Elsevier

Molecular Genetics and Metabolism

Volume 83, Issues 1–2, September–October 2004, Pages 6-15
Molecular Genetics and Metabolism

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Gaucher disease: complexity in a “simple” disorder

https://doi.org/10.1016/j.ymgme.2004.08.015Get rights and content

Abstract

Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype–phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed α-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.

Introduction

Gaucher disease (MIM 230800, 230900, and 231000) is one of many Mendelian disorders, which, while not considered to be complex, are certainly not simple [1], [2]! The disease results from the inherited deficiency of the enzyme glucocerebrosidase (EC.3.2.1.45), which cleaves the glycolipid glucocerebroside into glucose and ceramide. It is the most common of the sphingolipidoses and the most frequently inherited disorder among Ashkenazi Jews, among whom the carrier frequency is approximately 1 in 15 [3]. In Gaucher disease, storage primarily occurs throughout the reticulo-endothelial system. Lysosomes within macrophages become engorged with the stored glycolipid, giving rise to “Gaucher cells,” macrophages with a diagnostically characteristic appearance. By light microscopy, they are PAS positive, have displaced nuclei and a cytoplasm that has been described as resembling “wrinkled tissue paper.” Electron microscopy reveals twisted, elongated, tubular structures that totally distort the lysosome.

Clinically, Gaucher disease is characterized by vast phenotypic heterogeneity, with manifestations ranging from death in utero [4] to asymptomatic octogenarians [5]. The disorder classically has been divided into three types, based upon the presence or absence and rate of progression of neurologic manifestations. Type 1, non-neuronopathic Gaucher disease, is by far the most frequent type. Even among type 1 patients, there is variability both in presentation and disease progression. Among Ashkenazi Jews, based upon the known carrier frequency, it is clear that many, if not most, affected individuals go undiagnosed [6]. However, in some patients the disease manifestations are significant, and commonly include organomegaly, anemia, thrombocytopenia and bone involvement. In contrast, type 2, or acute neuronopathic Gaucher disease, is more stereotypic, with an onset by a few months of age and rapidly progressive and devastating neurologic deterioration. Most affected children succumb to the disease within the first year or two of life. Type 3, chronic neuronopathic Gaucher disease, encompasses multiple different phenotypes. Patients can have primarily visceral involvement with slowed horizontal saccadic eye movements, or can develop myoclonus, ataxia, seizures, or dementia. Recently, the clinical evaluation of diverse patients with Gaucher disease has led to the conclusion that Gaucher disease is more correctly characterized as a continuum of phenotypes, some of which defy classification into the classic three types (Fig. 1) [7]. Perhaps the most relevant distinction is that some patients have nervous system involvement and others do not. Even so, there are some cases where it is not clear if the observed neurologic manifestations are a primary consequence of the enzyme deficiency or a secondary effect [8], [9].

These observations raise an important question: Why is there such vast phenotypic variation in this presumably single gene disorder? It has long been known that there is no close correlation between the residual enzymatic activity or the amount of stored lipid and the patient phenotype [10]. Therefore, it was hoped that advances in molecular biology and the characterization of gene mutations would provide the needed answers. The gene encoding glucocerebrosidase (GBA) is located on chromosome 1q and includes 11 exons (GenBank No. J03059). There is a highly homologous pseudogene sequence located 16 kb downstream [11] (GenBank No. J03060). Both the gene and pseudogene are in the same orientation and they share 96% exonic homology. Importantly, some mutations or groups of mutations appear to originate from the pseudogene sequence. More that 200 different mutations have been identified in patients with Gaucher disease [12], [13], [14], [15], [16], [17], (http://life2.tau.ac.il/GeneDis/)]. They are distributed throughout the gene, with the majority being missense mutations, but frame-shift, splice-site, insertion and deletion mutations and recombinant alleles carrying multiple mutations have also been described. Several of the mutations, including N370S, L444P, IVS2 + 1G  A, c.84insG, R463C, and R496H, are more common, especially among patients with type 1 Gaucher disease, where they account for over 90% of the mutant alleles found in Ashkenazi Jewish patients [3], [17], [18], [19].

Section snippets

Genotype–phenotype correlations

A decade of genotype–phenotype studies has led to a limited number of relevant conclusions. It has become apparent that the same DNA mutations and even the same genotypes are found in patients with different types or clinical presentations of Gaucher disease. For example, among patients homozygous for L444P, both severely autistic children with seizures and successful college students with few symptoms have been described [20]. It has been observed that siblings with the identical genotype can

Difficulties in performing accurate genotyping

After the identification and sequencing of the gene for glucocerebrosidase in the 1980’s and the development of PCR as a widely available and simple diagnostic technique, most laboratories studying Gaucher disease developed strategies to screen for GBA mutations based upon the screening of PCR-amplified segments of DNA for the presence or absence of specific mutations [12], [17], [23], [24]. However, PCR-based mutation detection techniques have inherent limitations. A mutation can be

Lessons from mouse models

With the development of strategies to generate mouse models of human disease, there were great expectations that the creation of glucocerebrosidase-deficient mice would facilitate a better understanding of both the pathophysiology of Gaucher disease and the phenotypic consequences of specific human mutations. However, “the best laid plans of mice and men gang aft agley…” (R. Burns). Studies in mice led to totally unanticipated research directions and to important clinical insights, but to date,

The expanding spectrum of phenotypes associated with Gaucher disease

While our appreciation of the genetic complexity of the GBA locus has continued to evolve, our awareness of the clinical variation in Gaucher disease has also expanded. The analysis of patients with rare phenotypes may provide a vital tool for identifying interactions with genetic modifiers, as well as shedding light on other related disorders. Today, the Gaucher phenotype includes diverse features such as hydrops fetalis [52], congenital ichthyosis [32], calcification of the cardiac valves [53]

Further studies to elucidate the link between Gaucher disease and parkinsonism

Characterization of the clinical features, genotypes, and wherever possible, the pathologic findings in patients sharing the two phenotypes has continued [60], [63], [64], [65], [66] (Fig. 4). Generally, these subjects demonstrate relatively mild Gaucher symptoms but have early onset, L-dopa-refractory parkinsonian manifestations including tremor, bradykinesia, rigidity, and often cognitive decline. However, through the assessment of such patients, it has become increasingly clear that there is

Conclusion

Focusing on the complex nature of Mendelian disorders has proven to be a rewarding pursuit. Here, studies of Gaucher disease have provided us with insights and tools that can be applied to the study of other monogenic disorders, and that may ultimately be used to unravel complex diseases. Research into the association between Gaucher disease and parkinsonism demonstrates how the in-depth evaluation of a “simple” single gene disorder can provide a window into features of a common and complicated

Acknowledgments

The author thanks Mary LaMarca for the preparation of the figures, Marie Hall for her secretarial assistance and Mary LaMarca and Dr. Ozlem Goker-Alpan for their critical reading and helpful suggestions.

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