Gerpen, Jay A. van

AbstractBackgroundBlepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole‐exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation.MethodsWe performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis.ResultsCosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio‐cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia.ConclusionsOur WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.

ABSTRACTBackground: Dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes has been associated with the unique neuropathology of MSA. We hypothesized that apolipoprotein E, which is associated with neurodegeneration, may also play a role in the pathogenesis of MSA.Objective: This study evaluated genetic associations of Apolipoprotein E alleles with risk of MSA and α‐synuclein pathology, and also examined whether apolipoprotein E isoforms differentially affect α‐synuclein uptake in a oligodendrocyte cell.Methods: One hundred sixty‐eight pathologically confirmed MSA patients, 89 clinically diagnosed MSA patients, and 1,277 control subjects were genotyped for Apolipoprotein E. Human oligodendrocyte cell lines were incubated with α‐synuclein and recombinant human apolipoprotein E, with internalized α‐synuclein imaged by confocal microscopy and cells analyzed by flow cytometry.Results: No significant association with risk of MSA or was observed for either Apolipoprotein E ɛ2 or ɛ4. α‐Synuclein burden was also not associated with Apolipoprotein E alleles in the pathologically confirmed patients. Interestingly, in our cell assays, apolipoprotein E ɛ4 significantly reduced α‐synuclein uptake in the oligodendrocytic cell line.Conclusions: Despite differential effects of apolipoprotein E isoforms on α‐synuclein uptake in a human oligodendrocytic cell, we did not observe a significant association at the Apolipoprotein E locus with risk of MSA or α‐synuclein pathology. © 2018 International Parkinson and Movement Disorder Society

Key Clinical Message This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the CASR gene and a variant of uncertain significance in PDGFRB . The clinical phenotype is likely explained by the CASR variant, but we discuss how the PDGFRB variant could also participate in the phenotype.

AbstractIntroductionWe sought to assess the individual and combined contribution of limbic and neocortical α‐synuclein, tau, and amyloid β (Aβ) to duration of illness in dementia with Lewy bodies (DLB).MethodsQuantitative digital pathology of limbic and neocortical α‐synuclein, tau, and Aβ was assessed in 49 patients with clinically probable DLB. Regression modeling examined the unique and shared contribution of each pathology to the variance of illness duration.ResultsPatients with diffuse Lewy body disease had more severe pathology of each type and a shorter duration of illness than individuals with transitional Lewy body disease. The three pathologies accounted for 25% of the total variance of duration of illness, with 19% accounted for by α‐synuclein alone or in combination with tau and Aβ. When the diffuse Lewy body disease group was examined separately, α‐synuclein deposition significantly exceeded that of tau and Aβ. In this model, 20% of 24% total variance in the model for duration of illness was accounted for independently by α‐synuclein.DiscussionIn DLB, α‐synuclein is an important predictor of disease duration, both independently and synergistically with tau and Aβ.

Introduction: Alexander disease is a rare neurodegenerative disease caused by variants in the glial fibrillary acidic protein gene (GFAP). This disorder can develop as an infantile, juvenile or adult-onset form and is characterized by several clinical features, including macrocephaly, seizures, ataxia, and bulbar/pseudobulbar signs. While the majority of these patients have the more progressive infantile form which causes severe leukodystrophy and early death; the less common adult form is more variable (ie, onset age, symptoms), with bulbar dysfunction as the primary feature. Case Report: In our investigation, we describe a patient with progressive neuromuscular issues including dyspnea, dysphagia, dysarthria and progressive ataxia with palatal tremor. Conclusions: Through genetic testing, we determined that our patient has a novel variant in GFAP typical of Alexander disease.

Abstract Background Cognitive impairment is one of the core features of progressive supranuclear palsy. This study aimed to clarify the profile of cognitive impairment and its underlying pathology in progressive supranuclear palsy. Methods We retrospectively reviewed medical records to evaluate the pattern and severity of cognitive impairment in 121 autopsy‐confirmed progressive supranuclear palsy patients. A subset of 37 patients underwent neuropsychological evaluation as part of their clinical workup. The burden of progressive supranuclear palsy‐related tau pathology (neurofibrillary tangles/pretangles, coiled bodies, tufted astrocytes, and threads) was semiquantitatively scored in 20 vulnerable brain regions. Concurrent pathologies potentially associated with cognitive impairment, such as Alzheimer's‐type pathology, were also assessed. To evaluate possible genetic risk factors for cognitive impairment, genetic analysis for APOE and MAPT was performed. Results Ninety patients (74%) had documented cognitive impairment based on neurologic evaluation. In a subgroup with neuropsychological testing (n = 37), executive functioning was the most severely impaired cognitive domain. A global cognitive impairment index (Spearman's rho, −0.49; P = 0.005) and executive functioning were negatively correlated with total tau burden (Spearman's rho, −0.51; P = 0.003), but not correlated with the Alzheimer's‐type pathology. APOE ɛ4 carriers had more severe amyloid pathology, but total tau burden and a global cognitive impairment index did not differ from APOE ɛ4 noncarriers. Conclusion Cognitive impairment in progressive supranuclear palsy, most notably executive dysfunction, is associated with severity of progressive supranuclear palsy‐related tau pathology. © 2017 International Parkinson and Movement Disorder Society

