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1.
Tohoku J Exp Med ; 262(1): 29-31, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37967941

RESUMO

Juvenile myasthenia gravis (JMG) exhibits a more favorable response to glucocorticoids and has a better prognosis than adult myasthenia gravis. However, no established treatment exists for refractory JMG. Although thymectomy has been performed in several patients with refractory systemic JMG, there are few detailed clinical descriptions of patients who underwent thymectomy. Here, we present the case of a 10-year-old boy with refractory systemic JMG who was successfully treated with thymectomy. The patient developed symptoms, including dysphagia, malaise, diurnal ptosis, and weakness in the trunk muscles, and he was diagnosed with generalized JMG. Despite undergoing various treatments, including steroids, tacrolimus, steroid pulse therapy, intravenous immunoglobulin, azathioprine (AZT), and rituximab, his symptoms did not improve. Therefore, he underwent a thoracoscopic thymectomy 24 months after disease onset. Thymectomy led to remission, as demonstrated by a significant reduction in the quantitative myasthenia gravis score and anti-acetylcholine receptor antibody levels, which persisted for 43 months after surgery. Our case demonstrates the effectiveness of thymectomy in systemic JMG patients with positive anti-acetylcholine receptor antibodies, despite therapeutic failure with AZT and rituximab, within 2 years of disease onset.


Assuntos
Miastenia Gravis , Timectomia , Criança , Humanos , Masculino , Autoanticorpos , Progressão da Doença , Glucocorticoides/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/cirurgia , Rituximab , Resultado do Tratamento
2.
Clin Genet ; 92(2): 180-187, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28177126

RESUMO

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. MATERIALS AND METHODS: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. RESULTS: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%). CONCLUSION: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.


Assuntos
Calcinose/genética , Cistos do Sistema Nervoso Central/genética , Predisposição Genética para Doença , Leucoencefalopatias/genética , RNA Nucleolar Pequeno/genética , Adulto , Alelos , Encéfalo/fisiopatologia , Calcinose/epidemiologia , Calcinose/fisiopatologia , Cistos do Sistema Nervoso Central/epidemiologia , Cistos do Sistema Nervoso Central/fisiopatologia , Cistos/genética , Bases de Dados Factuais , Feminino , Heterozigoto , Humanos , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/fisiopatologia , Masculino , Mutação , Proteínas de Ligação a Telômeros/genética
3.
Hum Genome Var ; 11(1): 2, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38221519

RESUMO

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.

4.
Am J Med Genet A ; 161A(4): 850-5, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23494922

RESUMO

The 2q23.1 deletion syndrome has been recently recognized as a neurodevelopmental disorder associated with intellectual disability, epilepsy, and autism spectrum disorder. Recently, methyl-CpG-binding domain 5 gene (MBD5), located in the 2q23.1 region, has been considered as a single causative gene of this syndrome. We report on a female patient with a de novo reciprocal translocation between chromosomes 2 and 5. Chromosomal microarray testing revealed a cryptic 896 kb deletion that included MBD5. Although clinical manifestations of this patient are compatible with those of patients with 2q23.1 deletion syndrome, a focal pachygyria revealed by brain magnetic resonance imaging has never been observed in the previously reported cases. Obesity caused by hyperphagia was observed in our patient and 28% of the previously reported patients with the 2q23.1 deletion syndrome. For better medical management, appropriate dietary guidance against hyperphagia should be given to the patients' family.


Assuntos
Pontos de Quebra do Cromossomo , Deleção Cromossômica , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Obesidade/genética , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/patologia , Pré-Escolar , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 5 , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Fácies , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Imageamento por Ressonância Magnética
5.
J Hum Genet ; 56(8): 561-5, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21633362

