RESUMO
AIM: Assessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD). METHOD: 25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at <25â nmol/L, insufficient at 25-49â nmol/L, adequate at 50-75â nmol/L and optimal at >75â nmol/L. RESULT: 617 vitamin D samples were available from 197 boys (range 2-18â years)-69% from individuals on corticosteroids. Vitamin D-naïve boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000â IU (23 samples) or 6000â IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400â IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800â IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000â IU and 14 samples on 1500â IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230â nmol/L). CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000â IU and maintenance regimen of 1000-1500â IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD.
Assuntos
Corticosteroides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
INTRODUCTION: In this study we investigated muscle magnetic resonance imaging in congenital myasthenic syndromes (CMS). METHODS: Twenty-six patients with 9 CMS subtypes and 10 controls were imaged. T1-weighted (T1w) and short-tau inversion recovery (STIR) 3-Tesla MRI images obtained at thigh and calf levels were scored for severity. RESULTS: Overall mean the T1w score was increased in GFPT1 and DPAGT1 CMS. T1w scans of the AChR-deficiency, COLQ, and CHAT subjects were indistinguishable from controls. STIR images from CMS patients did not differ significantly from those of controls. Mean T1w score correlated with age in the CMS cohort. CONCLUSIONS: MRI appearances ranged from normal to marked abnormality. T1w images seem to be especially abnormal in some CMS caused by mutations of proteins involved in the glycosylation pathway. A non-selective pattern of fat infiltration or a normal-appearing scan in the setting of significant clinical weakness should suggest CMS as a potential diagnosis. Muscle MRI could play a role in differentiating CMS subtypes. Muscle Nerve 54: 211-219, 2016.
Assuntos
Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Síndromes Miastênicas Congênitas/diagnóstico por imagem , Síndromes Miastênicas Congênitas/patologia , Adolescente , Adulto , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Síndromes Miastênicas Congênitas/genética , Adulto JovemRESUMO
OBJECTIVE: To evaluate the response to salbutamol and ephedrine in the treatment of congenital myasthenic syndromes due to CHRNE mutations causing severe acetylcholine receptor (AChR)deficiency. METHODS: A cohort study of 6 patients with severe AChR deficiency, symptomatic despite optimal therapy with anticholinesterase and 3,4-diaminopyridine, were analyzed for their response to the addition of salbutamol or ephedrine to their medication. Baseline quantitative myasthenia gravis (QMG) (severity) scores were worse than 15 of 39. Patients were assessed in clinic with QMG and mobility scores. Pretreatment and 6- to 8-month follow-up scores were evaluated. RESULTS: All 6 patients tolerated treatment well and reported no side effects. There was a strong positive response to treatment over the 6- to 8-month assessment period with significant improvement in QMG (p = 0.027) and mobility scores. The analysis of subcomponents of the QMG score revealed marked improvement in upper (p = 0.028) and lower (p = 0.028) limb raise times. All patients reported enhanced activities of daily living at 6 to 8 months. CONCLUSIONS: Oral salbutamol and ephedrine appear to be effective treatments in severe cases ofAChR deficiency on pyridostigmine. They are well tolerated and improvement in strength can be dramatic. Classification of evidence: This study provides Class IV evidence that salbutamol or ephedrine improves muscle strength in patients with congenital myasthenia from severe AChR deficiency.
Assuntos
Albuterol/administração & dosagem , Efedrina/administração & dosagem , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/tratamento farmacológico , Receptores Colinérgicos/deficiência , Índice de Gravidade de Doença , Adolescente , Adulto , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
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.
Assuntos
Proteínas Musculares/genética , Músculo Esquelético , Miopatias da Nemalina/genética , Miopatia da Parte Central/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Consanguinidade , Estudos Transversais , Transtornos de Deglutição/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Limitação da Mobilidade , Músculo Esquelético/patologia , Miopatias da Nemalina/complicações , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miopatia da Parte Central/complicações , Miopatia da Parte Central/patologia , Insuficiência Respiratória/etiologia , Estudos Retrospectivos , Escoliose/etiologia , Adulto JovemRESUMO
Laryngospasm is a rare but potentially life-threatening occurrence in infants and usually has infective, allergic, metabolic, or anatomic causes. Underlying genetic conditions are rarely considered. Mutations in SCN4A encoding the voltage-gated sodium channel NaV1.4 have been implicated in a wide spectrum of neuromuscular disorders with variable onset, ranging from a rare form of congenital myasthenic syndrome to both hypokalemic and hyperkalemic forms of periodic paralysis and paramyotonia congenita. Here we report on 3 unrelated patients without family history presenting with recurrent, life-threatening episodes of laryngospasm from the first months of life. Clinical features more typically associated with SCN4A-related disorders such as generalized muscle hypertrophy with clinical or electrical myotonia evolved later in life. All patients were found to be heterozygous for the same SCN4A mutation, c.3917G>A; p.Gly1306Glu. Treatment with carbamazepine resulted in complete abolition of recurrent laryngospasm and alleviated symptoms associated with myotonia and muscle stiffness. We conclude that SCN4A mutations ought to be considered in the differential diagnosis of recurrent infantile laryngospasm because timely institution of treatment can be life-saving.
