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Dystrophinopathy is caused by alterations in the dystrophin gene. The severe phenotype, Duchenne muscular dystrophy (DMD), is caused by a lack of dystrophin in skeletal muscles, resulting in necrosis and regenerating fibers, inflammatory cells, and muscle fibrosis. Progressive muscle weakness is a characteristic finding of this condition. Here, we encountered a rare case of a 10-year-old patient with asymptomatic dystrophinopathy with no dystrophin expression and investigated the reason for the absence of muscle weakness to obtain therapeutic insights for DMD. Using RNA-seq analysis, gene expression in skeletal muscles was compared among patients with asymptomatic dystrophinopathy, three patients with typical DMD, and two patients without dystrophinopathy who were leading normal daily lives. Cathepsin K (CTSK), myosin heavy chain 3 (MYH3), and nodal modulator 3-like genes exhibited a >8-fold change, whereas crystallin mu gene (CRYM) showed a <1/8-fold change in patients with typical DMD compared with their expression in the patient with asymptomatic dystrophinopathy. Additionally, CTSK and MYH3 expression exhibited a >16-fold change (P < 0.01), whereas CRYM expression showed a <1/16-fold change (P < 0.01) in patients with typical DMD compared with their expression in those without dystrophinopathy. CTSK plays an essential role in skeletal muscle loss, fibrosis, and inflammation in response to muscles injected with cardiotoxin, one of the most common reagents that induce muscle injury. Increased CTSK expression is associated with muscle injury or necrosis in patients with DMD. The lack of muscle weakness in the patient with asymptomatic dystrophinopathy might be attributed to the low CTSK expression in the muscles. To the best of our knowledge, this is the first report to demonstrate that CTSK expression was significantly higher in the skeletal muscles of patients with DMD with a typical phenotype than in those without dystrophinopathy.
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Hashimoto's encephalopathy is an anti-thyroid antibody-positive autoimmune encephalopathy. We herein report the case of a 13-year-old male patient with subacute vertigo, muscle weakness in the extremities and gait disturbance who was diagnosed with Hashimoto's encephalopathy. He showed no severe impairment of consciousness and no seizures, and there were no abnormalities on the brain MRI. However, epileptic spike and wave complexes were observed on an electroencephalogram, and a decline in blood flow was diffusely observed on brain SPECT (single photon emission computed tomography). His thyroid function was normal, but he was positive for anti-thyroid antibodies, such as anti-TPO (thyroid peroxidase) antibodies. He was also positive for serum anti-NAE (NH2-terminal alpha-enolase) antibodies. Systemic corticosteroid therapy and high-dose intravenous immunoglobulin therapy were effective, greatly improving his quality of life.
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Encefalite/complicações , Doença de Hashimoto/complicações , Debilidade Muscular/etiologia , Vertigem/etiologia , Adolescente , Humanos , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada de Emissão de Fóton Único , Enzimas Ativadoras de Ubiquitina/análiseRESUMO
BACKGROUND: The purpose of this study was to evaluate the utility of a wrist actigraph for estimating muscle strength in Duchenne muscular dystrophy patients. METHODS: Twenty-two patients aged 4-19 years wore a wrist actigraph to monitor activities of daily living, and underwent a test of knee extension strength and the 6 min walk test. These measures were made at baseline and at 1 year later. The actigraph data were quantified using the zero crossing mode (ZCM), which indicates the frequency of movement, and the proportional integration mode (PIM), which indicates activity level or vigor of motion. RESULTS: The ZCM and PIM scores of ambulatory patients were higher than those of non-ambulatory patients (P < 0.001). The correlation coefficient between ZCM score and 6 min walk distance, ZCM score and knee extension strength, PIM score and 6 minute walk distance, and PIM score and knee extension strength was -0.44, 0.25, 0.58, and 0.63, respectively. This indicates that the PIM score had a moderate-good association with 6 min walk distance and knee extension strength. CONCLUSION: Muscle strength can be estimated using the PIM score calculated from actigraph data. The PIM score is a good tool for the estimation of muscle strength.
