Oral Presentations Session 1 Wednesday 29 January 2014 11.00–12.30 Unravelling the genetic cause in patients with inherited peripheral neuropathy S BURTON-JONES 1 , A MAJUMDAR 2 , R WHITTINGTON 1 , C BUXTON 1 , I SCURR 3 , P LUNT 3 , M WILLIAMS 1 , T ANTONIADI 1 1 Bristol Genetics Laboratory, Southmead Hospital, Bristol; 2Department of Paediatric Neurology, Frenchay Hospital, North Bristol NHS Trust; 3 Department of Clinical Genetics, St Michaels Hospital, Bristol A young male patient was diagnosed at the age of seven, with demyelinating neuropathy, affecting feet and hands, marked tremor and slow NCV (15m/s). There was family history with autosomal dominant inheritance. Genetic testing performed during a period of over 10 years has not resulted in a genetic diagnosis. Recent advances in sequencing technology during the last few years have made genetic testing for rare causes possible and cost effective. At Bristol Genetics Laboratory we have designed a gene panel assay, including 56 genes associated with the common and the rare causes of different types of neuropathy. Testing this patient revealed a missense variant c.1066G>C (p.Glu356Gln) in exon 4 of the EGR2 gene; all evidence supports that this is the likely cause of this patient’s neuropathy. The patient was not tested earlier for EGR2 mutations due to its exclusive association with severe congenital hypomyelinating neuropathy. A young female patient was diagnosed with hereditary sensory motor neuropathy with associated focal atrophy of cerebellum. Several family members were also affected, implying an underlying genetic cause. Testing this patient with the gene panel testing revealed two heterozygous variants in the GARS gene: c.803C>T (p.Thr268Ile) in exon 7 and c.1163G>A (p.Arg388Gln) in exon 9. We discuss the necessity of further investigation that is required to elucidate whether one of these or the combination is pathogenic. The gene panel approach overcomes the limitation imposed by basing testing decisions on the limited genotype-phenotype data available, especially for rare genes. It also presents us with the challenge of determining the clinical significance of novel variants. We discuss our approach in classifying novel variants; the importance of phenotypic information and the clinical compatibility of the sequencing findings in addressing this challenge efficiently.


The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials V RICOTTI 1 , DA RIDOUT 2 , E MERCURI 1,3 , R QUINLIVAN 1,4 , SA ROBB 1 , AY MANZUR 1 , F MUNTONI, 1,4 , ON BEHALF OF THE NORTHSTAR CLINICAL NETWORK 1 Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London; 2Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London; 3Department of Paediatric Neurology, Catholic University, Rome, Italy; 4MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London

Objective: With the emergence of experimental therapies for Duchenne Muscular Dystrophy, it is crucial to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to observe the motor function decline of ambulant DMD boys treated according to the standards of care; and describe this decline in the genetic subpopulations of different skippable deletions (by exon 44, 45, 46, 50, 51, 52, 53). Methods: Through the NorthStar Network and database, clinical data systematically collected from 2004 to 2012 on 483 DMD boys followed-up in 17 UK neuromuscular centres was included in the analysis. For the analysis of the genetic subpopulation we included data from 84 DMD boys followed-up in Rome. Our study focuses on the NorthStar Ambulatory Assessment (NSAA) as a primary outcome measure. Results: We reported that boys, who started steroids before 5 years of age, gain better motor function until age 7 (p=0.04). Including all treatment regimens, we observed that after age 7 when boys start declining, the slope is of approximately 3.5 units in NSAA per year. The median age at loss of ambulation was 13 years (95%CI 9.5–16), and 2 years prior to loss of ambulation, the mean total score for the NSAA was 13.5 units out of 34. When compared with the whole cohort of DMD boys, individuals skipable by exon 44 and 46 did better, declining at a slower rate (p=0.004), while populations skipable by exon 53 and 52 showed a faster decline (p=0.05). Conclusion: Our study provides helpful information on the current natural history of DMD. The analysis on motor function decline in different patient sub-population is of help when selecting inclusion criteria in the design for clinical trials. Acknowledgements: The support of Muscular Dystrophy Campaign for the NorthStar clinical Network: http://www.muscular-dystrophy. org/assets/0001/5872/NSCN_collaborating_centres.pdf is gratefully acknowledged.

