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We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

BackgroundBi-allelic pathogenic variants inGBA1are the cause of Gaucher disease (GD1), a lysosomal storage disorder resulting from deficient glucocerebrosidase. HeterozygousGBA1variants are also a common genetic risk factor for Parkinson’s disease (PD). GD manifests with considerable clinical heterogeneity and is also associated with an increased risk of PD.ObjectiveTo investigate the contribution of PD risk variants to risk of PD in patients with GD1.MethodsWe studied 225 patients with GD1, including 199 without PD and 26 with PD. All cases were genotyped and the genetic data was imputed using common pipelines.ResultsOn average, patients with GD1 with PD have a significantly higher PD genetic risk score than those without PD (P=0.021).ConclusionsOur results indicate that variants included in the PD genetic risk score were more frequent in patients with GD1 who developed PD, suggesting that common risk variants may affect underlying biological pathways.Supplemental datahere

Background Mutations in GBA1 are a common genetic risk factor for parkinsonism; however, penetrance is incomplete, and biomarkers of future progression to parkinsonism are needed. Both nigral sonography and striatal [18 F]-FDOPA PET assay dopamine system health, but their utility and coherence in this context are unclear. Objective The aim of this study is to evaluate the utility and coherence of these modalities in GBA1-associated parkinsonism. Methods A total of 34 patients with GBA1 mutations (7 with parkinsonism) underwent both transcranial studies for substantia nigra echogenicity and [18 F]-FDOPA PET to determine striatal tracer-specific uptake (Ki ). Results Larger nigral echogenic areas and reduced striatal Ki were exclusively observed in parkinsonian patients. Sonographic and PET measurements showed strong inverse correlations but only in individuals with clinical parkinsonism. Conclusions Close correspondence between nigral echogenicity and striatal presynaptic dopamine synthesis capacity observed only in GBA1 carriers with parkinsonism provides validation that these two modalities may conjointly capture aspects of the biology underlying clinical parkinsonism but raises questions about their utility as predictive tools in at-risk subjects. © 2021 International Parkinson and Movement Disorder Society.

The clinical phenotype of Gaucher disease type 3 (GD3), a neuronopathic lysosomal storage disorder, encompasses a wide array of neurological manifestations including neuro-ophthalmological findings, developmental delay, and seizures including progressive myoclonic epilepsy. Electroencephalography (EEG) is a widely available tool used to identify abnormalities in cerebral function, as well as epileptiform abnormalities indicating an increased risk of seizures. We characterized the EEG findings in GD3, reviewing 67 patients with 293 EEGs collected over nearly 50 years. Over 93% of patients had some form of EEG abnormality, most consisting of background slowing (90%), followed by interictal epileptiform discharges (IEDs) (54%), and photoparoxysmal responses (25%). The seven patients without background slowing were all under age 14 (mean 6.7 years). There was a history of seizures in 37% of this cohort; only 30% of these had IEDs on EEG. Conversely, only 56% of patients with IEDs had a history of seizures. These observed EEG abnormalities document an important aspect of the natural history of GD3 and could potentially assist in identifying neurological involvement in a patient with subtle clinical findings. Additionally, this comprehensive description of longitudinal EEG data provides essential baseline data for understanding central nervous system involvement in neuronopathic GD.

Background The link between Parkinson's disease (PD), the second most common neurodegenerative disorder, and nonneuronopathic Gaucher disease (GD) is well established. Currently, PD is primarily associated with nonneuronopathic GD; however, with currently available treatments, patients with chronic neuronopathic GD, who historically had a shortened life span, are now living well into their 50s and beyond. Cases We highlight 4 patients with chronic neuronopathic GD with parkinsonian features, describing their GD genotype and phenotype as well as the presentation and progression of their parkinsonism. Symptoms presented in their fourth or fifth decade of life, and include unilateral bradykinesia and/or tremor. Of the patients, 3 had cognitive impairment. The fourth patient has not shown cognitive decline 6 years after PD onset. Conclusion This small series highlights that PD is not exclusively associated with nonneuronopathic GD and that as the chronic neuronopathic GD population ages, the clinical spectrum and heterogeneity of neurological manifestations may include parkinsonism.