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Força Muscular , Distrofia Muscular de Duchenne/fisiopatologia , Actigrafia , Adolescente , Criança , Pré-Escolar , Humanos , Adulto JovemRESUMO
Introduction: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by muscle atrophy and progressive muscle weakness. Insurance-approved treatments in Japan include antisense oligonucleotide therapy, gene therapy, and small molecule therapy. The efficacy of these therapies varies depending on the timing of treatment initiation. Case presentation: We report the cases of two infants with SMA born in the same region. Patient 1, who had two copies of SMN2, was born before newborn screening (NBS) was started and received onasemnogene abeparvovec therapy at the age of 4 months. Patient 2, who had three copies of SMN2, was born after the start of NBS and was diagnosed and treated with onasemnogene abeparvovec before symptoms appeared. Unfortunately, Patient 1 became bedridden despite receiving gene therapy, while Patient 2 achieved normal motor development. Discussion: Our findings show that treatment timing is an essential factor affecting patients' motor neurodevelopmental outcomes, although our patients did have differences in the number of copies of SMN2. Therefore, a system should be established to allow all newborns to undergo publicly funded NBS for SMA.
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OBJECTIVE: Becker muscular dystrophy (BMD) is a milder variant of Duchenne muscular dystrophy (DMD), a lethal X-linked muscular disorder. Here, we aim to investigat the clinical involvement of skeletal, respiratory, cardiac, and central nervous systems in patients with BMD, as well as genotype-phenotype relationships. METHODS: This nationwide cohort study investigated the clinical manifestations and genotype-phenotype relationships in 225 patients with BMD having in-frame deletion from 22 medical centers. The primary outcome was to elucidate the association of genotype with skeletal muscle, respiratory, cardiac, and central nervous system disorders. Descriptive statistics were used to analyze the data. RESULTS: The average age of the subjects was 31.5 (range, 1-81) years. Initial symptoms of BMD were muscular (60%), followed by asymptomatic hypercreatine kinasemia (32.4%) and central nervous system disorders (5.3%). Gait disturbance was observed in 53.8% of patients and the average age at wheelchair introduction was 36.5 years. The ventilator introduction rate was 6.7% at an average age of 36.6 years. More than 30% of patients had an abnormal electrocardiogram and approximately 15% had heart failure symptoms. Cardiac function on echocardiography varied significantly among the patients. The frequencies of seizures and intellectual/developmental disability were 8.0% and 16.9%, respectively. Exon 45-47deletion (del) was the most common (22.6%), followed by exon 45-48del (13.1%). Patients with exon 45-49del patients demonstrated severe skeletal muscle damage. Patients with exon 45-47del and exon 45-55del patients did not require ventilator use. INTERPRETATION: The study provides important prognostic information for patients and clinicians to establish therapy plans and to implement preventative medicine.
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Doenças do Sistema Nervoso Central , Cardiopatias , Deficiência Intelectual , Distrofia Muscular de Duchenne , Humanos , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Distrofia Muscular de Duchenne/genética , Distrofina/genética , Estudos de Coortes , GenótipoRESUMO
PURPOSE: Children with medical complexity frequently experience difficulty breathing and swallowing and occasionally develop aspiration pneumonia. Long-term intubation may cause fatal trachea-innominate artery fistula (TIF). In the present study, we retrospectively evaluated the efficacy of laryngeal closure and laryngostomy in children with medical complexity. MATERIALS AND METHODS: Laryngeal closure and laryngostomy were performed in eight children with severe neuromuscular disorders who were incapable of oral ingestion and verbal communication. The laryngostoma was placed at a higher position compared to that in conventional tracheostomies for easier management of the airway and to prevent TIF. RESULTS: Aspiration was successfully prevented postoperatively in all cases. Laryngocutaneous fistula formation was not observed. Two patients successfully achieved oral ingestion capability and tracheal cannulas were removed in two patients. Among the six patients who needed a mechanical ventilator before surgery, two patients were weaned from mechanical ventilation. Five patients were successfully discharged from the hospital. Although two patients died because of their primary condition, pneumonia exacerbation was not observed in any of the patients. CONCLUSION: Compared to the conventional tracheostomy, our procedure improved airway management and function in children with medical complexity and reduced the risk of TIF.
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Fístula , Pneumonia Aspirativa , Doenças da Traqueia , Tronco Braquiocefálico/cirurgia , Criança , Fístula/cirurgia , Humanos , Pneumonia Aspirativa/etiologia , Estudos Retrospectivos , Doenças da Traqueia/cirurgia , Traqueostomia/efeitos adversos , Resultado do TratamentoRESUMO
Spinal muscular atrophy (SMA) is a degenerative neuromuscular disease that causes progressive muscle weakness and atrophy due to loss of the anterior horn cells of the spinal cord. Although effective treatments, such as gene therapy, have emerged in recent years, their therapeutic efficacy depends on a restricted time window of treatment initiation. For the treatment to be effective, it must be started before symptoms of the disease emerge. For this purpose, newborn screening (NBS) for SMA is conducted in many countries worldwide. The NBS program for SMA has been initiated in Japan in several regions, including the Kumamoto Prefecture. We started the NBS program in February 2021 and detected a patient with SMA after screening 13,587 newborns in the first year. Herein, we report our experience with the NBS program for SMA and discuss an issue to be approached in the future.
