HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia

The homotypic fusion and protein sorting (HOPS) complex is the structural bridge necessary for the fusion of late endosomes and autophagosomes with lysosomes. Recent publications linked mutations in genes encoding HOPS complex proteins with the aetiopathogenesis of inherited dystonias (i.e. VPS16, VPS41, and VPS11). Functional and microstructural studies conducted on patient-derived fibroblasts carrying mutations of HOPS complex subunits displayed clear abnormalities of the lysosomal and autophagic compartments. We propose to name this group of diseases HOPS-associated neurological disorders (HOPSANDs), which are mainly characterized by dystonic presentations. The delineation of HOPSANDs further confirms the connection of lysosomal and autophagic dysfunction with the pathogenesis of dystonia, prompting researchers to find innovative therapies targeting this pathway

TWNK in Parkinson's Disease: A Movement Disorder and Mitochondrial Disease Center Perspective Study

Background: Parkinsonian features have been described in patients harboring variants in nuclear genes encoding for proteins involved in mitochondrial DNA maintenance, such as TWNK. Objectives: The aim was to screen for TWNK variants in an Italian cohort of Parkinson's disease (PD) patients and to assess the occurrence of parkinsonism in patients presenting with TWNK-related autosomal dominant progressive external ophthalmoplegia (TWNK-adPEO). Methods: Genomic DNA of 263 consecutively collected PD patients who underwent diagnostic genetic testing was analyzed with a targeted custom gene panel including TWNK, as well as genes causative of monogenic PD. Genetic and clinical data of 18 TWNK-adPEO patients with parkinsonism were retrospectively analyzed. Results: Six of 263 PD patients (2%), presenting either with isolated PD (n = 4) or in combination with bilateral ptosis (n = 2), carried TWNK likely pathogenic variants. Among 18 TWNK-adPEO patients, 5 (28%) had parkinsonism. Conclusions: We show candidate TWNK variants occurring in PD without PEO. This finding will require further confirmatory studies. © 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the aging population, and no disease-modifying therapy has been approved to date. The pathogenesis of PD has been related to many dysfunctional cellular mechanisms, however, most of its monogenic forms are caused by pathogenic variants in genes involved in endolysosomal function (LRRK2, VPS35, VPS13C, and ATP13A2) and synaptic vesicle trafficking (SNCA, RAB39B, SYNJ1, and DNAJC6). Moreover, an extensive search for PD risk variants revealed strong risk variants in several lysosomal genes (e.g., GBA1, SMPD1, TMEM175, and SCARB2) highlighting the key role of lysosomal dysfunction in PD pathogenesis. Furthermore, large genetic studies revealed that PD status is associated with the overall “lysosomal genetic burden”, namely the cumulative effect of strong and weak risk variants affecting lysosomal genes. In this context, understanding the complex mechanisms of impaired vesicular trafficking and dysfunctional endolysosomes in dopaminergic neurons of PD patients is a fundamental step to identifying precise therapeutic targets and developing effective drugs to modify the neurodegenerative process in PD

Tremulous spastic ataxia in a patient with a homozygous truncating SYNE1 variant

We describe a case of severe adult-onset progressive tremulous cerebellar ataxia with pyramidal signs associated with a rare homozygous truncating pathogenic variant in the SYNE1 gene (p.Arg5371*). This contrasts the initial views on SYNE1-related ataxia as a relatively benign, slowly progressive condition, with important implications for clinic-genetic counselling

SLC25A46 mutations in patients with Parkinson's Disease and optic atrophy

Mutations in the gene encoding the mitochondrial carrier protein SLC25A46 are known to cause optic atrophy associated with peripheral neuropathy and congenital pontocerebellar hypoplasia. We found novel biallelic SLC25A46 mutations (p.H137R, p.A401Sfs*17) in a patient with Parkinson's disease and optic atrophy. Screening of six unrelated patients with parkinsonism and optic atrophy allowed us to identify two additional mutations (p.A176V, p.K256R) in a second patient. All identified variants are predicted likely pathogenic and affect very conserved protein residues. These findings suggest for the first time a possible link between Parkinson's Disease and SLC25A46 mutations. Replication in additional studies is needed to conclusively prove this link

Adult-onset KMT2B-related dystonia

KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.Monfrini et al. report twelve cases from five unrelated families carrying four rare KMT2B missense variants. DNA methylation array analysis allowed the identification of a common pattern in these patients differentiating them from controls and early-onset KMT2B-related dystonic patients. This work widens the clinical spectrum associated with KMT2B missense variants, linking altered KMT2B function to adult-onset dystonia

Harmonizing Genetic Testing for Parkinson's Disease: Results of the PARKNET Multicentric Study

Background and objective: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far. Methods: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic. Results: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive. Conclusions: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Are patients with GBA-Parkinson disease good candidates for deep brain stimulation? A longitudinal multicentric study on a large Italian cohort

Background: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce. Objective: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort. Methods: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS. Results: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up. Conclusions: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up

GBA ‐Related Parkinson's Disease: Dissection of Genotype–Phenotype Correlates in a Large Italian Cohort

Background Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. Objectives We determined the frequency of GBA ‐related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. Methods Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β‐glucocerebrosidase activity was measured. The Kaplan‐Meier method and Cox proportional hazard regression models were performed. Results Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA‐PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA‐PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA‐PD had the lowest β‐glucocerebrosidase activity. Conclusions GBA‐PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles