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Background <p>Gaucher disease (GD) is one of the most common lysosomal storage disorders, and has three clinical subtypes (Type 1, 2 and 3). Of the three subtypes, type 2 GD (GD2), also referred to as acute infantile neuronopathic GD is the most severe type. It is characterized by early and profound central nervous system involvement, and patients succumb to disease before two years of age due to severe neurological deterioration and associated complications. It is the rarest of the three subtypes with a reported proportion of &lt; 1% among all Gaucher subtypes. Furthermore, data from the Indian subcontinent on clinical profiles, molecular spectrum, and outcomes in GD2 remain scarce. The present study describes the clinical, biochemical, and molecular spectrum of GD2 cases in an Indian cohort.</p> Methods <p>This is a retrospective study comprising 19 patients referred by pediatricians from across India, who were diagnosed with GD based on β-Glucosidase enzyme activity and <i>GBA</i> gene study. Plasma chitotriosidase activity and β-glucosidase activity were measured in plasma sample and leukocytes respectively using fluorometric enzyme assays. Molecular confirmation was performed in all 19 patients by using one of the following tests: polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Sanger sequencing, targeted panel or whole exome sequencing study.</p> Results <p>The common clinical signs observed in the study cohort were hepatosplenomegaly, thrombocytopenia, oculomotor signs, failure to thrive and feeding difficulties. Molecular study revealed causative variants distributed across exons 3, 4, 5, 6, 7, 9, 10, and 11 of the <i>GBA1</i> gene, with exon 10 being the most common (<i>n</i> = 11/19). The variant c.1448T &gt; C (p.Leu483Pro) was identified in a compound heterozygous state in majority cases (<i>n</i> = 10/19). Furthermore, we also identified a rare recurrent missense variant c.371T &gt; G (p.Met124Arg) in exon 4 of the <i>GBA1</i> gene in 4 patients with GD2 from Gujarat, suggesting the possibility of a founder effect. Computational protein modeling and in-silico analysis predicted a destabilizing effect on GBA1 protein structure and stability.</p> Conclusion <p>Overall, the present study represents the largest case series of type 2 Gaucher disease reported from India to date and provides important insights into its clinical and molecular spectrum in the Indian population.</p>

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Clinical, biochemical and molecular spectrum of acute neuronopathic type 2 Gaucher disease from India

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  • 发表日期：

    2026年6月27日

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  • Jayesh Sheth,
  • Aadhira Nair,
  • Riddhi Bhavsar,
  • Mamta Muranjan,
  • Sheela Nampoothiri,
  • Dhanya Yesodharan,
  • Anupriya Kaur,
  • Raju C Shah,
  • Prajnya Ranganath,
  • Shagun Agrawal,
  • Aditi Baluni,
  • Niyati Saini,
  • Ashwin Dalal,
  • Frenny Sheth,
  • Harsh Sheth

摘要

Background

Gaucher disease (GD) is one of the most common lysosomal storage disorders, and has three clinical subtypes (Type 1, 2 and 3). Of the three subtypes, type 2 GD (GD2), also referred to as acute infantile neuronopathic GD is the most severe type. It is characterized by early and profound central nervous system involvement, and patients succumb to disease before two years of age due to severe neurological deterioration and associated complications. It is the rarest of the three subtypes with a reported proportion of < 1% among all Gaucher subtypes. Furthermore, data from the Indian subcontinent on clinical profiles, molecular spectrum, and outcomes in GD2 remain scarce. The present study describes the clinical, biochemical, and molecular spectrum of GD2 cases in an Indian cohort.

Methods

This is a retrospective study comprising 19 patients referred by pediatricians from across India, who were diagnosed with GD based on β-Glucosidase enzyme activity and GBA gene study. Plasma chitotriosidase activity and β-glucosidase activity were measured in plasma sample and leukocytes respectively using fluorometric enzyme assays. Molecular confirmation was performed in all 19 patients by using one of the following tests: polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Sanger sequencing, targeted panel or whole exome sequencing study.

Results

The common clinical signs observed in the study cohort were hepatosplenomegaly, thrombocytopenia, oculomotor signs, failure to thrive and feeding difficulties. Molecular study revealed causative variants distributed across exons 3, 4, 5, 6, 7, 9, 10, and 11 of the GBA1 gene, with exon 10 being the most common (n = 11/19). The variant c.1448T > C (p.Leu483Pro) was identified in a compound heterozygous state in majority cases (n = 10/19). Furthermore, we also identified a rare recurrent missense variant c.371T > G (p.Met124Arg) in exon 4 of the GBA1 gene in 4 patients with GD2 from Gujarat, suggesting the possibility of a founder effect. Computational protein modeling and in-silico analysis predicted a destabilizing effect on GBA1 protein structure and stability.

Conclusion

Overall, the present study represents the largest case series of type 2 Gaucher disease reported from India to date and provides important insights into its clinical and molecular spectrum in the Indian population.