Orthostatic Tremor and Orthostatic Myoclonus: Weight-bearing Hyperkinetic Disorders: A Systematic Review, New Insights, and Unresolved Questions

Background: Orthostatic tremor (OT) and orthostatic myoclonus (OM) are weight-bearing hyperkinetic movement disorders most commonly affecting older people that induce “shaky legs” upon standing. OT is divided into “classical” and “slow” forms based on tremor frequency. In this paper, the first joint review of OT and OM, we review the literature and compare and contrast their demographic, clinical, electrophysiological, neuroimaging, pathophysiological, and treatment characteristics. Methods: A PubMed search up to July 2016 using the phrases “orthostatic tremor,” “orthostatic myoclonus,” “shaky legs,” and “shaky legs syndrome” was performed. Results: OT and OM should be suspected in older patients reporting unsteadiness with prolonged standing and/or who exhibit cautious, wide-based gaits. Surface electromyography (SEMG) is necessary to verify the diagnoses. Functional neuroimaging and electrophysiology suggest the generator of classical OT lies within the cerebellothalamocortical network. For OM, and possibly slow OT, the frontal, subcortical cerebrum is the most likely origin. Clonazepam is the most useful medication for classical OT, and levetiracetam for OM, although results are often disappointing. Deep brain stimulation appears promising for classical OT. Rolling walkers reliably improve gait affected by these disorders, as both OT and OM attenuate when weight is transferred from the legs to the arms. Discussion: Orthostatic hyperkinesias are likely underdiagnosed, as SEMG is often unavailable in clinical practice, and thus may be more frequent than currently recognized. The shared weight-bearing induction of OT and OM may indicate a common pathophysiology. Further research, including use of animal models, is necessary to better define the prevalence and pathophysiology of OT and OM, in order to improve their treatment, and provide additional insights into basic balance and gait mechanisms

Expanded phenotype in a patient with spastic paraplegia 7

No abstract available

Anticipation in a family with primary familial brain calcification caused by an SLC20A2 variant

Aim of the study To describe a family with primary familial brain calcification (PFBC) due to SLC20A2 variant showing possible genetic anticipation. Materials and methods We conducted historical, genealogical, clinical, and radiologic studies of a family with PFBC. Clinical evaluations including neurological examination and head computed tomography (CT) scans of a proband and her father were performed. They provided additional information regarding other family members. To identify a causative gene variant, we performed whole-exome sequencing for the proband followed by segregation analysis in other affected members using direct sequencing. Results In this family, nine affected members were identified over four generations. The proband suffered from chronic daily headache including thunderclap headache. We identified an SLC20A2 (c.509delT, p.(Leu170*)) variant in three affected members over three generations. Interestingly, the age of onset became younger as the disease passed through successive generations, suggestive of genetic anticipation. Conclusions and clinical implications For clinical purpose, it is important to consider thunderclap headache and genetic anticipation in PFBC caused by SLC20A2 variants. Further investigation is required to validate our observation

Co-occurrence of a novel PDGFRB variant and likely pathogenic variant in CASR in an individual with extensive intracranial calcifications and hypocalcaemia

No abstract available

Spinocerebellar ataxia type 6 family with phenotypic overlap with Multiple System Atrophy

Aim of the study. Multiple system atrophy (MSA) and spinocerebellar ataxia (SCA) share similar symptomatology. We describe a rare occurrence of familial MSA that proved to be SCA6 upon genetic analysis.Materials and methods. Eighty MSA patients were enrolled in our study; blood samples were collected and genetic screening of the familial case for known SCA loci was performed.Results. A 68-year-old woman presented with recurrent and severe episodes of light-headedness, imbalance, frequent falls, neck and lower back stiffness, subjective arm and leg weakness, and numbness and tingling in both feet. One year later, her condition had declined; she experienced more falls, worsening instability, again more generalised but still subjective weakness, impaired fine motor movements, slurred speech, difficulty swallowing, episodes of choking, bladder incontinence, and constipation. Clinical suspicion included parkinsonism, MSA, and SCA. The patient was enrolled in our MSA study and was found to have 22 and 12 CAG repeats in CACNA1A. The other 79 clinical MSA patients were negative for SCA6 screening.Conclusions and clinical implications. While MSA and SCA may have similar presentations during early disease stages, the presence of both conditions on the list of differential diagnoses can be a diagnostic dilemma. Further analysis will aid in developing a biomarker to distinguish between the two conditions and guide proper management

A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia

Acute Flaccid Paralysis and West Nile Virus Infection

Acute weakness associated with West Nile virus (WNV) infection has previously been attributed to a peripheral demyelinating process (Guillain-Barré syndrome); however, the exact etiology of this acute flaccid paralysis has not been systematically assessed. To thoroughly describe the clinical, laboratory, and electrodiagnostic features of this paralysis syndrome, we evaluated acute flaccid paralysis that developed in seven patients in the setting of acute WNV infection, consecutively identified in four hospitals in St. Tammany Parish and New Orleans, Louisiana, and Jackson, Mississippi. All patients had acute onset of asymmetric weakness and areflexia but no sensory abnormalities. Clinical and electrodiagnostic data suggested the involvement of spinal anterior horn cells, resulting in a poliomyelitis-like syndrome. In areas in which transmission is occurring, WNV infection should be considered in patients with acute flaccid paralysis. Recognition that such weakness may be of spinal origin may prevent inappropriate treatment and diagnostic testing

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once