Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism characterised by life-threatening metabolic acidosis, ketoacidosis and hyperammonaemia through reduced biotin-dependent carboxylase activity. We report the presentation of a Polynesian neonate with severe metabolic acidosis secondary to holocarboxylase synthetase deficiency with the development of cholestatic liver disease thought to be secondary to holocarboxylase synthetase deficiency. This is only the second reported case of holocarboxylase synthetase deficiency associated with cholestatic liver disease. Both of these cases were a result of the same homozygous c.647T>G L216R pathogenic variants in the HLCS gene suggesting a possible genotype-phenotype correlation and broadening the phenotypic understanding of this disease.

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. 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. 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. 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.

In 2007, the Dutch newborn screening (NBS) program was expanded to include C5-OH as a marker to screen for three inborn errors of metabolism (IEMs): 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) and holocarboxylase synthetase deficiency (HLCSD). This study evaluates the effectiveness of C5-OH as an NBS marker by analyzing data from neonates screened in the Dutch NBS program from 2007 to 2023 and by reviewing the literature on various IEMs detected by an elevated NBS C5-OH concentration worldwide. Of the 126 neonates referred on the basis of elevated C5-OH concentrations in the Netherlands, 46 were true positive cases. No missed cases in the Netherlands have been reported so far, resulting in a positive predictive value of 38.3% and a negative predictive value of 100%. Strikingly, there was notable overlap between C5-OH concentrations of true and false positive cases. The systematic review included 58 articles and showed that C5-OH concentrations of patients with different IEMs reported in the literature were insufficiently distinctive to differentiate between these diseases. While C5-OH can be used to detect patients with 3-MCCD, HCLSD, and HMGCLD, its value is limited by the overlap of C5-OH concentrations between affected and unaffected neonates and among patients with different diseases. This emphasizes the need for improvement of the screening strategy and potentially the use of additional markers to increase its specificity.

Congenital biotinidase deficiency (CBD) is an uncommon inborn error of metabolism (IEM) that frequently manifests in infancy. Clinical manifestations vary from alopecia rash to severe neurological features like hypotonia, seizures, and developmental delay. Typical imaging manifestations will have symmetric restricted diffusion in the corona radiata, perirolandic white matter, posterior limb of the internal capsule (PLIC), parieto-occipital grey matter, brainstem, middle cerebellar peduncle (MCP), and splenium of the corpus callosum. Early diagnosis is essential because early treatment may reduce or prevent the severity of this disease. Herein, we report a case of CBD presented with breathlessness, alopecia, and hearing loss with typical imaging features, reversed with biotin supplementation in a six-year-old male child.

Holocarboxylase Synthetase Deficiency (HCSD) is an uncommon autosomal recessive genetic disorder that manifests with symptoms such as metabolic acidosis, lethargy, hypotonia, seizures, and persistent rashes, typically emerging during infancy. The HLCS gene has been identified as the source of pathogenic mutations associated with this condition. Cobalamin C (cblC) deficiency is another rare autosomal recessive disorder resulting from defects in cobalamin metabolism, attributable to mutations in the MMACHC gene. This disorder often leads to methylmalonic aciduria and homocystinuria and is classified into early-onset and late-onset types. The late-onset type is characterized by acute or chronic progressive neurological symptoms and behavioral disturbances. To date, there have been no documented cases worldwide of individuals diagnosed with both HCSD and cobalamin C deficiency. This report details the case of an 11-year-and-9-month-old female patient from China who presented with symptoms including vomiting, altered consciousness, and a rash. Laboratory evaluations indicated the presence of metabolic acidosis, methylmalonic aciduria, and homocystinuria. Genetic analysis revealed mutations in the MMACHC gene: c.482G > A (p.R161Q) and c.567dup (p.I190Yfs∗13). Additionally, two previously unreported mutations in the HLCS gene, c.1922G > T (p.G641V) and c.1754C > T (p.P585L), were identified. She was diagnosed with Holocarboxylase Synthetase Deficiency and Cobalamin C deficiency. The child showed significant improvement following treatment with hydroxocobalamin, betaine, and biotin. This article reports a case of adolescent onset HCSD and cobalamin C deficiency. Treatment with hydroxocobalamin, betaine, and biotin is effective. Two novel mutations in the HLCS gene causative for HCSD have been reported, providing a broader foundation for mutational screening and offering insights into the diagnosis and treatment of similar disorders.