Aisling Carr

A systematic review of population based epidemiological studies in Myasthenia Gravis

BackgroundThe aim was to collate all myasthenia gravis (MG) epidemiological studies including AChR MG and MuSK MG specific studies. To synthesize data on incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the condition and investigate the influence of environmental and technical factors on any trends or variation observed.MethodsStudies were identified using multiple sources and meta-analysis performed to calculate pooled estimates for IR, PR and MR.Results55 studies performed between 1950 and 2007 were included, representing 1.7 billion population-years. For All MG estimated pooled IR (eIR): 5.3 per million person-years (C.I.:4.4, 6.1), range: 1.7 to 21.3; estimated pooled PR: 77.7 per million persons (C.I.:64.0, 94.3), range 15 to 179; MR range 0.1 to 0.9 per millions person-years. AChR MG eIR: 7.3 (C.I.:5.5, 7.8), range: 4.3 to 18.0; MuSK MG IR range: 0.1 to 0.32. However marked variation persisted between populations studied with similar methodology and in similar areas.ConclusionsWe report marked variation in observed frequencies of MG. We show evidence of increasing frequency of MG with year of study and improved study quality. This probably reflects improved case ascertainment. But other factors must also influence disease onset resulting in the observed variation in IR across geographically and genetically similar populations.

Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.

See Martinez-Martinez et al. (doi:10.1093/brain/awu153) for a scientific commentary on this article. Carvajal-González et al. describe the first prospective cohort of patients with glycine receptor antibodies. The majority have progressive encephalomyelitis with rigidity and myoclonus. The antibodies bind to extracellular determinants on glycine receptor-α1 and to glycine receptors on spinal cord and brainstem neurons. The patients make a good recovery with immunotherapies.

Ovarian teratoma associated with anti-N-methyl D-aspartate receptor encephalitis: a report of 5 cases documenting prominent intratumoral lymphoid infiltrates.

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a recently described severe neurological disorder predominantly affecting young women, which presents with psychosis, memory deficits, seizures, and encephalopathy, often requiring prolonged hospitalization. The condition is frequently associated with an underlying neoplasm, most often an ovarian teratoma, and in such cases appears to be a para-neoplastic, immune-mediated encephalopathy. The histologic features of the teratomas associated with anti-NMDAR encephalitis have seldom been described in detail. Therefore, in this report, we have compared ovarian teratomas (4 mature and 1 immature) from 5 patients with anti-NMDAR encephalitis with 22 sporadic control teratomas (14 mature and 8 immature) that included neuroglial elements. The encephalitis-associated tumors ranged from 0.7 to 9.5 cm diameter, and 1 case was bilateral; the second teratoma was discovered 13 mo after the first when symptoms recurred. In comparison with control teratomas, the anti-NMDAR-associated tumors showed a more marked intratumoral lymphoid infiltrate that colocalized to the mature neuroglial elements. Reactive germinal centers (3 cases) and diffuse lymphoplasmacytic infiltrates within the neuroglial matrix (4 cases), and degenerative neuronal changes (2 cases), were seen only in the anti-NMDAR-positive cases. Pathologists encountering ovarian teratomas with these distinctive reactive lymphoid elements should consider the possibility of anti-NMDAR encephalitis, particularly because the neurological symptoms may develop after tumor resection. Careful histopathologic examination may be required to identify small, radiologically occult teratomas, and to demonstrate the presence of subtle neoplastic neuroglial components in teratomas associated with anti-NMDAR encephalitis.

Clinical features in a series of fast channel congenital myasthenia syndrome

Fast channel congenital myasthenic syndromes are rare, but frequently result in severe weakness. We report a case of 12 fast channel patients to highlight clinical features and management difficulties. Patients were diagnosed through genetic screening and identification of mutations shown to cause fast channel syndrome. Data was obtained from clinical notes, history, examination and follow up. Patterns of muscle weakness involved limb, trunk, bulbar, respiratory, facial and extraocular muscles. Patients responded to treatment with anticholinesterase medication and 3,4-diaminopyridine. Fast channel syndrome contrasted with AChR deficiency in the occurrence of severe respiratory crises in infancy and childhood. The death of two children even when on treatment and the family histories of sibling deaths re-inforces the need for accurate genetic diagnosis, optimised pharmacological treatment and additional supportive measures to manage acute respiratory crises. Referral to a specialist paediatric respiratory centre and regular resuscitation training for parents are recommended.

