Neuromuscular Disorders

Editorial Board

2010-03-01

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): Test development and reliability

2010-03-01

Abstract: The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (“CHOP INTEND”) to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5months (1.4–37.9months) with the Test of Infant Motor Performance and The Children’s Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach’s alpha. Intra-rater reliability of the resulting test was established by test–retest of 9 infants with SMA-I over a 2month period; Intraclass correlation coefficient (ICC) (3,1)=0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4)=0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5)=0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy.

Reliability of telephone administration of the PedsQL™ Generic Quality of Life Inventory™ and Neuromuscular Module™ in spinal muscular atrophy (SMA)

2010-03-01

Abstract: Clinical research visits are challenging for people with SMA because of limited mobility and intercurrent illnesses. Missing data threaten the validity of research results. Obtaining outcomes remotely would represent a solution. To evaluate reliability of telephone administration of the PedsQL™ Pediatric Generic Core Quality of Life Inventory™ 4.0 (Generic) and Neuromuscular Module™ 3.0 (NM) in SMA, we recruited 21 participants of a Natural History Study for telephone administration of both modules no more than 7days before or after an in-person study visit. We found excellent reliability between telephone and in-person administration of both modules with the NM slightly better than the Generic. Reliability of the child and parent forms was similar. We concluded that both modules can be administered reliably over the telephone to SMA patients and caregivers, expanding the utility of these tools in clinical trials. Notably, telephone administration is reliable in children as young as 8years.

Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene

2010-03-01

Abstract: The skeletal muscle ryanodine receptor plays a crucial role in excitation–contraction (EC) coupling and is implicated in various congenital myopathies. The periodic paralyses are a heterogeneous, dominantly inherited group of conditions mainly associated with mutations in the SCN4A and the CACNA1S genes. The interaction between RyR1 and DHPR proteins underlies depolarization-induced Ca2+ release during EC coupling in skeletal muscle. We report a 35-year-old woman presenting with signs and symptoms of a congenital myopathy at birth and repeated episodes of generalized, atypical normokalaemic paralysis in her late teens. Genetic studies of this patient revealed three heterozygous RYR1 substitutions (p.Arg2241X, p.Asp708Asn and p.Arg2939Lys) associated with marked reduction of the RyR1 protein and abnormal DHPR distribution. We conclude that RYR1 mutations may give rise to both myopathies and atypical periodic paralysis, and RYR1 mutations may underlie other unresolved cases of periodic paralysis with unusual features.

Early onset of cardiomyopathy and primary prevention of sudden death in X-linked Emery–Dreifuss muscular dystrophy

2010-03-01

Abstract: We report the case of 14-year-old boy with X-linked Emery–Dreifuss muscular dystrophy who developed sick sinus syndrome and required placement of an implantable intracardiac cardioverter-defibrillator (ICD) to prevent sudden death. He demonstrated no significant risk factors for sudden death such as depressed left ventricular ejection fraction, or spontaneous or inducible ventricular tachycardia. One month after implantation, the patient experienced one appropriate ICD discharge.

Desmin myopathy with severe cardiomyopathy in a Uruguayan family due to a codon deletion in a new location within the desmin 1A rod domain

2010-03-01

Abstract: Desmin myopathy is a heterogeneous neuromuscular disorder characterized by skeletal myopathy and cardiomyopathy, inherited mostly in an autosomal dominant pattern. We report a five generation Uruguayan family with severe cardiomyopathy and skeletal myopathy. Its most striking features are: atrial dilation, arrhythmia, conduction block and sudden death due to conduction impairment. Affected skeletal muscle shows alteration of mitochondria with paracrystallin inclusions and granulofilamentous material scattered in the muscle fibres. This family carries an unusual deletion p.E114del within the 1A rod domain of desmin. Transfected cells expressing the mutated desmin show punctuated and speckled cytoplasmic aggregates. The mutation causes a local conformational change in heptads a/d residues and charge positions. These findings lead to the hypothesis that coiled-coil interactions may be impaired, resulting in severe alterations in the desmin network. This is the first time that a mutation affecting this domain in the desmin molecule is described in a desminopathy.

Autoantibody profiles in two patients with non-autoimmune muscle disease implicate a role for gliadin autoreactivity

Nancy J. Olsen, Heidi Prather, Quan-Zhen Li, Dennis K. Burns — 2010-03-01

Abstract: The objective of this case study was to characterize autoreactivity in two patients with non-autoimmune forms of muscle disease who had positivity for antinuclear antibodies (ANA) and Ro (SSA) autoantibodies. Serum samples from these two patients were applied to an autoantigen protein array with more than 70 specificities and were compared to samples from healthy controls and patients with systemic lupus erythematosus. Both myopathy patients had high levels of gliadin autoreactivity in serum and one patient had an overall autoantibody profile with lupus-like features. The findings suggest that some disorders of muscle that are considered non-autoimmune, may in fact have autoimmune features. Further examination of the role of subclinical gluten autoreactivity in the pathogenesis of myopathy syndromes has the potential to suggest improved approaches to diagnosis and treatment of these conditions.

