Targeted Treatments for Inherited Neuromuscular Diseases of Childhood.

In the past decade, the number of genes linked to neuromuscular diseases of childhood has expanded dramatically, and this genetic information is forming the basis for gene-specific and even mutation-specific therapies. At the forefront of these advances are the two recently approved treatments for spinal muscular atrophy: one, an antisense oligonucleotide that modifies splicing of the SMN2 gene, and, the other, a gene therapy vector that delivers the SMN1 gene to motor neurons, both of which are allowing patients to acquire developmental milestones previously unseen in this fatal disease. This review highlights these advances and emerging targeted therapies for Duchenne muscular dystrophy and centronuclear myopathy, while also covering enzyme replacement therapy and small molecule-based targeted therapies for conditions such as Pompe's disease and congenital myasthenic syndromes. With these and other newer techniques for targeted correction of genetic defects, such as CRISPR/Cas9, there is now hope that treatments for many more genetic diseases of the nervous system will follow in the near future.

Presentation and Management Patterns of Lower Urinary Tract Symptoms in Adults Due to Rare Inherited Neuromuscular Diseases.

OBJECTIVE: To describe the urologic sequalae of several rare congenital neuromuscular diseases. METHODS: We retrospectively reviewed medical records at Gillette Specialty Healthcare (2014-2018) of patients presenting to urology clinic with lower urinary tract symptoms and select rare congenital diseases: muscular dystrophy, spinal muscular atrophy, and Rett syndrome. RESULTS: Muscular dystrophies (n = 19) are X-linked myogenic disorders characterized by progressive muscle wasting and weakness. Men present to the urologist at variable ages, typically with complaints of functional incontinence and normal cystometrograms; we manage them with oral anticholinergic medications, condom catheter, or suprapubic catheter. Spinal muscular atrophy (n = 6) is a rare autosomal recessive disease characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem leading to progressive muscle weakness and atrophy. Patients typically present with nephrolithiasis and urinary retention in late adolescence/early adulthood, but timing varies. Filling cystometrograms have been normal. We allow passive retention with intermittent catheterization and creation of catheterizable channels, when indicated. Rett syndrome (n = 5) is a rare, noninheritable genetic condition affecting females characterized by a brief period of normal development followed by loss of speech and purposeful hand use; there are characteristic behaviors. Patients present in early adulthood with complaints of urinary retention. We manage retention with permissive retention or sphincter chemodenervation. CONCLUSION: Several congenital neuromuscular conditions can cause lower urinary tract symptoms when these individuals become adults. We have discussed the clinical characteristics and management of select neurogenic and myogenic bladder conditions seen in adults with congenital conditions.

Neuromuscular disorders and chronic ventilation.

Morbidity and mortality have decreased in patients with neuromuscular disease due to implementation of therapies to augment cough and improve ventilation. Infants with progressive neuromuscular disease will eventually develop respiratory complications as a result of muscle weakness and their inability to compensate during periods of increased respiratory loads. The finding of nocturnal hypercapnia is often the trigger for initiating non-invasive ventilation and studies have shown that its use not only may improve sleep-disordered breathing, but also that it may have an effect on daytime function, symptoms related to hypercapnia, and partial pressure of CO2. It is important to understand the respiratory physiology of this population and to understand the benefits and limitations of assisted ventilation.

Use of dynamic spinal brace in the management of neuromuscular scoliosis: a preliminary report.

Neuromuscular scoliosis is difficult to treat with braces because the collapsing trunk with the spinal deformity cannot tolerate the hard materials used for most orthoses. The dynamic spinal brace (DSB) is a novel three-point support brace used in Japan. We present our preliminary findings of 52 pediatric patients with neuromuscular scoliosis treated using DSBs. A positive correlation was found between the Cobb angle at the initiation of bracing and the degree of scoliosis progression. We concluded that DSBs may be effective for early-stage scoliosis. We also found that DSB improved sitting stability and thereby caregiver satisfaction.