RESUMO

Microarray-based comparative genomic hybridization analysis identified a 737-kb microdeletion of Xq11.1, including the cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9), encoding collybistin, which has a pivotal role in formation of postsynaptic glycine and γ-aminobutyric acid receptor clusters, in a male patient with severe mental retardation and epilepsy. No overlapping deletion with this was identified in the database of genomic copy number variations. A cohort study of ARHGEF9 nucleotide sequence identified a nonsense mutation in another male patient with severe mental retardation and epilepsy. This mutation affects one of the three transcript variants of ARHGEF9, which was confirmed to be expressed in the brain by reverse transcription-PCR. Although this nonsense mutation was shared with the patient's mother, it was not observed in 100 normal individuals. Both male patients suffered epileptic seizures after 1 year of age. Brain magnetic resonance imaging revealed mild frontal atrophy in the first patient and right frontal polymicrogyria in the second patient. Three previously reported mutations of ARHGEF9 consisted of a missense mutation in a male patient with hyperekplexia and two chromosomal disruptions in two female patients. The common phenotypic effects of all ARHGEF9 mutations were mental retardation and epilepsy. Therefore, ARHGEF9 is likely to be responsible for syndromic X-linked mental retardation associated with epilepsy.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Anormalidades Múltiplas/genética , Processamento Alternativo , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos X/genética , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Isoformas de Proteínas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Troca de Nucleotídeo Guanina Rho
6.
Epilepsia ; 52(10): 1835-42, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21770923

RESUMO

PURPOSE: Genetic mutations of the cyclin-dependent kinase-like 5 gene (CDKL5) have been reported in patients with epileptic encephalopathy, which is characterized by intractable seizures and severe-to-profound developmental delay. We investigated the clinical relevance of CDKL5 alterations in both genders. METHODS: A total of 125 patients with epileptic encephalopathy were examined for genomic copy number aberrations, and 119 patients with no such aberrations were further examined for CDKL5 mutations. Five patients with Rett syndrome, who did not show methyl CpG-binding protein 2 gene (MECP2) mutations, were also examined for CDKL5 mutations. KEY FINDINGS: One male and three female patients showed submicroscopic deletions including CDKL5, and two male and six female patients showed CDKL5 nucleotide alterations. Development of early onset seizure was a characteristic clinical feature for the patients with CDKL5 alterations in both genders despite polymorphous seizure types, including myoclonic seizures, tonic seizures, and spasms. Severe developmental delays and mild frontal lobe atrophies revealed by brain magnetic resonance imaging (MRI) were observed in almost all patients, and there was no gender difference in phenotypic features. SIGNIFICANCE: We observed that 5% of the male patients and 14% of the female patients with epileptic encephalopathy had CDKL5 alterations. These findings indicate that alterations in CDKL5 are associated with early epileptic encephalopathy in both female and male patients.


Assuntos
Epilepsia/genética , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Encéfalo/patologia , Encéfalo/fisiopatologia , Pré-Escolar , Códon sem Sentido/genética , Variações do Número de Cópias de DNA/genética , Eletroencefalografia , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Lobo Frontal/patologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto/genética , Fatores Sexuais
7.
Sci Rep ; 11(1): 24229, 2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34930981

RESUMO

Although there is only symptomatic treatment for Fukuyama congenital muscular dystrophy (FCMD), several reports have suggested that steroid therapy could be effective for FCMD; however, no independent intervention studies have been conducted. This study aimed to evaluate the efficacy of steroid therapy for restoring motor functions in FCMD patients. This study involved 3-to-10-year-old FCMD patients who exhibited a decline in motor functions, requested steroid therapy. Patients with consent started oral administration of 0.5-mg/kg prednisolone every alternate day, which was increased to 1.0 mg/kg if the response was inadequate. We used the Gross Motor Function Measure (GMFM) to evaluate and compare the motor functions of all patients. Wilcoxon signed-rank test (significance level, P ≤ 0.05) was used for statistical analysis. At the onset of steroid therapy, 8.10 years (SD, 2.14 years) was the mean age of FCMD patients. The mean GMFM difference between before and after the steroid therapy was + 1.23 (SD, 1.10), and a P value of 0.015 represented significant improvement in GMFM. Our results indicate that steroid therapy may contribute to the maintenance and improvement of the motor functions of advanced-stage FCMD patients.Clinical Trial Registration Registration Number: UMIN000020715, Registration Date: Feb 1st, 2016 (01/02/2016).