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INTRODUCTION: Autosomal dominant mitochondrial DNA depletion syndrome (MTDPS-12A) is characterized by severe hypotonia from birth due to a mutation in the adenine nucleotide translocator 1 (ANT1). CASE REPORT: A 4-year-old female patient diagnosed with neonatal-onset mitochondrial disease, who had good cognitive function while receiving antiepileptic treatment, presented with sudden-onset status epilepticus with facial and limb myoclonus persisting for more than 30 min. Subsequently, she developed epileptic encephalopathy. Brain MRI showed progressive ventricular enlargement and marked white matter atrophy. She was unable to perform verbal communication or make eye contact and fingertip movements. She lacked any signs of cardiomyopathy. Sanger sequencing demonstrated a heterozygous de novo mutation of c.239G>A (p.Arg80His) in SLC25A4. Her right quadriceps muscle tissue showed lowered complexes I, III, and IV activities and mitochondria DNA depletion (mitochondria/nuclear DNA: 14.6 ± 2.2%) through the quantitative polymerase chain reaction. She was definitively diagnosed with MTDPS-12A. CONCLUSION: Status epilepticus causes encephalopathy in patients with MTDPS-12A. Reducing the energy requirement on the cardiac muscle and brain may be a treatment strategy for patients with MTDPS-12A. Therefore, seizure management and preventive treatment of status epilepticus are considered to be important for maintaining neurodevelopmental outcomes.
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Translocador 1 do Nucleotídeo Adenina/genética , Encefalopatias , DNA Mitocondrial/genética , Doenças Mitocondriais , Doenças Musculares , Estado Epiléptico , Encefalopatias/diagnóstico , Encefalopatias/etiologia , Pré-Escolar , Feminino , Humanos , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Musculares/diagnóstico , Doenças Musculares/etiologia , Estado Epiléptico/diagnóstico , Estado Epiléptico/etiologia , SíndromeRESUMO
BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by abnormalities in the DMD gene. The majority of DMD patients have out-of-frame deletion(s), which disrupt the reading frame; while some cases of DMD are caused by duplication or nonsense mutation(s). Most patients with BMD have in-frame deletion(s), which preserve the reading frame. The phenotype of BMD is generally milder than that of DMD. Antisense morpholino-mediated exon skipping, which changes out-of-frame deletions to in-frame deletions, is a promising therapeutic approach for DMD. It is necessary, however, to confirm the exon-skipping event in cells of DMD patients before the clinical trial. METHODS: Fibroblasts isolated from four DMD patients were induced to differentiate into the myogenic lineage by infection with Ad.CAGMyoD. The cells were then transfected with two types of morpholino. The exon-skipping event was analyzed on reverse transcription-polymerase chain reaction. RESULTS: Morpholino B30, which is located at the splicing enhancer of exon 51 of the DMD gene, yielded the desired exon 51-skipping event in all deletion patterns of cells tested. Morpholino I25, which is located at the exon donor, induced two different exon-skipping patterns, which are total or partial exon 51-skipping events. According to the sequence analysis, the unexpected unskipped regions were the 95 bp section and the 188 bp section of exon 51, showing that the cryptic splicing donor was newly produced with I25. Unfortunately, these cryptic splicing donors gave rise to out-of-frame patterns. Based on these in vitro results, B30 would presumably be an effective therapy. Interestingly, the cocktail of B30 and I25 appeared to yield a more efficient exon 51-skipping event. CONCLUSION: An in vitro system was developed that could easily screen the effectiveness of antisense sequences and identify good candidates for therapy with morpholino.
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Éxons , Terapia Genética , Morfolinos/uso terapêutico , Distrofia Muscular de Duchenne/terapia , Oligonucleotídeos Antissenso/uso terapêutico , Deleção de Sequência , Ensaios Clínicos como Assunto , DNA/genética , Fibroblastos , Humanos , Técnicas In Vitro , Distrofia Muscular de Duchenne/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Tionucleotídeos/uso terapêutico , TransfecçãoRESUMO
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear. METHODS: We have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples. RESULTS: A total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4). CONCLUSION: Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers.
