Motor and non-motor features in Parkinson's Disease patients carrying GBA gene mutations.

BACKGROUND: Mutations of the Glucocerebrosidase (GBA) gene are the most common genetic risk factor yet discovered for Parkinson's Disease (PD), being found in about 5-14% of Caucasian patients. OBJECTIVE: We aimed to assess motor and non-motor symptoms (NMS) in patients with GBA-related PD (GBA-PD) in comparison with idiopathic PD (iPD) subjects using standardized and validated scales. METHODS: Eleven (4 M, 7 F) patients with GBA-PD and 22 iPD patients, selected from the same cohort and matched for gender, age, and disease duration, were enrolled. The disease severity was assessed by Unified Parkinson's Disease Rating Scale-section III, gait disorder and falls by Freezing of Gait Questionnaire, and motor fluctuations by Wearing off questionnaire. NMS were evaluated using the following scales: Mini-Mental State Examination and extended neuropsychological battery, if required, Non-Motor Symptoms Scale, SCOPA-AUT Questionnaire, Apathy Evaluation Scale, Beck Depression Inventory, Epworth Sleepiness Scale, Restless Legs Syndrome Rating Scale, REM Sleep Behavior Disorder Screening Questionnaire, and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease. RESULTS: GBA-PD patients showed a more severe and rapidly progressive disease, and more frequent positive family history for PD, akinetic-rigid phenotype, postural instability, dementia, and psychosis in comparison to iPD. Two of three subjects carrying L444P mutation presented with early dementia. We also found a higher occurrence of fatigue, diurnal sleepiness, and intolerance to heat/cold in the carriers group. CONCLUSIONS: Our results confirm that NMS and a more severe and faster disease course more frequently occur among GBA-PD patients in comparison to iPD.

Screening for RFC-1 pathological expansion in late-onset ataxias: a contribution to the differential diagnosis.

We screened 62 late-onset ataxia patients for the AAGGG pathological expansion in the RFC-1 gene that, when biallelic, causes Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS). Nine patients tested positive. Six had a previous diagnosis of sporadic adult-onset ataxia (SAOA) and three of multisystem atrophy type C (MSA-C). Further six patients were heterozygous for the pathological RFC-1 expansion, four with an initial diagnosis of MSA-C and two of SAOA. In comparison with CANVAS, MSA-C patients had faster progression and shorter disease duration to walking with aids. An abnormal DaTscan does not seem to contribute to differential diagnosis between CANVAS and MSA-C.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Frequency and distribution of polyQ disease intermediate-length repeat alleles in healthy Italian population.

BACKGROUND: Huntington disease (HD) and spinocerebellar ataxia type 1-2-17 (SCA1-2-17) are adult-onset autosomal dominant diseases, caused by triplet repeat expansions in the HTT, ATXN1, ATXN2, and TBP genes. Alleles with a repeat number just below the pathological threshold are associated with reduced penetrance and meiotic instability and are defined as intermediate alleles (IAs). OBJECTIVES: We aimed to determine the frequencies of IAs in healthy Italian subjects and to compare the proportion of the IAs with the prevalence of the respective diseases. METHODS: We analyzed the triplet repeat size in HTT, ATXN1, ATXN2, and TBP genes in the DNA samples from 729 consecutive adult healthy Italian subjects. RESULTS: IAs associated with reduced penetrance were found in ATXN2 gene (1 subject, 0.1%) and TBP gene (0.82%). IAs at risk for meiotic instability were found in HTT (5.3%) and ATXN2 genes (2.7%). In ATXN1, we found a low percentage of IAs (0.4%). Alleles lacking the common CAT interruption within the CAG sequence were also rare (0.3%). CONCLUSIONS: The high frequencies of IAs in HTT and ATXN2 genes suggest a correlation with the prevalence of the diseases in our population and support the hypothesis that IAs could represent a reservoir of new pathological expansions. On the opposite, ATXN1-IA were very rare in respect to the prevalence of SCA1 in our country, and TBP- IA were more frequent than expected, suggesting that other mechanisms could influence the occurrence of novel pathological expansions.

Screening for Niemann-Pick type C disease in neurodegenerative diseases.

Niemann Pick type C (NP-C) is an autosomal recessive neurovisceral lysosomal storage disorder caused by NPC1 and NPC2 gene mutations. We screened for NP-C 24 patients with Progressive Supranuclear Palsy and 10 with Multiple System Atrophy cerebellar type (MSA-C). Among PSP patients, no NPC1 or NPC2 gene variants were detected. One patient with MSA-C (10%) resulted to carry a pathogenic missense NPC1 gene mutation (p.C184Y) in heterozygous state. NPC1 genes variants might represent a risk or susceptibility factor in the development of α-synucleinopathies such as MSA. The common pattern of lysosomal dysfunction might explain the pathophysiological link between these disorders.

Degenerative and acquired sporadic adult onset ataxia.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.