Congenital myopathies: Natural history of a large pediatric cohort.

OBJECTIVE: To assess the natural history of congenital myopathies (CMs) due to different genotypes. METHODS: Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012. RESULTS: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). CONCLUSIONS: We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling.

DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues in 23 children.

Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life.

In vitro and in vivo demonstration of physically and chemically in situ gelling NIPAAm-based copolymer system.

Poly(NIPAAm-co-hydroxyethylmethacarylate (HEMA)) acrylate and poly(NIPAAm-co-cysteine ethyl ester (CysOEt)) were synthesized and characterized by GPC(gel permeation chromatography), rheology, NMR (nuclear magnetic resonance), and Ellman's method. Upon mixing of these materials in aqueous solution, they formed gels immediately at body temperature owing to temperature-driven physical gelling, and gradually cured by chemical cross-linking through Michael-type addition reactions between thiols and acrylates. The rate of nucleophilic attack in the Michael-type addition reaction was shown to be highly dependent on the mole ratio of thiol to acrylate at neutral pH. Physical and chemical gelation improved the mechanical properties of the materials compared to purely physical gels. In vitro and in vivo results revealed that chemical and physical gels formed stiffer less viscoelastic materials compared to purely physical gels. Physical and chemical gel systems using thermosensitive polymer with acrylates and thermosensitive polymer with thiols showed minimum toxicity.

Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.

Michael-type addition reactions in NIPAAm-cysteamine copolymers follow second order rate laws with steric hindrance.

This work investigates the differential reaction rates seen among several Michael-Type acceptors when reacted with poly(NIPAAm-co-cysteamine). This work differs from many of the previous studies upon mercaptans in that it examines systems used for network and gel formation. We find that the reaction rates of poly(NIPAAm-co-cysteamine) cross-linked with Michael type acceptors follow traditional second order rate laws. In addition, we further confirm that these reactions are pH sensitive, reliant upon the pK (a) of the conjugated thiols, and on local chain chemistry. Additionally, this work determines that the reaction of difunctional acrylates with the macromolecular NIPAAm molecules leads to an apparent, but not significant, increase in the rate of reaction. The low magnitude of this increase is likely indicative of increased steric hindrance arising from network formation, or reduced diffusion in the NIPAAm polymer chains. Statistical analysis shows pH and ratio of thiol to acrylates significantly affect reaction rates (p < 0.05). The type of acrylate (PEGDA, PEGMA, or HEA) does not return as significant globally or within a pH range. Since localizing charge on a chain raises the effective pK (a) of nearby acids, gains in reaction rate from increasing chain functionality are shown to increase much less than would be expected from the increased concentration.

Spinal stability is improved by inducing a lumbar lordosis in boys with Duchenne Muscular Dystrophy: a pilot study.

The development of scoliosis in boys with Duchenne Muscular Dystrophy (DMD) is a significant, morbid event in the progression of the disease caused by progressive spinal musculature weakness. As an alternative to muscle activity, the spine can also be stabilised by locking the articular facet joints, which is achieved when the body is supported on a seat tilted anteriorly using a 'wedge', of the kind commonly recommended for low back pain. We tested spinal stability when using a seat tilted 15 degrees anteriorly in eight boys with DMD, without significant scoliosis, by measuring the ability to support a lateral load applied to the thorax through a sling and hawser. All eight boys tolerated lateral loading better with wedged seating and were able to support an average additional load of 95 g per kilogram of body weight compared to normal seating. Lateral load bearing was improved in 10 normal control boys by an average of 40 g per kilogram of body weight. These encouraging pilot findings indicate that there is a need for further studies on the effectiveness of passive mechanical factors in spinal stabilisation to delay the development of scoliosis in boys with DMD.

Simultaneously physically and chemically gelling polymer system utilizing a poly(NIPAAm-co-cysteamine)-based copolymer.

The objective of this work was to create an in situ physically and chemically cross-linking hydrogel for in vivo applications. N-Isopropylacrylamide (NIPAAm) was copolymerized with N-acryloxysuccinimide (NASI) via free radical polymerization. Poly(NIPAAm-co-NASI) was further modified to obtain poly(NIPAAm-co-cysteamine) through a nucleophilic attack on the carbonyl group of the NASI by the amine group of the cysteamine. Modification was verified by nuclear magnetic resonance. In addition to thermoresponsive physical gelling due to the presence of NIPAAm, this system also chemically gels via a Michael-type addition reaction when mixed with poly(ethylene glycol) diacrylate. The presence of both physical and chemical gelation resulted in material properties that are much improved compared to purely physical gels. The chemical gelation time of the copolymers was not significantly affected by the amount of thiol present due to the increased pKa of the copolymer containing more thiols. In addition, the swelling of the copolymers was highly dependent on the temperature and thiol content. Last, the rate of nucleophilic attack in the Michael-type addition reaction was shown to be highly dependent on pH and on the mole ratio of thiol to acrylate. Due to the improved mechanical properties, this material may be better suited for long-term functional replacement applications than other thermosensitive physical gels. With further development and biocompatibility testing, this material could potentially be applied as a temperature-responsive injectable biomaterial for functional embolization.

Neurocysticercosis masquerading as a cerebral infarct.

The differential diagnosis of acute focal neurologic deficit in childhood is diverse. We report the case of a child presenting with an acute hemiparesis persisting for longer than 24 hours following a focal seizure. The clinical history, examination findings, and results of cranial magnetic resonance imaging (MRI) were initially interpreted as consistent with an arterial ischemic cerebral infarction. Follow-up cranial MRI performed 9 months later revealed changes indicative of neurocysticercosis. Review of original neuroimaging resulted in a revision of the diagnosis to neurocysticercosis. The clinical history, together with neuroimaging findings, is highly compatible with a diagnosis of neurocysticercosis but unusual because it occurred in a child resident in a nonendemic area who had never traveled to an endemic area and whose diet excluded pork. The case reported raises two important issues. The first is the need to carefully consider the differential diagnosis of acute hemiparesis, including unusual causes. Second, it raises awareness of the potential for neurocysticercosis to occur in low-risk patients in nonendemic areas.