Novel Mutation in CACNA1A Associated with Activity-Induced Dystonia, Cervical Dystonia, and Mild Ataxia.

CACNA1A encodes the pore-forming α1 subunit of the neuronal voltage-gated Cav2.1 (P/Q-type) channels, which are predominantly localized at the presynaptic terminals of the brain and cerebellar neurons and play an important role in controlling neurotransmitter release. Mutations in CACNA1A have been associated with several autosomal dominant neurologic disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6. A 37-year-old woman presented with a history of slowly progressive, activity-induced stiffness, and pain in her right leg since age 15 and cervical dystonia since age 20. She denied any right leg stiffness or pain at rest, but when she began to walk, her right foot turned in and her right leg stiffened up. She also had neck pain, stiffness, and spams. There was no family history of similar symptoms. On physical exam, her strength, tone, and reflexes were normal in all extremities at rest. There was mild head titubation and very mild past pointing on finger-to-nose testing. MRI of the brain and spinal cord was unremarkable. This patient's clinical picture was felt to be most consistent with paroxysmal kinesigenic dyskinesia, as she has attacks of dystonia that are triggered by voluntary movement, last from a few seconds to a minute, and are relieved with rest. She was trialed on carbidopa/levodopa without improvement. A dystonia panel showed two potentially pathologic mutations, one in CACNA1A and the other in PNKP, along with a variant of unknown significance in ATP7B. The mutation in CACNA1A is C2324 G < A. It is heterozygous, autosomal dominant, and computer modeling suggests pathogenicity. This mutation has not been reported previously and is likely the cause of her paroxysmal dystonia; dystonia is sometimes seen during episodes of ataxia in EA2, and CACNA1A knockout mice exhibit dystonia and cerebellar atrophy. After receiving her genetic diagnosis, the patient was trialed on acetazolamide without improvement in her dystonia symptoms. This is the second case report of a patient with cervical dystonia and cerebellar ataxia associated with a mutation in CACNA1A.

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS.

OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).

Skill, confidence and support: conceptual elements of a child/youth caregiver training program in amyotrophic lateral sclerosis - the YCare protocol.

Aim: Pilot study of a novel caregiving training and support intervention for children and youth <19 years, who provide care for person living with amyotrophic lateral sclerosis. Materials & methods: Youth (n = 19) between the ages of 8-19 years, participated in skills training and support program (basic care, feeding/communication, assistive devices and social support). Results: Participants reported significant increase in confidence in tasks, including communication systems and respiratory equipment. Participants identified goal setting and creating behaviors to reach those goals. Benefits of training included that the day changed their perceptions of care and meeting 'like' peers. Conclusion: Results of the pilot YCare intervention underscores the need to assess how young caregivers feel and respond to new tasks when receiving support from developmentally similar peers.

Novel destabilizing Dynactin variant (DCTN1 p.Tyr78His) in patient with Perry syndrome.

INTRODUCTION: Perry syndrome, also recognized as Perry disease, is a rare autosomal dominant disorder characterized by midlife-onset atypical parkinsonism, apathy or depression, respiratory failure and weight loss caused by a mutation in the Dynactin (DCTN1) gene. CASE DESCRIPTION: A fifty-six years-old adopted male presented with atypical parkinsonism with bradykinesia and postural instability, apathy, weight loss, and recurrent respiratory failure due to central hypoventilation requiring tracheostomy. METHODS AND RESULTS: Clinical workup revealed a novel DCTN1 p.Tyr78His variant. Using bioinformatic protein structure modeling, we compare our patient's variant to known DCTN1 mutations and predict protein stability of each variant at the CAP-Gly domain of p150Glued. All eight variants causing Perry syndrome, as well as Tyr78His, are located at site expected to interact with MAPRE1 tail and are predicted to be destabilizing. Variants causing atypical parkinsonism with incomplete Perry syndrome phenotype (K56R and K68E) are not significantly destabilizing in silico. CONCLUSION: We propose p.Tyr78His as the ninth pathogenic DCTN1 variant causing Perry syndrome. Bioinformatic protein modeling may provide additional window to understand and interpret DCTN1 variants, as we observed non-destabilizing variants to have different phenotype than destabilizing variants.

US data on children and youth caregivers in amyotrophic lateral sclerosis.

