複合カルボキシラーゼ欠損症

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.

BACKGROUND: Biotinidase is an enzyme recycling endogenous biotin by hydrolyzing ε-N-biotinyl lysine (biocytin) to lysine and biotin. Biotin acts as a coenzyme in various carboxylation reactions. Biotinidase deficiency is rare, with an incidence of 1 per 112,271 individuals. OBJECTIVES: Genetic characterization of a 4-month-old boy born out of a consanguineous marriage presented with cutaneous manifestations, alopecia, developmental delay, hypotonia with absent neck holding, respiratory problems, and biotinidase deficiency. METHODS: Biochemical characterization was performed using tandem mass spectrometry and immunofluorescence enzyme assays. Pathogenic genetic variant was identified by Sanger sequencing of the BTD (biotinidase) gene in a patient and his parents. RESULTS: Biochemical characterization indicated elevated methylmalonylcarnitine/hydroxyisovalerylcarnitine and decreased biotinidase, citrulline, glycine, and ornithine levels, suggesting a profound biotinidase deficiency. Sequencing of BTD gene indicates the presence of a 7-bp deletion and a 3-bp insertion (98-104del7ins3) in a homozygous state, resulting in a change of amino acid from cystine to phenylalanine at the 33rd position, causing a frameshift and premature amino acid termination at the 68th position. CONCLUSIONS: A 7-bp deletion and a 3-bp insertion (98-104del7ins3) homozygous variation in the BTD gene segregating in a homozygous recessive manner in the family, causing truncated, nonfunctional biotinidase deficiency in the proband. This is a recurrent mutation and has the potential to be used as a biomarker for screening patients with biotinidase deficiency.

BACKGROUND AND OBJECTIVE: Congenital and developmental disorders should be detected early to avoid complications such as disability and death. The Philippine clinical practice guidelines (CPG) were developed to guide healthcare professionals on screening for congenital and developmental disorders among apparently healthy neonates and children. METHODS: Following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to CPG development recommended by the Department of Health (DOH), the steering committee, composed of clinical geneticists, developmental pediatricians, family and community medicine physicians, and ambulatory and community pediatricians, set the objectives of the CPG and formulated clinical questions in consultation with stakeholders. There were 15 priority guideline questions that covered various disorders including inborn errors of metabolism, critical congenital heart disease, developmental delay, learning disabilities, and autism. Evidence review experts systematically reviewed existing clinical practice guidelines, appraised, and summarized the evidence. A multisectoral panel formulated recommendations through a formal consensus based on the evidence summaries. The CPG was externally reviewed prior to publication. RESULTS: The CPG provides twenty (20) recommendations on fifteen (15) prioritized questions in the screening for certain congenital and developmental disorders. This CPG contains recommendations for the screening for critical congenital heart disease, thalassemia, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, developmental delay, and autism spectrum disorder. Recommendations against routine screening of cystic fibrosis, sickle cell disease, methionine adenosyltransferase deficiency, tyrosinemia, long chain 3-hydroxy acyl CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MTPD), carnitine palmitoyl transferase types 1 and 2 (CPT1, CPT2) and glutaric aciduria type 2 (GA2), biotidinase deficiency, beta-ketothiolase deficiency, holocarboxylase synthetase deficiency, and isovaleric acidemia were made. CONCLUSION: The consensus panel recommended the screening of certain conditions, based on the available evidence, the burden of disease, the cost of the confirmatory testing, and its applicability to the population. Although this CPG intends to influence the direction of health policies for the general population, it should not be the sole basis for recreating or abolishing practices that aim to improve the health conditions of many Filipinos, particularly those part of the workforce.

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.

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by a deficiency of mitochondrial propionyl-CoA carboxylase, leading to the accumulation of propionyl-CoA and toxic metabolites that disrupt TCA cycle flux and ammonia detoxification. Propionyl-CoA is generated from gut microbiome-derived propionate, propiogenic amino acids, odd-chain fatty acids, and cholesterol side chains. Its accumulation produces downstream metabolites such as propionylcarnitine and methylcitrate and promotes histone propionylation. These alterations collectively contribute to mitochondrial dysfunction, oxidative stress, and multi-organ pathology. Current clinical management focuses on reducing propionyl-CoA burden through dietary restriction and supportive therapies, but long-term outcomes remain suboptimal due to poor tolerability and progressive complications. Although liver transplantation improves hepatic metabolism, it does not fully correct extrahepatic disease. Gene-based approaches, including mRNA-based enzyme replacement and viral vector-mediated gene delivery, show promise but face challenges related to delivery efficiency, durability of expression, and immune responses. Emerging small-molecule strategies aim to reprogram metabolism by restoring the balance between propionyl-CoA and acetyl-CoA while replenishing cellular CoA pools. Precision metabolic therapy may combine acetate supplementation and NRF2 activation to enhance acetyl-CoA production and mitochondrial resilience, while suppressing propionyl-CoA formation through ACSS3 inhibition and propiogenic amino acid restriction. In parallel, CoA availability may be increased through activation of PANK1-3, inhibition of PANK4, and supplementation with CoA precursor compounds. We propose that rational combination therapy targeting multiple nodes of short-chain fatty-acid metabolism and CoA homeostasis will provide a more effective strategy than single-agent approaches for correcting metabolic imbalance in PA.