[Muscle biopsy in children: Usefulness in 2012]. / Intérêt de la biopsie musculaire chez l'enfant en 2012.

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5years; 155 (37%) biopsies were obtained before the child was 5years old. Final histopathological diagnoses were: congenital myopathy (n=193, including 15 structural congenital myopathies); progressive muscular dystrophy (n=75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n=17, including six primary merosinopathies); dermatomyositis (n=11); spinal muscular atrophy (n=9, including six atypical spinal muscular atrophies); metabolic myopathy (n=32, including 19 mitochondrial myopathies); encephalomyopathy (n=53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.

Clinical and skeletal muscle biopsy characteristics of 25 patients with floppy infant syndrome.

AIMS: Floppy infant syndrome (FIS) comprises of a group of disorders with a common symptom of generalized hypotonia at birth or in early life, which causes diagnostic challenge. In the current work, we aimed to describe the clinical and histopathological characteristics of FIS to help improve the diagnosis of this condition. METHODS: We collected information on the clinical characteristics, laboratory data, electrophysiological test results and detailed skeletal muscle biopsy histopathological features of 25 infants with FIS. We then discussed the final diagnoses and analyzed the neuromuscular features. RESULTS: Among the 25 infants with FIS, there were 7 cases of spinal muscular atrophy (SMA), 4 cases of congenital muscular dystrophy (CMD) (3 cases of merosin-deficient CMD and 1 case of Ullrich CMD), 8 cases of congenital myopathy (2 cases of central core disease, 1 case each of nemaline myopathy and centronuclear myopathy, and 4 cases of congenital fiber-type disproportion), and 6 cases of metabolic myopathy (3 cases of lipid storage myopathy, 2 cases of Pompe's disease, and 1 case of Leigh's syndrome). The histopathological characteristics of muscle biopsy were found to be distinct for these subgroups. CONCLUSIONS: FIS is caused by a variety of neuromuscular disorders that have common clinical manifestations, including SMA, CMD, congenital myopathies and metabolic myopathies. Skeletal muscle biopsy is an essential tool for the definite and differential diagnoses of FIS, especially of neuromuscular origin.

Congenital feeding and swallowing disorders.

Although poorly recognized and studied, congenital sucking, swallowing, and/or feeding disorders are common. They can be the symptoms that reveal a neuromuscular disease, or that complicate a neuromuscular disease. It is essential to know feeding physiology during fetal and infant development in order to understand the variety of its disorders and to direct correctly diagnostic and therapeutic processes. A good semiological analysis will identify the symptoms. Several investigations help to determine the mechanism of the trouble (fiber endoscopy, videofluoroscopy, facial and swallowing electromyography, esophageal manometry, etc.). Other investigations, in addition to clinical assessments, help to identify the cause of the whole picture (peripheral electromyography, brain MRI, genetic or metabolic investigations, etc.). The main causes of sucking, swallowing, and feeding disorders are lesions of the brainstem (malformations of the posterior fossa, neonatal brainstem tumors, agenesis of cranial nerves, clastic lesion of the posterior brain, craniovertebral anomalies, syndromes that involve the rhombencephalic development such as Pierre Robin sequence, CHARGE syndrome, etc.). Suprabulbar lesions, neuromuscular disorders, peripheral esophageal, digestive, and laryngeal anomalies and dysfunctions can also be involved. The main principles of the management of congenital sucking, swallowing, and feeding disorders are the following: cure the cause if possible, facilitate the sucking reflex, preventing deleterious consequences of aspiration, preventing malnutrition, and preventing posttraumatic anorexia. Advice can be given to caregivers and physiotherapists who take charge of these children.

[Tenotomy of carpal and digital flexor tendons for correction of congenital neuromyodysplasia in a calf]. / Tenotomie von Karpal- und Zehenbeugesehnen zur Korrektur der Neuromyodysplasie bei einem Kalb.

