Symptomatic patients with Gaucher disease (GD) (acid ␤-glucosidase [Gcase] deficiency) are treated with injectable human recombinant GCase. Treatment results in significant decreases in lipid storage in liver, spleen, and bone marrow, but the generalized osteopenia and focal bone lesions present in many adult patients are refractory to treatment. A double-blind, 2-arm, placebo-controlled trial of alendronate (40 mg/d) was performed in adults with GD who had been treated with enzyme for at least 24 months. Primary therapeutic endpoints were improvements in (1) bone mineral density (BMD) and content (BMC) at the lumbar spine, and (2) focal lesions in x-rays of long bones assessed by a blinded reviewer. There were 34 patients with GD type 1 (age range, 18-50 years) receiving enzyme therapy who were randomized for this study. After 18 months, ⌬BMD at the lumbar spine was 0.068 ؎ 0.21 and 0.015 ؎ 0.034 for alendronate and placebo groups, respectively (P ‫؍‬ .001). Long-bone x-rays showed no change in focal lesions or bone deformities in any subject in either arm. Alendronate is a useful adjunctive therapy in combination with enzyme replacement therapy (ERT) for the treatment of GD-related osteopenia in adults, but it cannot be expected to improve focal

A Caucasian male with Gaucher disease type 3, treated with continuous enzyme therapy (ET) for 11 years, experienced progressive mesenteric and retroperitoneal lymphadenopathy, lung disease, and neurological involvement leading to death at age 12.5 years. Autopsy showed significant pathology of the brain, lymph nodes, and lungs. Liver and spleen glucosylceramide (GluCer) and glucosylsphingosine (GluS) levels were nearly normal and storage cells were cleared. Clusters of macrophages and very elevated GluCer and GluS levels were in the lungs, and brain parenchymal and perivascular regions. Compared to normal brain GluCer (GC 18:0), GluCer species with long fatty acid acyl chains were increased in the patient’s brain. This profile was similar to that in the patient’s lungs, suggesting these lipids were present in brain perivascular macrophages. In the patient’s brain, generalized astrogliosis, and enhanced LC3, Ubiquitin, and Tau signals were identified in the regions surrounding macrophage clusters, indicating proinflammation, altered autophagy, and neurodegeneration. These findings highlight the altered phenotypes resulting from increased longevity due to ET, as well as those in poorly accessible compartments of brain and lung, which manifested progressive disease involvement despite ET.

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Purpose: Fabry disease is an X-linked lysosomal disorder due to mutations in the GLA gene. Manifestations of the disease are documented in hemizygous males. Recent studies have indicated that women with GLA mutations may report symptoms. The impact on their health-related quality of life is unclear. This study compares the quality of life of obligate heterozygotes to a historical healthy control population and to populations with multiple sclerosis and rheumatoid arthritis. Methods: The RAND-36 and Fabry-disease specific questions were administered to study participants. Study subjects were obligate heterozygotes for mutations in GLA. Mean scores in each of the subscales from the RAND-36 were compared between study subjects and previously published data from the