Publications by authors named "Tracey Willis"

27 Publications

  • Page 1 of 1

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study.

Neurology 2021 01 16;96(4):e587-e599. Epub 2020 Oct 16.

From the Dubowitz Neuromuscular Centre (F.T., M.S., M.L.M., F.M.) and Population, Policy and Practice Programme (D.R.), UCL GOS Institute of Child Health, London, UK; DINOGMI, University of Genoa (F.T.), IRCCS Istituto G. Gaslini, Italy; NIHR Great Ormond Street Hospital Biomedical Research Centre (D.R., F.M.), Great Ormond Street Institute of Child Health, University College London, and Great Ormond Street Hospital Trust, UK; Paediatric Neurology (G.C., M.P., E.M.), Catholic University; Centro Clinico Nemo (G.C., M.P., E.M.), Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; John Walton Muscular Dystrophy Research Centre (R.M.L., C.M.-B.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK; Departments of Neurology and Pediatrics (J.M., D.C.D.V.) and Departments of Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Paediatric Neurology and Centro Clinico Nemo (V.S., E.A.), Milan; Unit of Neuromuscular and Neurodegenerative Disorders (A.D., E.B.), Post-Graduate Bambino Gesù Children's Research Hospital, IRCCS, Rome; Department of Clinical and Experimental Medicine (S.M.), University of Messina Paediatric Neurology and Nemo Sud Clinical Centre; Center of Translational and Experimental Myology (C.B.), IRCCS Istituto Giannina Gaslini, Genova, Italy; University Hospitals Birmingham NHSFT (D.P.); Leeds Children Hospital (A.-M.C.); Evelina Children's Hospital (V.G.), London; The Robert Jones and Agnes Hunt Orthopaedic Hospital (T.W.), Oswestry; Sheffield Children's Hospital (M.O.), UK; Department of Neurology (B.T.D.), Boston Children's Hospital and Harvard Medical School, MA; Stanford University (J.D.), Medical Centre, Palo Alto, CA; Divisions of Pediatric Neurology (E.A.K.), Pulmonology (O.H.M.) and Physical Therapy (A.M.G.), The Children's Hospital of Philadelphia, and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia; and Divisions of Neurology (R.S.F.) and Pulmonary Medicine (A.A.N.N.), Department of Pediatrics, Nemours Children's Hospital, Orlando, FL.

Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).

Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.

Results: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.

Conclusions: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.
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http://dx.doi.org/10.1212/WNL.0000000000011051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905794PMC
January 2021

Neuromuscular diseases and advance care plans: traffic light system.

BMJ Support Palliat Care 2021 Mar 8;11(1):116. Epub 2020 Jun 8.

Medical, Severn Hospice, Telford, Shropshire, UK.

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http://dx.doi.org/10.1136/bmjspcare-2020-002336DOI Listing
March 2021

Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9.

Ann Clin Transl Neurol 2020 05 28;7(5):757-766. Epub 2020 Apr 28.

John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Objective: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities.

Methods: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain.

Results: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129).

Interpretation: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.
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http://dx.doi.org/10.1002/acn3.51042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261761PMC
May 2020

A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome-related disorders.

Clin Genet 2020 06 4;97(6):908-914. Epub 2020 Mar 4.

Centre for Rare Diseases and Personalised Medicine, University of Birmingham, Birmingham, UK.

Multiple pterygium syndrome (MPS) disorders are a phenotypically and genetically heterogeneous group of conditions characterized by multiple joint contractures (arthrogryposis), pterygia (joint webbing) and other developmental defects. MPS is most frequently inherited in an autosomal recessive fashion but X-linked and autosomal dominant forms also occur. Advances in genomic technologies have identified many genetic causes of MPS-related disorders and genetic diagnosis requires large targeted next generation sequencing gene panels or genome-wide sequencing approaches. Using the Illumina TruSightOne clinical exome assay, we identified a recurrent heterozygous missense substitution in TPM2 (encoding beta tropomyosin) in three unrelated individuals. This was confirmed to have arisen as a de novo event in the two patients with parental samples. TPM2 mutations have previously been described in association with a variety of dominantly inherited neuromuscular phenotypes including nemaline myopathy, congenital fibre-type disproportion, distal arthrogryposis and trismus pseudocamptodactyly, and in a patient with autosomal recessive Escobar syndrome and a nemaline myopathy. The three cases reported here had overlapping but variable features. Our findings expand the range of TMP2-related phenotypes and indicate that de novo TMP2 mutations should be considered in isolated cases of MPS-related conditions.
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http://dx.doi.org/10.1111/cge.13728DOI Listing
June 2020

Healthcare utilisation in children with SMA type 1 treated with nusinersen: a single centre retrospective review.