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Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatologia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Adolescente , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Gravidade do Paciente , Fenótipo , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
Smith-Magenis syndrome (SMS) is a complex disorder characterized by variable mental retardation, sleep disturbances, craniofacial and skeletal anomalies, self-injurious and attention-seeking behaviors, and speech and motor delays. The case of a 14-month-old girl with SMS who was experiencing spasm clusters and sleep disturbances with sleep-wake intervals of 1.5 to 2 h persisting from the neonatal period was examined. The patient's spasms stopped and interictal electroencephalography did not show epileptic discharges after undergoing a high-dose adrenocorticotropic hormone (ACTH) therapy. Moreover, the patient's sleep cycle stabilized 1 month after receiving the ACTH therapy. Dramatic reductions in the patient's self-injurious behaviors were also noted. At 1 year following ACTH treatment, the patient's improved sleep was maintained. High-dose ACTH treatment was considered to contribute to the normal adaptation of the hypothalamic-pituitary-adrenal axis by regulating the release of corticotropin-releasing hormone, resulting in improvement of the patient's infantile spasms and sleep disturbances.
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OBJECTIVE: The novel morpholino antisense oligonucleotide viltolarsen targets exon 53 of the dystrophin gene, and could be an effective treatment for patients with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to induce dystrophin expression and examined its safety in DMD patients. METHODS: In this open-label, multicenter, parallel-group, phase 1/2, exploratory study, 16 ambulant and nonambulant males aged 5-12 years with DMD received viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary endpoints were dystrophin expression and exon 53 skipping levels. RESULTS: In western blot analysis, mean changes in dystrophin expression (% normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46 (P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and 4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group (2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53 skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events were judged to be mild or moderate in intensity and none led to study discontinuation. INTERPRETATION: Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing trend in dystrophin expression and exon 53 skipping levels, and was safe and well tolerated. The decline in motor function appeared less marked in patients with higher dystrophin levels; this may warrant further investigation. This study supports the potential clinical benefit of viltolarsen.
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Distrofina/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos/farmacologia , Criança , Pré-Escolar , Distrofina/genética , Distrofina/metabolismo , Humanos , Japão , Masculino , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , Oligonucleotídeos/administração & dosagem , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacocinética , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Lesch-Nyhan disease (LND) is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase. Patients with LND experience involuntary movements, including dystonia, choreoathetosis, opisthotonos, ballismus, and self-injury. Alleviating these involuntary movements is important to improve the quality of life in patients with LND. Many clinicians have difficulty controlling these involuntary movements in their patients, and there are no established and effective treatments. A 6-month-old boy with LND presented with generalized dystonia and self-injury behavior that was alleviated after receiving S-adenosylmethionine (SAMe). His self-injury behavior completely resolved after he received SAMe and risperidone. Although he had often experienced inspiratory stridor because of laryngeal dystonia and frequently developed aspiration pneumonitis and bronchitis, no inspiratory stridor was noted after SAMe treatment. The patient is continuing to receive SAMe and risperidone. SAMe treatment alleviates dystonic movements and improves quality of life in pediatric patients with LND. Additional research is needed to determine the long-term safety and efficacy of SAMe and its appropriate dosage.
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Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.
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Aberrações Cromossômicas , Estudos de Associação Genética , Fenótipo , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Fácies , Feminino , Estudos de Associação Genética/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Adulto JovemRESUMO
Tay-Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage disease caused by a loss of lysosomal hexosaminidase-A (HEXA) activity and characterized by progressive neurodegeneration due to the massive accumulation of GM2 ganglioside in the brain. Here, we generated iPSCs derived from patients with TSD, and found similar potential for neural differentiation between TSD-iPSCs and normal iPSCs, although neural progenitor cells (NPCs) derived from the TSD-iPSCs exhibited enlarged lysosomes and upregulation of the lysosomal marker, LAMP1, caused by the accumulation of GM2 ganglioside. The NPCs derived from TSD-iPSCs also had an increased incidence of oxidative stress-induced cell death. TSD-iPSC-derived neurons showed a decrease in exocytotic activity with the accumulation of GM2 ganglioside, suggesting deficient neurotransmission in TSD. Our findings demonstrated that NPCs and mature neurons derived from TSD-iPSCs are potentially useful cellular models of TSD and are useful for investigating the efficacy of drug candidates in the future.
