Fatima Jaffer

BAG3 mutations: another cause of giant axonal neuropathy

Mutations in Bcl‐2 associated athanogene‐3 (BAG3) are a rare cause of myofibrillar myopathy, characterised by rapidly progressive proximal and axial myopathy, cardiomyopathy and respiratory compromise. Neuropathy has been documented neurophysiologically in previously reported cases of BAG3‐associated myofibrillar myopathy and in some cases giant axons were observed on nerve biopsies; however, neuropathy was not thought to be a dominant feature of the disease. In the context of inherited neuropathy, giant axons are typically associated with autosomal recessive giant axonal neuropathy caused by gigaxonin mutations but have also been reported in association with NEFL‐ and SH3TC2‐associated Charcot‐Marie‐Tooth disease. Here, we describe four patients with heterozygous BAG3 mutations with clinical evidence of a sensorimotor neuropathy, with predominantly axonal features on neurophysiology. Three patients presented with a significant neuropathy. Muscle magnetic resonance imaging (MRI) in one patient revealed mild to moderate atrophy without prominent selectivity. Examination of sural nerve biopsies in two patients demonstrated giant axons. This report confirms the association of giant axonal neuropathy with BAG3‐associated myofibrillar myopathy, and highlights that neuropathy may be a significant feature.

The clinical and genetic heterogeneity of paroxysmal dyskinesias

The contributions of different genes to inherited paroxysmal movement disorders are incompletely understood. Gardiner et al. identify mutations in 47% of 145 individuals with paroxysmal dyskinesias, with PRRT2 mutations in 35%, SLC2A1 in 10% and PNKD in 2%. New mutations expand the associated phenotypes and implicate overlapping mechanisms.

Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall–Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve.

Familial childhood-onset progressive cerebellar syndrome associated with the ATP1A3 mutation

The allelic disorders rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and CAPOS/CAOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural deafness) are caused by ATP1A3 mutations.1–3 Intermediate RDP-AHC phenotypes are emerging. Positional mutations 274, 583, 867, and 923 lead to both RDP and AHC, suggesting different pathomechanisms.4,5 The E818K mutation underlies all reported cases of CAPOS/CAOS, including an AHC-CAPOS overlap syndrome.6 We report a family with features of all 3 ATP1A3-spectrum disorders.

Atypical periodic paralysis and myalgia: A novel RYR1 phenotype

Objective To characterize the phenotype of patients with symptoms of periodic paralysis (PP) and ryanodine receptor (RYR1) gene mutations. Methods Cases with a possible diagnosis of PP but additional clinicopathologic findings previously associated with RYR1-related disorders were referred for a tertiary neuromuscular clinical assessment in which they underwent detailed clinical evaluation, including neurophysiologic assessment, muscle biopsy, and muscle MRI. Genetic analysis with next-generation sequencing and/or targeted Sanger sequencing was performed. Results Three cases with episodic muscle paralysis or weakness and additional findings compatible with a RYR1-related myopathy were identified. The McManis test, used in the diagnosis of PP, was positive in 2 of 3 cases. Genetic analysis of known PP genes was negative. RYR1 analysis confirmed likely pathogenic variants in all 3 cases. Conclusions RYR1 mutations can cause late-onset atypical PP both with and without associated myopathy. Myalgia and cramps are prominent features. The McManis test may be a useful diagnostic tool to indicate RYR1-associated PP. We propose that clinicopathologic features suggestive of RYR1-related disorders should be sought in genetically undefined PP cases and that RYR1 gene testing be considered in those in whom mutations in SCN4A, CACNA1S, and KCNJ2 have already been excluded.