BMJ Paediatr Open 2019 5;3(1):e000572. Epub 2019 Dec 5.

Paediatric Respiratory Service, University Hospital of North Midlands NHS Trust, Stoke-on-Trent, UK.

Background: Nusinersen has been used to treat spinal muscular atrophy type 1 (SMA1) in the UK since 2017. While initial trials showed neuromuscular benefit from treating SMA1, there is little information on the respiratory effects of nusinersen. We aimed to look at the respiratory care, hospital utilisation and associated costs in newly treated SMA1.

Methods: We reviewed the medical records of all children within the West Midlands with SMA1 treated with nusinersen at Royal Stoke University Hospital. Baseline demographics and hospital admission data were collected including: the reason for admission, total hospital days, days of critical care, days intubated, discharge diagnosis, doses of nusinersen and treatment complications.

Results: 11 children (six girls) received nusinersen between May 2017 and April 2019. Their median (range) age was 29 (7-97) months. The median (range) number of nusinersen doses per child was 6 (4-8). All children were receiving long-term ventilatory support; this was mask ventilation in nine and tracheostomy ventilation in two. The total number of hospital days since diagnosis was 1101 with a median (range) of 118 (7-235) days per child. This included general paediatric ward days 0 (0-63), High Dependency Unit 79 (7-173) days and Paediatric Intensive Care Unit 13 (0-109) days per child. This equated to a median (range) of 20 (2-72) % of their life in hospital. The estimated cost of this care was £2.2M.

Conclusion: Patients with SMA1 treated with nusinersen initially spend a considerable proportion of their early life in hospital. Parents should be counselled accordingly. These data suggest that for every 10 children started on nusinersen an extra HDU bed is required. This has a significant cost implication.
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http://dx.doi.org/10.1136/bmjpo-2019-000572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937078PMC
December 2019

Adult neuromuscular disorders: a joint palliative/neuromuscular clinic.

BMJ Support Palliat Care 2019 Sep 7. Epub 2019 Sep 7.

Medical, Severn Hospice, Telford, Shropshire, UK.

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http://dx.doi.org/10.1136/bmjspcare-2019-001821DOI Listing
September 2019

Clinical, histological, and genetic characterization of PYROXD1-related myopathy.

Acta Neuropathol Commun 2019 08 27;7(1):138. Epub 2019 Aug 27.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France.

Recessive mutations in PYROXD1, encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores. Further characterization of the structural muscle defects uncovered aggregations of myofibrillar proteins, and provided evidence for enhanced oxidative stress. Sequencing identified homozygous or compound heterozygous PYROXD1 mutations including the first deep intronic mutation reinforcing a cryptic donor splice site and resulting in mRNA instability through exonisation of an intronic segment. Overall, this work expands the PYROXD1 mutation spectrum, defines and specifies the histopathological hallmarks of the disorder, and indicates that oxidative stress contributes to the pathomechanism. Comparison of all new and published cases uncovered a genotype/phenotype correlation with a more severe and early-onset phenotypic presentation of patients harboring splice mutations resulting in reduced PYROXD1 protein levels compared with patients carrying missense mutations.
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http://dx.doi.org/10.1186/s40478-019-0781-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710884PMC
August 2019

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints.

Ann Clin Transl Neurol 2019 Jun 16;6(6):1033-1045. Epub 2019 May 16.

The John Walton Muscular Dystrophy Research Centre Institute of Genetic Medicine Newcastle University Newcastle Hospitals NHS Foundation Trust Central Parkway Newcastle Upon Tyne United Kingdom NE1 4EP.

Objective: Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years.

Methods: Twenty-three participants with LGMD R9, previously assessed over a 1-year period, were re-enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups.

