ORPHA: 2072, 355; DO: 0112250;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Gaucher disease, type IIIC | 231005 | Autosomal recessive | 3 | GBA1 | 606463 |
A number sign (#) is used with this entry because of evidence that Gaucher disease type IIIc (GD3C) is caused by homozygosity for an asp409-to-his (D409H) mutation in the gene encoding acid beta-glucosidase gene (GBA; 606463.0006) on chromosome 1q22.
Gaucher disease type IIIc (GD3C) is a rare variant of subacute neuronopathic Gaucher disease type III (231000), but is considered distinct because of its association with cardiovascular calcifications (Bohlega et al., 2000).
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.
Kurolap et al. (2019) reported 4 patients, including 2 Israeli Muslim Arab sibs (patients 1a and 1b), with GD3C. Patient 1a was diagnosed at 4 years of age with moderately impaired intellectual development, ocular apraxia, and aortic and cardiac valve calcifications. He was treated with enzyme replacement therapy (ERT). At age 18, he had a myocardial infarction, and he later died during valve replacement surgery. Patient 1b presented with mild cognitive impairment and opsoclonus. At 8 years of age, she had decreased blood counts and hepatosplenomegaly and began treatment with ERT, which was discontinued at the age of 14. She developed severe ascending and descending aortic calcifications, pulmonary and mitral valve calcifications, and severe pulmonic and mitral stenosis. At age 19, she was diagnosed with atrial fibrillation. At that time, she also had behavioral changes, and ERT was resumed. Cardiac CT angiography (CTA) at age 20 showed mitral and aortic valve calcification, coronary calcifications, and partially calcified stenosis of multiple coronary arteries. CTA also showed hepatosplenomegaly and interstitial lung disease. Pulmonary function tests showed restrictive lung disease and echocardiogram demonstrated pulmonary hypertension. She died due to cardiac arrest at age 20. Patient 2 was a 22-year-old Spanish man who was diagnosed with GD3C at 45 days of life due to hepatosplenomegaly. ERT was started at the age of 2 months and his hepatosplenomegaly resolved. He developed oculomotor apraxia at age 6 years and corneal opacities at age 12. At age 15, he was diagnosed with severe aortic calcification, aortic stenosis, and coronary artery disease. He underwent aortic valve replacement and coronary artery revascularization. At age 16, he had an acute myocardial infarction. Between the ages of 15 and 17, he had recurrent angina, requiring several cardiac procedures, and at age 20, he had a transient ischemic attack. At age 22, he was managed with acenocumarol, clopidogrel, atorvastatin, ramipril, bisoprolol, ivabradine, nitrates and eplerenone. No cognitive or behavioral concerns were reported. Patient 3 was a 4-year-old Israeli Arab Muslim girl who presented at the age of 7 months with splenomegaly. At age 10 months, she was admitted to the hospital due to a febrile illness and splenomegaly, and she was found to have mild thrombocytopenia. Initial ECG and echocardiogram were normal. She was started on ERT, and her platelet count and spleen size normalized. At age 1.5 years, she was treated with ambroxol. At age 4, she had normal growth and development, normal blood count, and no neurologic or cardiac abnormalities.
The transmission pattern of GD3C in the family reported by George et al. (2001) was consistent with autosomal recessive inheritance.
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 with Gaucher disease 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.
Abrahamov, A., Elstein, D., Gross-Tsur, V., Farber, B., Glaser, Y., Hadas-Halpern, I., Ronen, S., Tafakjdi, M., Horowitz, M., Zimran, A. Gaucher's disease variant characterized by progressive calcification of heart valves and unique genotype. Lancet 346: 1000-1003, 1995. [PubMed: 7475546] [Full Text: https://doi.org/10.1016/s0140-6736(95)91688-1]
Beutler, E., Kattamis, C., Sipe, J., Lipson, M. 1342C mutation in Gaucher's disease. Lancet 346: 1637 only, 1995. [PubMed: 7500785] [Full Text: https://doi.org/10.1016/s0140-6736(95)91975-9]
Bohlega, S., Kambouris, M., Shahid, M., Al Homsi, M., Al Sous, W. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIc). Neurology 54: 261-263, 2000. [PubMed: 10636167] [Full Text: https://doi.org/10.1212/wnl.54.1.261]
Casta, A., Hayden, K., Wolf, W. J. Calcification of the ascending aorta and aortic and mitral valves in Gaucher's disease. Am. J. Cardiol. 54: 1390-1391, 1984. [PubMed: 6507325] [Full Text: https://doi.org/10.1016/s0002-9149(84)80115-0]
Chabas, A., Cormand, B., Grinberg, D., Burguera, J. M., Balcells, S., Merino, J. L., Mate, I., Sobrino, J. A., Gonzalez-Duarte, R., Vilageliu, L. Unusual expression of Gaucher's disease: cardiovascular calcifications in three sibs homozygous for the D409H mutation. J. Med. Genet. 32: 740-742, 1995. [PubMed: 8544197] [Full Text: https://doi.org/10.1136/jmg.32.9.740]
George, R., McMahon, J., Lytle, B., Clark, B., Lichtin, A. Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation. Clin. Genet. 59: 360-363, 2001. [PubMed: 11359469] [Full Text: https://doi.org/10.1034/j.1399-0004.2001.590511.x]
Kurolap, A., del Toro, M., Spiegel, R., Gutstein, A., Shafir, G., Cohen, I. J., Barrabes, J. A., Feldman, H. B. Gaucher disease type 3c: new patients with unique presentations and review of the literature. Molec. Genet. Metab. 127: 138-146, 2019. [PubMed: 31130326] [Full Text: https://doi.org/10.1016/j.ymgme.2019.05.011]
Uyama, E., Takahashi, K., Owada, M., Okamura, R., Naito, M., Tsuji, S., Kawasaki, S., Araki, S. Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol. Scand. 86: 407-420, 1992. [PubMed: 1333717] [Full Text: https://doi.org/10.1111/j.1600-0404.1992.tb05109.x]
Uyama, E., Uchino, M., Ida, H., Eto, Y., Owada, M. D409H/D409H genotype in Gaucher-like disease. (Letter) J. Med. Genet. 34: 175 only, 1997. [PubMed: 9040001] [Full Text: https://doi.org/10.1136/jmg.34.2.175]