RESUMO
BACKGROUND: Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients. METHODS: Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance. RESULTS: There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016). CONCLUSION: This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.
Assuntos
Escoliose , Atrofias Musculares Espinais da Infância , Humanos , Pré-Escolar , Escoliose/diagnóstico por imagem , Escoliose/terapia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
BACKGROUND: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number. METHODS: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II). RESULTS: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not. CONCLUSIONS: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time.
Assuntos
Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Criança , Lactente , Humanos , Recém-Nascido , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Seguimentos , Oligonucleotídeos/uso terapêutico , Exame Neurológico , Atrofia Muscular Espinal/tratamento farmacológicoRESUMO
Emery-Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early contractures, progressive muscle weakness, and cardiac abnormalities. Different subtypes of EDMD have been described, with the two most common forms represented by the X-linked EDMD1, caused by mutations in the EMD gene encoding emerin, and the autosomal EDMD2, due to mutations in the LMNA gene encoding lamin A/C. A clear definition of the magnetic resonance imaging (MRI) pattern in the two forms, and especially in the rarer EDMD1, is still lacking, although a preferential involvement of the medial head of the gastrocnemius has been suggested in EDMD2. We report a 13-year-old boy with mild limb girdle muscle weakness, elbow and ankle contractures, with absence of emerin at muscle biopsy, carrying a hemizygous frameshift mutation on the EMD gene (c.153dupC/p.Ser52Glufs*9) of maternal inheritance. Minor cardiac rhythm abnormalities were detected at 24-hour Holter electrocardiogram and required ß-blocker therapy. MRI scan of the thighs showed a mild diffuse involvement, while tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius were the most affected muscles in the leg. We also provide a review of the muscular MRI data in EDMD patients and highlight the relative heterogeneity of the MRI patterns found in EDMDs, suggesting that muscle MRI should be studied in larger EDMD cohorts to better define disease patterns and to cover the wide disease spectrum.
Assuntos
Contratura , Distrofia Muscular de Emery-Dreifuss , Distrofia Muscular de Emery-Dreifuss Ligada ao Cromossomo X , Masculino , Humanos , Criança , Adolescente , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/patologia , Distrofia Muscular de Emery-Dreifuss/diagnóstico por imagem , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patologia , Mutação , Debilidade Muscular , Imageamento por Ressonância MagnéticaRESUMO
AIMS: SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype. METHODS: We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations. RESULTS: In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids. CONCLUSIONS: Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental.
Assuntos
Neuropatias Hereditárias Sensoriais e Autônomas , Doença dos Neurônios Motores , Doenças do Sistema Nervoso Periférico , Humanos , Serina C-Palmitoiltransferase/química , Serina C-Palmitoiltransferase/genética , Mutação , Esfingolipídeos , Serina/química , Serina/genéticaRESUMO
BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.
Assuntos
Cinesinas/genética , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Adulto , Idoso , Ataxia/congênito , Ataxia/genética , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To evaluate the effects of nusinersen on respiratory function of patients with type 1 spinal muscular atrophy. STUDY DESIGN: Observational, longitudinal cohort study. We collected respiratory data from 118 children with type 1 spinal muscular atrophy and differing pulmonary requirements and conducted a semistructured qualitative interview among a subsample of caregivers at baseline, 6 months, and 10 months after the first nusinersen treatment. Patients were stratified according to ventilation modalities and age at study entry. RESULTS: Most patients in our cohort remained stable (84/109 = 77%). More than 80% of the children treated before age 2 years survived, in contrast to the lower survival reported in natural history studies, and did so without tracheostomy or noninvasive ventilation (NIV) ≥16 hours. In those less than 2 years old, only 3 patients shifted from NIV ≤10 hours to NIV >10 hours, and the other 3 reduced the hours of NIV required. Most of the older patients remained stable; this included not only those on tracheostomy or NIV >10 hours but also 75% of those on NIV ≤10 hours. CONCLUSIONS: Our results suggest that nusinersen may produce some improvement in the progression of respiratory impairment, both in terms of survival and need for respiratory support ≥16 hours, especially before the age of 2 years.
Assuntos
Ventilação não Invasiva , Oligonucleotídeos/uso terapêutico , Respiração , Atrofias Musculares Espinais da Infância/fisiopatologia , Atrofias Musculares Espinais da Infância/terapia , Estudos de Coortes , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Atrofias Musculares Espinais da Infância/tratamento farmacológicoRESUMO
OBJECTIVE: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months. METHODS: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). RESULTS: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = ±13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = ±1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2. INTERPRETATION: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity. ANN NEUROL 2019;86:443-451.