Assuntos
Esteroides/uso terapêutico , Síndrome de Walker-Warburg/tratamento farmacológico , Administração Oral , Membrana Celular/metabolismo , Criança , Pré-Escolar , Feminino , Homozigoto , Humanos , Masculino , Proteínas de Membrana/genética , Destreza Motora , Prednisolona/uso terapêutico , Estudos Prospectivos , Análise de Regressão , Síndrome de Walker-Warburg/genética
8.
Neuromuscul Disord ; 31(3): 194-197, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33563515

RESUMO

Fukuyama congenital muscular dystrophy (FCMD) is the second most prevalent childhood-onset muscular dystrophy in Japan. It is an autosomal recessive disorder caused by the fukutin mutation (FKTN), characterized by muscle wasting and brain abnormalities. So far, serum creatine kinase (CK) is recognized as the only biomarker for FCMD. Recently, an ELISA assay to quantify the N-terminal fragment of titin in urine was developed. Urinary titin concentration is elevated in patients with Duchenne muscular dystrophy (DMD) compared to normal controls. Levels vary according to age with excellent sensitivity and specificity for detecting DMD, and they can be used as a diagnostic and disease progression marker. In this study, we measured the urinary titin concentration of 18 patients with FCMD. It was remarkably higher than normal controls and correlated with CK. Especially in homozygotes, the score for gross motor function measure, which is a quantitative motor scale for FCMD, was correlated with urinary titin concentration. Elevated urinary titin concentrations were thought to be reflective of a common pathophysiology with DMD. Urinary titin concentrations can assist with making the diagnosis of FCMD and to estimate the patient's motor function at that point.


Assuntos
Biomarcadores/urina , Conectina/urina , Síndrome de Walker-Warburg/urina , Feminino , Homozigoto , Humanos , Japão , Masculino , Mutação , Síndrome de Walker-Warburg/diagnóstico
9.
Brain Dev ; 42(5): 383-388, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32145987

RESUMO

OBJECTIVES: The objective of this study was to confirm the validity of a short form of gross motor function measure for Fukuyama congenital muscular dystrophy (GMFM for FCMD). METHODS: This study is a case series and was conducted at the Tokyo Women's Medical University. Fifteen patients with FCMD were assessed using both the GMFM for FCMD with 68 items, which was created as a motor function measure for patients with FCMD on the basis of Rasch analysis, and the original GMFM with 88 items. The correlation between the GMFM for FCMD and the Ueda classification was assessed. Time required for each assessment was also evaluated. RESULTS: We found significant correlation between the GMFM for FCMD and the Ueda classification (r = 0.935); furthermore, the mean assessment time tended to decrease when using the GMFM for FCMD. CONCLUSIONS: GMFM for FCMD may be an appropriate motor function scale for patients with FCMD and might help decrease the assessment time.


Assuntos
Atividade Motora , Índice de Gravidade de Doença , Síndrome de Walker-Warburg , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino
10.
Brain Dev ; 41(1): 43-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30077507

RESUMO

BACKGROUND: The leading cause of death in patients with Fukuyama congenital muscular dystrophy (FCMD) is congestive heart failure or respiratory dysfunction, which is same as that in Duchenne muscular dystrophy (DMD). Recent studies reported that renal dysfunction is a common complication and an increasing cause of death in advanced DMD. It can be attributable to circulatory instability or inappropriate use of drugs for treating cardiac dysfunction. METHODS: We retrospectively evaluated renal function in 38 genetically diagnosed patients with FCMD (range, 1.3-32.9 years; mean age, 13.7 ±â€¯6.9 years) using cystatin C. We examined possible relationships of cystatin C with blood natriuretic peptide and creatinine levels along with cardiac echocardiography findings. RESULTS: Twenty-five patients were treated for cardiac dysfunction. Elevated cystatin C level was detected only in two, who also showed proteinuria, glycosuria, hematuria, and extremely high ß2-microglobulin levels on urine tests, and were thus diagnosed with renal tubular cell damage. Because both patients were treated for intractable epilepsy with various antiepileptic drugs, including valproic acid (VPA), and had low serum carnitine levels, renal tubular cell damage was considered as an adverse effect of VPA. Unlike patients with DMD, no patient with FCMD had renal dysfunction. Such a rare occurrence of renal dysfunction can be attributable to mild cardiac dysfunction, short disease duration, and careful and early fluid management. CONCLUSION: Renal dysfunction is rare in patients with FCMD; however, renal tubular cell damage should be ascertained, particularly in those undergoing VPA treatment for epilepsy.