In a 7-day-old heifer calf, a bilateral flexural deformity of the forelimbs involving the digital flexor tendons, the suspensory ligament and the ulnar and radial carpal flexor tendons was diagnosed. After 2 weeks of conservative treatment consisting of manual stretching of the legs and the application of splints and wooden blocks, which were glued to the soles and extended beyond the tip of the claws, the right forelimb could be extended sufficiently to allow weight bearing, whereas the left forelimb could be passively extended to only approximately 120°. Therefore, tenotomy of the ulnar carpal flexor tendon, the digital flexor tendons and the suspensory ligament was carried out in the left leg. A support bandage was then applied to the leg for 8 weeks, after which the carpus and fetlock could be completely extended passively. Flexural deformity of the carpus caused by contracture of the carpal flexor tendons was treated by means of a tenotomy of the ulnar carpal flexor tendon proximal to the accessory carpal bone, which allowed preservation of the carpal tunnel and avoided the risk of iatrogenic damage to nerves and the carpal joint capsule.

Preterm birth and developmental problems in the preschool age. Part I: minor motor problems.

Nearly half of very preterm (VP) and extremely preterm (EP) infants suffers from minor disabilities. The paper overviews the literature dealing with motor problems other than cerebral palsy (CP) during infancy and preschool age. The term "minor motor problems" indicates a wide spectrum of motor disorders other than CP; "minor" does not mean "minimal", as a relevant proportion of the preterm infants will develop academic and behavioural problems at school age. Early onset disorders consist of abnormal general movements (GMs), transient dystonia and postural instability; these conditions usually fade during the first months. They were underestimated in the past; recently, qualitative assessment of GMs using Prechtl's method has become a major item of the neurological examination. Late onset disorders include developmental coordination disorder (DCD) and/or minor neurological dysfunction (MND): both terms cover partly overlapping problems. Simple MND (MND-1) and complex MND (MND-2) can be identified and MND-2 gives a higher risk for learning and behavioural disorders. A relationship between the quality of GMs and MND in childhood has been recently described. The Touwen infant neurological examination (TINE) can reliably detect neurological signs of MND even in infancy. However, the prognostic value of these disorders requires further investigations.

Kyphoscoliosis associated with congenital neuromuscular disease with uniform type 1 fibers.

OBJECTIVE: To report the first case of surgical treatment for severe kyphoscoliosis associated with respiratory disorder in a patient with congenital neuromuscular disease with uniform type 1 fibers (CNMDU1), including management of the possible onset of malignant hyperthermia (MH) in general anesthesia. CNMDU1 is rare among congenital neuromuscular diseases, and surgery for spinal deformity in CNMDU1 has not been described. Onset of MH in general anesthesia is a concern in this disease. METHODS: A 13-year-old female with motor retardation, suspected myopathy, and severe spinal deformity was followed at another pediatric hospital before referral to Meijo Hospital. Symptoms at the initial consultation were mild general muscular weakness and muscular atrophy. The rib hump was 60° and trunk balance was poor. The tendon reflex showed hyporeflexia, and blood tests were normal. Vital capacity was 0.69 L and forced expiratory volume percentage in 1 s was 75.5%, showing a restrictive and obstructive ventilatory defect. A plain radiograph showed severe kyphoscoliosis with thoracic scoliosis of 130° (T5-L1) and thoracic kyphosis of 110° (T2-T12) with almost no flexibility in bending or traction film. RESULTS: After preoperative halo traction for 2 months, one-stage anterior and posterior correction and fusion from T2 to L3 was conducted. MH did not occur, but recovery of respiratory function required 8 days by intubation after surgery. Postoperatively, thoracic kyphosis improved to 25° and thoracic scoliosis was 66° (correction rate: 49%). Pathological results of an intraoperative muscle biopsy from the paraspinal muscles confirmed the diagnosis of CNMDU1. At 6 years after surgery, the patient has no problems in daily life and no respiratory difficulty. CONCLUSION: Spinal deformity in CNMDU1 has a risk of severe progression, which makes early diagnosis by biopsy important. The surgery may be recommended before severe progression of spinal deformity and respiratory disorder. Perioperative MH is a concern, but can be managed by appropriate procedures.