Results: At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1-year follow-up study. In direct contrast to the 1-year follow-up, the 6-min walk test, 10-m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1- and 6-year studies.

Interpretation: These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.
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http://dx.doi.org/10.1002/acn3.774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562036PMC
June 2019

Randomised placebo-controlled trial of combination ACE inhibitor and beta-blocker therapy to prevent cardiomyopathy in children with Duchenne muscular dystrophy? (DMD Heart Protection Study): a protocol study.

BMJ Open 2018 12 19;8(12):e022572. Epub 2018 Dec 19.

John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne, Tyne & Wear, UK.

Introduction: Although cardiologists were 'late-comers' to the multidisciplinary team-contributing to the complex care of patients with Duchenne muscular dystrophy (DMD), they now recognise the importance of systematic cardiac surveillance and timely therapy to prolonged survival in patients with DMD. Empirical deployment of cardioactive medications has already improved outcomes, but the evidence base for clinical decision making is weak. Fundamental questions remain as to whether prophylactic therapy is justified and convincingly superior to prompt deployment of the same therapies once left ventricular (LV) dysfunction is detected. Even if it were, at what age should therapy be introduced and with what specific drugs?

Methods And Analysis: We are conducting a multicentre, parallel group, randomised, placebo-controlled study of combination therapy with an ACE inhibitor (perindopril) and a beta-blocker (bisoprolol) in boys with DMD aged 5-13 years, with normal LV function by echocardiographic criteria at the time of recruitment. Boys are being followed-up for a minimum of 3 years and a maximum of 5 years and undergo repeat assessments of LV function, heart rate and ECG, forced expiratory volume in the 1 s and forced vital capacity, adverse event reporting and quality of life at 6 monthly intervals.The primary outcome is change in LV function between active and placebo-treated participants over the course of the study.

Ethics And Dissemination: The study was approved by 'NRES Committee East Midlands - Derby'. The results will be disseminated through manuscript publications, an international workshop and presentations to scientific meetings and parent forums.

Translational Aspects: The study seeks to establish the evidence for prophylactic heart therapies for children with DMD, define the optimum age for their introduction and identify any safety concerns.

Article Summary: The protocol describes the design of an ongoing multicentre, double-blind, randomised placebo-controlled study to establish the evidence for the use of prophylactic heart therapies in children with DMD, define the optimum age for their introduction and identify any safety concerns.

Trial Registration Numbers: EudraCT2007-005932-10 and ISRCTN50395346; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-022572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303652PMC
December 2018

Charcot Marie Tooth disease type 2S with late onset diaphragmatic weakness: An atypical case.

Neuromuscul Disord 2018 12 5;28(12):1016-1021. Epub 2018 Oct 5.

University Hospital of North Midlands NHS Trust, United Kingdom.

Immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) mutations are associated with partial continuum between two extremes of rapidly lethal disorder of spinal muscular atrophy with respiratory distress type 1 (SMARD1), with infantile axonal neuropathy, diaphragmatic weakness and commonly death before 1 year of age, and Charcot-Marie-Tooth disease (CMT) type 2S with slowly progressive weakness and sensory loss but no significant respiratory compromise. We present an atypical case of CMT2S. A 9 month old boy presented with bilateral feet deformities and axonal neuropathy. Genetic testing revealed two heterozygous variants in the IGHMBP2 gene: c.1156 T > C p.(Trp386Arg) in exon 8 and c.2747G > A p.(Cys916Tyr) in exon 14, that were inherited from his father and mother respectively. At 9 years, he developed diaphragmatic weakness, following which he was established on non-invasive ventilation. Our case emphasizes the importance of life long respiratory surveillance for patients with CMT2S and expands the phenotype of this condition.
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http://dx.doi.org/10.1016/j.nmd.2018.09.008DOI Listing
December 2018

ECEL1 gene related contractural syndrome: Long-term follow-up and update on clinical and pathological aspects.

Neuromuscul Disord 2018 09 30;28(9):741-749. Epub 2018 Jun 30.

Dubowitz Neuromuscular Centre, UCL Institute of Child Health & Great Ormond Street Hospital for Children, 30 Guilford Street, London WC1N 1EH, United Kingdom; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, United Kingdom. Electronic address:

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease.
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http://dx.doi.org/10.1016/j.nmd.2018.05.012DOI Listing
September 2018

Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.