Assuntos
Laringismo/genética , Laringismo/terapia , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Laringismo/diagnóstico , Recidiva , Resultado do TratamentoRESUMO
AIM: Benign hereditary chorea is a dominantly inherited, childhood-onset hyperkinetic movement disorder characterized by non-progressive chorea and variable degrees of thyroid and respiratory involvement. Loss-of-function mutations in NKX2.1, a gene vital to the normal development and function of the brain, lungs, and thyroid, have been identified in a number of individuals. METHOD: Clinical data from individuals with benign hereditary chorea identified through paediatric neurology services were collected in a standardized format. The NKX2.1 gene was analysed by Sanger sequencing, multiplex ligation-dependent probe amplification, and microarray analysis. RESULTS: Six of our cohort were female and four male, median age at assessment was 8 years 6 months (range 1 y 6 mo-18 y). We identified 10 probands with NKX2.1 mutations; nine of these mutations are novel (including two whole-gene deletions) and one has been previously reported. Of the 10 individuals, eight presented with muscle hypotonia and four had evidence of hypothyroidism or respiratory involvement. Only three out of the 10 individuals had the full triad of 'brain-lung-thyroid syndrome' symptoms. Additional clinical characteristics occurring in individual participants included growth hormone deficiency, pes cavus, kyphosis, duplex kidney, and obsessive-compulsive disorder. INTERPRETATION: Our data suggest that the neurological phenotype is prominent in this condition and that many patients with benign hereditary chorea do not have the classic triad of brain-lung-thyroid syndrome. The extended phenotype may include obsessive-compulsive disorder and skeletal abnormalities.
Assuntos
Coreia/complicações , Coreia/genética , Mutação/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adolescente , Encéfalo/patologia , Criança , Pré-Escolar , Coreia/tratamento farmacológico , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Hipotireoidismo/complicações , Hipotireoidismo/genética , Lactente , Masculino , Hipotonia Muscular/complicações , Hipotonia Muscular/genética , Exame Neurológico , Fenótipo , Transtornos Respiratórios/complicações , Transtornos Respiratórios/genética , Glândula Tireoide/patologia , Fator Nuclear 1 de TireoideRESUMO
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.
Assuntos
Acrilamidas/química , Materiais Biocompatíveis/química , Polímeros/química , Acrilamidas/síntese química , Acrilamidas/toxicidade , Resinas Acrílicas , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/toxicidade , Cisteína/análogos & derivados , Cisteína/química , Cisteína/toxicidade , Elasticidade , Feminino , Géis , Concentração de Íons de Hidrogênio , Teste de Materiais , Poli-Hidroxietil Metacrilato/análogos & derivados , Poli-Hidroxietil Metacrilato/síntese química , Poli-Hidroxietil Metacrilato/química , Poli-Hidroxietil Metacrilato/toxicidade , Polímeros/síntese química , Polímeros/toxicidade , Ratos , Ratos Sprague-Dawley , ViscosidadeRESUMO
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.