OBJECTIVE: An estimated 1.4 million young caregivers (<19 years of age) in the United States provide care to ill family members yet remain hidden from state and national caregiving programs and services, including amyotrophic lateral sclerosis (ALS) caregiving services. Given the intensive care needs and acuity of ALS, appreciation of the young caregiver experience within the family context may have a significant impact on patient and family quality of life. This article seeks to identify family and youth caregiver characteristics and perceptions of care through interviews with 38 youth caregivers and their families with ALS. METHODS: Online adult surveys and follow-up youth interviews were conducted with families with ALS across the United States in this cross-sectional study. Participants were accessed through chapters of the ALS Association. Both thematic content analysis and descriptive statistics were used. RESULTS: Youth caregivers (n = 38) ranged in age from 8 to 18 years and spent an average of 5 h/d providing care for an average of 12 tasks. Persons with ALS relied on youth primarily due to cost and identified complex feelings about relying on youth caregivers, including feeling like a failure, guilty, but proud. CONCLUSION: Youth are intricately involved in all areas of caregiving in ALS. They are isolated and have little training or guidance in care, yet they are able to identify ways to manage their care burden. Results provide clear implications for health care professionals in designing best care and support practices for persons with ALS and their young caregivers.

Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.

Generation and propagation of the action potential.

The action potential is a regenerative electrical phenomenon observed on excitable cell membranes that allows the propagation of signals without attenuation. It is the cornerstone of neurophysiology. This chapter is a review of the action potential and its relationship to the signals that are studied in clinical neurophysiology. The first section traces the history of key scientific discoveries over the last 250 years that have led to our present-day understanding of the electrical properties of nerve and muscle. The second section considers the molecular and biophysical mechanisms that are responsible for the electrical potentials that can be measured across all eukaryotic cell membranes, but specifically in neurons, nerves, and muscle. Mechanisms underlying propagation action potentials within the nervous system are also examined. The concluding section is a brief overview of the normal "macroscopic" signals that are commonly recorded from the central and peripheral nervous system, and how they are derived from action potentials.

Siblings With Mutations in TRAPPC11 Presenting With Limb-Girdle Muscular Dystrophy 2S.

Limb-girdle muscular dystrophy 2S (LGMD2S) is an autosomal recessive condition due to mutations in the TRAPPC11 gene. It is recently described with only 9 prior reported individuals. In addition to the muscular dystrophy, some affected individuals have small head size, global developmental delay, seizures, cataracts, and liver problems. Siblings with an uncharacterized LGMD were assessed; whole-exome screening revealed compound heterozygous mutations in the TRAPPC11 gene. Their presentation helps confirm the emerging phenotype for LGMD2S.

Spinocerebellar Ataxia 7: A Report of Unaffected Siblings Who Married into Different SCA 7 Families.

Two families with spinocerebellar ataxia type 7 are presented. Although there are affected cousins, it is not the sibling parents that transmitted the mutation. It is assumed that the affected families share a common ancestor.

Elderly onset of weakness in facioscapulohumeral muscular dystrophy.

A 77-year-old male is presented. He had onset of proximal weakness 10 years earlier. His course was slowly progressive. Despite having phenotypic features of facioscapulohumeral muscular dystrophy (FSH), genetic testing for this was delayed because of his age of onset, lack of family history, and benign appearing muscle biopsy. This case is one of the oldest onset of weakness in genetically confirmed FSH and highlights the recognized expansion in phenotype that has occurred since the advent of genetic testing.

External neurolysis may result in early return of function in some muscle groups following brachial plexus surgery.

A retrospective chart review, of those individuals seen and operated on by the Multidisciplinary Brachial Plexus Clinic team at the University of Kentucky Chandler Medical Center, was undertaken to determine those individuals who had early return-of-function following surgery for BPI. Seven patients met our criteria, with four of them having substantial improvement of two or more points gained on the MRC rating scale, in one or more muscle groups within six to eight weeks after surgery. Those patients with return-of-function earlier than expected for axonal regrowth from nerve transfer or grafting, had evidence for continuity but no significant reinnervation before surgery in the muscle groups that improved. We theorize that this early improvement is related to a compression-induced dysfunction which inhibited reinnervation and was relieved by performing external neurolysis.

Sporadic Creutzfeldt-Jakob disease presenting as nonconvulsive status epilepticus case report and review of the literature.

