Pediatric Neuromuscular Disorders Research Articles

PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models.

Myotubular myopathy (MTM) is a devastating pediatric neuromuscular disorder of phosphoinositide (PIP) metabolism resulting from mutations of the PIP phosphatase MTM1 for which there are no treatments. We have previously shown phosphatidylinositol-3-phosphate (PI3P) accumulation in animal models of MTM. Here, we tested the hypothesis that lowering PI3P levels may prevent or reverse the MTM disease process. To test this, we targeted class II and III PI3 kinases (PI3Ks) in an MTM1-deficient mouse model. Muscle-specific ablation of Pik3c2b, but not Pik3c3, resulted in complete prevention of the MTM phenotype, and postsymptomatic targeting promoted a striking rescue of disease. We confirmed this genetic interaction in zebrafish, and additionally showed that certain PI3K inhibitors prevented development of the zebrafish mtm phenotype. Finally, the PI3K inhibitor wortmannin improved motor function and prolonged lifespan of the Mtm1-deficient mice. In all, we have identified Pik3c2b as a genetic modifier of Mtm1 mutation and demonstrated that PIK3C2B inhibition is a potential treatment strategy for MTM. In addition, we set the groundwork for similar reciprocal inhibition approaches for treating other PIP metabolic disorders and highlight the importance of modifier gene pathways as therapeutic targets.

G.P.384 - Use of next generation exome sequencing for the diagnosis of patients with pediatric neuromuscular disorders

G.P.384 - Use of next generation exome sequencing for the diagnosis of patients with pediatric neuromuscular disorders

1-A-D-12. Utility of quantitative and non-invasive surface EMG analysis for pediatric neuromuscular disorders

Needle electromyography is invaluable for diagnosis of pediatric neuromuscular disorders, although the procedure is too painful. In this study, we tested the utility of the Clustering Index (CI) method, a quantitative analysis for surface electromyography (SEMG), for the differential diagnosis of pediatric neuromuscular disorders. Subjects were 39 children with neuromuscular disorders (15 neurogenic and 24 myopathic patients). Their age averaged 8.8 ± 4.1 years. SEMG was recorded at the tibialis anterior muscle. Ankle dorsiflexion was achieved by instruction or by tickling the sole. The SEMG signal of one-second length with stable intensity was used as an epoch for further analyses. In total, 836 epochs from neurogenic patients and 992 epochs from myopathic patients were analyzed. CI and area for each epoch were calculated using a 10 ms window width, and the mean discriminant function was calculated for each subject. Using appropriate cut-off values, 7 from 15 neurogenic and 14 from 24 myopathic patients were correctly diagnosed as neurogenic or myopathic with 100% specificity. Especially, 4 of 7 spinal muscular atrophy patients and 9 of 12 Duchenne muscular dystrophy patients were correctly classified. The CI method is a non-invasive and promising tool for differential diagnosis between neurogenic and myopathic conditions in children.

P159 – 2412: First drug registry in Duchenne muscular dystrophy (DMD) to assess Translarna use, safety, and effectiveness in routine clinical practice

Objective A severe, relentlessly progressive neuromuscular disorder primarily affecting young males, DMD results from mutations in the gene for dystrophin, a protein required for muscle stability. ∼13% of patients have DMD due to a nonsense mutation (nm). Translarna (ataluren) restores dystrophin expression in patients with nmDMD and recently was the first treatment approved in Europe for this orphan genetic disorder. To fulfill a post-marketing commitment and generate data regarding long-term patient outcomes in the setting of routine clinical practice and patterns of use, an ataluren patient registry has been established. Methods This observational study is intended to enroll 200 patients across ∼50 care centers in Europe and other regions over ∼2 years. The study population will include patients who are receiving usual care treatment with commercial supply of Translarna (or receiving care within an early access program) and who provide consent. Patients will be followed for at least 5 years. Safety and efficacy data will be collected in conjunction with routine visits conducted as per usual care. Although there are no protocol-mandated procedures, it is expected that physicians and other caregivers will follow published treatment guidelines and standards of care. This study will be conducted in collaboration with TREAT-NMD and CINRG, organizations experienced in managing active DMD disease registries and natural history studies. Results Enrollment of the first patient is projected to occur in 1H2015. Conclusion Translarna is the first treatment approved for DMD, based upon demonstration of positive risk/benefit in clinical trials. Establishment of this registry further advances drug development in DMD and provides a mechanism to collect important information regarding real-world, long-term safety and effectiveness of Translarna as a treatment for this pediatric neuromuscular disorder.

