinical outcomes documented with biotin doses as low as 1.2 mg daily (Dupuis et al 1999;Bailey et al 2008;Tammachote et al 2010). Conversely, individuals with pathogenic variants outside of the biotin-binding domain are considered biotin-unresponsive and are the most severe cases (Mayende et al 2012).…”

Guidance for assessment of erythroderma in neonates and infants for the pediatric immunologist

“…Infants with the disease present with perioral, periorbital, and perineal lesions and may also have eczematous erythroderma and alopecia. If clinically suspected in neonates and corroborated by urine organic acid analysis, HSD should lead to neonatal intensive care and biotin substitution …”