Derralyn Hughes

Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells

Heterozygous GBA gene mutations are the most frequent Parkinson’s disease risk factor. Using Parkinson’s disease patient derived fibroblasts McNeill et al. show that heterozygous GBA mutations reduce glucosylceramidase activity, and are associated with endoplasmic reticulum and oxidative stress. Ambroxol treatment improved glucosylceramidase activity and reduced oxidative stress in these cells.

Hyposmia and cognitive impairment in Gaucher disease patients and carriers

The objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher disease patients (n = 30), heterozygous glucocerebrosidase mutation carriers (n = 30), and mutation‐negative controls matched by age, sex, and ethnicity (n = 30) were recruited. Assessment was done for olfactory function (University of Pennsylvania Smell Identification Test), cognitive function (Mini‐Mental State Examination, Montreal Cognitive Assessment), rapid eye movement sleep disorder, autonomic symptoms, and parkinsonian motor signs (Unified Parkinsons Disease Rating Scale part III, Purdue pegboard). Olfactory function scores were significantly lower in Gaucher disease patients (P = .010) and heterozygous carriers (P < .001) than in controls. Cognitive assessment scores were significantly lower in Gaucher disease patients (P = .002) and carriers (P = .002) than in controls. Unified Parkinsons Disease Rating Scale motor subscale scores were significantly higher in Gaucher disease patients (P < .001) and heterozygotes (P = .0010) than in controls. There was no difference in scores for symptoms of rapid eye movement sleep disorder or autonomic dysfunction. Impairment of olfaction, cognition, and parkinsonian motor signs occurs more frequently in Gaucher disease patients and carriers than in controls, which may indicate the early stages of neurodegeneration.

Peripheral neuropathy in adult type 1 Gaucher disease: a 2-year prospective observational study

Type 1 Gaucher disease is currently categorized as non-neuronopathic, although recent studies suggest peripheral neurological manifestations. We report prevalence and incidence data for peripheral neuropathy and associated conditions from a multinational, prospective, longitudinal, observational cohort study in patients with type 1 Gaucher disease, either untreated or receiving enzyme replacement therapy. The primary outcome parameters were the prevalence and incidence of polyneuropathy, evaluated by standardized assessments of neurological symptoms and signs, and electrophysiological studies. All diagnoses of polyneuropathy were adjudicated centrally. Secondary outcome parameters included the prevalence and incidence of mononeuropathy, other neurological or electrophysiological abnormalities not fulfilling the criteria for a mono- or polyneuropathy and general type 1 Gaucher disease symptoms. Furthermore, a literature search was performed to identify all studies reporting on prevalence and incidence of polyneuropathy in the general population. One hundred and three patients were enrolled [median (range) age: 42 (18-75) years; disease duration: 15 (0-56) years; 52% female]; 14 (13.6%) were untreated and 89 (86.4%) were on enzyme replacement therapy. At baseline, 11 patients [10.7%; 95% confidence interval (CI): 5.9-18.3] were diagnosed with sensory motor axonal polyneuropathy. Two (1.9%; 95% CI: 0.1-7.2) had a mononeuropathy of the ulnar nerve. The 2-year follow-up period revealed another six cases of polyneuropathy (2.9 per 100 person-years; 95% CI: 1.2-6.3). Patients with polyneuropathy were older than those without (P<0.001). Conditions possibly associated with polyneuropathy were identified in four patients only, being monoclonal gammopathy, vitamin B(1) deficiency, folic acid deficiency, type 2 diabetes mellitus, renal insufficiency, alcohol abuse and exposure to toxins related to profession. The 11 cases of polyneuropathy found at baseline were confirmed during follow-up. According to the literature, the prevalence of polyneuropathy in the general population was estimated between 0.09 and 1.3% and the incidence was estimated between 0.0046 and 0.015 per 100 person-years. Thus, we conclude that the prevalence and incidence of polyneuropathy in patients with type 1 Gaucher disease is increased compared with the general population.

Potential biomarkers of osteonecrosis in Gaucher disease.

BACKGROUND To investigate the relationship between chemokines and cytokines and osteonecrosis in Gaucher disease, we conducted multiplex assays in a cohort of 100 adult patients. METHODS Mean age was 45 years (18-86); 92 Gaucher patients received imiglucerase (median duration 8 years (2-18)). Forty-three had experienced osteonecrosis (ON), and eight had ON despite enzyme therapy. Serum cytokines/chemokines were determined by fluorimetric bead arrays in samples from Gaucher patients and healthy volunteers (10 males and 10 females). Intra-assay and inter-assay coefficients of variation were 2%-9.8% and 5.6%-15%, respectively. RESULTS VEGF and CCL5/RANTES did not differ between Gaucher and control samples. Concentrations of CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1, CXCL8/IL-8, IL-1ra and CCL18/PARC were elevated in Gaucher patients (p<0.05 for each). Median CCL4/MIP-1β, CXCL8/IL-8, CCL5/RANTES and CCL18/PARC concentrations were greater in the 43 osteonecrosis patients (88.6 pg/mL, 30.5 pg/mL, 89.6 ng/mL and 434 ng/mL, respectively) compared with the 57 patients who had no evidence of osteonecrosis (medians of 59.4, 13.3, 62.7 and 283, respectively, p<0.05). Moreover, the eight patients with ON despite imiglucerase had median concentrations of CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, CCL5/RANTES and CCL18/PARC (73.2, 120.9, 36.3 pg/mL, 105 and 767 ng/mL, respectively), which significantly exceeded the values in 84 patients now free of ON (52.3, 71.2, 16.5 pg/mL, 69.5 and 315 ng/mL, respectively, p<0.05). Treatment exposures were similar. CONCLUSION Numerous serum cytokines are elevated in Gaucher disease. CCL18/PARC, CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES and CXCL8/IL-8 are potential biomarkers of osteonecrosis and may allow prediction of this disabling complication.

Native T1 lowering in iron overload and Anderson Fabry disease; a novel and early marker of disease

Background T1 mapping is a powerful technique for ECV quantification; native T1 has been shown to increase in a variety of conditions including oedema, fibrosis and amyloid. Iron and fat lower T1. Anderson Fabry disease (AFD) is a fat storage disease, cardiac iron occurs in transfusion dependent patients. We hypothesised that T1 lowering would diagnose early cardiac involvement, track disease severity and discriminate from other mimic pathologies. Methods

Novel pathogenic mutations in the glucocerebrosidase locus

To determine the frequency of mutations responsible for Gauchers disease, we systematically sequenced the GBA1 gene as part of a molecular characterization of 73 adult patients in the United Kingdom. Five hitherto unknown pathogenic variants were identified, one of which is a splice site change; the others are novel missense mutations. Given that GBA1 gene mutations are an important risk factor for the development of Parkinsons disease, we contend that a complete analysis and molecular characterization of both the known and novel GBA1 variants will be needed before the biochemical processes underlying this genetic association can be fully understood.