ObjectiveTo gather natural history data to better understand the changing course of type 2 Gaucher disease (GD2) in order to guide future interventional protocols.MethodsA structured interview was conducted with parents of living or deceased patients with GD2. Retrospective information obtained included disease presentation, progression, medical and surgical history, medications, family history, management, complications, and cause of death, as well as the impact of disease on families.ResultsData from 23 patients were analyzed (20 deceased and 3 living), showing a mean age at death of 19.2 months, ranging from 3 to 55 months. Fourteen patients were treated with enzyme replacement therapy, 2 were treated with substrate reduction therapy, and 3 underwent bone marrow transplantation. Five patients received ambroxol and one was on N-acetylcysteine, both considered experimental treatments. Fifteen patients had gastrostomy tubes placed; 10 underwent tracheostomies. Neurologic disease manifestations included choking episodes, myoclonic jerks, autonomic dysfunction, apnea, seizures, and diminished blinking, all of which worsened as disease progressed.ConclusionsCurrent available therapies appear to prolong life but do not alter neurologic manifestations. Despite aggressive therapeutic interventions, GD2 remains a progressive disorder with a devastating prognosis that may benefit from new treatment approaches.

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [18 F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [18 F]-fluorodopa uptake (Ki ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of Ki and Ki change found significant effects of Parkinson disease. However, at baseline and over time, striatal [18 F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657.

Several genetic variants are associated with an increased risk for developing Parkinson's Disease (PD) and limited genotype/phenotype correlation. Specifically, mutations in GBA1, the gene coding for the lysosomal enzyme glucocerebrosidase, are associated with an earlier age of onset and faster disease progression. Given these phenotypic differences associated with GBA1 variants, we explored whether cortical thickness and other biomarkers of neurodegeneration differed in healthy controls and PD patients with and without GBA1 variants.To understand how different GBA1 variants influence PD phenotype early in the disease, we retrieved neuroimaging and biospecimen data from the Parkinson's Progression Markers Initiative database. Using FreeSurfer, we compared T1-weighted MRI images from healthy controls (N = 47) to PD patients with heterozygous N370S (N = 21), heterozygous E326K (N = 18) or heterozygous T369M (N = 8) variants, and GBA1 non-mutation carriers (N = 47).Cortical thickness in PD patients differed from controls in the parietal cortex, with E365K, T369M variants, and GBA1 non-mutation carriers showing more cortical thinning than N370S variants. Patients with N370S variants had significantly higher serum neurofilament light levels among all groups.Our results demonstrate significant cortical thinning in PD patients independent of genotype in superior parietal and postcentral regions when compared to the controls. They highlight the impact of GBA1 variants on cortical thickness in the parietal cortex. Finally, they suggest that recently diagnosed PD patients with N370S variants have a higher cortical thickness and increased active neurodegeneration when compared to PD patients without GBA1 mutations and PD patients with E326K or T369M variants.

BACKGROUND: Mutations in GBA1 are a common genetic risk factor for parkinsonism; however, penetrance is incomplete, and biomarkers of future progression to parkinsonism are needed. Both nigral sonography and striatal [(18)F]-FDOPA PET assay dopamine system health, but their utility and coherence in this context are unclear. OBJECTIVES: To evaluate the utility and coherence of these modalities in GBA1-associated parkinsonism. METHODS: Thirty-four patients with GBA1 mutations (seven with parkinsonism), underwent both transcranial studies for substantia nigra echogenicity and [(18)F]-FDOPA PET to determine striatal tracer specific uptake (K(i)). RESULTS: Larger nigral echogenic areas and reduced striatal K(i) were exclusively seen in parkinsonian subjects. Sonographic and PET measurements showed strong inverse correlations, but solely in individuals with clinical parkinsonism. CONCLUSIONS: Close correspondence between nigral echogenicity and striatal presynaptic dopamine synthesis capacity seen only in GBA1 carriers with parkinsonism provides validation that these two modalities may conjointly capture aspects of the biology underlying clinical parkinsonism but raises questions about their utility as predictive tools in at-risk subjects.

ObjectiveTo identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center.MethodsIndividuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator.ResultsMean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ.ConclusionsThe observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.