Microvasculopathic neuromuscular diseases: Lessons from hypoxia-inducible factors

Stefan Probst-Cousin, Bernhard Neundörfer, Dieter Heuss — 2010-03-01

Abstract: Dermatomyositis and vasculitic neuropathies are disorders with immune mediated ischemic injuries. Cellular responses to hypoxia include the hypoxia-inducible factor-1 (HIF-1)-induced transcription of genes involved in angiogenesis. To study their possible roles in those disorders, the immunohistochemical expression of HIF-1α, HIF-1β, HIF-2α, vascular endothelial growth factor (VEGF), VEGF-receptor (VEGF-R) and erythropoietin-receptor was investigated. Cases of normal nerves, diabetic neuropathy, normal muscles, polymyositis and inclusion-body-myositis served as controls. The latter were chosen because they represent comparable inflammatory disorders, however, in these ischemia/hypoxia is not supposed to play such a prominent pathogenetic role.Hypoxia-related proteins were not detected in normal controls. In polymyositis and inclusion-body-myositis, there was VEGF-R-expression in muscle fibers and HIF-2α reactivity in endothelial cells. In dermatomyositis, HIF-1α and HIF-1β were found in endothelial cells, whereas HIF-2α, erythropoietin-receptor, VEGF and VEGF-R additionally were observed in muscle fibers. In vasculitic and diabetic neuropathies, a variable focal expression of hypoxia-inducible factors, VEGF, VEGF-R and erythropoietin-receptor was seen in vessels.These observations suggest that the upregulation of hypoxia-related proteins may represent an adaptation mechanism of neuromuscular tissues to immune mediated deprivation of the blood supply.

Two novel mutations in thymidine kinase-2 cause early onset fatal encephalomyopathy and severe mtDNA depletion

2010-03-01

Abstract: Deficiency of thymidine kinase-2 (TK2) has been described in children with early onset fatal skeletal myopathy. TK2 is a mitochondrial deoxyribonucleoside kinase required for the phosphorylation of deoxycytidine and deoxythymidine and hence is vital for the maintenance of a balanced mitochondrial dNTP pool in post-mitotic tissues. We describe a patient with two novel TK2 mutations, which caused disease onset shortly after birth and death at the age of three months. One mutation (219insCG) generated an early stop codon, thus preventing the synthesis of a functional protein. The second mutation (R130W) resulted in an amino acid substitution, which caused a severe reduction (<3%) of TK2 enzyme activity. These two novel TK2 mutations cause an extremely severe phenotype with overwhelming central nervous system symptoms not commonly seen in patients with TK2-deficiency. We conclude that the severe clinical presentation in this patient was due to a virtual lack of mitochondrial TK2 activity.

A novel mutation in the tRNAIle gene (MTTI) affecting the variable loop in a patient with chronic progressive external ophthalmoplegia (CPEO)

Andres Berardo, Jorida Çoku, Bulent Kurt, Salvatore DiMauro, Michio Hirano — 2010-03-01

Abstract: We describe a 62-year-old woman with chronic progressive external ophthalmoplegia (CPEO), multiple lipomas, diabetes mellitus, and a novel mitochondrial DNA (mtDNA) mutation at nucleotide 4302 (4302A>G) of the tRNAIle gene (MTTI). This is the first mutation at position 44 in the variable loop (V loop) of any mitochondrial tRNA.The muscle biopsy revealed 10% ragged-red/ragged-blue fibers and 25% cytochrome c oxidase (COX)-deficient fibers.No deletions or duplications were detected by Southern blot analysis. The 4302A>G transition was present only in the patient’s muscle and single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient than in normal fibers. Like tRNALeu(UUR), tRNAIle appears to be a “hot spot” for mtDNA mutations causing CPEO.

A pioneer in neuropathology: Alix Joffroy (1844–1908), J.-M Charcot’s pupil

D. Tiberghien — 2010-03-01

The nosography developed in the mid XIXth century was that of neuromuscular diseases. Many disorders were confused among the vast group of muscular atrophies. Gradually, the following diseases were distinguished among others: infantile paralysis, amyotrophic lateral sclerosis, labio-glosso-laryngé paralysis… French doctors Charcot, Duchenne de Boulogne… and other European doctors: Eulenburg, Meryon… participated in this heroic march forward of neurology. One name remains unknown to these neurologists and anatomopathologists: Alix Joffroy (1844–1908). The anatomopathologist tradition developed at the turn of the XXth century. Joffroy was one whose work led to a big advance in neurology by contributing to the establishment of the first foundations of modern spinal anatomopathology. We provide here a brief history of his anatomopathological works mainly relating to the neuromuscular diseases followed by two subjects that interested him more particulary: Basedow disease and general paralysis.

Motoneuron transplantation rescues the phenotype of SMARD1 (spinal muscular atrophy with respiratory distress type 1). J Neuroscience 2009; 29: 11761–11771

2010-03-01

Commentary 2 on “Motoneuron transplantation rescues the phenotype of SMARD1

2010-03-01

Letter 1

Michael W. Munn — 2010-03-01

The following letters to the editor have been received in response to the editorial in the February issue of Neuromuscular Disorders (1) in relation to the review in the January 2010 issue of Lancet Neurology on management of Duchenne dystrophy (2).

