Makiko Osawa

An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7–1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micro-polygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31 (refs 2–4). We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3′ untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

Congenital progressive muscular dystrophy of the Fukuyama type - clinical, genetic and pathological considerations.

The Fukuyama type congenital muscular dystrophy (FCMD), which was firstly described by one of the authors in 1960, is now recognized as an independent subtype of progressive muscular dystrophy in Japan. Recent advances in clinical, pathological and etiological studies of this syndrome were extensively reviewed. A long-term observation on a large number of cases revealed a wide spectrum of clinical features and courses, and comprehensive laboratory examinations including cranial computed tomography disclosed several new findings. A sharp dichotomy exists in the study of etiology; the genetic or intrauterine infection theories, with reasonable grounds for each. The most conspicuous is the fact that FCMD had been seldom described in countries other than Japan. If attention and interest on FCMD expand in a worldwide scale, the elucidation of basic pathogenesis of this disorder will be facilitated rapidly.

Mutations in EFHC1 cause juvenile myoclonic epilepsy

Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures. We previously mapped and narrowed a region associated with JME on chromosome 6p12–p11 (EJM1). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca2+ channel (Cav2.3). EFHC1 and Cav2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Cav2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca2+ currents that were reversed by the mutations associated with JME.

Long-Term Outcomes of Pediatric Moyamoya Disease Monitored to Adulthood

The long-term outcomes of 25 patients with childhood moyamoya disease (18 with the transient ischemic attack [TIA] type and seven with the non-TIA type), who were monitored to adulthood (older than 20 years of age), were evaluated in terms of residual clinical symptoms, intellectual development, and activities of daily living. Surgical treatment was performed in ten patients, encephaloduroarteriosynangiosis in nine, and superficial temporal artery to middle cerebral artery anastomosis plus encephalomyosynangiosis in one. Only seven with the TIA type (three surgically and four medically treated) demonstrated good activities of daily living without TIA or headache and normal IQ. Two patients with the TIA type and three with the non-TIA type demonstrated poor outcomes. Three of these patients with poor outcomes had renal artery stenosis. Surgery was effective in nine. Since the long-term outcomes of patients with childhood moyamoya disease are generally poor, surgical treatment is believed to be an effective procedure for preventing the progression of clinical symptoms.

Severe myoclonic epilepsy in infants – a review based on the Tokyo Women's Medical University series of 84 cases

Severe myoclonic epilepsy in infants (SME) is one of the most malignant epileptic syndromes recognized in the latest classification of epileptic syndromes. The clinical details and electroencephalographic (EEG) characteristics have been elucidated by Dravet et al. The diagnosis of SME depends largely on the combination of clinical and EEG manifestations at different ages, of which the presence of myoclonic seizures appears to be the most important. However, because of the inclusion of different types of myoclonic attack and the lack of strict criteria for diagnosing SME, there has been some confusion as to whether patients without myoclonic seizures or myoclonus should be classified as SME, despite other identical clinical symptoms (SME borderlands (SMEB) group). Among the various clinical manifestations characterizing SME, special attention has been paid to seizures easily precipitated by fever and hot baths in Japan. We have demonstrated that the onset of myoclonic attack in these patients is very sensitive to the elevation of body temperature itself rather than its etiology. Using simultaneous EEG and rectal temperature monitoring during hot water immersion, we showed that epileptic discharges increased in frequency, and eventually developed into seizures at temperatures over 38 degrees C. We believe that the unique fever sensitivity observed in SME is similar to, but more intense than that of febrile convulsions. We have also identified a group of cases who have had innumerous myoclonic and atypical absence seizures daily which were sensitive to the constant bright light illumination. In these cases, spike discharges increased or decreased depending on the intensity of constant light illumination. Although these cases form the most resistant SME group, they lost the constant light sensitivity with increasing age, leaving only relatively common types of fever-sensitive grand mal seizures (FSGM) at the age of around 5 years. In the long run, only convulsive seizures continue, while myoclonic or absence seizures and photosensitivity disappear with advancing age, thus it is conceivable that SMEB constitutes a basic epileptic condition underlying SME. There is a clinical continuum that extends from the mildest end of SMEB to the severest end of SME with constant light sensitivity, with intermediates of frequent or infrequent myoclonic and absence seizures in-between. This spectrum concept appropriately explains the clinical variabilities between SME and SMEB during early childhood.

