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Background: Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis., Case: The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261-1G > A], not previously reported as causative of a human phenotype. Low levels of α -fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%)., Conclusion: We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific β-tubulin isotype, β-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/β-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases., (© 2018 Wiley Periodicals, Inc.)

Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal P5B-type ATPase which has functional domains similar to other P-type ATPases which mainly transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate Zn2+, while ATP13A2 from other species have different substrate selectivity. Until now, fourteen mutations in ATP13A2 have been associated with KRS, while other mutations have been reported in association with neuronal ceroid lipofuscinosis (NCL) and early-onset PD. Experimentally, these disease- associated ATP13A2 mutations have been shown to confer loss-of-function to the protein by disrupting its protein structure and function to varying degrees, ranging from impairment in ATPase function to total loss of protein, confirming their pathogenicity. Loss of functional ATP13A2 has been shown to induce Zn2+ dyshomeostasis. Disturbances in Zn2+ homeostasis impair mitochondrial and lysosomal function which leads to loss of mitochondrial bioenergetic capacity and accumulation of lysosomal substrates such as α-synuclein and lipofuscin. Additionally, ATP13A2 appears to be involved in α-synuclein externalisation through its Zn2+-regulating activity. In this review, we will discuss all the reported KRS/NCL-associated ATP13A2 mutations along with several PD-associated mutations which have been experimentally assessed, in respect to their impact on the protein structure and function of ATP13A2., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Importance: To our knowledge, the efficacy of transferring next-generation sequencing from a research setting to neuromuscular clinics has never been evaluated., Objective: To translate whole-exome sequencing (WES) to clinical practice for the genetic diagnosis of a large cohort of patients with limb-girdle muscular dystrophy (LGMD) for whom protein-based analyses and targeted Sanger sequencing failed to identify the genetic cause of their disorder., Design, Setting, and Participants: We performed WES on 60 families with LGMDs (100 exomes). Data analysis was performed between January 6 and December 19, 2014, using the xBrowse bioinformatics interface (Broad Institute). Patients with LGMD were ascertained retrospectively through the Institute for Neuroscience and Muscle Research Biospecimen Bank between 2006 and 2014. Enrolled patients had been extensively investigated via protein studies and candidate gene sequencing and remained undiagnosed. Patients presented with more than 2 years of muscle weakness and with dystrophic or myopathic changes present in muscle biopsy specimens., Main Outcomes and Measures: The diagnostic rate of LGMD in Australia and the relative frequencies of the different LGMD subtypes. Our central goals were to improve the genetic diagnosis of LGMD, investigate whether the WES platform provides adequate coverage of known LGMD-related genes, and identify new LGMD-related genes., Results: With WES, we identified likely pathogenic mutations in known myopathy genes for 27 of 60 families. Twelve families had mutations in known LGMD-related genes. However, 15 families had variants in disease-related genes not typically associated with LGMD, highlighting the clinical overlap between LGMD and other myopathies. Common causes of phenotypic overlap were due to mutations in congenital muscular dystrophy-related genes (4 families) and collagen myopathy-related genes (4 families). Less common myopathies included metabolic myopathy (2 families), congenital myasthenic syndrome (DOK7), congenital myopathy (ACTA1), tubular aggregate myopathy (STIM1), myofibrillar myopathy (FLNC), and mutation of CHD7, usually associated with the CHARGE syndrome. Inclusion of family members increased the diagnostic efficacy of WES, with a diagnostic rate of 60% for "trios" (an affected proband with both parents) vs 40% for single probands. A follow-up screening of patients whose conditions were undiagnosed on a targeted neuromuscular disease-related gene panel did not improve our diagnostic yield., Conclusions and Relevance: With WES, we achieved a diagnostic success rate of 45.0% in our difficult-to-diagnose cohort of patients with LGMD. We expand the clinical phenotypes associated with known myopathy genes, and we stress the importance of accurate clinical examination and histopathological results for interpretation of WES, with many diagnoses requiring follow-up review and ancillary investigations of biopsy specimens or serum samples.

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Importance: Mutations in the GNAL gene have recently been shown to cause primary torsion dystonia. The GNAL-encoded protein (Gαolf) is important for dopamine D1 receptor function and odorant signal transduction. We sequenced all 12 exons of GNAL in 461 patients from Germany, Serbia, and Japan, including 318 patients with dystonia (190 with cervical dystonia), 51 with hyposmia and Parkinson disease, and 92 with tardive dyskinesia or acute dystonic reactions., Observations: We identified the following two novel heterozygous putative mutations in GNAL: p.Gly213Ser in a German patient and p.Ala353Thr in a Japanese patient. These variants were predicted to be pathogenic in silico, were absent in ethnically matched control individuals, and impaired Gαolf coupling to D1 receptors in a bioluminescence energy transfer (BRET) assay. Two additional variants appeared to be benign because they behaved like wild-type samples in the BRET assay (p.Ala311Thr) or were detected in ethnically matched controls (p.Thr92Ala). Both patients with likely pathogenic mutations had craniocervical dystonia with onset in the fifth decade of life. No pathogenic mutations were detected in the patients with hyposmia and Parkinson disease, tardive dyskinesias, or acute dystonic reactions., Conclusions and Relevance: Mutations in GNAL can cause craniocervical dystonia in different ethnicities. The BRET assay may be a useful tool to support the pathogenicity of identified variants in the GNAL gene.

