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Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.
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KIF1A-related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long-term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long-term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow-up period was 30 years (4-44 years). This long-term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age-related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age-related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long-term follow-up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype-genotype correlation.
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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.
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Miastenia Gravis , Timectomía , Niño , Humanos , Masculino , Autoanticuerpos , Progresión de la Enfermedad , Glucocorticoides/uso terapéutico , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/cirugía , Rituximab , Resultado del TratamientoRESUMEN
Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.
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Paraplejía , Rizotomía , Humanos , Rizotomía/métodos , Femenino , Paraplejía/rehabilitación , Paraplejía/cirugía , Cuidados Posoperatorios , Preescolar , Resultado del Tratamiento , Variación GenéticaRESUMEN
Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. A few case reports have described hMPV encephalitis or encephalopathy. Neuroimaging data on patients with hMPV encephalitis are scarce. We report a patient with trisomy 13 who developed severe hMPV pneumonia, multifocal cerebral and cerebellar hemorrhagic infarctions and extensive cerebral white matter demyelination. Although adult respiratory distress syndrome and disseminated intravascular coagulation contributed to the devastating central nervous system (CNS) lesions, endothelial dysfunction of the CNS caused by hMPV infection probably also played a pathophysiological role in this case.
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Encefalitis , Metapneumovirus , Infecciones por Paramyxoviridae , Neumonía Viral , Infecciones del Sistema Respiratorio , Sustancia Blanca , Adulto , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/diagnóstico por imagen , Niño , Encefalitis/complicaciones , Humanos , Lactante , Infecciones por Paramyxoviridae/complicaciones , Neumonía Viral/complicaciones , Síndrome de la Trisomía 13/complicaciones , Sustancia Blanca/diagnóstico por imagenRESUMEN
Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.
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Ataxia Cerebelosa , Discapacidad Intelectual , Adenosina Trifosfatasas , Humanos , Discapacidad Intelectual/genética , Hipotonía Muscular , Náusea , Proteínas de Transferencia de Fosfolípidos , Hermanos , SíndromeRESUMEN
The tropomyosin-receptor kinase fused gene (TFG) has recently been implicated in several distinct hereditary disorders, including the autosomal-recessive form of complicated hereditary spastic paraplegia called SPG57. Previously, three homozygous variants of the TFG gene were reported in five families with SPG57, in which early onset spastic paraplegia, optic atrophy, and peripheral neuropathy were variably identified. Here, we present the first Japanese patient with SPG57, and have added a homozygous p.Ile66Thr variant as the fourth SPG57 genotype.
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Mutación , Paraplejía/genética , Polineuropatías/genética , Proteínas/genética , Corteza Sensoriomotora/patología , Adulto , Edad de Inicio , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Masculino , Paraplejía/patología , Linaje , Polineuropatías/patología , Corteza Sensoriomotora/metabolismoRESUMEN
The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.
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Secuencia de Aminoácidos , Displasia Ectodérmica/genética , Insuficiencia de Crecimiento/genética , Cardiopatías Congénitas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Eliminación de Secuencia , Preescolar , Displasia Ectodérmica/patología , Facies , Insuficiencia de Crecimiento/patología , Cardiopatías Congénitas/patología , Humanos , Leucina , Masculino , Índice de Severidad de la EnfermedadRESUMEN
Here we report a Japanese patient with new compound heterozygous truncating variants in the PCDH12 gene. As compared to the previously reported families who had congenital microcephaly, intrauterine growth retardation, intracranial calcification, and neonatal seizure associated with dysplasia of the midbrain-hypothalamus-optic tract, the present patient showed no midbrain-hypothalamus dysplasia or congenital/postnatal microcephaly, but dyskinetic cerebral palsy and severe intellectual disability as well as multifocal epilepsy. To understand phenotypic spectrum associated with PCDH12 variants, more reports are needed.
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Cadherinas/genética , Parálisis Cerebral/genética , Discinesias/genética , Epilepsia/genética , Adolescente , Anticonvulsivantes/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Parálisis Cerebral/diagnóstico por imagen , Discinesias/diagnóstico por imagen , Electroencefalografía , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Fenotipo , ProtocadherinasRESUMEN
Myosin-binding protein C1 (MYBPC1) encodes myosin-binding protein C, slow type (sMyBP-C), an accessory protein that regulates actomyosin cross-linking, stabilizes thick filaments, and modulates contractility in muscle sarcomeres and has recently been linked to myopathy with tremor. The clinical features of MYBPC1 mutations manifesting in early childhood bear some similarities to those of spinal muscular atrophy (SMA), such as hypotonia, involuntary movement of the tongue and limbs, and delayed motor development. The development of novel therapies for SMA has necessitated the importance of differentiating SMA from other diseases in the early infancy period. We report the characteristic tongue movements of MYBPC1 mutations, along with other clinical findings, such as positive deep tendon reflexes and normal peripheral nerve conduction velocity testing, which could help in considering other diseases as differential diagnoses.