Spontaneously Fluctuating Motor Cortex Excitability in Alternating Hemiplegia of Childhood: A Transcranial Magnetic Stimulation Study

Background Alternating hemiplegia of childhood is a very rare and serious neurodevelopmental syndrome; its genetic basis has recently been established. Its characteristic features include typically-unprovoked episodes of hemiplegia and other transient or more persistent neurological abnormalities. Methods We used transcranial magnetic stimulation to assess the effect of the condition on motor cortex neurophysiology both during and between attacks of hemiplegia. Nine people with alternating hemiplegia of childhood were recruited; eight were successfully tested using transcranial magnetic stimulation to study motor cortex excitability, using single and paired pulse paradigms. For comparison, data from ten people with epilepsy but not alternating hemiplegia, and ten healthy controls, were used. Results One person with alternating hemiplegia tested during the onset of a hemiplegic attack showed progressively diminishing motor cortex excitability until no response could be evoked; a second person tested during a prolonged bilateral hemiplegic attack showed unusually low excitability. Three people tested between attacks showed asymptomatic variation in cortical excitability, not seen in controls. Paired pulse paradigms, which probe intracortical inhibitory and excitatory circuits, gave results similar to controls. Conclusions We report symptomatic and asymptomatic fluctuations in motor cortex excitability in people with alternating hemiplegia of childhood, not seen in controls. We propose that such fluctuations underlie hemiplegic attacks, and speculate that the asymptomatic fluctuation we detected may be useful as a biomarker for disease activity.

EMERGENCY NEUROMUSCULAR ADMISSIONS ARE AVOIDABLE: A REGIONAL AUDIT OF UNPLANNED HOSPITAL ADMISSIONS OF NEUROMUSCULAR PATIENTS 2009–2011: FINAL RESULTS AND RECOMMENDATIONS

Introduction Neuromuscular diseases (NMD) require long–term multi–disciplinary care. In 2010–11 there were 5.3 million emergency admissions of which 213,000 related to neurological disorders. 13% of these (∼28,000) were secondary to NMD. With each admission costing ∼£3000 per day, it is estimated that this leads to costs of £81 m nationally (£28 m in four specialised commissioning groups [SCG]: London, East of England, South–East Coast and South–Central). Fundamentally, avoidable admissions have an adverse effect on quality of life. Studies have shown that strengthening links between specialist and primary care, integration of health and psychosocial care and hospital at home interventions are associated with lower emergency admission rates. The aims were to: 1. Determine the proportion of avoidable emergency admissions directly attributable to NMD 2. Determine what proportion of patients are known to specialist neuromuscular services and compare characteristics of such admissions against centres without a specialist service 3. Identify reasons for emergency admissions and preventable measures. Methodology A retrospective case note audit was conducted across 12 trusts in four SCG regions. Emergency admissions in patients with NMD were identified by SCG IT teams using secondary user services data and ICD–10 codes for neuromuscular and metabolic disorders between January 2009 and June 2011. In the absence of national clinical standards of care for NMD, consensus criteria to identify avoidable admissions were developed by an expert panel (Table 1). Data analysis was undertaken independently by London SCG. Results There were 576 unplanned admissions for 395 patients. Of 395 patients, 65% had a pre–existing NMD and 25% of these were known to specialist NMD services. Of 576 separate admissions, 65% were at hospitals with a specialist service and 74% of these admissions were in patients with a pre–existing NMD. Overall, 37.5% of unplanned admissions were avoidable and 5% potentially avoidable. Further analysis showed that of the admissions directly attributable to NMD, 63% were avoidable and 5.7% potentially avoidable. There was no difference in preventability of admissions between hospitals with and without specialist NMD services (p=0.79). The main measures that may have prevented an avoidable admission were: On–going disease monitoring, access to specialist services (nurse specialist, therapists, equipment and cardiorespiratory care), and implementation of an emergency plan. 20% of patients known to NMD services had a documented emergency plan. 58% of inpatients were reviewed by a neurologist. Conclusions Over one–third of emergency admissions were avoidable, majority occurring in patients with pre–existing NMDs. Only a quarter of neuromuscular patients are known to a specialist and 20% have an emergency plan in place. Key recommendations were developed for the national working specification after consultation with the All Party Parliamentary Group for Muscular Dystrophy to reduce fragmentation of care. These are: 1. Monitoring of patients and access to neuromuscular services between appointments 2. Specialist NMD centres to lead coordination of care across sub–specialties 3. Strengthen links with social services and local hospitals to enable advice 4. All patients with a known NMD should have a documented referral to the neurology team during admission and an emergency plan on discharge.

