Clinical and genetic analysis of four Chinese patients with holocarboxylase synthetase deficiency and metabolic acidosis.

Background: Holocarboxylase synthetase (HLCS) deficiency is an autosomal recessive organic acidaemia. This paper aimed to describe the clinical, biochemical and molecular features of four Chinese patients with HLCS deficiency, and to research the novel mutation.

Methods: Tandem mass spectrometric analysis of elevated 3-hydroxyisovaleryl carnitine (C5OH) on dried blood spots was performed. Next-generation sequencing was then used to make a definite diagnosis, and the related variants were checked in several databases.

Results: The four patients exhibited varying degrees of clinical symptoms, abnormal biochemical analysis and acylcarnitine profile. A total of six mutations in the HLCS gene were identified, including one novel missense mutation [c.1505 A > G (p.Gln502Arg)], and one frameshift mutation [c.2159delT (p.Leu720Profs*31)]. The variation c.1505 A > G (p.Gln502Arg) is predicted to be possibly damaging by several in silico prediction programs. Another frameshift variation, c.2159delT (p.Leu720Profs*31), is classified as uncertain significance.

Conclusions: A novel variation c.1505 A > G (p.Gln502Arg) expands the mutational spectrum of the HLCS gene. Patient 4 is the first patient diagnosed as HLCS deficiency carrying the c.2159delT (p.Leu720Profs*31) variation. The results may contribute to a better understanding of the clinical course and genetic characteristics of patients with HLCS deficiency.