Letter 2

Filippo Buccella, Pat Furlong, Sally Hofmeister, Elizabeth Vroom — 2010-03-01

The Lancet Neurology review is a reflection onhow treatment and care of Duchenne dystrophy has been performed in the past and how selected publications about specific aspects of care are judged by panels of experts using the Rand method. Parents hope that care will be better in the near future, or even now, than what is described in this publication. It suggests that over 80 experts in the field developed these recommendations. While the community appreciates this investment of time and talent, there is some concern that consensus in Duchenne tends to end up somewhere in the middle. Duchenne is progressive. Each day muscle cells are lost, resulting in decline in function and subsequent compromise of activities of daily life. Care must be proactive – preventive, anticipatory and individualized.

Letter 3

Ros Quinlivan — 2010-03-01

The authors of the Lancet article have clearly put in a great deal of hard work and effort in order to produce their extensive document outlining care guidelines for DMD. However, the recent editorial by Professor Dubowitz highlights some very important considerations. There is no doubt that an article such as the Lancet care pathway will influence commissioners who ultimately hold the purse strings for service development. The DMD care pathway is complex and aims to make recommendations for all eventualities. Because of the dearth of good quality scientific research the authors have used a novel consensus approach to arrive at a conclusion for best practice.

Letter 4

Brian Tseng — 2010-03-01

These documents published in Lancet Neurology January 2010 will help families, DMD centers, care providers and clinicians consider their areas of DMD care that may not otherwise include some of these recommendations. Referrals to other specialists may be an important response to these “care guidelines” and will facilitate both specialists and insurance carriers to consider these recommendations. A dedicated primary doctor is needed to help families coordinate and understand the complex and vital care needed for a family and son(s) touched by a dystrophin mutation. Invariably families must maintain a copy of their own medical records and bring to their appointments. One critical question asked by families is, “Who is keeping track of all this multidisciplinary, comprehensive care with their son(s)?” Certainly in the USA, medical care like medical records can be fragmented and specialists tend to work in silos. This is a care barrier that must be overcome. Families and providers must recognize these care guidelines are starting points, not endpoints for establishing the best of comprehensive medical care in DMD. We must still all insist on well-designed prospective clinical research to further prove the best of care.

Letter 5

Brenda L. Wong — 2010-03-01

The jury is still out on the issue of the timing of starting steroids for patients with Duchenne muscular dystrophy (DMD). Glucocorticoid therapy is an effective therapy to slow the progression of this relentlessly progressive disease. Ideally, if corticosteroids were without side effects, they would be initiated as soon as the diagnosis of DMD is certain. However, as long term corticosteroid therapy is associated with significant side effects, that in turn negatively impact motor function and cardiopulmonary health (in particular endocrine complications of growth suppression, insulin resistance (weight gain) and steroid induced osteopenia), many providers in the past delay the initiation of steroids till there is obvious decline/loss of motor function (“about to go off the feet stage”).

Letter 6

Haluk Topaloglu — 2010-03-01

I personally find the prednisone dosage recommended in the Lancet Neurology article extremely high. Consider this scene: a DMD boy, 5years old. How can one give him 0.75mg/kg/day of prednisone continuously for say 10–15years? I have noted that the paper mentions reducing by 25–33% if necessary, but still in the long run it may turn out to be a health hazard. Some clinicians advocate lower dosages, and our group has been one of them. We were able to prolong ambulation and prevent scoliosis in a group of children with DMD with a 0.75mg/kg alternate day regimen .

Letter 7

Victor Dubowitz — 2010-03-01

In relation to the supportive management of Duchenne dystrophy with KAFOs and Corticosteroids, I think there is a major problem with the opinion of experts without personal clinical experience. They may get it wrong.

Richard H.T. Edwards PhD, FRCP (1939–2009)

Victor Dubowitz — 2010-03-01

Richard Edwards died suddenly on 5th December at his home in Snowdonia, North Wales. He was one of the early pioneers in the field of Neuromuscular medicine and made an enormous contribution to the Neuromuscular field through his research and he was also passionate in ensuring that his patients had the best possible clinical care.

Adrian Wills — 2010-03-01

I found this multi-author text a very useful reference work. The first chapter deals with the generalities of neuro-pharmacology and subsequent chapters are system-orientated e.g. movement disorders, epilepsy, migraine etc. Each chapter is organised fairly consistently along the lines of basic science, clinical features and treatment including dosage regimes (not consistent) and a description of potential side effects. I particularly enjoyed the chapters on epilepsy and neuro-muscular disease.

Heinz Jungbluth — 2010-03-01

“Quantitative muscle ultrasound in childhood neuromuscular disorders”, the doctoral thesis by Sigrid Pillen provides a comprehensive account of the current and future role of (quantitative) muscle ultrasound (US) in the diagnosis of childhood (and adult) neuromuscular disease and will benefit both the physician with previous experience applying this technique as well as newcomers to the field.

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