Background Gaucher disease type 2 (GD2) is defined by acute neurological decline, failure to thrive, and early demise. Currently, there is no clear standard for evaluating, staging, and counseling regarding neurological decline in GD2. Due to the high prevalence of progressive dysphagia secondary to acute neurological involvement, we aimed to identify key components of swallow function which could serve as markers of disease progression in GD2. Methods A post-hoc analysis of modified barium swallow studies was performed. Six parameters of swallowing were scored in a retrospective chart review of eleven infants with GD2. Mixed effects regression, principal component analysis (PCA), and a transition analysis were used to evaluate swallow function and model disease progression. Results All patients exhibited impaired swallow function. There was no association between any of the swallow parameters and age, indicating non-linear disease progression. PCA and transition analysis identified five parameters capturing multiple dimensions of swallowing which defined two distinct disease states. Conclusion A five-parameter swallow evaluation was sufficient to identify distinct states of GD2 and model prospective outcomes. This multi-dimensional evaluation could be a useful efficacy parameter for future therapeutic trials in GD2 and other neurodegenerative disorders of infancy.

BACKGROUND: Cytoplasmic inclusions of α-synuclein in brainstem neurons are characteristic of idiopathic Parkinson’ disease. Parkinson’s disease also entails α-synuclein buildup in sympathetic nerves. Among genetic forms of Parkinson’s disease the relative extents of sympathetic intra-neuronal accumulation of α-synuclein have not been reported. OBJECTIVE: This cross-sectional observational study compared magnitudes of intra-neuronal deposition of α-synuclein in common and rare genetic forms of Parkinson’s disease. METHODS: α-Synuclein deposition was quantified by the α-synuclein-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (N=3), PRKN (biallelic [N=7] and monoallelic [N=3]), LRRK2 (N=7), GBA (N=7), or PARK7/DJ1 (biallelic [N=1] and monoallelic [N=2]). 25 of the mutation carriers had Parkinson’s disease and 5 did not. Data were also analyzed from 19 idiopathic Parkinson’s disease patients and 16 control participants. RESULTS: α-Synuclein deposition varied as a function of genotype (F=16.7, p

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are a risk factor for parkinsonism. Pursuing the potential mechanisms underlying this risk in aging neurons, we propose a new network uniting three major lysosomal proteins: (i) cathepsin D (CTSD), which plays a major role in α-synuclein (SNCA) degradation and prosaposin (PSAP) cleavage; (ii) PSAP, essential for GCase activation and progranulin (PGRN) transport; and (iii) PGRN, impacting lysosomal biogenesis, PSAP trafficking, and CTSD maturation. We hypothesize that alterations to this network and associated receptors modify lysosomal function and subsequently impact both SNCA degradation and GCase activity. By exploring the interactions between this protein trio and each of their respective transporters and receptors, we may identify secondary risk factors that provide insight into the relationship between these lysosomal proteins, GCase, and SNCA, and reveal novel therapeutic targets.

BACKGROUND: Consistent with nigrostriatal dopamine depletion, low cerebrospinal fluid (CSF) concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, characterizes Parkinson’s disease (PD) even in recently diagnosed patients. Whether low CSF levels of DOPAC or DOPA, the precursor of dopamine, identify pre-clinical PD in at- risk healthy individuals has been unknown. METHODS: Participants in the intramural NINDS PDRisk study entered information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. After at least 3 risk factors were confirmed by on-site screening, 26 subjects had CSF sampled for cerebrospinal fluid levels of catechols and were followed for at least 3 years. RESULTS: Of 26 PDRisk subjects, 4 were diagnosed with PD (Pre-Clinical PD group); 22 risk-matched (mean 3.2 risk factors) subjects remained disease-free after a median of 3.7 years (No-PD group). The Pre-Clinical PD group had lower initial DOPA and DOPAC levels than did the No-PD group (p=0.0302, p=0.0190). All 3 subjects with both low DOPA (

Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67phox and Rab7. The decreased Rab7 expression leads to impaired fusion of phagosomes with lysosomes. Moreover, there is defective translocation of p67phox to phagosomes, resulting in reduced intracellular production of reactive oxygen species. These factors contribute to defective deposition and clearance of apoptotic cells in phagolysosomes, which may have an impact on the inflammatory response and contribute to the organomegaly and inflammation seen in patients with Gaucher disease.

Autosomal resessive Mendelian disorders usually result from two inherited disease-causing mutations. However, this is not always the case. Focusing on Gaucher disease, which results from mutations in GBA1, we found that more comprehensive genotyping revealed important exceptions. For example, patients with uniparental disomy or new mutations do not inherit a mutation from each parent. Furthermore, we identified patients found to carry more than one GBA1 mutation on the same allele. It is essential to examine the entire GBA1 gene in order to establish an accurate genotype. Missing the second mutation can complicate genotype/phenotype studies and result in improper genetic counseling.