Skelet Muscle 2018 07 30;8(1):23. Epub 2018 Jul 30.

John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Background: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.

Methods: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.

Results: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.

Conclusions: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.
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http://dx.doi.org/10.1186/s13395-018-0170-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066920PMC
July 2018

Mobility shift of beta-dystroglycan as a marker of gene-related muscular dystrophy.

J Neurol Neurosurg Psychiatry 2018 07 3;89(7):762-768. Epub 2018 Feb 3.

Dubowitz Neuromuscular Centre, MRC Centre for Neuromuscular Diseases, UCL Great Ormond Street Institute of Child Health, London, UK.

Background: Defects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.

Methods: We describe clinical, genetic and biochemical findings of 21 patients with -associated dystroglycanopathy.

Results: We report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormal -linked glycosylation of β-DG.

Conclusions: Our data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect in
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http://dx.doi.org/10.1136/jnnp-2017-316956DOI Listing
July 2018

Two Cases of Spinal Muscular Atrophy Type II with Eosinophilic Oesophagitis.

J Neuromuscul Dis 2017;4(4):357-362

Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK.

Although primarily characterised by loss of motor neurons from the anterior horn of spinal cord and muscle atrophy, spinal muscular atrophy (SMA) is now recognised as a multi-systemic disorder. Here, we report two SMA Type II patients with eosinophilic oesophagitis (EoE), a rare, chronic immune/antigen-mediated condition. One patient presented with dysphagia and poor weight gain, and the second patient had symptoms of gastro-oesophageal reflux (GOR) and poor weight gain. In both patients, macroscopic observations during gastroscopy indicated typical signs of EoE, which were verified during histological examination of oesophageal biopsies. Given that there is a specific treatment strategy for EoE, these cases highlight the importance of considering this condition in clinical investigations - especially for patients with SMA - who have GOR, discomfort, and oral aversion.
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http://dx.doi.org/10.3233/JND-170260DOI Listing
July 2019

Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy.

Muscle Nerve 2018 03 7;57(3):380-387. Epub 2017 Nov 7.

MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Central Parkway Newcastle upon Tyne NE1 3 BZ, United Kingdom.

Introduction: Earlier small case series and clinical observations reported on chronic pain playing an important role in facioscapulohumeral dystrophy (FSHD). The aim of this study was to determine the characteristics and impact of pain on quality of life (QoL) in patients with FSHD.

Methods: We analyzed patient reported outcome measures collected through the U.K. FSHD Patient Registry.

Results: Of 398 patients, 88.6% reported pain at the time of study. The most frequent locations were shoulders and lower back. A total of 203 participants reported chronic pain, 30.4% of them as severe. The overall disease impact on QoL was significantly higher in patients with early onset and long disease duration. Chronic pain had a negative impact on all Individualised Neuromuscular Quality of Life Questionnaire domains and overall disease score.

Discussion: Our study shows that pain in FSHD type 1 (FSHD1) is frequent and strongly impacts on QoL, similar to other chronic, painful disorders. Management of pain should be considered when treating FSHD1 patients. Muscle Nerve 57: 380-387, 2018.
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http://dx.doi.org/10.1002/mus.25991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836962PMC
March 2018

Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation.

Health Technol Assess 2017 05;21(27):1-120

Paediatric Neurology, Sheffield Children's Hospital, Sheffield, UK.

Background: Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent.

Objectives: To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work.

Design: Parallel-group, single-blind, randomised pilot trial with nested qualitative research.

Setting: Six paediatric neuromuscular units.

Participants: Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications.

Interventions: Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents ( = 8) and professionals ( = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise.

Main Outcome Measures: Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs.

Results: Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT ( = 8) or control ( = 4). People in the AT ( = 8) and control ( = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient.

Limitations: The focus on delivery in hospitals limits generalisability.

Conclusions: Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended.

Trial Registration: Current Controlled Trials ISRCTN41002956.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 21, No. 27. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta21270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494511PMC
May 2017

Developing standardized corticosteroid treatment for Duchenne muscular dystrophy.

Contemp Clin Trials 2017 07 24;58:34-39. Epub 2017 Apr 24.

