Integrating Whole-Genome Sequencing in Clinical Genetics: A Novel Disruptive Structural Rearrangement Identified in the Dystrophin Gene (DMD).

While in most patients the identification of genetic alterations causing dystrophinopathies is a relatively straightforward task, a significant number require genomic and transcriptomic approaches that go beyond a routine diagnostic set-up. In this work, we present a Becker Muscular Dystrophy patient with elevated creatinine kinase levels, progressive muscle weakness, mild intellectual disability and a muscle biopsy showing dystrophic features and irregular dystrophin labelling. Routine molecular techniques (Southern-blot analysis, multiplex PCR, MLPA and genomic DNA sequencing) failed to detect a defect in the DMD gene. Muscle DMD transcript analysis (RT-PCR and cDNA-MLPA) showed the absence of exons 75 to 79, seen to be present at the genomic level. These results prompted the application of low-coverage linked-read whole-genome sequencing (WGS), revealing a possible rearrangement involving DMD intron 74 and a region located upstream of the PRDX4 gene. Breakpoint PCR and Sanger sequencing confirmed the presence of a ~8 Mb genomic inversion. Aberrant DMD transcripts were subsequently identified, some of which contained segments from the region upstream of PRDX4. Besides expanding the mutational spectrum of the disorder, this study reinforces the importance of transcript analysis in the diagnosis of dystrophinopathies and shows how WGS has a legitimate role in clinical laboratory genetics.

Focal myositis with neurogenic atrophy: A case report.

Focal myositis is a very rare form of inflammatory myopathy, with unknown etiology. We describe a 44-year-old previously healthy man who noticed a painless swelling on his left forearm, following trauma over the left cubital fossa. The swelling grew progressively over 2 years. He had otherwise no weakness complaints. Physical and neurological examinations were otherwise normal. Creatine kinase and aldolase levels were increased (1,009 U/L and 11.9 U/L, respectively); autoimmunity panel was negative. MRI showed diffuse edema and gadolinium enhancement of muscles innervated by the median nerve. EMG revealed repetitive complex discharges and patterns of continuous muscular activity. The mass was biopsied disclosing findings consistent with focal myositis. Focal myositis with muscular atrophy is a rare situation; the inflammatory mechanism is yet to be defined, but it seems to be a situation with slow progression, with tendency to stabilization.
.

Epidemiology of myasthenia gravis in Northern Portugal: Frequency estimates and clinical epidemiological distribution of cases.

INTRODUCTION: In this study we estimated the prevalence, incidence, and mortality of myasthenia gravis (MG) in northern Portugal and characterized the clinical features of the patients identified. METHODS: We used 2 data sources: clinical records from the hospitals and pyridostigmine prescription registers. RESULTS: On December 31, 2013, we estimated a point prevalence of 111.7 patients per million population. The highest prevalence was observed in the group >65 years of age, especially in men (288.1 per million). During 2013, we estimated an incidence rate of 6.3 per million per year. Among women, the incidence rate was highest in the 15-49-year age group; in men, incidence increased with age up to 22.1 per million in those >65 years old. The MG-related mortality rate was 0.5 per million. CONCLUSIONS: These figures are in keeping with similar studies and emphasize the importance of diagnosis and management of MG in elderly populations. Muscle Nerve 54: 413-421, 2016.

Refractory CIDP successfully treated with autologous haematopoietic stem cell transplantation in a patient with monoclonal gammopathy of undetermined significance (MGUS) and rheumatoid arthritis.

Autologous haematopoietic stem cell transplantation is an emerging treatment option in refractory chronic inflammatory demyelinating polyradiculoneuropathy. We describe a case of a 46-year-old male, with history of IgG/lambda monoclonal gammopathy, who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy at 27 years of age. After an initial 10-year period of corticotherapy response, the patient experienced severe relapses and disease progression, evolving to a refractory state. First-line and escalating treatment could not achieve clinical stabilization, leading to severe disability. Pre-treatment with ibrutinib was initiated and autologous haematopoietic stem cell transplantation was performed without significant complications. Marked clinical improvement was observed in the following months, both subjective and objective. A significant proportion of the patients who respond to the first-line immunosuppressive therapy eventually become treatment-refractory. Autologous haematopoietic stem cell transplantation may be a treatment option, offering long-term remission with an overall acceptable side effect and risk profile.

MuSK myasthenia gravis and pregnancy.

Muscle specific kinase (MuSK) myasthenia gravis (MG, MuSK-MG) is a rare subgroup of MG affecting mainly women during childbearing years. We investigated the influence of pregnancy in the course of MuSK-MG and pregnancy outcomes in females with MuSK-MG. A multicentre cohort of 17 women with MuSK-MG was studied retrospectively; 13 of them with ≥1 pregnancy. MuSK-MG onset age was 35,4 years; 23,0% had other autoimmune disorder; 46,2% were treatment refractory. Thirteen women experienced 27 pregnancies, either after MG onset (group I) (n = 4; maternal age at conception = 29.8 years) or before MG onset (group II) (n = 23; maternal age at conception = 26.2 years). In group I pregnancy occurred in average 9.8 years after the MG onset; it occurred in average 17.0 years before MG in group II. In group I, all were on steroids at time of conception, one on azathioprine and another receiving IVIG regularly. There were mild exacerbations that responded to treatment adjustments. There were no relapses in the 12 months following the delivery. There was no pre-eclampsia, birth defects or stillbirths in either group; 3 miscarriages in group II. One case of neonatal MG was recorded. In this small series, pregnancy did not seem to precipitate MuSK-MG or to have a major influence in the MuSK-MG course, and there was no apparent negative impact in pregnancy outcomes in those where pregnancy followed the MG onset. The weight was lower in the newborn of the group I mothers, although none had low birth weight.