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.

Objective: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family., Methods: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients., Results: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls., Interpretation: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia., (Copyright © 2012 American Neurological Association.)

Hereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

Objective: To evaluate the frequency and clinical spectrum of the recently identified p.D620N mutation in the VPS35 gene in Parkinson disease (PD) in an international sample., Design: Genetic analysis by DNA sequencing and detailed clinical and neuropsychiatric assessment as well as neuroimaging in mutation carriers., Setting: Tertiary referral centers in Germany, Serbia, Chile, and the United States., Patients: One thousand seven hundred seventy-four patients with PD., Main Outcome Measure: Frequency of the p.D620N mutation., Results: A single mutation carrier was identified. The mutation carrier was a 60-year-old German man who had tremor-dominant PD since the age of 45 years. Longitudinal follow-up over 13 years revealed a disease progression from Hoehn and Yahr stage 1 to 3. There was evidence of mild cognitive impairment on the Montreal Cognitive Assessment. No abnormalities were observed by multimodal neuroimaging. He had a family history consistent with autosomal dominant inheritance. An affected paternal aunt and 3 reportedly unaffected siblings were also found to be mutation carriers., Conclusion: VPS35 mutations are a rare cause of PD in different populations. The clinical phenotype may be indistinguishable from idiopathic PD with the possible exception of an earlier age at onset. Genetic analysis of the extended family revealed incomplete penetrance of the p.D620N mutation.

Background: Mutations in parkin have been associated with autosomal recessive early-onset Parkinson's disease (PD). Here, we report on unusual phenotypic variability within a family with mutations in parkin., Methods: The proband and her parents were clinically assessed. Mutation analysis was performed using genomic DNA and complementary DNA. The protein expression of Parkin and Mitofusin 2 was examined by western blotting., Results: The proband was a compound heterozygote with no detectable Parkin and presented with early-onset PD. The father, a single heterozygote with reduced expression of Parkin, had mild loss of arm swing. The mother, who had only very mild rigidity, was unexpectedly found to be a homozygote with no Parkin expression. The proband, but not the parents, met the Queen Square Brain Bank criteria for PD. Parkin-dependent ubiquitination of Mitofusin 2 was impaired in the mother and the proband., Conclusion: We report the first case of a homozygous mutation carrier in parkin who had no functional protein and only mild signs of parkinsonism in her seventh decade, whereas her daughter developed typical early-onset PD. This family demonstrates phenotypic variability in parkin-related parkinsonism. © 2012 Movement Disorder Society., (Copyright © 2012 Movement Disorder Society.)

Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To identify peripheral nerve abnormalities in hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (spastic paraplegia 4, SPG4) using standard nerve conduction (NCS) and novel tests of axonal excitability., Methods: Eleven patients with known mutations in spastin were assessed with NCS for the upper and lower limbs, and axonal excitability testing on the median nerve., Results: Standard nerve conduction studies revealed a sensorimotor neuropathy in two patients. Excitability studies on median motor axons showed an isolated abnormality (increased strength-duration time constant), but those on sensory axons were normal in nine patients with normal routine nerve conduction studies., Conclusions: Peripheral neuropathy occurs in HSP patients with SPG4 mutations, but axonal excitability studies provide limited additional evidence for subclinical peripheral nerve dysfunction, and add little further to standard nerve conduction studies., Significance: The features of HSP due to SPG4 mutations include sensorimotor polyneuropathy. The value of excitability studies is limited in individual patients., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating and missense mutated ATP13A2 were retained in the endoplasmic reticulum (ER). Both mutant proteins were degraded by the proteasomal but not the lysosomal pathways. In addition, ATP13A2 mRNA with c.3253delC was degraded by nonsense-mediated mRNA decay (NMD), which was protected by cycloheximide treatment. To validate our findings in a biologically relevant setting, we used patient-derived human olfactory neurosphere cultures and fibroblasts and demonstrated persistent ER stress by detecting upregulation of unfolded protein response-related genes in the patient-derived cells. We also confirmed NMD degraded ATP13A2 c.3253delC mRNA in the cells. These findings indicate that these novel ATP13A2 mutations are indeed pathogenic and support the notion that mislocalization of the mutant ATP13A2, resultant ER stress, alterations in the proteasomal pathways and premature degradation of mutant ATP13A2 mRNA contribute to the aetiology of KRS., (© 2011 Wiley-Liss, Inc.)

