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Objectives <p>Organic acidemias (OADs) are inherited disorders of branched chain amino acid catabolism, typically presenting in neonatal or infantile period, with encephalopathy, metabolic acidosis, and seizures. While an early clinical and biochemical recognition is pivotal for immediate survival, molecular characterization is essential for accurate diagnosis, genetic counseling, and future preventive strategies in families.</p> Methods <p>A study was performed on 394 patients/families suspected of OADs between year 2010 to 2025. Molecular studies were performed in biochemically diagnosed cases, using targeted Sanger sequencing, or next-generation sequencing. Cases were classified according to age and type of clinical presentations: acute, sub-acute/chronic, or presymptomatic/ newborn screening.</p> Results <p>A molecular confirmation was achieved in 293 patients from 283 families (95.4% diagnostic yield). Glutaric acidemia type 1 (100 cases) and methylmalonic acidemia (98 cases) were most common disorders identified. One-fourth of variants were novel (61/221, 27.6%) across 16 genes. Homozygosity was observed in 71.5% families. Apart from previously described recurrent variants in GCDH c.1204C&gt;T, MMACHC c.394C&gt;T and BTD c.38_44delGCGCTGinsTCC identified in index study, BCKDHB c.1065delT variant was noted to be geographically clustered in north-western India. High number of variants, including unique novel variants underscores the distinct genetic landscape of the Indian population. The prevalence of homozygous variants, many in the absence of consanguinity, suggests the impact of endogamy.</p> Conclusions <p>Molecular characterization of OADs in India provides a critical framework for future studies in addition to clinical care advancements. This study adds 61 new variants to the global scientific record, facilitating improved prenatal diagnosis and early intervention strategies.</p>

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Organic Acidemias in India: Clinical and Molecular Spectrum

  • 期刊论文

  • 发表日期：

    2026年7月10日

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  • Sunita Bijarnia-Mahay,
  • Deepti Gupta,
  • Ratna D. Puri,
  • Renu Saxena,
  • Sudha Kohli,
  • Jyotsna Verma,
  • Divya C. Thomas,
  • Papai Roy,
  • Veronica Arora,
  • Swasti Pal,
  • Praveen Kumar,
  • R. K. Sabharwal,
  • Sudhisha Dubey,
  • Sujatha Jagadeesh,
  • Chaitanya Datar,
  • Radha Rama Devi Akella,
  • I. C. Verma

摘要

Objectives

Organic acidemias (OADs) are inherited disorders of branched chain amino acid catabolism, typically presenting in neonatal or infantile period, with encephalopathy, metabolic acidosis, and seizures. While an early clinical and biochemical recognition is pivotal for immediate survival, molecular characterization is essential for accurate diagnosis, genetic counseling, and future preventive strategies in families.

Methods

A study was performed on 394 patients/families suspected of OADs between year 2010 to 2025. Molecular studies were performed in biochemically diagnosed cases, using targeted Sanger sequencing, or next-generation sequencing. Cases were classified according to age and type of clinical presentations: acute, sub-acute/chronic, or presymptomatic/ newborn screening.

Results

A molecular confirmation was achieved in 293 patients from 283 families (95.4% diagnostic yield). Glutaric acidemia type 1 (100 cases) and methylmalonic acidemia (98 cases) were most common disorders identified. One-fourth of variants were novel (61/221, 27.6%) across 16 genes. Homozygosity was observed in 71.5% families. Apart from previously described recurrent variants in GCDH c.1204C>T, MMACHC c.394C>T and BTD c.38_44delGCGCTGinsTCC identified in index study, BCKDHB c.1065delT variant was noted to be geographically clustered in north-western India. High number of variants, including unique novel variants underscores the distinct genetic landscape of the Indian population. The prevalence of homozygous variants, many in the absence of consanguinity, suggests the impact of endogamy.

Conclusions

Molecular characterization of OADs in India provides a critical framework for future studies in addition to clinical care advancements. This study adds 61 new variants to the global scientific record, facilitating improved prenatal diagnosis and early intervention strategies.