Quantitative Analysis of Surface Electromyography for Pediatric Neuromuscular Disorders (P6.269)

Quantitative Analysis of Surface Electromyography for Pediatric Neuromuscular Disorders (P6.269)

Prevalence of congenital muscular dystrophy in Italy: a population study.

We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries.

G.P.306 : Pediatric Neuromuscular Diseases Patient Profiles from Family Perspective in Turkey

This study aimed to determine general knowledge levels of the families about pediatric neuromuscular diseases and specify their descriptive profiles. Participants and methods: A family seminar was announced to 560 patient families who come from different regions of Turkey and followed regularly at our pediatric neuromuscular disorders unit. The questionnaire which covered child's overall health status (10 questions), child's disease (14 questions) and family's knowledge level about the diseases (14 questions) was sent to families before the seminar. Evaluations were based on 156 full replies. Results: Children's mean age was 10.9±5.9 years. Mean of disease duration was 7.2±4.3 year. The age of diagnosis was 4.4±2.4 years. Clinical diagnoses were as follows: Duchenne Muscular Dystrophy (%77), Spinal Muscular Atrophy (%12.2) and the other neuromuscular diseases (%10.8). %20.4 of the cases had a family history. %21.3 of the families had more than one child with disease. Most of the children (%69.9) diagnosed with the DNA analysis tests. Families reported that their children were affected negatively in the following aspects inquired: physical (%59.5), psychological (%31.4), intellectual (%25) and social (%9.7). Most experienced difficulties in basic daily life of the children were reported as transfer activities (walking % 84, stairs % 89), wearing clothes (%76), personal hygiene (%73) and eating (%40). Children were also affected in joining game activities and going to school. %77.2 of the families expressed their need of informative seminars. Conclusion: Informing families about neuromuscular diseases which cause progressive inabilities must be on an escalating scale. Better interaction is what we all need.

G.P.162: The impact of reduced ankle range of movement on the functional abilities of patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is one of the most common progressive paediatric neuromuscular disorders. With decreasing power, DMD boys develop increasing contractures. When ambulant, ankles and long finger flexors are frequently the first to become tight but as weakness increases the iliotibial band, hips, knees and elbows contract and spinal asymmetry occurs. At Great Ormond Street Hospital we see a cohort of approximately 150 ambulant DMD boys biannually. In clinic the boys have assessments of muscle power, joint range measured by goniometery, North Star Ambulatory Assessment, 10 m walk/run test and timed rise from the floor. In DMD a major focus of physiotherapy intervention is maintenance of optimum range of movement (ROM) at the ankle, as highlighted in the TREAT–NMD standards of care. This is achieved by active and passive stretches, orthotics, serial casting and in exceptional cases surgery. While the recommendations are based on an assumption that the increase in ROM at the ankles will improve function, there is little evidence to sustain this. An audit was conducted involving 50 ambulant boys with DMD from our cohort. Longitudinal data covering 5 years was analysed. 10 m walk, timed rise from floor and lower limb muscle strength (MRC grading) was compared against ankle ROM. We established a correlation between increased ankle tightness and decrease in speed over 10 m with time taken to rise from the floor. In the same cohort, MRC grading of quadriceps, hamstrings and hip extensor power was plotted against ankle ROM, only a weak relationship between contractures and power was identified. Our study confirms that reduced ankle ROM has a major impact on functional abilities of boys with DMD, specifically the functions of walking and rising from the floor which require passive ankle ROM past 90°. In view of the relevance of Achilles tendon tightness on function in DMD, we propose it should be considered when devising inclusion criteria of clinical trials.

Referral and diagnostic trends in pediatric electromyography in the molecular era

Major advances in genetic analysis and neuroimaging have modified the traditional diagnostic approach for neuromuscular disorders. The purpose of this study was to investigate the role of electromyography (EMG) in the molecular era. We retrospectively surveyed reports of all EMG studies performed at Boston Children's Hospital from 2001 through 2011. Data were collected on study numbers, patient ages, referring provider subspecialty, study indication, electrophysiological diagnosis, and study utility. A total of 2100 studies were performed. The volume increased from ~160 to ~250 studies/year. There was a trend toward studying older children. Neurologists, including neuromuscular specialists, constituted the major referral pool, whereas referrals from orthopedics increased steadily. Polyneuropathies followed by mononeuropathies were the most common indications and diagnoses. Fifty-seven percent of studies were normal. EMG provided meaningful information in 94% of cases. EMG continues to play a cardinal role in the diagnosis of pediatric neuromuscular disorders, although its practice paradigm is evolving.

