Faculty Bibliography
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208
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
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.
PMID: 33242422
ISSN: 1097-4199
CID: 5429222
Frequency and burden of gastrointestinal symptoms in familial dysautonomia
PURPOSE/OBJECTIVE:Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (HSAN-3) that is clinically characterized by impaired pain and temperature perception and abnormal autonomic function. Patients with FD have gastrointestinal dysmotility and report a range of gastrointestinal symptoms that have yet to be systematically evaluated. The aim of this study was to establish the frequency and severity of gastrointestinal symptoms in patients with FD. METHODS:The validated National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) survey questionnaire, together with additional FD-specific questions, were distributed to 202 living patients with genetically confirmed FD who had been identified from the New York University FD Patient Registry or, when relevant, to their respective caretaker. As a comparison group, we used a general US adult population for whom PROMIS scores were available (N = 71,812). RESULTS:Of the 202 questionnaires distributed, 77 (38%) were returned, of which 53% were completed by the patient. Median age of the respondents was 25 years, and 44% were male. Gastrostomy tube was the sole nutrition route for 25% of the patients, while 53% were reliant on the gastrostomy tube only for liquid intake. The prevalence of gastrointestinal symptoms was significantly higher in each of the eight domains of PROMIS in patients with FD than in the controls. Gastrointestinal symptoms as measured by raw scores on the PROMIS scale were significantly less severe in the FD patient group than in the control population in all domains with the exception of the abdominal pain domain. The surveys completed by caregivers reported the same burden of symptoms as those completed only by patients. CONCLUSION/CONCLUSIONS:Gastrointestinal symptoms affect nearly all patients with FD. Gastrointestinal symptoms are more prevalent in adult patients with FD than in the average US adult population but are less severe in the former.
PMID: 33025279
ISSN: 1619-1560
CID: 4631552
alpha-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy
ISI:000650825200001
ISSN: 0001-6322
CID: 4893752
alpha-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy (May, 10.1007/s00401-021-02324-0, 2021) [Correction]
ISI:000653594500001
ISSN: 0001-6322
CID: 4894282
Autoantibodies blocking M3 muscarinic receptors cause postganglionic cholinergic dysautonomia
A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M1 -M5 ) we identified in the patient's serum antibodies that selectively bound to M3 receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M3 receptor activation. Thus, autoantibodies against M3 acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.
PMID: 32833276
ISSN: 1531-8249
CID: 4583782
Maternal Breastfeeding or Wet Nursing? Religion, Persecution, and Ideology in the 17th Century
PMID: 32960079
ISSN: 1556-8342
CID: 4624592
Clinical Trials for Neurogenic Orthostatic Hypotension: A Comprehensive Review of Endpoints, Pitfalls, and Challenges
Neurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.
PMID: 32906173
ISSN: 1098-9021
CID: 4609432
Can Autonomic Testing and Imaging Contribute to the Early Diagnosis of Multiple System Atrophy? A Systematic Review and Recommendations by the Movement Disorder Society Multiple System Atrophy Study Group
Background/UNASSIGNED:In the current consensus diagnostic criteria, the diagnosis of probable multiple system atrophy (MSA) is based solely on clinical findings, whereas neuroimaging findings are listed as aid for the diagnosis of possible MSA. There are overlapping phenotypes between MSA-parkinsonian type and Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and between MSA-cerebellar type and sporadic adult-onset ataxia resulting in a significant diagnostic delay and misdiagnosis of MSA during life. Objectives/UNASSIGNED:In light of an ongoing effort to revise the current consensus criteria for MSA, the Movement Disorders Society Multiple System Atrophy Study Group performed a systematic review of original articles published before August 2019. Methods/UNASSIGNED:We included articles that studied at least 10 patients with MSA as well as participants with another disorder or control group for comparison purposes. MSA was defined by neuropathological confirmation, or as clinically probable, or clinically probable plus possible according to consensus diagnostic criteria. Results/UNASSIGNED:We discuss the pitfalls and benefits of each diagnostic test and provide specific recommendations on how to evaluate patients in whom MSA is suspected. Conclusions/UNASSIGNED:This systematic review of relevant studies indicates that imaging and autonomic function tests significantly contribute to increasing the accuracy of a diagnosis of MSA.
PMCID:7533961
PMID: 33043073
ISSN: 2330-1619
CID: 4631592
Acute Sensory and Autonomic Neuronopathy: A Devastating Disorder Affecting Sensory and Autonomic Ganglia
Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.
PMID: 32906171
ISSN: 1098-9021
CID: 4609422
Special Issue on Dysautonomia
PMID: 33111287
ISSN: 1098-9021
CID: 4679182
