RARE DISEASE
Multiple carboxylase deficiency
Multiple carboxylase deficiency
Multiple carboxylase deficiency
Synonyms: MCD
Synonyms: MCD
Synonyms: MCD
Drug discovery
0
drugs
With orphan designations
Overview
Multiple carboxylase deficiency (MCD) is an autosomal recessive disorder of biotin metabolism caused by defects in HLCS (holocarboxylase synthetase) or BTD (biotinidase) genes, impairing carboxylase enzymes critical for macronutrient breakdown. Untreated, it manifests with metabolic acidosis, hyperammonemia, dermatitis, alopecia, seizures, and developmental delays. Diagnosis is confirmed via newborn screening (elevated C5-OH acylcarnitine), urine organic acids, and genetic testing. Early, lifelong biotin supplementation (10–200 mg/day) prevents or reverses symptoms [1][2][7][12].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare skin diseases
Research Papers
63 drug discovery papers about Multiple carboxylase deficiency. Recent publications:
63 drug discovery papers about Multiple carboxylase deficiency. Recent publications:
2026-08-13 | Characterization of a Novel BTD Hypomorphic Variant in a Patient with Complex Neurodevelopmental Delay: Resolving Actionable Metabolic Vulnerabilities Beyond Borderline Plasma Biochemistry.
Plasma biochemistry often presents significant limitations in diagnosing borderline metabolic disorders, particularly within complex neurodevelopmental phenotypes. Here, we present the clinical genomic evaluation of a six-year patient presenting with early-onset hypotonia and severe gastrointestinal complications whose newborn screening panel did not evaluate biotinidase (BTD) activity. While initial baseline plasma biochemistry yielded borderline residual BTD function (46% of the population mean), targeted sequencing identified a novel, compound heterozygous hypomorphic variant (p.Thr459Met) in trans with the common p.Asp424His allele. In vitro functional validation confirmed that p.Thr459Met induces severe protein misfolding and intracellular retention, impairing enzyme secretion. Biotin supplementation triggered a documented and favorable therapeutic improvement, establishing this borderline enzymatic background as an actionable metabolic vulnerability unmasked by chronic gastrointestinal stressors. This study underscores the critical value of functional genomic characterization over static enzymatic biomarkers to identify highly treatable metabolic components within heterogeneous clinical landscapes.
2026-06-25 | Multiple Carboxylase Deficiency in an Infant Presenting With Severe Metabolic Acidosis and Sepsis-Like Features: A Case Report and Literature Review.
Multiple carboxylase deficiency (MCD) is a rare, treatable inborn error of biotin metabolism that may present in children in the first year of life with life-threatening metabolic crises. We report a 4-month-old child presenting with persistent seizures, eczematous rash near the orifices, unjustified loss of hair with baldness, and severe metabolic acidosis, initially mimicking septicemia. Urine organic acid investigation showed elevated levels of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, methylcitrate, and lactate that lead towards MCD. This diagnosis remains unconfirmed, as confirmatory testing (serum biotinidase activity and genetic analysis) was not available at our center. Early initiation of biotin (10 mg/day) led to rapid clinical and biochemical recovery. This particular case depicts the importance of biotin-responsive metabolic disorders in the first year of a child presenting with the classic triad of seizures, dermatitis, and alopecia with metabolic acidosis. Early recognition and prompt initiation of biotin therapy can result in rapid clinical recovery. Timely diagnosis is crucial to prevent avoidable morbidity and long-term neurological sequelae. This case highlights the importance of considering MCD in children. In the first year of life, unexplained metabolic acidosis as timely treatment can be lifesaving.
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.
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.
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.
2026-08-13 | Characterization of a Novel BTD Hypomorphic Variant in a Patient with Complex Neurodevelopmental Delay: Resolving Actionable Metabolic Vulnerabilities Beyond Borderline Plasma Biochemistry.
Plasma biochemistry often presents significant limitations in diagnosing borderline metabolic disorders, particularly within complex neurodevelopmental phenotypes. Here, we present the clinical genomic evaluation of a six-year patient presenting with early-onset hypotonia and severe gastrointestinal complications whose newborn screening panel did not evaluate biotinidase (BTD) activity. While initial baseline plasma biochemistry yielded borderline residual BTD function (46% of the population mean), targeted sequencing identified a novel, compound heterozygous hypomorphic variant (p.Thr459Met) in trans with the common p.Asp424His allele. In vitro functional validation confirmed that p.Thr459Met induces severe protein misfolding and intracellular retention, impairing enzyme secretion. Biotin supplementation triggered a documented and favorable therapeutic improvement, establishing this borderline enzymatic background as an actionable metabolic vulnerability unmasked by chronic gastrointestinal stressors. This study underscores the critical value of functional genomic characterization over static enzymatic biomarkers to identify highly treatable metabolic components within heterogeneous clinical landscapes.
2026-06-25 | Multiple Carboxylase Deficiency in an Infant Presenting With Severe Metabolic Acidosis and Sepsis-Like Features: A Case Report and Literature Review.
Multiple carboxylase deficiency (MCD) is a rare, treatable inborn error of biotin metabolism that may present in children in the first year of life with life-threatening metabolic crises. We report a 4-month-old child presenting with persistent seizures, eczematous rash near the orifices, unjustified loss of hair with baldness, and severe metabolic acidosis, initially mimicking septicemia. Urine organic acid investigation showed elevated levels of 3-hydroxyisovaleric acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, methylcitrate, and lactate that lead towards MCD. This diagnosis remains unconfirmed, as confirmatory testing (serum biotinidase activity and genetic analysis) was not available at our center. Early initiation of biotin (10 mg/day) led to rapid clinical and biochemical recovery. This particular case depicts the importance of biotin-responsive metabolic disorders in the first year of a child presenting with the classic triad of seizures, dermatitis, and alopecia with metabolic acidosis. Early recognition and prompt initiation of biotin therapy can result in rapid clinical recovery. Timely diagnosis is crucial to prevent avoidable morbidity and long-term neurological sequelae. This case highlights the importance of considering MCD in children. In the first year of life, unexplained metabolic acidosis as timely treatment can be lifesaving.
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.
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.
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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