A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma

Among 249 patients with teratoma‐associated encephalitis, 211 had N‐methyl‐D‐aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody‐positive patients rarely developed prominent brainstem–cerebellar symptoms, 22 (58%) antibody‐negative patients developed a brainstem–cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12–41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem–cerebellar syndrome. ANN NEUROL 2014;75:435–441

Rhabdomyolysis after co-prescription of statin and fusidic acid

Avoid co-prescription of fusidic acid with statins to reduce the risk of rhabdomyolysis

MFN2 deletion of exons 7 and 8: founder mutation in the UK population.

Mitofusin 2 (MFN2) mutations are the most common cause of axonal Charcot‐Marie‐Tooth disease (CMT2). The majority are inherited in an autosomal dominant manner but recessive and semi‐dominant kindreds have also been described. We previously reported a deletion of exons 7 and 8 resulting in nonsense‐mediated decay, segregating with disease when present in trans with another pathogenic MFN2 mutation. Detailed clinical and electrophysiological data on a series of five affected patients from four kindreds and, when available, their parents and relatives were collected. MFN2 Sanger sequencing, multiplex ligation probe amplification, and haplotype analysis were performed. A severe early‐onset CMT phenotype was seen in all cases: progressive distal weakness, wasting, and sensory loss from infancy or early childhood. Optic atrophy (four of five) and wheelchair dependency in childhood were common (four of five). All were compound heterozygous for a deletion of exons 7 and 8 in MFN2 with another previously reported pathogenic mutation (Phe216Ser, Thr362Met, and Arg707Trp). Carrier parents and relatives were unaffected (age range: 24–82 years). Haplotype analysis confirmed that the deletion had a common founder in all families.

A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK

Background Hereditary transthyretin amyloidosis (ATTR) is usually characterised by a progressive peripheral and autonomic neuropathy often with associated cardiac failure and is due to dominantly inherited transthyretin mutations causing accelerated amyloid deposition. The UK population is unique in that the majority of patients have the T60A missense mutation in ATTR where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland. The neuropathy phenotype is less well described than the cardiac manifestations in this group. Methods We present the findings from an observational cohort study of patients with ATTR attending the National Hospital Inherited Neuropathy Clinic between 2009 and 2013. Detailed clinical neurological and electrophysiological data were collected on all patients alongside correlating autonomic and cardiac assessments. Follow-up data were available on a subset. Results Forty-four patients with genetically confirmed ATTR were assessed; 37 were symptomatic; mean age at onset=62 years, range=38–75 years; 75.7% male. T60A was the most common mutation (17/37), followed by V30M (5/37). A severe, rapidly progressive, predominantly length dependent axonal sensorimotor neuropathy was the predominant phenotype. T60A patients were distinguished by earlier and more frequent association with carpal tunnel syndrome; a predominance of negative sensory symptoms at onset; significant vibration deficits; and a non-length dependent progression of motor deficit. Progression of the neuropathy was observed over a relatively short follow-up period (2 years) in 20 patients with evidence of clinically measurable annual change in Medical Research Council (MRC) sum score (–1.5 points per year) and Charcot Marie Tooth Neuropathy Score (CMTNS:2.7 points per year), and a congruent trend in the electrophysiological measures used. Conclusion The description of the ATTR neuropathy phenotype, especially in the T60A patients, should aid early diagnosis as well as contribute to the understanding of its natural history.

Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy

Hereditary transthyretin amyloidosis (ATTR) is a genetically and clinically heterogeneous disease manifesting with predominant peripheral and autonomic neuropathy; cardiomyopathy, or both. ATTR V122I is the most common variant associated with non-neuropathic familial amyloid cardiomyopathy. We present an unusual case of V122I amyloidosis with features of amyloid neuropathy and myopathy, supported by histological confirmation in both sites and diffuse tracer uptake on (99m)Tc-3,3-Diphosphono-1,2-Propanodicarboxylic acid (DPD) scintigraphy throughout skeletal and cardiac muscle. A 64 year old Jamaican man presented with cardiac failure. Cardiac MR revealed infiltrative cardiomyopathy; abdominal fat aspirate confirmed the presence of amyloid, and he was homozygous for the V122I variant of transthyretin. He also described general weakness and EMG demonstrated myopathic features. Sural nerve and vastus lateralis biopsy showed TTR amyloid. The patient is being treated with diflunisal, an oral TTR stabilising agent. Symptomatic myopathy and neuropathy with confirmation of tissue amyloid deposition has not previously been described. Extracardiac amyloidosis has implications for diagnosis and treatment.

Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT

Objective: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). Methods: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. Results: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. Conclusions: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions.