Clinical and Molecular Characterization of Rare Inherited Metabolic Disorders in a Tertiary Care Genetics Clinic

DOI 10.66715/ijcar/2026.v2.i1.127138 | Original Research  Paper | 2026 | Volume 2 | Issue 1 | Page 127-138

1. Dr. C. Vinothini, Assistant professor, Department of Microbiology, EG. S Pillay Arts and science college, Nagapattinam

2. Prof.Dr. V. Balasubramanian, DEAN, PRINCIPAL, SCHOOL OF PHARMACY, JOY UNIVERSITY, TIRUNELVELI, TAMIL NADU.

3. Dr. Shahan Layek, Independent Researcher, West Bengal, India

4. Dr. Narendra Sharma, Lecturer, Department of Anatomy, Dr. Rajendra Gode Medical College and Hospital, Amravati, Maharashtra.
   

Corresponding Dr. Narendra Sharma,

Lecturer, Department of Anatomy,

Dr. Rajendra Gode Medical College and 

Hospital, Amravati, Maharashtra.

Clinical and Molecular Characterization of Rare Inherited Metabolic Disorders in a Tertiar.

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Abstract

Background: Rare inherited metabolic disorders (IMDs) comprise a heterogeneous group of genetic diseases caused by defects in metabolic pathways, resulting in the accumulation of toxic metabolites or deficiency of essential biochemical products. Although individually uncommon, these disorders collectively contribute substantially to pediatric morbidity and mortality. Early diagnosis through clinical evaluation, biochemical investigations, and molecular genetic testing is essential for timely intervention, genetic counseling, and improved patient outcomes.

Aim: To clinically and molecularly characterize patients with rare inherited metabolic disorders attending a tertiary care genetics clinic and to evaluate the spectrum of clinical presentations, biochemical abnormalities, and underlying pathogenic genetic variants.

Materials and Methods: A prospective observational study was conducted at a tertiary care genetics clinic involving 120 patients with suspected inherited metabolic disorders. Detailed clinical histories, pedigree analyses, physical examinations, and developmental assessments were performed. Biochemical investigations included plasma amino acid profiling, urine organic acid analysis by gas chromatography–mass spectrometry (GC–MS), tandem mass spectrometry (MS/MS), serum ammonia, lactate, and enzyme assays where indicated. Molecular diagnosis was established using targeted next-generation sequencing (NGS) panels, whole-exome sequencing (WES), or Sanger sequencing for variant confirmation. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Results: A definitive molecular diagnosis was achieved in 89 (74.2%) patients. Disorders of amino acid metabolism (31.5%) were the most frequent, followed by organic acidemias (22.5%), lysosomal storage disorders (18.0%), fatty acid oxidation disorders (12.4%), mitochondrial disorders (8.9%), and urea cycle defects (6.7%). Developmental delay (72%), seizures (46%), hypotonia (41%), failure to thrive (38%), and hepatomegaly (27%) were the predominant clinical manifestations. Pathogenic or likely pathogenic variants were identified in genes including PAH, GAA, GALT, MMACHC, OTC, ASS1, ACADM, and GLA, with 15 novel variants detected. Early diagnosis enabled disease-specific treatment and genetic counseling in the majority of affected families.

Conclusion: Comprehensive integration of clinical assessment, biochemical investigations, and advanced molecular diagnostics significantly improves the diagnostic yield of rare inherited metabolic disorders. Early molecular characterization facilitates precision medicine, targeted therapeutic interventions, informed reproductive counseling, and family screening, thereby improving long-term clinical outcomes in affected individuals.