Microdeletion in Xq28 with a polymorphic inversion in a patient with FLNA-associated progressive lung disease.

Lung phenotype was reported as a novel phenotype in patients with mutations in the filamin A gene (FLNA) in 2011. FLNA mutations can result in pulmonary hyperinflation during the neonatal period or early infancy with progressive respiratory failure, culminating in a diagnosis of FLNA-associated progressive lung disease, particularly if the patient has periventricular nodular heterotopia and cardiac complications, such as patent ductus arteriosus, atrial septal defect, and pulmonary hypertension. We report the first Japanese case of FLNA-associated progressive lung disease caused by a microdeletion in Xq28 encompassing the FLNA gene with a polymorphic inversion.

Mandibulofacial dysostosis with microcephaly: A case presenting with seizures.

We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.

A recurrent KCNT1 mutation in two sporadic cases with malignant migrating partial seizures in infancy.

We performed analysis of KCNT1 in two unrelated patients with malignant migrating partial seizures in infancy. Both patients had intractable focal seizures since two months of age. Their seizures were characterized by a shift of epileptic focus during a single seizure and were resistant to most antiepileptic drugs but responded to vagus nerve stimulation in one and clorazepate in the other. Bidirectional sequencing for KCNT1 was analyzed by standard Sanger sequencing method. A de novo c.862G>A (p.Gly288Ser) missense mutation was identified at the pore region of KCNT1 channel in both patients, whereas all KCNT1 mutations in the previous reports were identified mostly in the intracellular C-terminal region. Computational analysis suggested possible changes in the molecular structure and the ion channel property induced by the Gly288Ser mutation. Because the G-to-A transition was located at CG dinucleotide sequences as previously reported for KCNT1 mutations, the recurrent occurrence of de novo KCNT1 mutations indicated the hot spots of these locations.

PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy.

Abnormalities in the protocadherin 19 (PCDH19) gene cause early-onset epilepsy exclusively in females. We aimed to explore the genetic and clinical characteristics of PCDH19-related epilepsy by focusing on its early features and treatment efficacy. PCDH19 was analyzed in 159 Japanese female patients with early-onset epilepsy via direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis. We identified 17 patients with PCDH19 abnormalities: point mutations were observed in 14 patients and whole PCDH19 deletions were detected in 3 patients. One affected sister of a proband with a mild phenotype was also analyzed. The frequency of PCDH19 deletion among all probands identified in Japan was 12.5% (3/24, including 7 probands reported previously by us). Clinical features included early onset (mean age at onset, 8.6 months), recurrent clusters of brief seizures (17/18), fever sensitivity (18/18), tonic seizures (13/18, probably including focal tonic seizures), tonic-clonic seizures (8/18), focal seizures often with subsequent generalization (17/18), intellectual disabilities (15/18), and autistic traits (13/18). Three patients exhibited delay in motor milestones before seizure onset. In 16 patients, seizures appeared in clusters from the onset of the disease. Among 6 patients for whom detailed information at onset was available, 2 onset patterns were identified: a biphasic course of short seizure clusters (each within days) in 2 patients and a prolonged course of clusters (from weeks to a month) in 4 patients. In both cases, initial seizures started during fever and transiently disappeared with the decline of fever; however, afebrile clusters recurred. In the former patients, motor development was delayed before onset, and seizures appeared in strong clusters from the onset of the disease. In the latter patients, initial development was normal and initial seizures were mild, but were followed by strong clusters lasting several weeks, even without fever. Treatment using phenytoin, potassium bromide, and clobazam showed high efficacy. Although focal seizures were the main feature in PCDH19-epilepsy, the efficacy of carbamazepine was poor. This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs. Our data will facilitate early diagnosis and development of a treatment strategy for better clinical management of patients with PCDH19-related epilepsy.

An electroclinical study of absence seizures in Dravet syndrome.

We studied clinical and EEG manifestations of absence seizures (AS) in children with Dravet syndrome (DS) to clarify their characteristic features and differences from those of typical AS (TAS). The subjects were 12 children with DS. We retrospectively analyzed electroclinical characteristics of AS. We analyzed a total of 102 ictal EEGs characterized by generalized spike-and-wave (GSW) and semiology of 78 video-taped AS. The mean age at the onset of AS and at the time of the study was 16.2±7.1 months and 40.3±22.1 months, respectively. Ictal EEG showed the focality of initial discharge in 49/102 (48%), a duration ranging from 2 to 180 s (mean: 10.2±22.6 s; median: 4.0 s), frequency ranging from 2 to 4 Hz (median=3.0 Hz), and irregular and disorganized GSW morphology in 66/102 (65%). AS manifested with eyelid-myoclonus and generalized myoclonus in 9/54 (17%) and 34/78 (44%), respectively. In conclusion, AS in DS were characterized by an early-onset age, a high incidence of irregular and disorganized 3 Hz GSW morphology, and the frequent association of generalized myoclonic movement as well as the absence of automatism as compared to TAS. The results should be appreciated in the differential diagnosis of early-onset AS, the treatment of AS in DS and also a further clinical and genetic study for DS.