University of Rochester Medical Center, United States.

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.
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http://dx.doi.org/10.1016/j.cct.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279424PMC
July 2017

Aquatic therapy for boys with Duchenne muscular dystrophy (DMD): an external pilot randomised controlled trial.

Pilot Feasibility Stud 2017 27;3:16. Epub 2017 Mar 27.

Paediatric Neurology, Sheffield Children's Hospital, Sheffield, UK.

Background: Standard treatment of Duchenne muscular dystrophy (DMD) includes regular physiotherapy. There are no data to show whether adding aquatic therapy (AT) to land-based exercises helps maintain motor function. We assessed the feasibility of recruiting and collecting data from boys with DMD in a parallel-group pilot randomised trial (primary objective), also assessing how intervention and trial procedures work.

Methods: Ambulant boys with DMD aged 7-16 years established on steroids, with North Star Ambulatory Assessment (NSAA) score ≥8, who were able to complete a 10-m walk test without aids or assistance, were randomly allocated (1:1) to 6 months of either optimised land-based exercises 4 to 6 days/week, defined by local community physiotherapists, or the same 4 days/week plus AT 2 days/week. Those unable to commit to a programme, with >20% variation between NSAA scores 4 weeks apart, or contraindications to AT were excluded. The main outcome measures included feasibility of recruiting 40 participants in 6 months from six UK centres, clinical outcomes including NSAA, independent assessment of treatment optimisation, participant/therapist views on acceptability of intervention and research protocols, value of information (VoI) analysis and cost-impact analysis.

Results: Over 6 months, 348 boys were screened: most lived too far from centres or were enrolled in other trials; 12 (30% of the targets) were randomised to AT ( = 8) or control ( = 4). The mean change in NSAA at 6 months was -5.5 (SD 7.8) in the control arm and -2.8 (SD 4.1) in the AT arm. Harms included fatigue in two boys, pain in one. Physiotherapists and parents valued AT but believed it should be delivered in community settings. Randomisation was unattractive to families, who had already decided that AT was useful and who often preferred to enrol in drug studies. The AT prescription was considered to be optimised for three boys, with other boys given programmes that were too extensive and insufficiently focused. Recruitment was insufficient for VoI analysis.

Conclusions: Neither a UK-based RCT of AT nor a twice weekly AT therapy delivered at tertiary centres is feasible. Our study will help in the optimisation of AT service provision and the design of future research.

Trial Registration: ISRCTN41002956.
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http://dx.doi.org/10.1186/s40814-017-0132-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367005PMC
March 2017

A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness.

J Neurol 2016 Jul 13;263(7):1427-33. Epub 2016 May 13.

Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 45, Gothenburg, Sweden.

Myosin heavy chain (MyHC) is a major structural component of the striated muscle contractile apparatus. In adult human limb skeletal muscle, there are three major MyHC isoforms, slow/beta cardiac MyHC, MyHC IIa and MHC IIx, which are important for the functional characteristics of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression dependent on the mutated isoform, and also the type and location of the mutation. Myosin myopathy with external ophthalmoplegia is associated with mutations in MYH2, encoding for MyHC IIa that is mainly expressed in type 2A muscle fibers and is inherited in dominant as well as recessive manner. We present a family with myopathy with early onset proximal muscle weakness, facial muscle involvement and ophthalmoplegia. Muscle biopsy demonstrated lack of type 2A muscle fibers and genetic work up demonstrated that the disease was caused by a novel recessive MYH2 mutation: c.1009-1G>A resulting in skipping of exon 12, which is predicted to result in a frame shift and introducing at premature stop codon at position 347 (p.Ser337Leufs*11).
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http://dx.doi.org/10.1007/s00415-016-8154-8DOI Listing
July 2016

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness.

Neurology 2016 Jul 11;87(3):295-8. Epub 2016 May 11.