Background: Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy., Methodology/principal Findings: In this study, we investigated the impact of Parkin mutations on mitochondrial function and morphology in a human cellular model. Fibroblasts were obtained from three members of an Italian PD family with two mutations in Parkin (homozygous c.1072delT, homozygous delEx7, compound-heterozygous c.1072delT/delEx7), as well as from two relatives without mutations. Furthermore, three unrelated compound-heterozygous patients (delEx3-4/duplEx7-12, delEx4/c.924C>T and delEx1/c.924C>T) and three unrelated age-matched controls were included. Fibroblasts were cultured under basal or paraquat-induced oxidative stress conditions. ATP synthesis rates and cellular levels were detected luminometrically. Activities of complexes I-IV and citrate synthase were measured spectrophotometrically in mitochondrial preparations or cell lysates. The mitochondrial membrane potential was measured with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide. Oxidative stress levels were investigated with the OxyBlot technique. The mitochondrial network was investigated immunocytochemically and the degree of branching was determined with image processing methods. We observed a decrease in the production and overall concentration of ATP coinciding with increased mitochondrial mass in Parkin-mutant fibroblasts. After an oxidative insult, the membrane potential decreased in patient cells but not in controls. We further determined higher levels of oxidized proteins in the mutants both under basal and stress conditions. The degree of mitochondrial network branching was comparable in mutants and controls under basal conditions and decreased to a similar extent under paraquat-induced stress., Conclusions: Our results indicate that Parkin mutations cause abnormal mitochondrial function and morphology in non-neuronal human cells.

We investigated a 62-year-old man who had mild clinical features of myotonia congenita. He was found to have a novel heterozygous G-to-A nucleotide substitution at position 1652 in exon 15 of the CLCN1 gene. Clinicogenetic studies performed on his family revealed that his asymptomatic son also shared the mutation. We conclude that a novel chloride channel mutation (G1652A) has caused a mild form of autosomal-dominant myotonia congenita (Thomsen disease) in this family.

Background: Age-related macular degeneration (AMD), a chronic neurodegenerative and neovascular retinal disease, is the leading cause of blindness in elderly people of western European origin. While structural and functional alterations in mitochondria (mt) and their metabolites have been implicated in the pathogenesis of chronic neurodegenerative and vascular diseases, the relationship of inherited variants in the mitochondrial genome and mt haplogroup subtypes with advanced AMD has not been reported in large prospective cohorts., Methodology/prinicipal Findings: We examined the relationship of inherited mtDNA variants with advanced AMD in 1168 people using a three-stage design on samples from 12-year and 10-year prospective studies on the natural history of age-related eye disease. In Stage I we resequenced the entire genome in 99 elderly AMD-free controls and 215 people with advanced AMD from the 12-year study. A consistent association with AMD in 14 of 17 SNPs characterizing the mtDNA T haplogroup emerged. Further analysis revealed these associations were driven entirely by the T2 haplogroup, and characterized by two variants in Complex I genes (A11812G of MT-ND4 and A14233G of MT-ND6). We genotyped T haplogroups in an independent sample of 490 cases and 61 controls from the same study (Stage II) and in 56 cases and 246 controls from the 10-year study (Stage III). People in the T2 haplogroup were approximately 2.5 times more likely to have advanced AMD than their peers (odds ratio [OR] = 2.54, 95%CI 1.36-4.80, P

We determined the prevalence of two common leucine-rich repeat kinase 2 (LRRK2) gene mutations in Australian patients with Parkinson's disease (PD). Of 830 affected patients, eight were heterozygous for the G2019S mutation, and two were heterozygous for the R1441H (4,322 G > A) mutation. In addition, one familial patient had a novel A1442P (4,324 G > C) mutation. Haplotype analysis showed that all LRRK2 G2019S-positive individuals carried the common founder haplotype 1 and a putative founder haplotype for the R1441H mutation carriers. Clinically, patients with LRRK2 mutations had typical levodopa responsive Parkinsonism with tremor being the commonest presenting feature. Patients with the G2019S mutation in our series had a similar age of onset of symptoms when compared with patients with other LRRK2 mutations or sporadic PD, although they were more likely to have a family history of PD (2.4% of Australian patients with familial PD and 0.3% of Australian patients with sporadic PD). Our results demonstrate that the G2019S mutation carriers share the same ancestors who migrated to Australia originally from Europe and that other LRRK2 mutations (R1441H and A1442P) can be found in this population., ((c) 2007 Movement Disorder Society.)

We aimed to establish the population prevalence of the MELAS 3243A>G mtDNA mutation in a large Caucasian-based population (n=2954; 99% Caucasian, 57% women and mean age of 66.4 years). All participants underwent comprehensive clinical evaluation including audiologic testing. We detected the 3243A>G mutation in seven subjects using standard polymerase chain reaction/restriction fragment length polymorphism methods, establishing a population prevalence of 236/100000 (0.24%; 95% CI 0.10-0.49%); much higher than previously reported. All had mild to moderate hearing loss. Our findings indicate that subjects with the 3243A>G mtDNA mutation could be markedly under-recognised in the community.

BackgroundThe penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.ObjectivesThe objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.MethodsSymptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.ResultsA total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91).ConclusionsRegular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

Abstract: We report the first Australian families with inclusion-body myopathy, Paget’s disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases. [Copyright &y& Elsevier]