Key Clinical MessageHereditary spastic paraplegia is a group of clinically and genetically heterogeneous neurodegenerative disorders, often characterized by weakness and spasticity in the lower limbs. In our study, we describe a spastic paraplegia type 7 patient with an expanded phenotype who was diagnosed after the discovery of pathogenic variants in SPG7.

ABSTRACTBackgroundThis study aimed to determine the frequency of transactive response DNA binding protein 43 kDa pathology in PSP, the clinical features of patients with this pathology, and genetic risk factors for it.MethodsHippocampal sections were screened with immunohistochemistry for transactive response DNA binding protein 43 kDa in 945 PSP cases. A subset of 261 cases that were negative in hippocampus was screened in the amygdala. The density and disruption of this pathology, as well as regional tau burden, and clinical and genetic characteristics were analyzed.ResultsWe observed transactive response DNA binding protein 43 kDa pathology in 47 cases in the hippocampus and an additional 9 cases that only affected the amygdala. Hippocampal sclerosis was the strongest risk factor, followed by Alzheimer's disease pathology, argyrophilic grain disease, and older age at death. Five stages of transactive response DNA binding protein 43 kDa pathology were identified in PSP: Stage A had pathology only in the amygdala (16%); stage I had pathology confined to the hippocampus and entorhinal cortex (9%); stage II included both regions of stage A and I (38%); stage III spread further to medial occipitotemporal gyrus (20%); and stage IV had pathology in the dorsolateral frontal lobe (18%). Anatomical areas vulnerable to PSP pathology had varying degrees of this pathology in stage II and later. PSP with transactive response DNA binding protein 43 kDa pathology were older at disease onset and had lower median MMSE scores; however, the latter was driven by concurrent pathologies.ConclusionsDistribution and clinical characteristics of transactive response DNA binding protein 43 kDa pathology in PSP were influenced by concurrent pathologies. This is the first study to observe that PSP‐vulnerable regions are also susceptible to this non‐tau pathology. © 2016 International Parkinson and Movement Disorder Society.

ABSTRACTBackgroundThe objectives of this study were to elucidate any potential association between α‐synuclein pathology and cognitive impairment and to determine the profile of cognitive impairment in multiple system atrophy (MSA) patients. To do this, we analyzed the clinical and pathologic features in autopsy‐confirmed MSA patients.MethodsWe retrospectively reviewed medical records, including neuropsychological test data, in 102 patients with autopsy‐confirmed MSA in the Mayo Clinic brain bank. The burden of glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were semiquantitatively scored in the limbic regions and middle frontal gyrus. We also assessed concurrent pathologies potentially causing dementia including Alzheimer's disease, hippocampal sclerosis, and cerebrovascular pathology.ResultsOf 102 patients, 33 (32%) were documented to have cognitive impairment. Those that received objective testing, deficits primarily in processing speed and attention/executive functions were identified, which suggests a frontal‐subcortical pattern of dysfunction. Of these 33 patients with cognitive impairment, 8 patients had concurrent pathologies of dementia. MSA patients with cognitive impairment had a greater burden of neuronal cytoplasmic inclusions in the dentate gyrus than patients without cognitive impairment, both including and excluding patients with concurrent pathologies of dementia.ConclusionsThe cognitive deficits observed in this study were more evident on neuropsychological assessment than with cognitive screens. Based on these findings, we recommend that clinicians consider more in‐depth neuropsychological assessments if patients with MSA present with cognitive complaints. Although we did not identify the correlation between cognitive deficits and responsible neuroanatomical regions, a greater burden of neuronal cytoplasmic inclusions in the limbic regions was associated with cognitive impairment in MSA. © 2016 International Parkinson and Movement Disorder Society