Re-evaluation of the phenotype caused by the common MATR3 p.Ser85Cys mutation in a new family

Peer reviewe

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance.

Despite being a canonical presenting feature of mitochondrial disease, the genetic basis of progressive external ophthalmoplegia remains unknown in a large proportion of patients. Here we show that mutations in SPG7 are a novel cause of progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions. After excluding known causes, whole exome sequencing, targeted Sanger sequencing and multiplex ligation-dependent probe amplification analysis were used to study 68 adult patients with progressive external ophthalmoplegia either with or without multiple mitochondrial DNA deletions in skeletal muscle. Nine patients (eight probands) were found to carry compound heterozygous SPG7 mutations, including three novel mutations: two missense mutations c.2221G>A; p.(Glu741Lys), c.2224G>A; p.(Asp742Asn), a truncating mutation c.861dupT; p.Asn288*, and seven previously reported mutations. We identified a further six patients with single heterozygous mutations in SPG7, including two further novel mutations: c.184-3C>T (predicted to remove a splice site before exon 2) and c.1067C>T; p.(Thr356Met). The clinical phenotype typically developed in mid-adult life with either progressive external ophthalmoplegia/ptosis and spastic ataxia, or a progressive ataxic disorder. Dysphagia and proximal myopathy were common, but urinary symptoms were rare, despite the spasticity. Functional studies included transcript analysis, proteomics, mitochondrial network analysis, single fibre mitochondrial DNA analysis and deep re-sequencing of mitochondrial DNA. SPG7 mutations caused increased mitochondrial biogenesis in patient muscle, and mitochondrial fusion in patient fibroblasts associated with the clonal expansion of mitochondrial DNA mutations. In conclusion, the SPG7 gene should be screened in patients in whom a disorder of mitochondrial DNA maintenance is suspected when spastic ataxia is prominent. The complex neurological phenotype is likely a result of the clonal expansion of secondary mitochondrial DNA mutations modulating the phenotype, driven by compensatory mitochondrial biogenesis

Gaining insight into how women conceptualize satisfaction: Western Australian women's perception of their maternity care experiences

BACKGROUND: The concept of maternal satisfaction is challenging, as women's and clinicians' expectations and experiences can differ. Our aim was to investigate women's experiences of maternity care in an urban tertiary obstetric setting, to gain insight into conceptualization of satisfaction across the childbirth continuum. METHODS: This mixed method study was conducted at a public maternity hospital in Western Australia. A questionnaire was sent to 733 women two weeks post birth, which included an invitation for an audio-recorded, telephone interview. Frequency distributions and univariate comparisons were employed for quantitative data. Thematic analysis of interview transcripts was undertaken to extract common themes. RESULTS: A total of 54 % (399 of 733) returned the questionnaire. Quantitative results indicated that women were less likely to feel: involved if they did not have a spontaneous vaginal birth (P?=?0.020); supported by a midwife if they had a caesarean (P?=?<0.001); or supported by an obstetrician if they had a spontaneous vaginal birth (P?=?<0.001). Qualitative findings emerged from 63 interviews which highlighted the influence that organization of care, resources and facilities had on women's satisfaction. These paradigms unfolded as three broad themes constructed by four sub-themes, each illustrating a dichotomy of experiences. The first theme 'how care was provided' encompassed: familiar faces versus a different one every time and the best place to be as opposed to so disappointed. The second theme 'attributes of staff' included: above and beyond versus caring without caring and in good hands as opposed to handled incorrectly. The third theme 'engaged in care' incorporated: explained everything versus did not know why and had a choice as opposed to did not listen to my needs. CONCLUSIONS: Quantitative analysis confirmed that the majority of women surveyed were satisfied. Mode of birth influenced women's perception of being involved with their birth. Being able to explore the diversity of women's experiences in relation to satisfaction with their maternity care in an urban, tertiary obstetric setting has offered greater insight into what women value: a sensitive, respectful, shared relationship with competent clinicians who recognise and strive to provide woman focused care across the childbirth continuum

Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene

The skeletal muscle ryanodine receptor plays a crucial role in excitation–contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca2+ release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Clinical case studies in neurology: approaches to common neurological problems from King's College Hospital

The book provides a summary of clinical cases presented at the King's College Hospital Neurology Grand Round. Approximately 50 cases will be discussed, over two to four pages in a practical, easy-to-read format for residents in training and consultants. Cases and reviews will be concise to ensure difficult concepts remain in easily digested chunks. In the first part case histories are summarized, followed by discussion of the differential diagnosis. The second part is focused on the examination, followed by a discussion of the way the differential diagnosis has evolved. The third part analyses any relevant investigation results with the likely diagnoses to consider. Finally the actual diagnosis is discussed with a review of the current state of knowledge. A brief overview, with up-to-date references, is provided at the end of each case

Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy

Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount. Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology

Pearls & Oy-sters: resolution of hemichorea following endarterectomy for severe carotid stenosis

Carotid artery stenosis should be considered in the differential diagnosis of unilateral chorea, even in the absence of preceding presentation with stroke or transient ischaemic attacks.Carotid endarterectomy may reduce contralateral chorea in patients with critical carotid artery stenosis.<br/