small molecules

2025-07-24 | Study on the Mechanism of HLCS Gene Deficiency and Biotin Compensation Inhibiting Skeletal Muscle Development

Background Holocarboxylase synthetase (HLCS) facilitates the binding of biotin to biotin-dependent carboxylase enzymes (ACC, MCC, PC, and PCC) for carboxylation reactions. This research demonstrates a significant association between single nucleotide polymorphisms (SNPs) in the HLCS gene and the lean meat percentage (LEA) and growth characteristics of Duroc pigs. To deepen our understanding of HLCS functionality, we conducted validation experiments using skeletal muscle cell models. Results Interference with HLCS at the cellular level led to a significant increase in the expressions of ACC and PC, resulting in inhibited proliferation and myogenic differentiation of skeletal muscle cells. Biotin, a coenzyme of carboxylase commonly used to address HLCS deficiency, unexpectedly resulted in a notable decrease in HLCS gene expression and a significant inhibition of myogenic muscle differentiation in our experiment. To further investigate the impact of biotin on muscle development, varying concentrations of biotin were added to the mice's base diet. It was observed that the expression of the HLCS gene in muscle tissue decreased, consequently hindering muscle tissue development. Subsequent research revealed that following biotin supplementation, glycolysis and lipid catabolism in skeletal muscle cells and tissues were disrupted. Examination of the relevant signaling pathways indicated abnormal protein expression and phosphorylation in the MAPK and TGFβ signaling pathways upon the addition of biotin. Conclusions The HLCS gene plays a crucial role in skeletal muscle development in pigs, and biotin has been found to mitigate the hindrance resulting from HLCS deficiency. Conversely, under normal functioning of the HLCS gene, supplementation of biotin can impede muscle development.

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2025-04-23 | Mechanism of holocarboxylase synthetase and biotin supplementation in promoting adipose development

Pig back fat (BF) thickness is a key indicator for evaluating lipid deposition in pigs. Consuming pork belly with thick BF can increase cholesterol intake and negatively impact human health. Holocarboxylase synthetase (HLCS) is a crucial ligase that binds biotin to carboxylases, affecting the function of biotin-dependent carboxylases. The relationship between single-nucleotide polymorphisms (SNPs) in <italic>HLCS</italic> and BF in pigs, along with the direct effects of <italic>HLCS</italic> on adipocyte development, remains unclear. While biotin is used to treat HLCS deficiency, its role in adipocyte development is not well understood. This study identified two <italic>HLCS</italic> SNPs associated with 100-kg BF in 592 Duroc pigs. In 3T3-L1 cells, <italic>HLCS</italic> interference reduced cell proliferation and decreased protein levels of phosphorylated p38 (p-p38) and phosphorylated signal-regulated kinase1/2 (p-ERK1/2) in the MAPK signaling pathway. Exogenous biotin promoted <italic>HLCS</italic> expression and alleviated the inhibitory effects of <italic>HLCS</italic> interference on lipogenesis-related genes, lipolysis-related genes, glycolysis-related genes, and p-ERK1/2 and p-p38 protein expression in adipocytes. In conclusion, <italic>HLCS</italic> is a significant candidate gene for pig BF development, with its interference adversely affecting adipocyte growth. Exogenous biotin not only stimulated HLCS expression but also influenced lipid metabolism by regulating carboxylase activity, glycolysis, and lipid synthesis/degradation through the MAPK pathway. This study provides new insights into HLCS function and the therapeutic role of biotin in HLCS deficiency, offering a theoretical foundation for molecular breeding of pigs with reduced BF.

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2025-04-15 | Clinical diagnosis, treatment, and genetic analysis of adolescent onset holocarboxylase synthetase deficiency and cobalamin C deficiency: A case report and literature review.

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.

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2025-03-07 | Holocarboxylase Synthetase Deficiency: Clinical, Biochemical and Molecular Findings in Five Malaysian Patients Including a Newborn Presenting as Collodion Baby.

Holocarboxylase synthetase (HLCS) is a rare autosomal recessive disorder of biotin metabolism. The mutation spectrum is known to correlate with clinical phenotypes and responsiveness to biotin therapy. Five patients diagnosed with HLCS deficiency between 2015 and 2024 were recruited. Their medical records were retrospectively analyzed for clinical, laboratory, and molecular data. The diagnosis was confirmed through urine organic acid analysis, acylcarnitine profiling of blood spots, and next-generation sequencing (NGS). All patients had skin rashes, either preceding metabolic decompensation or during follow-up. Four patients presented in a decompensated state with respiratory distress (100%, 4/4), seizures (50%, 2/4), metabolic acidosis (100%, 4/4), and encephalopathy (100%, 4/4). Most patients (4/5) had late-onset presentations and responded well to biotin. One patient died before treatment could be given. Of the four who survived, biotin doses of 10-30 mg daily maintained metabolic stability. The oldest patient, now 30 years old, was able to have two successful pregnancies with biotin dose adjustments. Molecular analysis identified 4 mutations: of these, c.1522C>T (p.Arg508Trp) is a known recurrent biotin-responsive mutation, accounting for 50% of mutant alleles. The c.271del variant had not been previously reported in the literature. This is the first report of HLCS deficiency in a Malaysian population, highlighting the c.1522C>T (p.Arg508Trp) variant as a target for rapid molecular screening. Most patients in this cohort have good outcomes from biotin supplementation, emphasizing the need for early intervention to prevent irreversible neurological damage.