From Newborn Screening and Metabolic Diagnostics (Z.L., P.N.C.), University Medical Center Hamburg-Eppendorf, Hamburg; Friedrich-Baur Institute, Department of Neurology (S.W., B.S.-W., M.C.W., P.R., T.K., B.S.), and Department of Neuropediatrics, Dr. Von Haunersche Kinderklinik (W.M.-F.), Ludwig Maximilian University of Munich, Germany; The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust (T.A.W.), Oswestry; Institute of Genetic Medicine (T.E., M.G., V.S.), Newcastle University; Salford Royal NHS Foundation Trust (M.R.), Salford; UCL Institute of Neurology and National Hospital (R.Q.), Queen Square, London; Department of Neurology (D.H.-J.), Oxford University Hospital, UK; and Department of Neurology (S.Z., M.D.), Halle University, Germany.

Objective: We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation.

Methods: DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry. Samples with reduced enzyme activity were subsequently investigated for GAA gene mutations.

Results: Of 3,076 patients with DBS samples, 232 patients (7.6%) showed low GAA enzyme activity. Of these 232 patients, 55 (24%) presented with isolated hyperCKemia and 176 (76%) with hyperCKemia and LGMW. With both features present, 94% of the patients showed a low enzymatic activity. Mutational analysis found GAA gene mutations in 74 patients (2.4%); herein 70 patients were heterozygote for the common GAA gene splice-site mutation c.-32-13T>G. The most common clinical presentation in the confirmed Pompe cohort was a limb-girdle phenotype (85.3%) combined with ventilatory insufficiency (61%). Isolated hyperCKemia was found in 12%, while 2.7 had hyperCKemia and ventilatory insufficiency only.

Conclusions: In a large cohort of unselected adult patients with hyperCKemia and/or LGMW, we found a prevalence of late-onset Pompe disease of 2.4%. Therefore, targeted screening of such a population should be encouraged in clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000002758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955273PMC
July 2016

Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.

J Neurol 2016 Jul 9;263(7):1401-8. Epub 2016 May 9.

John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

Facioscapulohumeral dystrophy (FSHD) is a rare inherited neuromuscular disease estimated to affect 1/15,000 people. Through basic research, remarkable progress has been made towards the development of targeted therapies. Patient identification, through registries or other means is essential for trial-readiness. The UK FSHD Patient Registry is a patient initiated registry that collects standardised and internationally agreed dataset of self-reported clinical details combined with professionally verified genetic information. It includes four additional questionnaires to capture patient reported outcomes related to pain, quality of life and scapular fixation. Between 2013 and 2015, 518 patients registered 243 males, 241 females with a mean age of 47.8 years. Most of the patients have FSHD type 1 (91.7 %), and weakness of the facial (59.2 %) was the most prevalent symptom at onset, followed by shoulder-girdle muscles (53.3 %) and distal (22.45 %) or proximal lower limb weakness (14.8 %). 85.57 % patients were ambulant or ambulant with assistance at the time of registration, 7.9 % report respiratory insufficiency. The registry has demonstrated utility with the recruitment of patients for a natural history study of infantile onset FSHD, and the longitudinal analysis of patient-related outcomes will provide much-needed baseline information to power future trials. The internationally agreed core dataset enables national registries to participate in a "Global FSHD registry". We suggest that the registry's ability to interoperate with other large datasets will be instrumental for sharing and exploiting data globally.
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http://dx.doi.org/10.1007/s00415-016-8132-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929161PMC
July 2016

Quantitative magnetic resonance imaging in limb-girdle muscular dystrophy 2I: a multinational cross-sectional study.

PLoS One 2014 28;9(2):e90377. Epub 2014 Feb 28.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p<0.005). MRI is non-invasive, objective and does not rely on patient effort compared to clinical and physical measures that are currently employed. We demonstrated (i) that the quantitative Dixon technique is an objective quantitative marker of disease and (ii) new observations of gender specific patterns of muscle involvement in LGMD2I.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090377PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938727PMC
October 2014

Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I: a multicentre longitudinal study.

PLoS One 2013 14;8(8):e70993. Epub 2013 Aug 14.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.

Background: Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups.

Objective: To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period.

Methods: 32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale.

Results: There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T₁w images.

Conclusions: Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070993PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743890PMC
March 2014

Subepicardial dysfunction leads to global left ventricular systolic impairment in patients with limb girdle muscular dystrophy 2I.

Eur J Heart Fail 2013 Sep 10;15(9):986-94. Epub 2013 Apr 10.

Newcastle Magnetic Resonance Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.