BACKGROUND Although the association between mutations in GBA1 and parkinsonism is well established, most GBA1 mutation carriers never develop parkinsonism, implicating the contribution of other genetic, epigenetic, and/or environmental modifiers. OBJECTIVES To identify factors predisposing to or offering protection from parkinsonism among siblings with Gaucher's disease) discordant for Parkinson disease (PD). METHODS This prospective, longitudinal study included nine sib pairs with Gaucher disease, but discordant for PD. Assessments included neurological, neuropsychological, olfactory, motor, nonmotor evaluations, and transcranial sonography. Validated mood and nonmotor questionnaires assessed fatigue, olfactory dysfunction, sleepiness, sleep disturbances, anxiety, and/or depression. RESULTS There was no relationship between Gaucher treatments, genotype, or splenectomy and PD. Male sex predominance, younger age, and milder Gaucher disease symptoms were observed among the patients with PD. Substantia nigral echogenicity, olfactory dysfunction, serum triglycerides levels, and 9-hole peg scores, but not caffeine, alcohol, or tobacco use, environmental exposures, uric acid, or glucose levels, differed significantly between groups. CONCLUSIONS Longitudinal evaluation of discordant sib pairs may help identify PD risk factors. © 2019 International Parkinson and Movement Disorder Society.

Among the known genetic risk factors for Parkinson disease, mutations in GBA1 , the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons. These cells exhibited decreased glucocerebrosidase activity and stored the glycolipid substrates glucosylceramide and glucosylsphingosine, demonstrating their similarity to patients with Gaucher disease. Dopaminergic neurons from patients with Type 2 and Type 1 Gaucher disease with parkinsonism had reduced dopamine storage and dopamine transporter reuptake. Levels of α-synuclein, a protein present as aggregates in Parkinson disease and related synucleinopathies, were selectively elevated in neurons from the patients with parkinsonism or Type 2 Gaucher disease. The cells were then treated with NCGC607, a small-molecule noninhibitory chaperone of glucocerebrosidase identified by high-throughput screening and medicinal chemistry structure optimization. This compound successfully chaperoned the mutant enzyme, restored glucocerebrosidase activity and protein levels, and reduced glycolipid storage in both iPSC-derived macrophages and dopaminergic neurons, indicating its potential for treating neuronopathic Gaucher disease. In addition, NCGC607 reduced α-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease. SIGNIFICANCE STATEMENT Because GBA1 mutations are the most common genetic risk factor for Parkinson disease, dopaminergic neurons were generated from iPSC lines derived from patients with Gaucher disease with and without parkinsonism. These cells exhibit deficient enzymatic activity, reduced lysosomal glucocerebrosidase levels, and storage of glucosylceramide and glucosylsphingosine. Lines generated from the patients with parkinsonism demonstrated elevated levels of α-synuclein. To reverse the observed phenotype, the neurons were treated with a novel noninhibitory glucocerebrosidase chaperone, which successfully restored glucocerebrosidase activity and protein levels and reduced glycolipid storage. In addition, the small-molecule chaperone reduced α-synuclein levels in dopaminergic neurons, indicating that chaperoning glucocerebrosidase to the lysosome may provide a novel therapeutic strategy for both Parkinson disease and neuronopathic forms of Gaucher disease.

Enzyme replacement therapy is standard of care for patients with Gaucher disease, as it significantly improves skeletal, visceral, and hematological symptoms. Few pathological studies have documented the extent of pathological findings in treated patients. Autopsy findings in five treated patients, who ultimately developed parkinsonism, ranged from the complete absence of Gaucher pathology to extensive involvement of multiple tissues, without correlation to age, genotype, spleen status, or dose/duration of therapy. Additional autopsies may elucidate modifiers and biomarkers contributing to disease burden and response to therapy.