ECG ABNORMALITIES IN ALTERNATING HEMIPLEGIA: A BROADENED PHENOTYPE

Introduction Alternating hemiplegia of Childhood (AH) caused by de novo mutations in ATP1A3, is characterised by recurrent plegic and dystonic episodes, seizures, non-paroxysmal neurological features, and dysautonomia. Premature mortality is observed and attributed to sudden unexpected death in epilepsy. A single case of asystole in AH is reported. Other neuronal channelopathies have cardiac involvement, and since ATP1A3 is expressed in cardiomyocytes, we hypothesised that ECG abnormalities are present in AH. Methods 52 patients fulfilling the diagnostic criteria for AH were recruited, and screened for ATP1A3 mutations. ECGs were analysed for heart rate, cardiac axis, PR, QRS, RR, and QTc intervals, repolarisation patterns, and J-point abnormalities. Results 53.8% exhibited abnormal resting 12-lead ECGs independent of seizures or AH episodes; 48.1% had repolarisation abnormalities. The proportion of intraventricular conduction delay or partial right bundle branch block was greater in this cohort compared to the general population. ECG abnormalities were significantly greater in patients >16 years than in those <16 years (p=0.0095), and also within the most common mutation group (D801N; p=0.045). Conclusions These ECG abnormalities reflect impaired repolarisation reserve in AH in an age-dependent manner, and may account for some cases of premature mortality observed. Long-term cardiac surveillance in AH is recommended.

AVOIDING UNPLANNED HOSPITAL ADMISSIONS IN PATIENTS WITH NEUROMUSCULAR DISEASES: A REGIONAL COLLABORATIVE AUDIT OF HOSPITAL ADMISSIONS

Background Neuromuscular diseases require long-term multi-disciplinary care. In 2010, there were 5368 unplanned admissions for metabolic and neuromuscular conditions in England (Hospital Episodes Statistics 2007–2008). Unplanned admissions are those that occur at short notice and when there is a perceived need for clinical care (Department of Health). However, some unplanned admissions may be preventable through integrated care pathways. Preventing such admissions would reduce NHS costs, and improve quality of life for the patients. Aims and objectives The aims of the audit were to determine the proportion of unplanned admissions, the nature of events leading to an unplanned admission, and if and admission was deemed to be preventable, what measures could be taken to avoid these. Methods A retrospective case note audit of unplanned admissions was conducted in eight trusts across four Specialised Commissioning Groups between 2009 and 11. Neuromuscular and metabolic ICD-10 codes were used to identify patients with an unplanned admission. In the absence of national standards, consensus criteria for a potentially preventable admission were developed by an expert group of neuromuscular consultants. These included: diagnoses directly attributable to or complications of a neuromuscular disease, documentation of emergency plans, whether there was contact with healthcare professionals prior to admission and re-admissions. Results There were 266 unplanned admissions for 200 patients. 68% were in patients with an established neuromuscular condition (of which 59.7% were directly attributable to this).42.1% of all admissions were potentially avoidable, 53% unavoidable and a decision not made in 4.9%.72.4% of admissions were in patients with established diagnosis and unknown to a specialist neuromuscular service (55% potentially avoidable).7.2% of patients with established diagnosis had emergency plans.Delayed access to a specialist, lack of disease monitoring, emergency plans and provision of equipment were factors leading to admission. Conclusions and further work 42.1% of unplanned admissions were deemed to be preventable of which a significant proportion were directly attributable to neuromuscular disease. Less than one-third of patients with a neuromuscular diagnosis were known to a specialist neuromuscular service. Results of a total of 576 admissions from twelve participating NHS trusts will be presented to the All Party Parliamentary Group for Muscular Dystrophy in June 2012 with the recommendations from this meeting to be announced thereafter.