A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

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Homonymous hemianopia (HH) is a frequent deficit resulting from lesions to post-chiasmal brain structures with a significant negative impact on activities of daily living. To address the question how patients with HH may compensate their visual field defect in a naturalistic environment, we performed a driving simulation experiment and quantitatively analyzed both eye and head movements using a head-mounted pupil camera. 14 patients with HH and 14 matched healthy control subjects participated in the study. Based on the detection performance of dynamically moving obstacles, which appeared unexpectedly along the sides of the road track, we divided the patient group into a high- and a low-performance group. Then, we compared parameters of eye and head movements between the two patient groups and the matched healthy control group to identify those which mediate successful detection of potentially hazardous objects. Differences in detection rates could not be explained by demographic variables or the extent of the visual field defect. Instead, high performance of patients with HH in the naturalistic setting of our driving simulation depended on an adapted visual exploratory behavior characterized by a relative increase in the amplitude and a corresponding increase in the peak velocity of saccades, widening horizontally the distribution of eye movements, and by a shift of the overall distribution of saccades into the blind hemifield. The result of the group comparison analyses was confirmed by a subsequent stepwise regression analysis which identified the horizontal spread of eye movements as single factor predicting the detection of hazardous objects.

Introduction: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. Methods: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. Results: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. Discussion: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies.Muscle Nerve 57: [33][34][35][36][37][38][39] 2018 The differential diagnosis of acute neuropathies is limited and includes immune, toxic, infectious, and metabolic causes. While the diagnosis of acute inflammatory demyelinating polyneuropathy (e.g., classical Guillain-Barr e syndrome [GBS]) can be established with relative certainty on clinical and electrodiagnostic grounds, the differential diagnosis of acute symmetric axonal polyneuropathy, particularly when accompanied by normal cerebrospinal fluid (CSF) protein, extends beyond axonal GBS variants. Severe acute axonal neuropathy with a GBS-like pattern has been described with alcohol abuse, 1-3 after bariatric surgery (BS) 3 and gastrectomy, 4,5 and in anorexia. 6 Vomiting and weight loss have been described as risk factors. The etiology has been unclear, but multifactorial nutritional deficiencies have been postulated. The differentiation from GBS variants such as acute motor and sensory axonal neuropathy (AMSAN) or MillerFisher syndrome, toxic (arsenic) or metabolic (porphyria) neuropathies is important, as treatment differs. In a retrospective search of our electromyography (EMG) database, we identified 13 patients with this condition. MATERIALS AND METHODSOne of us (E.L.L.) collected the first 5 patients in this series between 2009 and 2015 from his EMG practice at our center. With approval from our local institutional review board, we systematically studied this neuropathy using a computerized search of the University of Rochester EMG database and electronic medical record from August 1999 to December 2015 including the original 5 patients. Search terms were "vomiting" or "alcoholism," and "axonal neuropathy." Inclusion criteria were presence of an axonal neuropathy and vomiting or alcoholism as well as an acute to subacute onset of symptoms. Exclusion criteria were known neuropathy or underlying conditions known to be associated with neuropathy (dia...

ObjectiveTo determine the frequency and relative importance of the most meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to identify the demographic and clinical features that are associated with the greatest disease burden in this population.MethodsWe performed a cross-sectional study involving 328 participants with FSHD. Collectively, participants reported the prevalence and relative importance of 274 symptoms and 15 symptomatic themes. We assessed the association between symptomatic theme prevalence and participants' age, sex, disease duration, pain level, employment status, and education.ResultsParticipants answered >48,000 questions regarding their disease burden. The symptomatic themes with the highest prevalence in our sample were problems with shoulders or arms (96.9%), limitations with activities (94.7%), core weakness (93.8%), fatigue (93.8%), limitations with mobility and walking (93.6%), changed body image due to the disease (91.6%), and pain (87.7%). Problems with shoulders and arms and limitations with mobility and walking had the greatest effect on participants' lives. Employment status and the report of pain had the most extensive association with the prevalence of symptoms, with employment being associated with 8 of 15 of the symptomatic themes and pain being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD experienced a similar prevalence of all symptomatic themes.ConclusionsAdults with FSHD experience a variety of symptoms that play an important role in their disease burden. These symptoms have a variable prevalence and importance in the FSHD population and are associated with disease duration, employment status, and pain level.