Subject(s)
Charcot-Marie-Tooth Disease/genetics , Chromosomes, Human, Pair 1/genetics , Gaucher Disease/genetics , Genetic Predisposition to Disease/genetics , Uniparental Disomy/genetics , Charcot-Marie-Tooth Disease/complications , Child, Preschool , Chromosome Mapping , DNA Mutational Analysis , Gaucher Disease/complications , Genetic Markers/genetics , Glucosylceramidase/deficiency , Glucosylceramidase/genetics , Hearing Loss, Sensorineural/genetics , Hepatomegaly/genetics , Homozygote , Humans , Inheritance Patterns/genetics , Male , Microsatellite Repeats/genetics , Mutation , Myelin P0 Protein/genetics , Pupil Disorders/geneticsABSTRACT
The synucleinopathies are neurodegenerative disorders defined by inclusions composed of aberrantly fibrillized alpha-synuclein, but factors contributing to this process remain largely unknown. The authors examined the glucocerebrosidase gene in 75 autopsy specimens with different synucleinopathies and identified mutations in 23% of cases of dementia with Lewy bodies, expanding on previous findings in subjects with Parkinson disease. Mutations in this lysosomal protein may interfere with the clearance or promote aggregation of alpha-synuclein.
Subject(s)
Glucosylceramidase/genetics , Lewy Body Disease/genetics , Mutation , Adult , Aged , Aged, 80 and over , Asparagine/genetics , Autopsy , Brain/pathology , DNA Mutational Analysis/methods , Female , Humans , Isoleucine/genetics , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Male , Middle Aged , Parkinson Disease/genetics , Parkinson Disease/pathology , Risk Factors , Synucleins/metabolism , Threonine/geneticsSubject(s)
Gaucher Disease/diagnosis , Skin Abnormalities/pathology , Diagnosis, Differential , Epidermis/metabolism , Epidermis/pathology , Gaucher Disease/classification , Gaucher Disease/genetics , Glucosylceramidase/analysis , Glucosylceramidase/deficiency , Humans , Ichthyosis/diagnosis , Ichthyosis/genetics , Male , PrognosisABSTRACT
BACKGROUND: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. METHODS: The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines. RESULTS: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. CONCLUSION: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.
Subject(s)
Gaucher Disease/diagnosis , Gaucher Disease/genetics , Glucosylceramidase/genetics , Child, Preschool , Female , Genotype , Glucosylceramidase/metabolism , Homozygote , Humans , Infant , Male , Phenotype , Point MutationABSTRACT
An association between Gaucher disease and Parkinson disease has been demonstrated by the concurrence of Gaucher disease and parkinsonism in rare patients and the identification of glucocerebrosidase mutations in probands with sporadic Parkinson disease. Using a different and complementary approach, we describe 10 unrelated families of subjects with Gaucher disease where obligate or confirmed carriers of glucocerebrosidase mutations developed parkinsonism. These observations indicate that mutant glucocerebrosidase, even in heterozygotes, may be a risk factor for the development of parkinsonism. Understanding the relationship between altered glucocerebrosidase and the development of parkinsonian manifestations will provide insights into the genetics, pathogenesis, and treatment of Parkinson disease.
