Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes.
BACKGROUND
Type 1 Gaucher disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption.


METHODS
Prenatal carrier screening of 8069 AJ adults for 6 common GD mutations was performed. Gaucher disease manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory, and imaging studies.


RESULTS
Among the 8069 AJ screenees, 524 GD carriers (1:15) and 9 previously unrecognized GD homozygotes (1:897) were identified, consistent with the rate expected (1:949; P > .99). Six of these homozygotes and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York City metropolitan area were evaluated (age range of the homozygotes, 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P, or R496H mutations. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%), and bone infarcts (14%). Dual energy X-ray absorptiometry studies of 25 homozygotes found 60% with osteopenia or osteoporosis.


CONCLUSIONS
Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical treatment.
Balwani
Manisha
M
Comprehensive Gaucher Disease Treatment Center, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.
Fuerstman
Laura
L
Kornreich
Ruth
R
Edelmann
Lisa
L
Desnick
Robert J
RJ
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002353:Carrier State; D005260:Female; D005776:Gaucher Disease / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D005787:Gene Frequency; D005820:Genetic Testing / Q000379:methods*; D006579:Heterozygote; D006596:Hexosaminidases / Q000097:blood; D006720:Homozygote; D006801:Humans; D007585:Jews / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype
D015415:Biomarkers; D006596:Hexosaminidases; C086400:chitotriosidase