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2024-12-05 | Case report: A case of holocarboxylase synthetase deficiency with respiratory tract as the initial symptom.

Holocarboxylase synthetase deficiency (HLCSD) is a rare autosomal recessive genetic disorder caused by mutations in the holocarboxylase synthetase (HLCS) gene, which affects multiple systems. Common clinical manifestations include metabolic acidosis, rash, feeding difficulties, and growth retardation, with predominant involvement of the nervous system, skin, and hair. However, respiratory symptoms as the initial manifestation are relatively rare. We report the case of a 1 year and 4-month-old Chinese male patient who presented with a 2-day history of cough, followed by half a day of wheezing and shortness of breath. Despite supportive treatment with antibiotics upon admission, the infant continued to experience rapid and deep breathing accompanied by groaning, and obvious wheezing. Blood gas analysis revealed metabolic acidosis that was difficult to correct. Blood tandem mass spectrometry showed elevations in C50H, C3, C4OH, and urine organic acid analysis revealed elevations in lactate, 3-hydroxybutyric acid, 3-hydroxyisovaleric acid, acetoacetic acid, 3-methylcrotonylglycine, and methylcitric acid. Genetic testing revealed two variants in the HLCS gene in the infant: NM_001352514: exon6: c.1088T>A: p.V363D variant and exon11: c.2434C>T: p.R812* heterozygous variant, resulting in HLCSD. Ultimately, the diagnosis of HLCSD was established, and oral biotin treatment achieved good clinical efficacy. This article summarizes the clinical data of a case of HLCSD in an infant, primarily presenting with respiratory symptoms. It provides a comprehensive summary of the etiology, diagnosis, and treatment, offering insights for the diagnosis of rare diseases by clinical physicians.

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antibodies

2023-02-22 | Successful treatment with secukinumab of psoriasis-like dermatitis in a patient with holocarboxylase synthetase deficiency.

Holocarboxylase synthetase deficiency (HSD) is a rare autosomal recessive disorder of biotin metabolism. Typical manifestations include irreversible metabolic disorders and erythroderma-like dermatitis. Most patients respond well to biotin supplementation. Psoriasis-like phenotype associated with this disease has been rarely reported in the literature and experiences with the use of biologics in patients with HSD are still lacking. We reported a rare case of recurrent psoriasis-like skin lesions in a 6-year-old child with HSD. The patient did not respond to initial therapy with high-dose oral biotin. Immunofluorescence staining showed an increased number of interleukin (IL)-17A+ cells in his skin lesions. Based on this finding, the patient was successfully treated with human anti-IL-17A monoclonal antibody (secukinumab). He did not report any side effects and remained healthy during the 2-year follow-up. We provide a comprehensive review of the reported cases of HSD with psoriasis-like dermatitis to date. The psoriasis-like phenotype of HSD is controversial in treatment and IL-17A inhibitor is an alternative therapeutic option.

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gene therapies

2026-06-22 | Holocarboxylase synthetase deficiency: pathogenesis, clinical features, diagnosis, treatment, and research prospects.

Holocarboxylase Synthetase Deficiency (HLCSD) is a rare autosomal recessive inborn error of metabolism caused by biallelic mutations in the HLCS gene. The encoded enzyme, holocarboxylase synthetase (HLCS), plays a critical role in biotin metabolism by activating five essential carboxylases, including pyruvate carboxylase (PC) and propionyl-CoA carboxylase (PCC), thereby regulating key processes such as gluconeogenesis, fatty acid synthesis, and branched-chain amino acid catabolism [1, 14]. HLCS dysfunction leads to the accumulation of toxic metabolites (e.g., 3-hydroxyisovaleric acid, methylcitric acid), resulting in severe manifestations like metabolic acidosis and hyperammonemia [6]. This review systematically consolidates current knowledge on the molecular mechanisms, clinical spectrum, diagnostic approaches, and therapeutic strategies for HLCSD. It critically addresses core controversies, including genotype-phenotype correlations and variability in biotin treatment response, and proposes a multidimensional "gene-enzyme activity-metabolic phenotype-treatment response" framework. Studies confirm that early diagnosis via newborn screening, coupled with standardized biotin supplementation, achieves biochemical normalization and clinical symptom resolution in over 85% of patients and reduces the risk of neurological sequelae [10, 33, 35]. However, biotin-unresponsive cases and rare phenotypes present ongoing diagnostic and therapeutic challenges, necessitating further exploration of novel interventions to advance the precision medicine approach for HLCSD. What is Known: • Holocarboxylase synthetase defi ciency (HLCSD) is a rare autosomal recessive metabolic disorder caused by HLCSbiallelic mutations, and biotin supplementation is the mainstream treatment for most patients. • Distinct population-specifi c HLCS mutation hotspots exist, and residual enzyme activity is closely correlated with disease severity and age of onset. What is New: • A multidimensional framework of gene-enzyme activity-metabolic phenotype-treatment response was proposed tointerpret phenotypic heterogeneity and variable biotin responsiveness in HLCSD. • This review systematically summarized rare clinical phenotypes, diagnostic pitfalls, emerging detection technologies and novel therapeutic directions including gene therapy and epigenetic intervention.

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