Severe muscle damage following viral infection in patients with Fukuyama congenital muscular dystrophy.

Fukuyama congenital muscular dystrophy (FCMD), which is characterized by cortical migration defect and eye abnormalities, is the most common subtype of CMD in Japan. Fukutin (FKTN), the responsible gene for FCMD, encodes a protein involved in the glycosylation of alpha-dystroglycan. We have experienced some patients with FCMD who showed sudden exacerbation of muscle weakness with marked elevation of serum creatine kinase (CK) and urinary myoglobin levels a few days after a febrile episode of viral infection, occasionally leading to death. To describe this peculiar phenomenon, we focused on 12 patients who developed a sudden exacerbation of muscle weakness among 96 genetically defined FCMD patients and hospitalized because of a febrile illness at Tokyo Women's Medical University between 1997 and 2008. All the 12 patients were homozygous for a 3-kb insertion mutation of FKTN. The patients developed exacerbation of muscle weakness ranging from paralysis to loss of head control. The onset was concentrated in summer, and coxsackieviruses and enteroviruses were most often detected, especially in infantile patients. Eight of the 12 patients were treated with corticosteroids and recovered within 2 weeks. Four patients were treated without steroid, and needed 18.5 days on mean for improvement. None developed renal failure. The reason for muscle damage induced by viral infection remains unknown; however, physicians should consider its risk, sometimes leading to death, and draw it to parents' attention, especially in the defervescent stage.

PCDH19 mutation in Japanese females with epilepsy.

PURPOSE: To determine the significance of PCDH19 mutations in Japanese females with epilepsy and to delineate their phenotypes. METHODS: PCDH19 sequencing analysis was performed in 116 females with various epilepsies, including 97 with Dravet syndrome (83.6%). They were referred for SCN1A analysis, and 52 carried SCN1A mutations. RESULTS: Seven heterozygous mutations in exon 1 were identified in 7 patients (6.0%): 2 frameshift, 2 nonsense, and 3 missense mutations. One patient was a monozygotic twin, and her sister with mild phenotype carried the same mutation. The main clinical features among these 8 patients included early seizure onset (≤25 months of age), seizure clusters (7/8), fever-associated seizures (7/8), single seizure type (6/8), and late deterioration of intellect (5/8). Seizure durations were generally up to a few minutes, and only one patient developed status epilepticus once. The main seizure types were generalized tonic-clonic (4/8), tonic (3/8) and focal seizures, with (2/8) or without secondary generalization (3/8). Myoclonic, atonic and absence seizures were extremely rare. Two patients had Dravet syndrome (25%), and this proportion was significantly smaller than that in the total subjects (p<0.01). CONCLUSION: PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. Dravet syndrome was rare in our cohort.

Retrospective multiinstitutional study of the prevalence of early death in Dravet syndrome.

PURPOSE: A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. METHODS: A questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and their prevalence of early death. KEY FINDINGS: Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome died. Data from 59 of these patients were analyzed. The patients' ages at death ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The analysis showed that the risk of mortality remained high up to approximately 12 years of age. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and acute hepatopathy in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and reached a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a sharp peak at 6 years of age. Seven of 10 patients who underwent an SCN1A mutation analysis exhibited positive mutations without a specific mutation site. SIGNIFICANCE: In the present study, the prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was the highest in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. After approximately 12 years of age, the risk of mortality declined sharply. Neither the treatment nor the number of seizures was associated with any cause of mortality. In addition, it is difficult to predict which factors lead to a fatal outcome.

Mortality in Dravet syndrome: search for risk factors in Japanese patients.

A questionnaire survey was conducted in Japan to investigate the causes and prevalence of death related to Dravet syndrome. The questionnaire was delivered to 246 hospitals at which physicians were treating childhood epilepsy to gain information about the total number of patients with Dravet syndrome and the prevalence of early death due to the disorder. Responses to the survey were collected from 91 hospitals, and a total of 63 of 623 patients with Dravet syndrome had died. Data from 59 of these patients were analyzed. The age at death for these patients ranged from 13 months to 24 years and 11 months, with a median age of 6 years and 8 months. The causes of mortality included sudden death in 31 patients (53%), acute encephalopathy with status epilepticus (SE) in 21 patients (36%), drowning in 6 patients (10%), and other causes in one patient (1%). The incidence of sudden death reached a first peak at 1-3 years of age and a second peak at 18 years and older. In contrast, the incidence of acute encephalopathy with SE reached a peak at 6 years of age. Seven of the 10 patients who underwent SCN1A mutation analysis exhibited positive mutations but exhibited no consistent phenotype. The prevalence of Dravet syndrome-related mortality was 10.1%. The incidence of sudden death and acute encephalopathy with SE was higher in infancy (1-3 years) and at early school ages (with a peak at 6 years), respectively. Neither the treatment nor the number of seizures was associated with any cause of mortality. Factors leading to a fatal outcome are difficult to predict.

