Gaucher Disease, Type Iiic

A number sign (#) is used with this entry because of accumulating evidence that the disorder is due to homozygosity for an asp409-to-his (D409H) mutation in the gene encoding acid beta-glucosidase gene (GBA; 606463.0006).

Gaucher disease type IIIC is a variant of subacute neuronopathic Gaucher disease type III (231000), but is considered distinct because of its association with cardiovascular calcifications (Bohlega et al., 2000).

Clinical Features

Casta et al. (1984) reported a 15-year-old boy with Gaucher disease associated with calcification of the aortic and mitral valves.

Uyama et al. (1992) described 3 adult Japanese sibs, 2 males and a female, with supranuclear gaze palsies since early childhood, corneal opacities, and valvular heart disease associated with beta-glucosidase deficiency. The common manifestations of Gaucher disease were not evident, although the gaze palsies were suggestive of type III Gaucher disease. Other features included communicating hydrocephalus, deafness, and deformed toes. Postmortem examination demonstrated thickened leptomeninges with perivascular fibrosis, nonrheumatic calcified aortic and mitral stenosis with marked fibrosis, and mild infiltration of Gaucher cells in the reticuloendothelial organs. Ultrastructural studies of connective tissues disclosed proliferation of abundant vacuolated Gaucher cells resembling foam cells in addition to classic Gaucher cells found only in bone marrow.

Abrahamov et al. (1995) reported 12 Arab-Israeli patients with Gaucher disease associated with cardiovascular calcifications. Corneal opacities were a common feature.

Chabas et al. (1995) reported 3 Spanish sisters with Gaucher disease type IIIC. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement.

George et al. (2001) described a 17-year-old Palestinian patient with Gaucher disease who presented with severe aortic and mitral valvular calcification, as well as calcification of the ascending aorta, the aortic arch, and the ostia of the coronary arteries. Two older brothers had died of congestive heart failure and severe valvular calcification.

Molecular Genetics

In 3 Spanish sisters with Gaucher disease type III associated with cardiovascular calcifications, Chabas et al. (1995) identified a homozygous asp409-to-his mutation (D409H; 606463.0006) in the GBA gene.

In the 3 Japanese sibs reported by Uyama et al. (1992), Uyama et al. (1997) identified homozygosity for the D409H mutation.

Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome.

George et al. (2001) identified homozygosity for the D409H mutation in a 17-year-old Palestinian patient with Gaucher disease and cardiovascular calcifications.