Assuntos
Nefropatias/epidemiologia , Síndrome de Walker-Warburg/epidemiologia , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Biomarcadores/sangue , Criança , Pré-Escolar , Eletrocardiografia , Feminino , Humanos , Lactente , Nefropatias/diagnóstico por imagem , Nefropatias/fisiopatologia , Masculino , Síndrome de Walker-Warburg/diagnóstico por imagem , Síndrome de Walker-Warburg/tratamento farmacológico , Síndrome de Walker-Warburg/fisiopatologia , Adulto Jovem
11.
Neuromuscul Disord ; 28(10): 857-862, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30174172

RESUMO

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.


Assuntos
Caveolinas/genética , Imageamento por Ressonância Magnética , Músculo Esquelético/diagnóstico por imagem , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/genética , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Masculino
13.
Neuromuscul Disord ; 27(1): 45-49, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27818010

RESUMO

Fukuyama congenital muscular dystrophy (FCMD) is the second most common muscular dystrophy in Japan. FCMD is an autosomal recessive disorder caused by mutations in the fukutin gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities, and mental retardation associated with cortical migration defects, and most patients are never able to walk. To date, the development of a quantitative motor scale for FMCD has been difficult due to the moderate-to-severe intellectual impairment that accompanies FCMD. Gross motor function measure (GMFM), originally developed as a quantitative motor scale for cerebral palsy, can precisely and quantitatively assess motor function without complicated instructions, and was recently reported to be useful in the assessment of Down syndrome and spinal muscular atrophy. To confirm the validity of GMFM for the assessment of FCMD, 41 FCMD patients (age range: 0.6-24.4 years) were recruited for this study. The GMFM scores correlated significantly with those of two previously used motor scales, and the time-dependent change in GMFM scores was consistent with the natural course of FCMD. The inter-rater reliability, based on determinations made by four physiotherapists blinded to each other's assessment results, was excellent. We concluded GMFM to be a useful and valid measure of motor function in FCMD patients.


Assuntos
Transtornos dos Movimentos/diagnóstico , Índice de Gravidade de Doença , Síndrome de Walker-Warburg/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos dos Movimentos/etiologia , Reprodutibilidade dos Testes , Síndrome de Walker-Warburg/complicações , Adulto Jovem
14.
Brain Dev ; 38(3): 324-30, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26363734

RESUMO

BACKGROUND: Fukuyama congenital muscular dystrophy (FCMD), characterized by intellectual impairment associated with cortical migration defects, is an autosomal recessive disorder caused by mutation in the fukutin gene. It is the second most common type of muscular dystrophy in Japan. Respiratory dysfunction, along with cardiomyopathy, can be life-threatening in patients with advanced-stage FCMD. However, few reports have focused on this issue. METHODS: We retrospectively studied respiratory dysfunction and therapeutic management in 48 genetically diagnosed FCMD patients (mean age 11.0 years; range 3.6-31.9 years). RESULTS: Mechanical ventilation was initiated at a median age of 12.1 years in 16 patients, 14 of whom received non-invasive positive pressure ventilation (NPPV) while the other 2 underwent tracheostomy with invasive ventilation (TIV). The two TIV cases had unexpectedly required the initiation of ventilatory support at the ages of 15.7 and 18.0 years, respectively, because of unsuccessful extubation followed by serious respiratory infections, despite rather good respiratory function before these episodes. Patients carrying a compound heterozygous founder mutation or with a severe phenotype tended to need ventilatory support 2-3 years earlier than homozygous patients and those with the typical or mild phenotype. Mechanical insufflation-exsufflation (MI-E) interventions were also employed in six patients with serious dysphagia and were well-tolerated in all cases. CONCLUSION: For respiratory management, it is important to regularly evaluate respiratory function in FCMD patients over 10 years of age, since intellectual impairment and insomnia often mask the signs of respiratory dysfunction. Most patients, despite poor cooperation due to intellectual impairment, can tolerate NPPV and MI-E provided that a carefully worked-out plan is adopted.


Assuntos
Terapia Respiratória/métodos , Síndrome de Walker-Warburg/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Ventilação não Invasiva , Respiração Artificial , Estudos Retrospectivos , Adulto Jovem
15.
Brain Behav ; 3(4): 476-86, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24381816

RESUMO

The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM 1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM 1-mutations according to the "adjusted-age" at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM 1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.

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