alpha-synuclein and Thrombophilia

Gaucher disease (GD) is a lysosomal disorder caused by inherited deficiency of glucocerebrosidase (GCase), resulting in the accumulation of glucocerebroside in macrophages, termed "Gaucher cells," leading to multiorgan involvement, with hepatosplenomegaly, cytopenias, pulmonary hypertension, and skeletal complications. Various mutations, encoding the GCase gene, cause acute or chronic neuronopathic forms of the disease. The hallmark of GD is the macrophages infiltrating organs, bone marrow, and nervous system compromising their function by inflammation, infarcts, fibrosis, and neuronal damage. Coagulation abnormalities are frequent among GD patients due to reduced production and chronic consumption of coagulation factors. Splenic and bone infarcts often occur in GD patients, but hypercoagulability is not frequent. Detection of thrombophilic risk factors in GD patients may predict a more severe course of the disease. Clinical and genetic studies revealed an association between reduced GCase activity in carriers of GD mutations and GD patients and occurrence of Parkinson disease (PD) and showed that GCase gene mutations are risk factors for PD development. The mechanisms underlying the association of PD and GD are not yet elucidated and should be further explored, particularly the potential involvement of inflammation and coagulation in the neurovascular unit.

Topics: alpha-Synuclein; Blood Coagulation Factors; Gaucher Disease; Glucosylceramidase; Humans; Mutation; Parkinson Disease; Risk Factors; Thrombophilia

To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD).. The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity.. Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation.. Mutations in the beta-synuclein gene may predispose to DLB.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Amino Acid Sequence; Amino Acid Substitution; Animals; beta-Synuclein; Brain Chemistry; Cattle; Codon; Cystic Fibrosis; Disease Progression; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Humans; Japan; Lewy Body Disease; Male; Mice; Middle Aged; Molecular Sequence Data; Mutation, Missense; Nerve Tissue Proteins; Parkinson Disease; Pedigree; Point Mutation; Rats; Sequence Alignment; Sequence Homology, Amino Acid; Species Specificity; Synucleins; Thrombophilia; Washington