Safety and yield of muscle biopsy in pediatric patients in the modern era

BackgroundMuscle and skin biopsies are commonly used diagnostic procedures in the evaluation of pediatric neuromuscular and genetic disorders. However, few modern reports have documented their diagnostic yield and clinical utility. We reviewed our experience at a tertiary care center. MethodsWe retrospectively studied consecutive pediatric patients who underwent muscle biopsy at our institution between January 2008 and April 2012. ResultsOf 169 patients, 97 (57%) were male, and the median (range) age was 7years (9days to 18years). In 101 patients (60%), a pathologic diagnosis was made. Histologic results of biopsy were completely normal in 45 patients (27%). Minimal abnormalities not sufficient to make a definitive pathologic diagnosis were reported in 23 patients (14%). Sensitivity and specificity of preoperative electromyography in detecting muscle pathology were 58% and 56%, respectively. No complications occurred from the use of general anesthesia. The only complication was a right femoral vein laceration when the right vastus medialis muscle was chosen as a biopsy site. ConclusionMuscle biopsy in children is safe and useful in establishing the best management plan for patients with suspected neuromuscular disorders. This finding contradicts those of previous studies.

Update in electromyography

It is easy to forget the contribution of electromyography (EMG) to the investigation of paediatric peripheral neuromuscular disease, and this review highlights its continued importance. The discovery that Brown-Vialetto-van Leare disease, when associated with disorder of riboflavin metabolism, may be treatable has raised awareness of the importance of EMG for its early detection. Unexpected discovery of motor neuronopathy, which may be useful for the definition of the phenotype of several conditions, now has an added significance. The investigation of disorders of peripheral nerve cannot proceed without nerve conduction studies but particular interest has been shown in its role in the management of obstetric brachial plexus palsy, with investigation within 1 month now recommended. The key role of neurophysiology in identifying abnormalities of the neuromuscular junction, and therefore leading investigators to a diagnosis of myasthenia, is once again highlighted. EMG in muscle disease continues to have a role, particularly when identifying myotonia. Paediatric EMG, while a daunting technical challenge to some practitioners, remains a valuable investigative tool for the specialists in paediatric neuromuscular disorders and will continue to deliver important diagnostic information, often as quickly and accurately as other more recent innovations.

Editorial introductions

Editorial introductions

P.1.11 Development of a registry and a database for a nation-wide Italian collaborative network on congenital muscular dystrophy

Congenital muscular dystrophies (CMD) are rare diseases and small patient number represents the major impediment to progress in research and care. Classically the term CMD includes a group of genetically, clinically and biochemically distinct entities sharing clinical and pathological features such as early presentation of weakness and hypotonia and dystrophic features on muscle biopsy. In the last years the identification of several new genes responsible for different forms of CMD has not only expanded the spectrum of the known forms of CMD (to date over 20 genes responsible for CMD forms have been identified) but has produced exciting progresses in the understanding of the mechanisms underlying this group of disorders. However the real incidence and prevalence of CMD in populations is not sufficiently known. The aim of this Project is to establish the prevalence of CMD in Italy by harmonizing a nation-wide network including all the tertiary care centers. The possibility to join an international database will also provide the opportunity to make the data available for larger international studies and to contribute to a better understanding of the prevalence of CMD in the different countries. Preliminary results show 302 cases of CMD in Italy subdivided into: 47% dystroglycanopathies, 25% laminin alpha2 deficient CMD, 14% collagen VI deficient CMD, 6% mutations in SEPN1, 4% laminopathies, 4% others. All the patients with dystroglycanopathies and CMD phenotype have been screened for the first 6 known genes and they are being screened for the recently recognized new genes. As the study includes all the Italian tertiary care centers for pediatric neuromuscular disorders, we can presume that our findings will provide an estimate of at least all the cases of CMD.

Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals.

Integrating Palliative Care in Life-Limiting Pediatric Neuromuscular Conditions: The Case of SMA-Type 1 and Duchene Muscular Dystrophy

Aims: The unpredictability and life-limiting nature of chronic, pediatric neuromuscular disorders raise significant physical, psychosocial, spiritual, and social difficulties for affected individuals and their families, and create special challenges for the healthcare team. Drawing on the principles of pediatric palliative care (PPC), we explored these challenges in the context of Duchenne Muscular Dystrophy and Spinal Muscular Atrophy-Type 1 and identified opportunities for and barriers to the integration of PPC worldwide. Methods: We convened an international interdisciplinary consortium of 53 clinicians, families, and advocates from seven countries. Facilitated small groups explored the key aspects of palliative care integration into the two diseases. Results: Participants identified four transition points in the disease trajectories (i.e., peri-diagnostic, treatment decision making, life-threatening events, and end of life) and opportunities for PPC at each phase. Interpretation: Patients, families, and clinicians can openly discuss their challenges and create a shared vision of quality care for children with NMDs, and that opportunities exist to integrate PPC at each point of transition in the progression of NMDs.