Familial hereditary neuralgic amyotrophy (HNA) in an 11-year-old PF CHINNERY 1,2,3,4 , A LIM 1 , V RAMESH 1 1 Paediatric Neurology, Newcastle-upon-Tyne Hospitals; 2Institute of Genetic Medicine, University of Newcastle-upon-Tyne; 3Paediatric Neurology, Newcastle-upon-Tyne University Hospitals; 4Institute of Genetic Medicine, Newcastle University

Background: Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant neurological disorder, characterised by acute onset of neuralgic pains in the upper limb followed by muscle wasting within weeks of the onset of symptoms (amyotrophy). Presentation is typi-


© The Authors. Developmental Medicine & Child Neurology © 2014 Mac Keith Press, 56 (Suppl. 1), 2–58 DOI: 10.1111/dmcn.12350

cally in the second or third decade. Childhood presentation is rare and not widely reported. SEPT9 is the only gene in which mutations are known to cause HNA. Aim and Methods: We present a case of HNA in an 11-year-old boy with review of current literature, to provide comparison with adult phenotype, diagnostic criteria clinical management. Results: An 11-year-old male presented with acute onset severe neuralgic pains in his right shoulder girdle accompanied by flu-like symptoms. One week later, weakness of right shoulder abduction and external rotation was noted. Clinical diagnosis of HNA was made. He was started on oral steroids with good effect. His mother and elder brother had exhibited similar symptoms in the past; the parent recognised it in our patient. MRI imaging on them had been reported as normal. SEPT9 gene mutation was sought in affected members of the family by CGH micro-array. They confirmed SEPT9 mutation in the patient, his brother and mother. Currently there is no effective therapy. Steroids have been used in adults to ameliorate duration of pain and improve recovery. SEPT9 gene mutations should be sought. Conclusion: HNA presenting in childhood is rare and its prevalence unknown. Paediatric phenotype may be different from adults in terms of severity and recovery period. European CMT Consortium criteria are useful for clinical diagnosis. Sept 9 mutation should be sought in families with suggestive history.

Familial dominant congenital spinal muscular atrophy due to BICD2 mutation V RAMESH 1 , H GRIFFIN 2 , A PYLE 2 , J DUFF 2 , PF CHINNERY 2,3 , R HORVATH 2,3 1 Department of Paediatric Neurology, Newcastle-upon-Tyne University Hospitals; 2Institute of Genetic Medicine, Newcastle-upon-Tyne University; 3 Department of Neurology, Newcastle-upon Tyne University Hospitals

Background: Autosomal dominant congenital spinal muscular atrophy (DCSMA) is a disorder anterior horn cells showing lower limb predominance with congenital foot deformities, delayed walking, minimal involvement of upper limbs and a stable course. BICD 2 is an adaptor protein important in cellular trafficking in developing motor neurons and their maintenance. Mutations in BICD2 gene have recently been reported to cause DCSMA. Aim and Methods: We present a series of five patients, a mother, her three children, and an unrelated 16 year old male with DCSMA, and mutation in the BICD2 gene. Results: The children’s mother (35 years old) was born with pes cavus and walked independently by 20 months of age. She had thin legs, bilateral pes cavus, foot drop and ‘scapular winging’. She showed proximal > distal weakness in all four limbs. She was hyporeflexic. Cranial nerves, sensation and sphincter function were normal. EMG showed severe chronic neurogenic changes in all limbs indicative of segmental motor neuronopathy with normal nerve conduction. No deletions were detected in SMN gene. CK was normal. Her three children (5-year-old female and 4-year-old male twins) all were term born with feet deformities, walked between 20 and 24 months. All had thin legs, lower limb dominant proximal > distal weakness, hyporeflexia. The 16-year-old male is similar. The mother and one affected child and the second index patient underwent whole exome sequencing. The previously reported heterogenous pathogenic mutation c.320C >T (p.Ser107Leu) was found and confirmed by Sanger sequencing in all five individuals. Conclusion: Lower limb dominant early onset SMA phenotype should prompt search for mutations in BICD2. The c.320C>T (p.Ser107Leu) mutation has been previously reported in three families with similar