Assuntos
Proteínas Musculares/genética , Síndromes Miastênicas Congênitas/diagnóstico , Criança , Humanos , Síndromes Miastênicas Congênitas/genéticaRESUMO
OBJECTIVE: To assess the current use of glucocorticoids (GCs) in Duchenne muscular dystrophy in the UK, and compare the benefits and the adverse events of daily versus intermittent prednisolone regimens. DESIGN: A prospective longitudinal observational study across 17 neuromuscular centres in the UK of 360 boys aged 3-15 years with confirmed Duchenne muscular dystrophy who were treated with daily or intermittent (10 days on/10 days off) prednisolone for a mean duration of treatment of 4 years. RESULTS: The median loss of ambulation was 12 years in intermittent and 14.5 years in daily treatment; the HR for intermittent treatment was 1.57 (95% CI 0.87 to 2.82). A fitted multilevel model comparing the intermittent and daily regiments for the NorthStar Ambulatory Assessment demonstrated a divergence after 7 years of age, with boys on an intermittent regimen declining faster (p<0.001). Moderate to severe side effects were more commonly reported and observed in the daily regimen, including Cushingoid features, adverse behavioural events and hypertension. Body mass index mean z score was higher in the daily regimen (1.99, 95% CI 1.79 to 2.19) than in the intermittent regimen (1.51, 95% CI 1.27 to 1.75). Height restriction was more severe in the daily regimen (mean z score -1.77, 95% CI -1.79 to -2.19) than in the intermittent regimen (mean z score -0.70, 95% CI -0.90 to -0.49). CONCLUSIONS: Our study provides a framework for providing information to patients with Duchenne muscular dystrophy and their families when introducing GC therapy. The study also highlights the importance of collecting longitudinal natural history data on patients treated according to standardised protocols, and clearly identifies the benefits and the side-effect profile of two treatment regimens, which will help with informed choices and implementation of targeted surveillance.
Assuntos
Glucocorticoides/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Esquema de Medicação , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN). METHODS: A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function. RESULTS: Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme. CONCLUSIONS: We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
Assuntos
Doença de Charcot-Marie-Tooth/genética , DNA Mitocondrial , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação , Adolescente , Adulto , Idoso de 80 Anos ou mais , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Feminino , Genótipo , Neuropatia Hereditária Motora e Sensorial/genética , Neuropatia Hereditária Motora e Sensorial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
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.
Assuntos
Inibidores da Colinesterase/uso terapêutico , Miopatias Congênitas Estruturais/tratamento farmacológico , Miopatias Congênitas Estruturais/fisiopatologia , Junção Neuromuscular/fisiopatologia , Transmissão Sináptica/fisiologia , Adolescente , Animais , Biópsia , Criança , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Eletromiografia , Feminino , Técnicas de Inativação de Genes , Humanos , Lactente , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Junção Neuromuscular/efeitos dos fármacos , Proteínas Tirosina Fosfatases não Receptoras/genética , Brometo de Piridostigmina/farmacologia , Brometo de Piridostigmina/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos , Resultado do Tratamento , Peixe-Zebra , Proteínas de Peixe-Zebra/genéticaRESUMO
Arthrogryposis can occur in isolation or as part of a syndrome. Amyoplasia, the commonest type of arthrogryposis, has been well described in literature, but neurogenic arthrogryposis, a rarer but significantly heterogeneous variant, has not. We conducted a single-centre, 10-year retrospective study of all children with arthrogryposis at the Dubowitz Neuromuscular Centre, London, UK to describe the various phenotypes of arthrogryposis with special reference to the neurogenic variant including presentation, associated features and long-term outcome. Twenty-seven children with arthrogryposis were identified (13 males) and 25 survivors followed-up for 6.4 ± 2.32 yrs. Perinatal history, presenting clinical features, investigations, final diagnosis and long-term outcomes were recorded. All four limbs were involved in 19 (ankles>wrists>elbows) whilst 8 had isolated upper (UL) or lower limb (LL) involvement. Twelve children had neurogenic arthrogryposis confirmed by a combination of clinical examination, EMG and/or muscle pathology. CK was normal in all children with neurogenic arthrogryposis. Three children in this cohort had abnormal brain MRIs and global developmental delay. Long-term follow up did not show deterioration of muscle power in any of our 12 children with neurogenic arthrogryposis, although contractures lead to temporary worsening of function ability in some (n = 3). Most children improved with physiotherapy and well-fitted orthoses. Our study suggests that neurogenic arthrogryposis is usually a non-progressive disorder and in the absence of concomitant brain abnormalities, allows the clinician to offer an optimistic prognosis to the family.