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Células-Tronco Pluripotentes Induzidas/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Terminações Pré-Sinápticas/fisiologia , Doença de Tay-Sachs/fisiopatologia , Humanos , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Células-Tronco Neurais/fisiologia , Neuritos/fisiologia , Sinapsinas/metabolismo , Doença de Tay-Sachs/metabolismo , Regulação para Cima/fisiologiaRESUMO
BACKGROUND: Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. METHODS: Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). RESULTS: Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. CONCLUSION: A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.
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Transtornos do Neurodesenvolvimento/genética , Povo Asiático/genética , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Predisposição Genética para Doença , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
One cause of X-linked dilated cardiomyopathies is mutation of the dystrophin gene. We report the case of a young boy who suffered from dilated cardiomyopathy caused only by dystrophin-deficient cardiac muscle, but who did not present with any clinical signs of skeletal myopathy. Sequence analysis of the patient's dystrophin gene revealed the presence of a novel single point mutation at the first exon-intron boundary, inactivating the 5' splice site consensus sequence of the first intron. The lack of muscle weakness observed clinically can be explained by expression of the brain and Purkinje dystrophin isoforms in skeletal muscle.
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Cardiomiopatia Dilatada/genética , Sequência Consenso/genética , Distrofina/genética , Mutação Puntual/genética , Sítios de Splice de RNA/genética , Adolescente , Distrofina/metabolismo , Humanos , Masculino , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
OBJECTIVE: To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants. METHODS: A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins. RESULTS: WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells. CONCLUSIONS: Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.
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OBJECTIVE: Clinical severity of alternating hemiplegia of childhood (AHC) is extremely variable. To investigate genotype-phenotype correlations in AHC, we analyzed the clinical information and ATP1A3 mutations in patients with AHC. METHODS: Thirty-five Japanese patients who were clinically diagnosed with AHC participated in this study. ATP1A3 mutations were analyzed using Sanger sequencing. Detailed clinical information was collected from family members of patients with AHC and clinicians responsible for their care. RESULTS: Gene analysis revealed 33 patients with de novo heterozygous missense mutations of ATP1A3: Glu815Lys in 12 cases (36%), Asp801Asn in 10 cases (30%), and other missense mutations in 11 cases. Clinical information was compared among the Glu815Lys, Asp801Asn, and other mutation groups. Statistical analysis revealed significant differences in the history of neonatal onset, gross motor level, status epilepticus, and respiratory paralysis in the Glu815Lys group compared with the other groups. In addition, 8 patients who did not receive flunarizine had severe motor deteriorations. CONCLUSIONS: The Glu815Lys genotype appears to be associated with the most severe AHC phenotype. Although AHC is not generally seen as a progressive disorder, it should be considered a disorder that deteriorates abruptly or in a stepwise fashion, particularly in patients with the Glu815Lys mutation.
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Hemiplegia/genética , Transtornos das Habilidades Motoras/genética , Paralisia Respiratória/genética , ATPase Trocadora de Sódio-Potássio/genética , Estado Epiléptico/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Hemiplegia/complicações , Hemiplegia/fisiopatologia , Heterozigoto , Humanos , Lactente , Masculino , Transtornos das Habilidades Motoras/etiologia , Transtornos das Habilidades Motoras/fisiopatologia , Mutação de Sentido Incorreto/genética , Paralisia Respiratória/etiologia , Paralisia Respiratória/fisiopatologia , Índice de Gravidade de Doença , Estado Epiléptico/etiologia , Estado Epiléptico/fisiopatologia , Adulto JovemRESUMO
Congenital fiber type disproportion (CFTD) is a form of congenital myopathy, which is defined by type 1 myofibers that are 12% smaller than type 2 myofibers, as well as a general predominance of type 1 myofibers. Conversely, myasthenia gravis (MG) is an acquired immune-mediated disease, in which the acetylcholine receptor (AChR) of the neuromuscular junction is blocked by antibodies. Thus, the anti-AChR antibody is nearly specific to MG. Herein, we report on a case of CFTD with increased anti-AChR antibody levels. A 23-month-old boy exhibited muscle hypotonia and weakness. Although he could walk by himself, he easily fell down and could not control his head for a long time. His blood test was positive for the anti-AChR antibody, while a muscle biopsy revealed characteristics of CFTD. We could not explain the relationship between MG and CFTD. However, we considered different diagnoses aside from MG, even when the patient's blood is positive for the anti-AChR antibody.