Left ventricular function in adults with muscular dystrophies: genotype-phenotype correlations.

BACKGROUND: Left ventricular dysfunction (LVD) is a clinical manifestation of muscular dystrophy (MD) in adults and an important prognostic factor. However, there is a lack of recommendations concerning cardiac followup of these patients. The aim of this work was to evaluate the prevalence of systolic LVD in adults with MD. METHODS: The patients, referred from a Neuromuscular Diseases Unit, underwent clinical evaluation, ECG and transthoracic echocardiogram. Serum troponin I and NT-proBNP were also evaluated. Systolic LVD was defined by an ejection fraction of <0.45 and/or shortening fraction of <0.25. RESULTS: During a one-year period, we evaluated 24 consecutive patients, 16 men, age 33 +/- 12 years (age at myopathy diagnosis 23 +/- 12 years). They had the following MD: dystrophinopathies--four patients (Duchenne: 1, Becker: 3); Steinert myotonic dystrophy--nine patients; limb-girdle myopathies--six patients; facioscapulohumeral (FSH) myopathies--four patients; and one dysferlinopathy (Miyoshi myopathy). The MD diagnosis, based on clinical and histological criteria, was genetically confirmed in 18 cases (75%). Five patients (20.8%) had thoracic pain, four (16.6%) dyspnea and one a history of syncope. ECG abnormalities were present in 14 cases (58.3%). Stolic LVD or left ventricular remodeling were present in six patients (25%): three with dystrophinopathies, one with limb-girdle myopathy, one with FSH dystrophy and one with myotonic dystrophy. Three patients (12.5%) were diagnosed with heart failure according to the European Society of Cardiology criteria. Three of the five patients with left ventricular dysfunction had elevation of NT-proBNP. One patient with Becker dystrophy had slight elevation of troponin I. In patients with systolic LVD or LV remodeling, the mutations identified were: deletion in intron 1 to exon 49 (one Duchenne MD patient) and deletions in exons 45 to 51 (two Becker MD patients) in the dystrophin gene; deletion of D4Z4 repeats in the DFS locus (4q35) (one patient with FSH MD); and 1300-1500 CTG triplet repeats in the DMPK gene (one patient with myotonic dystrophy). CONCLUSIONS: These results, although preliminary, show that a high percentage of patients with genetically determined skeletal myopathies exhibit cardiac myocyte functional impairment, with severe LVD and heart failure, justifying periodic cardiovascular evaluation. In the future, phenotype-genotype correlations could help to determine the best cardiac surveillance in MD patients.

Clinical reasoning: a 49-year-old woman with progressive motor deficit.

A previously healthy 49-year-old woman presented with progressive motor deficit. The complaints started the year before with weakness of the right arm. Over the subsequent months, she developed weakness in the left arm, followed by both legs, and, finally, difficulty speaking, with nasal voice, and swallowing. It was increasingly difficult to attend to her chores, and, by the time she sought medical attention, she needed help with all daily activities. In the last few weeks, she also complained of diffuse joint and muscle pain. Medical and family history were unremarkable.

The role of breast MRI in the investigation of anti-Yo positive paraneoplastic cerebellar degeneration.

Paraneoplastic neurological syndromes are a group of rare and heterogeneous disorders complicating cancer through immune-mediated mechanisms. They typically arise before the diagnosis of malignancy, thus constituting its first clinical manifestation. A thorough search for the underlying tumour is necessary, as adequate tumour management is essential for both neurological prognosis and overall survival. The authors present the case of a 43 year-old woman who presented with a subacute cerebellar syndrome associated with the paraneoplastic anti-Yo antibody. Although paraneoplastic aetiology was immediately suspected, the diagnosis of the underlying tumour was not straightforward, as is often the case. This case report highlights the importance of directing tumour search for the most probable anatomic locations, according to patient demographics and risk factors as well as the type of onconeural antibodies present, and also the need to use the most sensitive diagnostic modalities appropriate for each target organ.

Vasculitic neuropathy.

Vasculitic neuropathy corresponds to the occurrence of vasculitis at the level of vasa nervorum, resulting in ischemic damage of the peripheral nerve and axonal degeneration. Vasculitic neuropathy commonly occurs in association with systemic diseases and may be the initial manifestation or arise in the course of established disease. Although rare, vasculitis can be confined to the peripheral nervous system - non-systemic vasculitic neuropathy. This paper aims to review the classification, diagnosis and treatment of vasculitic neuropathy.