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Atrofia Muscular Espinal , Temblor , Preescolar , Humanos , Mutación/genética , Lengua/metabolismoRESUMEN
Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype-genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.
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Artrogriposis , Epilepsias Mioclónicas , Síndromes Epilépticos , Trastornos del Movimiento , Femenino , Humanos , Artrogriposis/genética , Epilepsias Mioclónicas/genética , Mutación Missense , Trastornos del Movimiento/genética , Fenotipo , Canal de Sodio Activado por Voltaje NAV1.1/genética , MutaciónRESUMEN
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating disease of the peripheral nervous system with unknown etiology. Alopecia universalis, an advanced form of alopecia areata (AA), is a condition characterized by complete hair loss. Here we report the first case of childhood CIDP associated with AA who was successfully treated with a combination of intravenous immunoglobulin (IVIg) and corticosteroids. CASE REPORT: This case describes a nine-year-old Japanese girl who developed alopecia, progressive muscle weakness, and eventually loss of walking ability (at ages 2, 4, and 7, respectively). She was treated with IVIg and prednisolone combination therapy, which improved muscle weakness and alopecia. She was positive for serum IgG-GM2 type anti-glycolipid antibodies, which may be associated with this rare combination of diseases.
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Alopecia Areata , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Femenino , Humanos , Niño , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Debilidad Muscular , Alopecia/complicaciones , Alopecia/tratamiento farmacológico , Alopecia Areata/complicacionesRESUMEN
BACKGROUND: Pyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that causes lactic acidosis and neurodevelopmental changes. Five causative genes have been identified: PDHA1, PDHB, DLAT, DLD, and PDHX. Four neurological phenotypes have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome, and relapsing ataxia. Of these, neonatal encephalopathy has the worst mortality and morbidity and there is no effective treatment. SUBJECTS AND METHODS: We studied two girls who were clinically diagnosed with PDHC deficiency as neonates; they were subsequently found to have PDHA1 mutations. The clinical diagnosis was based on white matter loss and a lateral ventricular septum on fetal MRI, spasticity of the lower extremities, and lactic acidosis worsening after birth. Intravenous ketogenic diets were started within 24 h after birth. The ketogenic ratio was increased until the blood lactate level was controlled, while monitoring for side effects. RESULTS: In both cases, the lactic acidosis improved immediately with no apparent side effects. Both children had better developmental outcomes than previously reported cases; neither exhibited epilepsy. CONCLUSIONS: Intravenous ketogenic diet therapy is a treatment option for neonatal-onset PDHC deficiency. Further studies are needed to optimize this therapy.
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Dieta Cetogénica , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/dietoterapia , Femenino , Humanos , Lactante , Recién Nacido , Nutrición ParenteralRESUMEN
INTRODUCTION: Early disease control with disease-modifying drugs is important for improving the prognosis of multiple sclerosis (MS) in children. Dimethyl fumarate (DMF) is an oral disease-modifying drug for MS in adults with relatively stable disease; however, its use in young children has not been heavily documented in the current literature. We report the case of a pediatric patient with relapsing-remitting MS who was treated with DMF. CASE REPORT: A 3-year-old boy with a history of common cold symptoms developed unsteadiness and somnolence. Magnetic resonance imaging revealed multiple white matter lesions. Symptoms were recurrent, and DMF was prescribed at 6 years of age due to a relapse episode with oculomotor disability and facial paralysis. However, disease progression continued, and new lesions were noted at age 7; thus, the dose of DMF was increased to 240 mg/day. No relapse has been observed for over three years; sequelae or severe side effects were absent. CONCLUSIONS: DMF may be a useful oral disease-modifying drug for preventing recurrence in young children with MS.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Adulto , Niño , Preescolar , Dimetilfumarato/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inducido químicamente , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
OBJECTIVE: To describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A. METHODS: Clinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient. RESULTS: The patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A, which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA. CONCLUSION: The dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype.