Assuntos
Oligonucleotídeos/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Feminino , Seguimentos , Humanos , Lactente , Masculino , Índice de Gravidade de Doença , Atrofias Musculares Espinais da Infância/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Resultado do TratamentoRESUMO
TSFM is a nuclear gene encoding the elongation factor Ts (EFTs), an essential component of mitochondrial translational machinery. Impaired mitochondrial translation is responsible for neurodegenerative disorders characterized by multiple respiratory chain complex defects, multisystemic involvement, and neuroradiological features of Leigh-like syndrome. With the use of a next-generation sequencing (NGS)-based multigene panel for mitochondrial disorders, we identified the novel TSFM homozygous variant c.547G>A (p.Gly183Ser) in a 5-year-old boy with infantile early onset encephalocardiomyopathy, sensorineural hearing loss, and peculiar partially reversible neuroimaging features. Our findings expand the phenotypic spectrum of TSFM-related encephalopathy, offering new insights into the natural history of brain involvement and suggesting that TSFM should be investigated in pediatric mitochondrial disorders with distinctive neurologic and cardiac involvement.
Assuntos
Encefalopatias/genética , Cardiomiopatias/genética , Variação Genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fatores de Alongamento de Peptídeos/genética , Biópsia , Encéfalo/diagnóstico por imagem , Encefalopatias/complicações , Cardiomiopatias/complicações , Pré-Escolar , Deficiências do Desenvolvimento/genética , Transporte de Elétrons , Perda Auditiva Neurossensorial/complicações , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Doenças Mitocondriais/genética , Hipotonia Muscular/genética , Neuroimagem , Análise de Sequência com Séries de Oligonucleotídeos , Biossíntese de ProteínasRESUMO
We present a 13-year-old patient with persistent increase of serum Creatine Kinase (CK) and myalgia after exertion. Skeletal muscle biopsy showed marked reduction of dystrophin expression leading to genetic analysis of DMD gene by MLPA, which detected a single deletion of exon 78. To the best of our knowledge, DMD exon 78 deletion has never been described in literature and, according to prediction, it should lead to loss of reading frame in the dystrophin gene. To further assess the actual effect of exon 78 deletion, we analysed cDNA from muscle mRNA. This analysis confirmed the absence of 32 bp of exon 78. Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids. Albeit loss of reading frame usually leads to protein degradation and severe phenotype, in this case, we demonstrated that deletion of DMD exon 78 can be associated with a functional protein able to bind DGC complex and a very mild phenotype. This study adds a novel deletion in DMD gene in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease.
Assuntos
Creatina Quinase/sangue , Distrofina/genética , Éxons , Deleção de Genes , Distrofia Muscular de Duchenne/diagnóstico , Adolescente , Biópsia , Códon de Terminação , DNA Complementar/genética , Humanos , Masculino , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/genética , Mialgia/fisiopatologia , Fases de Leitura Aberta , Fenótipo , RNA Mensageiro/genéticaRESUMO
BACKGROUND: Fundoplication is considered a mainstay in the treatment of gastro-esophageal reflux. However, the literature reports significant recurrences and limited data on long-term outcome. AIMS: To evaluate our long-term outcomes of antireflux surgery in children and to assess the results of redo surgery. METHODS: We retrospectively analyzed all patients who underwent Nissen fundoplication in 8 consecutive years. Reiterative surgery was indicated only in case of symptoms and anatomical alterations. A follow-up study was carried out to analyzed outcome and patients' Visick score assessed parents' perspective. RESULTS: Overall 162 children were included for 179 procedures in total. Median age at first intervention was 43 months. Comorbidities were 119 (73 %), particularly neurological impairments (73 %). Redo surgery is equal to 14 % (25/179). Comorbidities were risk factors to Nissen failure (p = 0.04), especially children suffering neurological impairment with seizures (p = 0.034). Follow-up datasets were obtained for 111/162 = 69 % (median time: 51 months). Parents' perspectives were excellent or good in 85 %. CONCLUSIONS: A significant positive impact of redo Nissen intervention on the patient's outcome was highlighted; antireflux surgery is useful and advantageous in children and their caregivers. Children with neurological impairment affected by seizures represent significant risk factors.