Perfil clínico de patología neuromuscular hereditaria en el Instituto de Rehabilitación Infantil Teletón, Valparaíso, Chile / Clinical profile of patients with neuromoscular hereditary diseases in Child Rehabilitation Institute Teletón, Valparaiso, Chile

Introducción: Las enfermedades neuromusculares (ENM) son una causa importante de discapacidad progresiva en el niño. Objetivo: Describir el perfil clínico de las consultas por ENM hereditarias, atendidas actualmente en Instituto de Rehabilitación Infantil Teletón (IRI), Valparaíso. Pacientes y Método: estudio descriptivo, retrospectivo. Selección y análisis de pacientes con ENM en control activo, del registro estadístico de IRI Valparaíso. Resultados: Total 115 pacientes, hombres 70 por ciento. Edad promedio 14,9 años (rango: 1-28 a). Motivo de consulta más frecuente: trastorno de la marcha (49,5 por ciento). Las etiologías encontradas fueron: muscular (67 por ciento), neuropatías (21 por ciento) y enfermedad de motoneurona (10 por ciento). Los diagnósticos más frecuentes fueron: Distrofinopatías 30 por ciento, Charcot Marie Tooth 21,7 por ciento, Miopatías Congénitas 15,6 por ciento, Atrofia Muscular Espinal 10 por ciento, Distrofia Miotónica 7,8 por ciento. Discusión: El sexo masculino fue más prevalente lo que puede atribuirse a la mayor frecuencia de Distrofinopatías dentro de las ENM. La latencia para el diagnóstico es variable según la patología, siendo en promedio 3,2 años. Las frecuencias de diagnósticos encontrados coinciden parcialmente con la epidemiología descrita.

Introduction: Neuromuscular diseases (NMD) are a major cause of progressive disability in children. Objective: To describe the clinical profile of hereditary NMD consultations, currently being attended in IRI Valparaíso. Patients and Method: Selection and analysis of actually attending NMD patients from the IRI statistical registration. Results: 115 patients were identified, 70 percent men. Mean age 14.9 years (1-28). The most frequent cause for consultation was gait disorder (49.5 percent. Etiologies were: muscular (67 percent), neuropathy (21 percent) and motor neuron disease (10 percent). The most common diagnoses were: dystrophinopathies (30 percent), Charcot Marie Tooth 21.7 percent, Congenital Myopathy (15.6 percent), Spinal Muscular Atrophy (10 percent), Myotonic Dystrophy (7.8 percent). Discussion: Prevalence was higher for males, which is attributed to the higher frequency of dystrophinopathies. Time for diagnosis was variable depending on the disease, with a mean of 3,2 years. The frequency of NMD were partially coincidental with previously reported epidemiologic data.

Submucosal nerve hypertrophy in congenital laryngomalacia.

OBJECTIVES/HYPOTHESIS: To determine the neuropathologic findings in tissue obtained from children with laryngomalacia at a tertiary-care pediatric hospital. STUDY DESIGN: Retrospective review of consecutive cohort compared with a control group. METHODS: We reviewed supra-arytenoid pathology specimens from 43 children with severe laryngomalacia and 13 age-matched pediatric autopsy controls. Histopathologic comparison was made of nerve hypertrophy (including nerve perimeter and surface area) among experimental and control pathologic specimens. RESULTS: There exists a statistically significant increase in nerve perimeter (P = .001) and nerve surface area (P = .02) in supra-arytenoid specimens in patients with severe laryngomalacia compared with age-matched autopsy supra-arytenoid tissue. CONCLUSIONS: The pathologic finding of nerve hypertrophy in children with laryngomalacia provides new evidence to support neurologic dysfunction as the etiologic theory of laryngomalacia.