High-dose chemotherapy followed by autologous and allogeneic peripheral blood stem cell transplantation for recurrent disseminated trilateral retinoblastoma.

INTRODUCTION: Trilateral retinoblastoma (TRb) is an intracranial neurogenic tumor associated with unilateral or bilateral retinoblastoma and has very poor prognosis. Patients typically die from leptomeningeal tumor dissemination. CASE REPORT: A 3-year-old girl who had been diagnosed with TRb had a disseminated relapse after a tumorectomy, cerebrospinal irradiation, and conventional chemotherapy. The disseminated tumor disappeared after the first autologous peripheral blood stem cell transplantation (PBSCT) with high-dose melphalan and thiotepa. During the second complete remission, a second autologous PBSCT with high-dose busulfan and melphalan was performed. Seven months after the first PBSCT, the second relapse occurred, and we subsequently performed an allogeneic PBSCT with myeloablative chemotherapy consisting of melphalan, thiotepa, and cyclophosphamide. The patient showed clinical improvement after the allogeneic PBSCT. CONCLUSION: Although high-dose chemotherapies have a curative effect for some patients with TRb, the prognoses of disseminated tumors are still poor. Further examination of the high-dose chemotherapy is necessary for the time, the conditioning drugs, and the hematopoietic stem cell sources.

Double high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation for primary disseminated medulloblastoma: a report of 3 cases.

We performed double high-dose chemotherapy followed by peripheral blood stem cell transplantation (PBSCT) in 3 children with medulloblastoma and primary leptomeningial dissemination, including spinal metastasis. After resection of the main tumor mass, 30.6 Gy whole craniospinal radiation therapy and 4 or 5 courses of conventional chemotherapy with vincristine (1.5 mg/m), carboplatin (560 mg/m), ifosfamide (9000 mg/m), and etoposide (500 mg/m), and 2 courses of high-dose thiotepa (680 mg/m) and melphalan (240 mg/m) therapy with PBSCT were administered. Two patients with low erythroblastic leukemia viral oncogene homolog 2 (ERBB2) gene expression achieved long-term survival (41 mo and 40 mo) but the patient with high ERBB2 expression relapsed 9 months after the second PBSCT.

Cardiac involvement in Fukuyama-type congenital muscular dystrophy.

BACKGROUND: Fukuyama-type congenital muscular dystrophy is an autosomal recessive disorder characterized by generalized skeletal muscle weakness and hypotonia from early infancy and by mental retardation. Little is known about cardiac involvement in patients with Fukuyama-type congenital muscular dystrophy. This study evaluated whether cardiac involvement exists in patients with Fukuyama-type congenital muscular dystrophy. METHODS AND RESULTS: We evaluated left ventricular function using M-mode and Doppler echocardiography in 34 patients with Fukuyama-type congenital muscular dystrophy. The age ranged from 6 months to 30 years (median: 6 years). A total of 64 recordings were analyzed. Left ventricular dimensions and parameters of systolic function measured included left ventricular end-diastolic dimension, left ventricular fractional shortening, left ventricular wall thickness, and the mean velocity of circumferential fiber shortening and end-systolic wall stress relationship. Left ventricular end-diastolic dimension z score >2 was observed in 2 patients (6%). Left ventricular fractional shortening <0.28 and/or reduced mean velocity of circumferential fiber shortening in the mean velocity of circumferential fiber shortening-end-systolic wall stress relationship were observed in 16 patients (47%). A significant correlation between age and left ventricular fractional shortening was observed, and left ventricular fractional shortening decreased with age. Of 12 patients >15 years of age, 10 (83%) showed decreased left ventricular systolic function. Left ventricular fractional shortening was normal in most patients <10 years of age, and it was reduced in most patients >15 years of age. Five patients died of heart failure or respiratory problems, and a histologic examination confirmed the presence of myocardial fibrosis. No patients showed increased left ventricular wall thickness or a conduction abnormality on electrocardiograms. CONCLUSION: Cardiac involvement exists in patients with Fukuyama-type congenital muscular dystrophy and becomes evident in older children in the second decade. A cardiac evaluation, including echocardiograms and subsequent follow-up, is important, especially in patients >10 years of age.