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Queen Square Centre for Neuromuscular Diseases

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University of Cape Town

Division of Neurology, Department of Medicine, Groote Schuur Hospital and the Neuroscience Institute of the University of Cape Town

Co-PI:
Prof Jeannine M Heckmann; MB ChB; FCP (SA); MMed; PhD

Jeanine Heckmann

Clinical neuromuscular expertise, patients and geographical region:
We have dedicated clinics and expertise in myasthenia gravis, ALS and inherited neuromuscular diseases in addition to a routine electrophysiology diagnostic service. We provide tertiary level service to state patients, primarily within the Cape Town metropole and surrounds (2-4 million people), in addition to private/insured patients and those from other provinces nationally.

UCT Groote Schuur Hospital

Genetics and preclinical science expertise and facilities: The South African National Health laboratory services provide confirmatory genetic testing for the following neuromuscular diseases; myotonic dystrophy type 1, CMT type 1, dystrophinopathies, RYR-1, SMA and the most common mitochondrial cytopathies (MELAS, mitochondrial deletion syndromes, MERRF, NARP). We have a genetic counselling service provided by the UCT division of Human Genetics. We also collaborate with the UCT computational biology group to dissect the genomic architecture of our local populations and their disease risk.

Current research programmes: We have been involved in the specific treatment needs of South Africans with myasthenia gravis (MG) for more than 10 years, including self-initiated treatment trials to assess the efficacy of cheaper drugs, in addition to being one of the top recruiters for the international thymectomy in MG trial. We have described a unique treatment-resistant subphenotype of MG and are involved in molecular genetic studies to determine the pathogenesis of this subphenotype.

We are involved in local and international collaborations (CReATe consortium) related to the study of ALS pecifically involved in phenotyping and genotyping Africans with ALS.

Top five publications from the past five years: Nel M, Mulder N, Europa TA, Heckmann JM. Using whole genome sequencing in an African subphenotype of myasthenia gravis to generate a pathogenetic hypothesis. Frontiers in Genetics 2019 doi: 10.3389/fgene.2019.00136.

Heckmann JM, Nel M. 2018. A unique subphenotype of myasthenia gravis. Ann N Y Acad Sci 2018; 1412(1):14-20. doi: 10.1111/nyas.13471. 018.

Europa TA, Nel M, Heckmann JM Myasthenic ophthalmoparesis: time to resolution after initiating immune therapies. Muscle & Nerve 2018 doi 10.1002/mus.26172.

Centner CM, Little F, Van der Watt JJ, Vermaak JR, Dave JA, Levitt NS, Heckmann JM. Evolution of sensory neuropathy after initiation of antiretroviral therapy. Muscle & Nerve 2018; 57:371-379.

Nel M, Jalali Sefid Dashti M, Gamieldien J, Heckmann JM. Exome sequencing identifies targets in the treatment-resistant ophthalmoplegic subphenotype of Myasthenia Gravis. Neuromuscular Dis 2017; 27:816-825.

How the new international centre will benefit research and clinical programmes: The study of neuromuscular diseases in Africa has been a neglected field of research. In addition, there is an unmet clinical need for definitive molecular diagnoses to accompany accurate phenotyping. The ultimate goal of the collaboration within the ICGNMD is to develop and expand neuromuscular expertise in South Africa, foster clinical and research ties with the UK experts/centres, and develop the expanding field of genomics in the Neuroscience Institute of UCT.

Department of Paediatric Neurology, Red Cross War Memorial Children's Hospital, Neuroscience Institute, University of Cape Town

Co-Investigator:
Prof Jo M Wilmshurst; MB BS; MRCPaed; FCPaed MD (HOD Paediatric Neurology)

Jo Wilmshurst

UCT Red Cross Children's Hospital

Clinical neuromuscular expertise, patients and geographical region: Dedicated neuromuscular centre. Coordinates a weekly clinical out-patient multidisciplinary service. Manages some 400 clinic visits a year. Range of neuromuscular conditions assessed from hereditary (SMA, DMD, congenital myopathies, LGMD, CMT etc.) through to monophasic disorders e.g. AIDP. Majority of chronic attendees are hereditary. Service is multidisciplinary with active involvement from physiotherapy, respiratory technologists, genetics counsellors, MDF counsellors etc. The centre is an accredited DMD care centre following formal review by the Parent Project from the USA. Children are referred from throughout South Africa. International guidelines are followed for management.

Genetics and preclinical science expertise and facilities: Access to SMA, DMD and CMT testing, as well as common local variants for RYR1 mutations. Expertise in muscle and nerve biopsy analysis with access to immune-histochemical stains and EM.

Current research programmes: Neuromuscular research activities include studies on peripheral neuropathies (PN), Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), congenital myopathies (CM) and centronuclear myopathy (CM)/RYR1 mutations in the SA paediatric population. Research on PN includes aetiology, demographics and management of pain of Guillain-Barre Syndrome, and various case studies including riboflavin transporter deficiencies. For DMD diagnostics using fibroblasts, epidemiology and demographics of DMD, and longitudinal course of children with DMD are investigated. For LGMD and CM studies on the delineation of genotype-phenotype are underway. On CM research, in collaboration with GOSH/UCL, several studies relating to RYR1 mutations and HyperCKaema are ongoing.

Top five publications from the past five years: Tyers L, Davids LM, Wilmshurst JM, Esterhuizen AI. Skin cells for use in an alternate diagnostic method for Duchenne muscular dystrophy. Neuromuscul Disord. 2018 Jul;28(7):553-563. doi: 10.1016/j.nmd.2018.05.001. Epub 2018 May 10.2.

Chaya S. Zampoli M, , Gray D Booth, J, Riordan G, Ndondo, A, Fieggen, K, Rusch, JA, van der Watt, G, Pillay, K, van der Westhuizen FH, Menezes,M, Wilmshurst, JM. The first case of riboflavin transporter deficiency in sub-Saharan Africa. Sem Ped Neurol 2018 Jul;26:10-142.

Esterhuizen AI, Greenberg LJ, Ballo R, Goliath RG, Wilmshurst JM. Duchenne muscular dystrophy in the Western Cape, South Africa: Where do we come from and where are we going? S Afr Med J. 2016 May 25;106(6).

Rokach O, Sekulic-Jablanovic M, Voermans N, Wilmshurst J, Pillay K, Heytens L, Zhou H, Muntoni F, Gautel M, Nevo Y, Mitrani-Rosenbaum S, Attali R, Finotti A, Gambari R, Mosca B, Jungbluth H, Zorzato F, Treves S. Epigenetic changes as a common trigger of muscle weakness in congenital myopathies. Hum Mol Genet. 2015Aug 15;24(16):4636-47.3.

Alina Izabela Esterhuizen, J M Wilmshurst, R G Goliath, L J Greenberg. Duchenne muscular dystrophy: High-resolution melting curve analysis as an affordable diagnostic mutation scanning tool in a South African cohort. SAMJ. 2014; 104 (11):779-784.

How the new international centre will benefit research and clinical programmes: Access to genetic testing in these patients will permit motivation for targeted therapies, will allow better counselling for affected families and will open new understandings of disease expression in the African setting. The latter may enable improved and targeted therapies to be developed.