Assuntos
Fundoplicatura/estatística & dados numéricos , Refluxo Gastroesofágico/cirurgia , Reoperação/estatística & dados numéricos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Complicações Pós-Operatórias , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Mitochondrial disorders are a heterogeneous group of diseases sharing a defect of the oxidative phosphorylation system. Point mutations in the mitochondrial DNA are a common cause of mitochondrial disorders and frequently affect the sequences encoding mitochondrial transfer RNAs. The m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) is traditionally reported in patients with clinical features of the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome and in mitochondrial diabetes. Here we describe the clinical, pathological, and molecular features of an Italian child and his asymptomatic mother, carrying the m.3271T>C mutation in the mitochondrial tRNA(Leu(UUR)) gene, in association with an unusual clinical phenotype dominated by hypertrophic cardiomyopathy and provide review literature of cases with this mutation. To the best of our knowledge, there are no reports describing the association of this mutation with cardiomyopathy, and our cases suggest that the m.3271T>C mutation has to be taken into account in the diagnostic approach of maternally inherited cardiomyopathies.
Assuntos
Cardiomiopatia Hipertrófica/genética , Mutação Puntual , RNA de Transferência de Leucina/genética , Adolescente , Cardiomiopatia Hipertrófica/patologia , Pré-Escolar , Feminino , Humanos , Síndrome MELAS/genética , Masculino , Pessoa de Meia-IdadeRESUMO
We describe a new autosomal recessive white matter disorder ('hypomyelination and congenital cataract') characterized by hypomyelination of the central and peripheral nervous system, progressive neurological impairment and congenital cataract. We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521-amino acid membrane protein. Our study highlights the essential role of hyccin in central and peripheral myelination.
Assuntos
Catarata/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Proteínas Oncogênicas/deficiência , Proteínas Oncogênicas/genética , Animais , Células COS , Catarata/etiologia , Criança , Chlorocebus aethiops , Genes Recessivos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/etiologia , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Proteínas Oncogênicas/metabolismo , LinhagemRESUMO
Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01âmL/m2, pâ=â0.03) while for dp116 were correlated with decreased EF (-4.14%, pâ=â<0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, pâ=â0.002, and -10.62âmL/m2, pâ=â0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.
Assuntos
Cardiomiopatias , Distrofia Muscular de Duchenne , Humanos , Distrofina/genética , Distrofina/metabolismo , Haplótipos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/complicações , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Isoformas de Proteínas/genética , Proteínas de Ligação a TGF-beta Latente/genéticaRESUMO
WDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
Assuntos
Ciliopatias , Genes Ligados ao Cromossomo X , Repetições WD40 , Animais , Humanos , Masculino , Encéfalo , Ciliopatias/genética , Cognição , Peixe-Zebra/genéticaRESUMO
BACKGROUND: Spinal muscular atrophy (SMA) type 1 is a severe condition leading to early respiratory failure. Treatment options have become available, yet respiratory outcome measures in SMA type 1 are limited. The aim of this study was to assess the respiratory pattern in SMA type 1 patients via structured light plethysmography (SLP). SLP measures the thoraco-abdominal movements by projecting a light grid onto the anterior thoraco-abdominal surface. METHODS: Cross-sectional study of consecutive children with SMA type 1. All children underwent motor assessment (CHOP-INTEND) and one-minute tidal breathing recording by SLP in supine position while self-ventilating in room air. The Respiratory rate, the abdominal vs. chest contribution to breath (Relative Expired Abdomen%, Relative Expired Chest%) and the severity of thoraco-abdominal paradox (Phase Angle) were acquired. RESULTS: Nineteen patients were included, median (IQR) age 2.3 years (1.4-7.9). Their respiratory pattern captured via SLP showed a raised median (IQR) respiratory rate per age of 33.5 bpm (26.6-41.7), a prevalent abdominal contribution to tidal breathing with median (IQR) Relative Expired Abdomen 77% (68-90) vs. Chest 23% (10-32). Thoracoabdominal paradox was detected (median Phase Angle 48.70°) and its severity correlated negatively with CHOP-INTEND (r -0.8, p < 0.01). CONCLUSIONS: SLP captured and quantified the respiratory features of infants and children with SMA type 1.
RESUMO
INTRODUCTION: POMT2-related limb girdle muscular dystrophy (LGMDR14) is a rare muscular dystrophy caused by mutations in the POMT2 gene. Thus far only 26 LGMDR14 subjects have been reported and no longitudinal natural history data are available. CASE REPORT: We describe two LGMDR14 patients followed for 20 years since infancy. Both patients presented a childhood-onset, slowly progressive pelvic girdle muscular weakness leading to loss of ambulation in the second decade in one patient, and cognitive impairment without detectable brain structural abnormalities. Glutei, paraspinal, and adductor muscles were the primarily involved muscles at MRI. DISCUSSION: This report provides natural history data on LGMDR14 subjects, with a focus on longitudinal muscle MRI. We also reviewed the LGMDR14 literature data, providing information on the LGMDR14 disease progression. Considering the high prevalence of cognitive impairment in LGMDR14 patients, a reliable application of functional outcome measures can be challenging, therefore a muscle MRI follow-up to assess disease evolution is recommended.
Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofias Musculares , Humanos , Criança , Seguimentos , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/genética , Músculo Esquelético/diagnóstico por imagem , Distrofias Musculares/genética , Imageamento por Ressonância Magnética , MutaçãoRESUMO
Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R) localized in the cytosolic N-terminus of the TRPV4 protein, upstream of the ankyrin-repeat domain, where the great majority of disease-associated mutations reside. In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C). Functional analysis of the novel p.P97R mutation in a heterologous system demonstrated a loss-of-function mechanism. Protein localization studies in muscle, skin, and cultured skin fibroblasts from both patients showed normal protein expression. No TRPV4 mutations were detected in four children with dSMA without bone or vocal cord involvement. Adding to the clinical and molecular heterogeneity of TRPV4-associated diseases, our results suggest that molecular testing of the TRPV4 gene is warranted in cases of congenital dSMA with bone abnormalities and vocal cord paralysis.
Assuntos
Atrofia Muscular Espinal/genética , Mutação , Canais de Cátion TRPV/genética , Adulto , Criança , Pré-Escolar , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Variação Genética , Genótipo , Humanos , Íntrons , Masculino , Atrofia Muscular Espinal/congênito , Linhagem , Fenótipo , Paralisia das Pregas Vocais/patologiaRESUMO
Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the MEGF10 gene (OMIM #614399). Phenotypic spectrum of EMARDD is variable, ranging from severe infantile forms in which patients are ventilator-dependent and die in childhood, to milder chronic disorders with a more favorable course (mild variant, mvEMARDD). Here we describe a 22 years old boy, offspring of consanguineous parents, presenting a congenital myopathic phenotype since infancy with elbow contractures and scoliosis. The patient developed a slowly progressive muscle weakness with impaired walking, rhinolalia, dysphagia, and respiratory involvement, which required noninvasive ventilation therapy since the age of 16 years. First muscle biopsy revealed unspecific muscle damage, with fiber size variation, internal nuclei and fibrosis. Myofibrillar alterations were noted at a second muscle biopsy including whorled fibres, cytoplasmic inclusion and minicores. Exome sequencing identified a homozygous mutation in MEGF10 gene, c.2096G > C (p.Cys699Ser), inherited by both parents. This variant, not reported in public databases of mutations, is expected to alter the structure of the protein and is therefore predicted to be probably damaging according to ACMG classification. In conclusion, we found a new likely pathogenic mutation in MEGF10, which is responsible for a progressive form of mvEMARDD with myofibrillar alterations at muscle biopsy. Interestingly, the presence of MEGF10 mutations has not been reported in Italian population. Early diagnosis of MEGF10 myopathy is essential in light of recent results from in vivo testing demonstrating a potential therapeutic effect of SSRIs compounds.
Assuntos
Transtornos de Deglutição , Doenças Musculares , Miotonia Congênita , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Doenças Musculares/diagnóstico , Mutação , Músculo Esquelético/patologiaRESUMO
The aim of this study is to retrospectively assess onset and progression of scoliosis in type II SMA patients not treated with the approved disease modifying treatments. Scoliosis was evaluated by measuring the scoliosis angle on X-ray obtained in the anteroposterior view in sitting position (Cobb's angle method). Eighty-four patients had at least one assessment of scoliosis angle (287 assessments). There was a positive correlation between age and scoliosis angles (p<0.001) with a progressive increase of scoliosis with age. When subdividing the population by HFMSE score (<10; 11-22;> 22), there was a progressive increase in scoliosis angles with decreasing HFMSE scores. The difference between HFMSE categories was significant (p<0.001). Fifty-four patients had at least two assessments at 6-month distance and were retained for the longitudinal analysis. Using a mixed model, age, functional status and scoliosis angle at baseline were predictive on scoliosis progression. The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74-6.52). Our results confirm the progression of scoliosis in untreated type II SMA providing details of the progression in relation to different variables. With different therapeutical options being available in many countries, our findings will provide reference data for establishing possible differences in the trajectories of progression with treated type II individuals.
Assuntos
Escoliose , Humanos , Escoliose/diagnóstico por imagem , Seguimentos , Estudos Retrospectivos , RadiografiaRESUMO
The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.