Creutzfeldt-Jakob disease (CJD) is the most common transmissible human spongiform encephalopathy. Seizures and status epilepticus (SE) are an uncommon finding in CJD. We report a 64-year-old woman with rapid cognitive decline who had electroencephalographic (EEG) changes suggestive of nonconvulsive status epilepticus (NCSE). She was later diagnosed with sporadic CJD (sCJD). We also reviewed the literature for published cases on this topic. MEDLINE was employed to identify all published reports of CJD and SE. We identified 8 references with a total of 12 cases with CJD and NCSE. sCJD should be considered in the differential diagnosis of any patient who presents with rapid cognitive decline and EEG changes consistent with status epilepticus.

Melatonin-analog, beta-methyl-6-chloromelatonin, supplementation in spinal cord injury.

Spinal cord injury (SCI) is a devastating condition. Melatonin supplementation has been shown to lessen SCI, but its use has been limited by its side effect profile. In this work, rats underwent a moderate-to-severe contussional SCI with either placebo or beta-methyl-6-chloromelatonin, 10mg/kg or 100mg/kg supplementation. The 10mg/kg supplementation demonstrated benefit; the 100mg/kg dosage was limited by toxicity. This is the first work to assess a melatonin analog in SCI.

Exacerbation of spinal cord injury due to static compression occurring early after onset.

OBJECT: The authors used a rat model to assess spinal cord compression following an incomplete spinal cord injury (SCI). METHODS: Incomplete SCI was created in the thoracic spinal cord in a novel application of a rodent spinal cord compression model. A moderate impaction force was applied instantaneously to the spinal cord and was followed by 0 seconds, 10 seconds, 30 seconds, or 5 minutes of continued compression (termed "dwell"). The different groups were assessed by behavioral testing with the Basso, Beattie, Bresnahan locomotor rating scale, and with histological injury quantification and morphometrical analysis. RESULTS: Compression after the SCI resulted in worsened Basso, Beattie, Bresnahan scale scores; however, the duration of compression was not significant. Compression did not significantly affect the percentage of spared total tissue, percent spared total white matter, or percent spared total gray matter. Percent spared tissue at the epicenter of injury was statistically worsened by compression but not in a time-dependent manner. CONCLUSIONS: The authors' results suggest that spinal cord compression after the initial injury is an additional mechanism by which SCI worsens, and that the mechanism of this injury occurs rapidly. These data, however, do not support duration of compression as a significant variable.

Coxsackie B meningoencephalitis in a patient with acquired immunodeficiency syndrome and a multiple sclerosis-like illness.

Both Coxsackie infection and multiple sclerosis (MS) are rare in human immunodeficiency virus (HIV) infection. We report a 35-year-old woman with known HIV infection of 12 years' duration and a clinical illness of 4 years' duration consistent with MS. The latter was characterized by optic neuritis, bilateral abducens palsies, recurrent Bell's palsy, hemiparesis, and ataxia coupled with white matter abnormalities on magnetic resonance imaging (MRI). Autopsy revealed Coxsackie B meningoencephalitis; no other infectious disease were detected and no histopathological features of MS were evident. We suggest that the relapsing-remitting neurological disease in this patient was the consequence of Coxsackie B meningoencephalitis. This is the first case report, to the best of our knowledge, of an enteroviral meningoencephalitis complicating human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS).

Myasthenia gravis associated with etanercept therapy.

Etanercept is an antagonist of tumor necrosis factor alpha that was developed to treat rheumatoid arthritis. In this report we present a patient who developed myasthenia gravis while taking etanercept and had resolution of symptoms after stopping it. This is the first report of this potential side effect and is of additional interest, because etanercept has been proposed as a treatment for myasthenia gravis.

Proximal sciatic nerve intraneural ganglion cyst.

Intraneural ganglion cysts are nonneoplastic, mucinous cysts within the epineurium of peripheral nerves which usually involve the peroneal nerve at the knee. A 37-year-old female presented with progressive left buttock and posterior thigh pain. Magnetic resonance imaging revealed a sciatic nerve mass at the sacral notch which was subsequently revealed to be an intraneural ganglion cyst. An intraneural ganglion cyst confined to the proximal sciatic nerve has only been reported once prior to 2009.