S.P.37 The New Zealand Neuromuscular Disease Registry turns one – Data from the first year

Abstract The New Zealand Neuromuscular Disease Registry was launched in September 2011. One year on we present data from participants recruited to the registry in its first year of operation. Patient registries for rare diseases have become increasingly recognised as an important step in facilitating research and propagating standards of care. The Muscular Dystrophy Association (MDA) of New Zealand, working in consort with interested clinicians and in collaboration with the Office for Population Health and Genomics in Western Australia has established the New Zealand Neuromuscular Disease Registry, which was launched in September 2011. Unlike many other registries in the rare disease field the NZ Neuromuscular disease Registry is not disease-specific, instead it covers a range of both paediatric and adult neuromuscular disorders including the muscular dystrophies, spinal muscular atrophies, hereditary neuropathies, congenital myopathies, myasthenia, myotonic syndromes, metabolic myopathies, inherited ataxias and inflammatory myopathies. This has allowed us to efficiently obtain ethics committee approval for all these conditions with one application. The nation-wide registry links into reputable international anonymised disease-specific registries including the Global TREAT NMD databases for DMD and SMA and the data collected from each participant is dependent upon the neuromuscular condition they have and the requirements of the international registry to which the NZ Registry is linked. In the case of participants who have conditions for which we have not identified an international database, the minimum data collected on each participant by the registry is basic demographic information as well as confirmation of diagnosis by genetic test. Here we report on the full range of data collected including clinical and molecular information for the first year of the registry.

Child Neurology Residency Training in Neuromuscular Disorders

The field of pediatric neuromuscular disorders provides rich training experiences in child neurology residency programs. Specific learning objectives include skills in examination and assessment, familiarity with muscle and nerve studies, and indications for biopsies. This review also specifies which neuromuscular disorders are most important to cover within the resident's scope of knowledge, as well as the relationship of this field to the core competencies of residency training. Appropriate settings for inclusion of these skills in child neurology residency programs are suggested.

Integrating pediatric palliative care across the spectrum of life threatening pediatric neuromuscular disorders focused on Spinal muscular atrophy type I and Duchenne muscular dystrophy

Integrating pediatric palliative care across the spectrum of life threatening pediatric neuromuscular disorders focused on Spinal muscular atrophy type I and Duchenne muscular dystrophy

Overview of paediatric neuromuscular disorders and related pulmonary issues: diagnostic and therapeutic considerations

Pulmonary compromise is common in neuromuscular disease. Respiratory failure may be a presenting feature of neuromuscular disease and remains a major cause of morbidity and mortality. This article will review the current understanding of the more commonly encountered neuromuscular disorders in childhood and emphasize related pulmonary issues.

Sleep in Pediatric Pulmonary Diseases

Sleep problems are common in pediatric patients with chronic respiratory disorders. Nocturnal awakenings are frequent in children with asthma. Chronobiologic rhythms impact the pathophysiology of nocturnal asthma. Poor sleep quality can lead to impaired school performance, neurocognitive defects and attention problems in children. As lung function worsens sleep disruption becomes more prominent in patients with cystic fibrosis. Bronchopulmonary dyplasia has been associated with hypoxia during sleep. These infants have been reported to have reduced total sleep time, sleep fragmentation and reduced REM sleep. Nocturnal respiratory variations are exaggerated at night in children with sickle cell disease and the nocturnal hypoxia has been associated with painful crisis. Adenotonsillar hypertrophy with attendant obstructive sleep apnea worsen these episodes in sickle cell disease. In children with kyphoscoliosis hypoventilation at night worsens during REM sleep. Nocturnal hypoventilation generally precedes respiratory failure. Sleep-disordered breathing with excessive daytime sleepiness has been well described in pediatric neuromuscular disorders. Abnormal sleep patterns including sleep-disordered breathing occur in infants with apnea of prematurity and sudden infant death syndrome. Further research in this diverse group of sleep disorders in children exploring the pathophysiology and treatment is essential.