GBA1 – Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome (GD type IIIC) is an autosomal recessive subtype of Gaucher disease presenting with ophthalmoplegia and progressive cardiovascular calcification. Two unrelated individuals homozygous for the D409H variant (c.1342G>C (p.Asp448His)) developed severe aortic and valvular calcification leading to fatal cardiovascular complications and third-degree atrioventricular block, despite ongoing enzyme replacement therapy ([PMID:30410382], [PMID:39582444]). Both probands exhibited the characteristic phenotype of ophthalmoplegia with cardiac calcification in late childhood, supporting a specific genotype-phenotype correlation.

In vitro and cellular studies demonstrate that the D409H variant causes misfolding and endoplasmic reticulum retention of glucocerebrosidase, resulting in near-absent enzyme activity consistent with pathogenic haploinsufficiency ([PMID:15982918]). These functional assays confirm the deleterious impact of D409H on protein trafficking and catalytic function.

Key Take-home: Homozygosity for GBA1 D409H is specifically associated with GD type IIIC; patients carrying this variant warrant annual echocardiographic monitoring to enable early detection of cardiovascular calcification.

References

• The application of clinical genetics • 2018 • Aortic calcification in Gaucher disease: a case report. PMID:30410382
• The Turkish journal of pediatrics • 2024 • Challenging clinical management of a patient with Gaucher disease type IIIC homozygous for the D409H mutation, aortic valve calcification and porcelain aorta. PMID:39582444
• The international journal of biochemistry & cell biology • 2005 • Impaired trafficking of mutants of lysosomal glucocerebrosidase in Gaucher's disease. PMID:15982918

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