Retrograde lacrimal duct airflow during nasal positive pressure ventilation.

Noninvasive ventilation is widely used for chronic respiratory failure in children with neuromuscular disorders, thus avoiding the need for tracheostomy. However, the pressures required to support ventilation in these children may be considerably higher than those necessary to treat obstructive sleep apnea. The complications of nasal positive airway pressure are numerous, including skin breakdown, conjunctivitis, nasal congestion, airway dryness, pneumothorax, and bowel obstruction. Ophthalmologic complaints are particularly common, largely attributed to an air leak in the mask. In the present case, we demonstrate, through two modalities-video and CT scan-retrograde airflow through the nasolacrimal duct causing sleep disruption and eye irritation in a profoundly hypotonic 14-month-old boy with chronic respiratory failure on bilevel ventilation during sleep.

The Dega osteotomy: a versatile osteotomy in the treatment of developmental and neuromuscular hip pathology.

BACKGROUND: The purpose of this study is to evaluate the use of the Dega osteotomy in the treatment of hip pathology resulting from both developmental dysplasia (DDH) and neuromuscular disease (NM). METHODS: We retrospectively reviewed the results of one surgeon's operative experience with the Dega osteotomy for the treatment of DDH and NM. Forty-four patients (50 hips) with an average length of follow-up of 53 months were identified. The Dega was customized at the time of surgery to provide more anterior or posterior coverage depending on the needs of the individual hip. RESULTS: In all cases, there were no intraoperative complications and all hips were well reduced postoperatively. In the DDH group, there were 22 children (26 hips), who underwent surgery at a mean age of 3.1 years. Thirteen hips had a concomitant open reduction and 4 had a femoral osteotomy. There were 5 complications: 2 femoral head lateralizations, 2 avascular necroses (asymptomatic), and 1 traumatic dislocation. One patient (1 hip) had a reoperation. All patients had unlimited physical activity with no limp with an improvement in the acetabular index from 37 degrees preoperatively to 13 degrees at last follow-up. In the NM group, there were 22 children (24 hips), who underwent surgery at a mean age of 6.3 years. Twenty-three hips had concomitant procedures performed. At an average of 56 months postoperatively, all patients were pain-free. There were 5 complications: 1 graft dislodgement, 1 graft collapse, and 3 femoral head lateralizations. Three patients (3 hips) had a reoperation. Acetabular index improved from 36 degrees preoperatively to 14 degrees, and the migration percentage ranged from 84% to 14%. CONCLUSIONS: In this series of Dega osteotomies, one of the largest in the English literature, the osteotomy seems safe and effective in the treatment of both DDH and NM hip disease. The Dega osteotomy is utilitarian, as it may provide increased acetabular coverage anteriorly or posteriorly depending on where it is hinged. LEVEL OF EVIDENCE: Therapeutic study, clinical case series: level IV.

Trismus-pseudocamptodactyly syndrome: case report ten years after.

BACKGROUND: In 1969, Hecht and Beals described for the first time a rare dominant autosomal syndrome characterised by reduced mouth opening, pseudocamptodactyly, short stature, and foot deformities. Recent studies have confirmed that TPS is caused by a mutation of MYH8 that is common to another disease called Carney syndrome. CASE REPORT: The authors describe the long term follow-up of a case presented in 2003, ten years after the first surgical procedure: a 14-year-old girl, affected by this rare syndrome, had underwent an early (at 4 years) surgical treatment of bilateral coronoidotomies to ensure safe airway management to allow subsequent surgical treatment to correct foot deformities. After six years, a complete relapse of the trismus occurred. Three years later, the patient underwent a second surgery of bilateral coronoidotomies to definitely solve trismus. At the 18 months follow-up, the mouth opening was stable.