Aim: The mechanisms of cardiac dysfunction in limb girdle muscular dystrophy 2I (LGMD2I) are unclear. This study assessed deficits in cardiac morphology, function, and metabolism quantitatively in patients with a confirmed genetic diagnosis of the homozygous c.826C > A FKRP (fukutin-related protein) mutation, using a comprehensive magnetic resonance (MR) examination.

Methods And Results: Ten patients (7 male and 3 female) and 10 matched control subjects were recruited prospectively. Cardiac morphology by cine imaging, cardiac torsion and strain by MR tagging, and cardiac energetics by phosphorus-31 MR spectroscopy were measured. LGMD2I subjects were found to have a significant reduction in peak cardiac torsion (3.9 ± 1.3° vs. 6.4 ± 1.5°, P = 0.04), and in the ratio of torsion to endocardial strain (0.31 ± 0.05 vs. 0.51 ± 0.14, P = 0.03), compared with control subjects. The impairment in torsion correlated strongly with reduction in EF (r = 0.93, P < 0.001). Peak circumferential and longitudinal strains were preserved in the patients, however [LGMD2I, 16.4 ± 3.2% vs. 18.3 ± 3.5%, non-significant (NS); and LGMD2I, 17.0 ± 3.0% vs. 18.4 ± 3.5%, NS]. Cardiac cine analysis demonstrated reduced EF (47 ± 7% vs, 58 ± 4%, P = 0.02) and stroke volume (61 ± 11 mL vs. 81 ± 13 mL, P = 0.04), though no evidence of LV hypertrophy was found. The ratio of phosphocreatine to ATP (PCr/ATP) was reduced in the LGMD2I subjects compared with controls (1.50 ± 0.24 vs. 1.94 ± 0.12, P = 0.0001).

Conclusions: The loss of torsion with preservation of circumferential and longitudinal strain in LGMD2I is a unique finding and suggests subepicardial dysfunction with abnormal transmission of force across the cardiac wall.
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http://dx.doi.org/10.1093/eurjhf/hft057DOI Listing
September 2013

Presymptomatic late-onset Pompe disease identified by the dried blood spot test.

Neuromuscul Disord 2013 Jan 10;23(1):89-92. Epub 2012 Oct 10.

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.

Pompe disease or glycogen storage disease type II is an autosomal recessive disorder caused by mutations in the GAA gene leading to muscle weakness. Here we describe a 15 years old presymptomatic patient with normal muscle MRI, unspecific muscle biopsy findings but abnormal acid maltase activity in a dried blood spot test. Sequencing the GAA-gene identified a heterozygous novel splice-site and a heterozygous previously described mutation. The case highlights the variability in clinical phenotype and difficulties to diagnose late-onset Pompe disease. Dried Blood Spot (DBS) might be the most sensitive tool to pick up mildly symptomatic patients.
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http://dx.doi.org/10.1016/j.nmd.2012.09.004DOI Listing
January 2013

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X).

Eur J Hum Genet 2010 Feb 9;18(2):157-62. Epub 2009 Sep 9.

Department of Genetics and Molecular Pathology, Neurogenetics Laboratory, SA Pathology, Adelaide, Australia.

Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C>G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C>G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.
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http://dx.doi.org/10.1038/ejhg.2009.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987188PMC
February 2010

New mutations, genotype phenotype studies and manifesting carriers in giant axonal neuropathy.

J Neurol Neurosurg Psychiatry 2007 Nov 19;78(11):1267-70. Epub 2007 Jun 19.

Department of Molecular Neuroscience, Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

Giant axonal neuropathy (GAN; MIM 256850) is a severe childhood onset autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system. Bomont and colleagues identified a novel ubiquitously expressed gene they named Gigaxonin on chromosome 16q24 as the cause of GAN in a number of families. We analysed five families with GAN for mutations in the Gigaxonin gene and mutations were found in four families; three families had homozygous mutations, one had two compound heterozygous mutations and one family had no mutation identified. All families had the typical clinical features, kinky hair and nerve biopsy. We report some unusual clinical features associated with GAN and Gigaxonin mutations as well as confirm the heterogeneity in GAN and the identification of two families with manifesting carriers.
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http://dx.doi.org/10.1136/jnnp.2007.118968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117591PMC
November 2007