Assuntos
Artrogripose/diagnóstico , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Doenças Musculares/diagnóstico , Fenótipo , Adolescente , Artrogripose/epidemiologia , Sistema Nervoso Central/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Músculo Esquelético/anormalidades , Doenças Musculares/epidemiologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Método Simples-CegoRESUMO
OBJECTIVE: The congenital myasthenic syndromes (CMS) are a group of genetic disorders of neuromuscular transmission causing fatigable weakness. Symptoms may be present from birth, but diagnosis is often delayed for several years, notably in post-synaptic CMS due to mutations in the DOK7 gene. Recently, we noted a subgroup of children with CMS in whom congenital stridor and bilateral vocal cord palsy predated other symptoms. All had mutations in the DOK7 gene. The purpose of this study was to review our population of DOK7 CMS patients with congenital stridor and assess whether there were other phenotypic features which might raise suspicion of a diagnosis of CMS in the neonatal period, in the absence of limb weakness and ptosis and prompt earlier referral for neurophysiological investigation, genetic diagnosis and appropriate treatment. METHODS: A retrospective case review of 11 DOK7 CMS patients at a tertiary referral centre. RESULTS: Six patients were identified with DOK7 mutations and congenital stridor, four requiring intubation soon after birth. Four patients had a diagnosis of bilateral vocal cord palsy and three required tracheostomy, successfully decannulated in one after 3 years. All six patients had difficulty with feeding, with weak suck and swallow necessitating nasogastric feeding in five, two of whom required gastrostomy. Despite all six children having had neonatal symptoms, the mean age at CMS diagnosis was 5 years and 9 months. CONCLUSION: CMS, particularly caused by mutations in the DOK7 gene, is a rare but treatable cause of congenital stridor in the neonate. A combination of congenital stridor, especially with an apparently idiopathic bilateral vocal cord palsy and weak suck and swallow should alert the clinician to the possibility of CMS and prompt early referral for neurophysiology and genetic investigations. Confirmation of a CMS diagnosis enables treatment to be initiated, informed management of the VCP and anticipation of myasthenic symptoms, particularly life-threatening respiratory decompensation. Treatment may allow early decannulation or possible avoidance of tracheostomy. At least 12 genes are known to cause CMS; the presence of congenital stridor may help target genetic diagnosis.
Assuntos
Proteínas Musculares/genética , Mutação , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Sons Respiratórios , Criança , Pré-Escolar , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/terapia , Eletromiografia , Humanos , Recém-Nascido , Intubação Gastrointestinal , Transtornos Respiratórios/etiologia , Transtornos Respiratórios/terapia , Traqueostomia , Paralisia das Pregas Vocais/etiologiaRESUMO
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.
Assuntos
Acrilamidas/química , Materiais Biocompatíveis/química , Cisteamina/química , Modelos Químicos , Reologia/métodos , Simulação por Computador , Dureza , Cinética , Teste de Materiais , Transição de FaseRESUMO
Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies. The locus responsible for CMT4C was previously assigned to the chromosome 5q23 region by homozygosity mapping and mutations in the SH3TC2 (KIAA1985) gene have been subsequently identified mainly in families around the Mediterranean basin but also frequently in European Gypsies. No English families have been reported to date. To determine the frequency, phenotype and neuropathology of CMT due to SH3TC2 mutations we screened 23 English autosomal recessive (AR) demyelinating CMT families. Five families with AR demyelinating CMT and SH3TC2 mutations were identified, four families were homozygous for the R954X mutation and the fifth family was compound heterozygous for the R954X and E657K mutations. There was significant clinical variation between these families with some cases presenting with a severe childhood onset neuropathy with respiratory and cranial nerve involvement, compared to other families with mild scoliosis and foot deformity. Characteristic sural nerve neuropathology was seen in three families with frequent demyelinating fibres surrounded by excess Schwann cell lamellae forming basal lamina onion bulbs and abnormally long and attenuated Schwann cell processes. One patient homozygous for the R954X mutation had a 20-year history of an inflammatory neuropathy that was superimposed onto the hereditary form, indicating that structural alterations to the SH3TC2 gene could possibly predispose to peripheral nerve inflammation.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Predisposição Genética para Doença/genética , Inflamação/genética , Mutação/genética , Proteínas/genética , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/fisiopatologia , Criança , Transtornos Cromossômicos/genética , Doenças dos Nervos Cranianos/genética , Análise Mutacional de DNA , Feminino , Deformidades Congênitas do Pé/genética , Genes Recessivos/genética , Testes Genéticos , Genótipo , Humanos , Inflamação/patologia , Inflamação/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Fenótipo , Insuficiência Respiratória/genética , Escoliose/genética , Nervo Sural/metabolismo , Nervo Sural/patologia , Nervo Sural/fisiopatologiaRESUMO
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.
Assuntos
Distrofia Muscular de Duchenne/terapia , Escoliose/prevenção & controle , Coluna Vertebral/fisiologia , Adolescente , Criança , Humanos , Masculino , Procedimentos Ortopédicos/métodos , Projetos Piloto , Suporte de Carga/fisiologiaRESUMO
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.