phenotype of different ethnic origin (Austrian, Australian, USA). We suggest that this locus could be a mutational hotspot, or may represent an old European founder. References: Oates EC et al. Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia. Am J Human Genet. 2013 May 9.

Exploring end-of-life planning issues for young men with Duchenne muscular dystrophy (DMD), their parents and the professionals that support them: a scoping and feasibility study D ABBOTT 1 , H PRESCOTT 2 , K FORBES 1 , A MAJUMDAR 3 1 University of Bristol; 2Lifetime Services, RUH, Bath; 3Department of Paediatric Neurology, North Bristol NHS Trust

Introduction: Advances in medical technology have meant that many young men with DMD now live longer than previously. We explored how we might conduct feasible, ethical research about how families communicate about, and cope with, changes in health, prognosis, and end-of-life (EOL) issues. Previous research suggested young men with DMD and their families are reluctant to talk about EOL issues. Objectives: To investigate the feasibility of a piece of work exploring end-of-life planning with young men with DMD – and their parents. To explore the ethical issues around such a study and what would make participation acceptable for potential participants? Methods: We carried out a short scoping and feasibility study including a literature and policy review, and semi-structured interviews with seven key local professionals. We explored the views of five families of young men with DMD about the feasibility, desirability and best methodological approach in a study. Results: Parents’ and professionals’ views about end-of-life planning varied. Some professionals did not feel it was their role to undertake these discussions but felt it was crucial that someone did. Some parents were reluctant to have the subject broached; others had strong views about how it should be approached. All agreed that research on this topic was needed and could be managed sensitively with proper planning. A future challenge is that we failed to identify any young men with DMD prepared to discuss the issues. Conclusions: This scoping study suggests that EOL research in DMD is understudied and feasible; these preliminary findings are worth exploring further.

Does the use of cardiac MRI improve the pre-operative risk assessment in patients with Duchenne muscular dystrophy? E PARISH 1 , A BRUNKLAUS 1 , F MUNTONI 1 , S SCUPLAK 2 , M FENTON 3 , M HUGHES 3 , AY MANZUR 1 1 Dubowitz Neuromuscular Centre, Great Ormond Street Hospital; 2 Department of Paediatric Anaesthesia, Great Ormond Street Hospital; 3 Department of Paediatric Cardiology, Great Ormond Street Hospital

Objective: Children affected by Duchenne muscular dystrophy (DMD) often require tenotomy or scoliosis spinal surgery. DMD-related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been evaluated as a tool for pre-operative assessment of heart function in DMD. Our aim was to establish whether CMR versus echocardiography improves the preoperative risk assessment in DMD.

Oral Presentations 3

Methods: Case records were reviewed of 63 consecutive DMD boys who underwent pre-surgical evaluation at a single tertiary neuromuscular centre between 2008 and 2013. Using a structured form, retrospective data collection included past history, treatment, pre-operative assessments and surgical outcomes. Results: Of 63 DMD patients aged 7–18 years underwent pre-operative assessment for a total of 67 procedures (42 spinal, 19 foot, six gastrostomy surgery). Echocardiogram data were available for 64 procedures since 2008. CMR was routinely performed on 32 patients since 2010. Echocardiogram revealed a mean left ventricular (LV) fractional shortening (FS) of 29% (8–42). 25% (16/64) had abnormal FS (

British Paediatric Neurology Association Abstracts of the 2014 Annual Meeting, 29-31 January 2014, Winchester, UK.

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