Gaucher Disease (Type I)
The histology of the lesional cells is the classic "wrinkled tissue paper" cytoplasm of a Gaucher cell, supported by the PAS and CD68 positivity. Therefore, bony involvement by Gaucher disease is the cause of this vertebral body fracture. Indeed, the patient's childhood diagnosis was Type 1 Gaucher disease with an N370S mutation in the glucocerebrosidase gene.
Gaucher disease is an autosomal recessive condition affecting 1 in 40,000 individuals, and is thus the most common lysosomal storage disease. The underlying defect is mutations in the glucocerebrosidase (gba) gene found at 1q21, whose enzyme product (GBA) is highly expressed in macrophages and primarily responsible for glucocerebroside metabolism (3). Glucocerebroside mainly arises in hematopoietic centers as a membrane waste product of senescent leukocytes and erythrocytes. In patients homozygous for gba mutations lysosomal degradation is impaired and glucocerebroside accumulation in phagocytic cells leads to the formation of characteristic 'Gaucher cells' in various tissues throughout the body (3). Symptoms arise as a consequence of anatomic distortion caused by the significant infiltration of these large glycolipid filled cells.
Gaucher disease has been subtyped based on the tissues affected (3). Gaucher disease Type 1 (GDT1) accounts for 80-95% of cases and is usually referred to as the 'chronic non-neuronopathic form' given the relative sparing of the nervous system, and Gaucher cell accumulation is mainly confined to tissue with a high hematopoietic turnover and glucocerebroside output, primarily the spleen and bone marrow. Accumulation in the spleen leads to hepatosplenomegaly with accompanying anemia and thrombocytopenia often requiring splenectomy. Skeletal involvement includes cytokine mediated abnormal osteoblastic and osteoclastic activity and replacement of the bone marrow with Gaucher cells, leading to osteopenia, avascular necrosis, growth retardation, pain and pathological fractures (3). Type II and Type III Gaucher disease, also known as the 'acute and subacute neuronopathic forms', have significant neurological involvement leading to death in childhood (3). There have been over 300 mutations identified in gba but genotype-phenotype correlations are generally poor, with the main exception being the N370S mutant, thought to be 'neuro-protective' and diagnostic for GDT1 (3). The chronic non-neuronopathic form was long thought to completely spare the CNS of gba related disease. This dogma was initially challenged by a series of case reports describing the common occurrence of early onset Parkinson's disease in GDT1 patients and their families (4, 6). These observations were substantiated in a cohort that yielded a 21 fold increased risk of Parkinson's disease in GDT1 patients (1). The prospect that even unaffected carriers of gbamutations are at risk for Parkinsonism is supported by a multicenter international case control study which reported that among patients with Parkinson's disease, 7% were carries of a gba-mutated allele (odds ratio: 5.43 vs control), making it the most significant genetic risk factor for Parkinson's disease (7, 8).
The literature describing the autopsy neuropathology of patients with GDT1 and Parkinson's disease is limited, but one report of four such patients described alpha-synuclein immunopositive Lewy bodies in the substantia nigra and CA2-CA4 hippocampal regions (9). Interestingly, compared to surrounding areas, they show that CA2-CA4 is an area of the brain that specifically expresses GBA even in normal non-gba-mutant carriers.
Another recent study of interest has confirmed the immunohistochemical presence of GBA in Lewy bodies of gba-mutant carriers, something not seen in Lewy bodies of non-carriers (2). This implies that GBA may be intimately involved in the pathogenesis of Lewy bodies, a prospect that has been supported experimentally (5).
Contributed by P. Diamandis, D. Amato, J. Finkelstein, and J. Keith