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ATPasas Transportadoras de Cobre/genética , Atrofias Musculares Espinales de la Infancia/diagnóstico , Atrofias Musculares Espinales de la Infancia/genética , Adulto , Humanos , Masculino , Atrofias Musculares Espinales de la Infancia/patología , Atrofias Musculares Espinales de la Infancia/fisiopatologíaRESUMEN
People with severe motor and intellectual disabilities syndrome (SMIDS) have multiple comorbidities and high mortality rates. This study examined whether there is a difference in the efficacy and tolerability of perampanel (PER) between patients with drug-resistant epilepsy with or without SMIDS. The study identified 65 patients with drug-resistant epilepsy who underwent PER treatment as adjunctive therapy. The 50 % responder rate was 22 % (14/65) overall and 11 % (5/44) in patients with SMIDS versus 43 % (9/21) in patients without SMIDS (p <0.01). Although the overall 50 % responder rate was similar to those of previous reports, PER was less efficacious in the patients with SMIDS; nevertheless, PER was tolerated in the patients with SMIDS.
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Epilepsia Refractaria , Discapacidad Intelectual , Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/tratamiento farmacológico , Japón , Nitrilos , Piridonas/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The coexistence of falcine and occipital sinuses is rare and its natural course has not been reported. CASE REPORTS: Two patients with persistent falcine and occipital sinuses are described. Both patients had straight sinuses. In one, both the transverse and sigmoid sinuses were hypoplastic and the patient had an acquired Chiari I malformation. The other patient had no other venous anomalies and had a normal posterior cranial fossa. CONCLUSION: The coexistence of falcine and occipital sinuses can lead to an acquired Chiari I malformation. These cases suggest the importance of checking other venous and brain anomalies in this situation.
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Senos Craneales/anomalías , Duramadre/anomalías , Lóbulo Occipital/anomalías , Adolescente , Malformación de Arnold-Chiari/fisiopatología , Humanos , Lactante , Japón , MasculinoRESUMEN
BACKGROUND: The clinical severity of Sandhoff disease is known to vary widely. Furthermore, long-term follow-up report is very limited in the literature. CASE PRESENTATION: We present a long-term follow-up report of a patient with juvenile-onset Sandhoff disease with a motor neuron disease phenotype. The patient had compound heterozygous variants of HEXB (p.Trp460Arg, p. Arg533His); the Trp460Arg was a novel variant. Long-term follow-up revealed no intellectual deterioration, swallowing dysfunction, or respiratory muscle dysfunction despite progressive weakness of the extremities and sensory disturbances. CONCLUSION: We need to be aware of Sandhoff disease in patients with juvenile-onset motor neuron disease.
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Enfermedad de la Neurona Motora/etiología , Enfermedad de Sandhoff/genética , Adulto , Edad de Inicio , Estudios de Seguimiento , Humanos , Fenotipo , Enfermedad de Sandhoff/complicacionesRESUMEN
BACKGROUND: Generalized epilepsy and tremor phenotypes have been reported in some genetic disorders. Among them benign adult familial myoclonus epilepsy (BAFME) has been confirmed as a clearly defined clinical and genetic entity. On the other hand, non-progressive tremor and generalized epilepsy phenotypes have also been reported in patients with DHDDS variants. CASE PRESENTATION: We report on a long term follow-up of patient with de novo missense variant of DHDDS, who revealed non progressive nature. This 18-year-old woman presented non-progressive tremor since her early infancy. She had rare seizures. Her tremor was considered as cortical myoclonic tremor with giant somatosensory evoked potentials. CONCLUSION: In patients with early onset, non-progressive tremor and rare generalized epilepsy phenotypes, DHDDS variants may be considered in the genetic differential diagnosis.
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Transferasas Alquil y Aril/genética , Epilepsias Mioclónicas/genética , Epilepsia Generalizada/genética , Adulto , Transferasas Alquil y Aril/metabolismo , Electroencefalografía , Epilepsias Mioclónicas/fisiopatología , Epilepsia Generalizada/fisiopatología , Potenciales Evocados Somatosensoriales/fisiología , Femenino , Estudios de Seguimiento , Humanos , Japón , Mutación Missense/genética , Linaje , FenotipoRESUMEN
Mutations in methyl-CpG-binding protein 2 (MECP2) in males can lead to various phenotypes, ranging from neonatal encephalopathy to intellectual disability. In this study, using Nord's method of next-generation sequencing in three siblings, we identified a 0.6â¯kb deletion involving the transcriptional repression domain (TRD). Two males and one female had intellectual disability and apnea, but none met the criteria of Rett syndrome. Both males had sick sinus syndrome and severe tracheomalacia that resulted in early death. The mother, with skewed X-inactivation, had no symptoms. Therefore, this mutation is pathological for both males and females, resulting in sick sinus syndrome and severe tracheomalacia with strong reproducibility in males. Deletions involving major domains in MECP2 can result in a severe phenotype, and deletion of the TRD domain can cause severe autonomic nervous system dysregulation in males in these cases.