Summary Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

Introduction: Identification of an association between mutations in the glucocerebrosidase gene (GBA1) and the development of parkinsonism has contributed to a greater understanding of the role of lysosomal function in neuronal degeneration. This review will discuss the phenotypic presentation of patients with GBA1-associated parkinsonism. Some treatment strategies will be discussed although treatment studies in this cohort are limited.Areas covered: Current literature suggests that parkinsonism associated with GBA1 mutations may have specific characteristics distinct from idiopathic Parkinson’s disease or parkinsonism due to other genetic mutations. In this review, we performed an electronic search in the PubMed database for papers using the terms ‘Parkinson disease’, ‘parkinsonism’, ‘Gaucher disease’, and ‘GBA1’. Papers were selected if they discussed or described clinical presentation, treatment and current research efforts related to these terms.Expert opinion: Although there are no studies identifyin...

Gaucher disease, the inherited deficiency of the enzyme glucocerebrosidase, is the most common of the lysosomal storage disorders. Type 2 Gaucher disease, the most severe and progressive form, manifests either prenatally or in the first months of life, followed by death within the first years of life. The rarity of the many lysosomal storage disorders makes their diagnosis a challenge, especially in the newborn period when the focus is often on more prevalent illnesses. Thus, a heightened awareness of the presentation of these rare diseases is necessary to ensure their timely consideration. This review, designed to serve as a guide to physicians treating newborns and infants with Gaucher disease, discusses the presenting manifestations of Type 2 Gaucher disease, the diagnostic work-up, associated genotypes and suggestions for management. We also address the ethical concerns that may arise with this progressive and lethal disorder, since currently available treatments may prolong life, but do not impact the neurological manifestations of the disease.

Gaucher disease (GD) is a recessively inherited autosomal lysosomal storage disease, the most severe of which is type 2, an acute neuronopathic form. We report an affected infant who inherited one mutant allele, Arg257Gln (c.887G>A; p.Arg296Gln) from his father, while the second, Gly202Arg (c.721G>A; p.Gly241Arg) arose by either maternal germline mosaicism or as a de novo mutation. This is the first time mutation Gly202Arg has been reported to be inherited non-traditionally. This report is part of a growing literature suggesting that Gaucher disease can be inherited via germline or de novo mutations, and emphasizes that it is critical for clinicians to consider such inheritance when making diagnostic decisions or providing genetic counseling.

Introduction By the time a person develops the motor manifestations of Parkinson's disease (PD), substantial loss of nigrostriatal dopamine neurons has already occurred. There is great interest in identifying biomarkers that can detect pre-clinical PD. Braak's neuropathological staging concept imputes early autonomic involvement. Here we report results from a small prospective cohort study about the utility of neuroimaging evidence of cardiac sympathetic denervation in predicting PD among individuals with multiple PD risk factors. Methods Subjects provided information about family history of PD, olfactory dysfunction, dream enactment behavior, and orthostatic hypotension at a protocol-specific website. From this pool, 27 people with at least 3 risk factors confirmed underwent cardiac 18 F-dopamine positron emission tomographic scanning and were followed for at least 3 years. Interventricular septal and left ventricular free wall concentrations of 18 F-dopamine-derived radioactivity were measured. Results Of the 27 subjects, 4 were diagnosed with PD within the 3-year follow-up period (Pre-Clinical PD group); 23 risk-matched (mean 3.2 risk factors) subjects remained disease-free (No-PD group). Compared to the No-PD group, the Pre-Clinical PD group had lower initial values for septal and free wall concentrations of 18 F-dopamine-derived radioactivity (p = 0.0248, 0.0129). All 4 Pre-Clinical PD subjects had evidence of decreased cardiac sympathetic innervation in the interventricular septum or left ventricular free wall, in contrast with 3 of 23 (13%) No-PD subjects (p = 0.0020 by Fisher's exact test). Conclusion People with multiple PD risk factors and diagnosed with PD within 3 years have evidence of antecedent cardiac sympathetic denervation. The findings fit with Braak's staging concept.

Mutations in the glucocerebroside gene, GBA1 , result in Gaucher disease, a rare lysosomal storage disorder. GBA1 mutations are also an important genetic risk factor for Parkinson disease. It was initially observed that some patients with Gaucher disease and their first-degree relatives developed parkinsonism. Screening of large cohorts then revealed that GBA1 mutations were more frequent in patients with Parkinson disease than controls. Patients with GBA1 -associated parkinsonism exhibit varying parkinsonian phenotypes but tend to have an earlier age of onset and more prominent cognitive deficits. Understanding this relationship will provide further insights into the genetics, pathogenesis, and treatment of Parkinson disease.