Study on the Early-Onset Variant of Benign Childhood Epilepsy with Occipital Paroxysms Otherwise Described as Early-Onset Benign Occipital Seizure Susceptibility Syndrome

Summary: Purpose: We studied the early‐onset variant of benign childhood epilepsy with occipital paroxysms (EVBCEOP) proposed by Panayiotopoulos, to confirm whether his five criteria are sufficient to delineate EVBCEOP as a new epileptic syndrome, as well as to predict a good outcome prospectively at the time of the first examination.

Long‐Term Prognosis of Lennox‐Gastaut Syndrome

Summary: We investigated the long‐term prognosis of Lennox‐Gastaut syndrome (LGS) in 72 patients followed up for >10 years. Long‐term seizure and intellectual outcomes were poor, as previously reported. The diagnosis of LGS was first made in the age range from 2 to 15 years with peak occurrence at 5 years. Progressive IQ score deterioration with age was apparent. At the last examination, 33% of patients with cryptogenic and 55% with symptomatic LGS had lost the characteristics of LGS, and their seizure disorders were classifiable as symptomatic generalized epilepsies, severe epilepsy with multiple independent spike foci, or localization‐related epilepsies. Disabling drop attacks appeared in 46% of patients and tended to occur at older than 10 years. Gait deterioration was recognized in 12 patients and seemed to be due largely to, progression of the epileptic encephalopathy. The gait disturbances, as well as increased frequency of violent drop attacks, were disabling in daily life and resulted in some patients being wheelchair bound.

STXBP1 mutations cause not only Ohtahara syndrome but also West syndrome—Result of Japanese cohort study

We performed STXBP1 mutation analyses in 86 patients with various types of epilepsies, including 10 patients with OS, 43 with West syndrome, 2 with Lennox‐Gastaut syndrome, 12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 5 with other undetermined types of epilepsy. In all patients, the etiology was unknown, but ARX and CDKL5 mutations were negative in all cases. All coding exons of STXBP1 were analyzed by direct‐sequencing. Two de novo nucleotide alterations of STXBP1 were identified in two patients with Ohtahara and West syndrome, respectively. No de novo or deleterious mutations in STXBP1 were found in the remaining 84 patients with various types of symptomatic epilepsies. This is the first case report showing that STXBP1 mutations caused West syndrome from the onset of epilepsy. STXBP1 analysis should be considered as an etiology of symptomatic West syndrome without explainable cause.

Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy

Background: Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in 20% of Hispanic families with JME. Objective: To examine what percentage of consecutive JME clinic cases have mutations in Myoclonin1/EFHC1. Methods: We screened 44 consecutive patients from Mexico and Honduras and 67 patients from Japan using heteroduplex analysis and direct sequencing. Results: We found five novel mutations in transcripts A and B of Myoclonin1/EFHC1. Two novel heterozygous missense mutations (c.755C>A and c.1523C>G) in transcript A occurred in both a singleton from Mexico and another singleton from Japan. A deletion/frameshift (C.789del.AV264fsx280) in transcript B was present in a mother and daughter from Mexico. A nonsense mutation (c.829C>T) in transcript B segregated in four clinically and seven epileptiform-EEG affected members of a large Honduran family. The same nonsense mutation (c.829C>T) occurred as a de novo mutation in a sporadic case. Finally, we found a three-base deletion (−364○%–362del.GAT) in the promoter region in a family from Japan. Conclusion: Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Honduras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1. These results represent the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group. GLOSSARY: CAE = childhood absence epilepsy; FS = febrile seizures in infancy/childhood; GM = grand mal tonic clonic seizure; JME = Juvenile myoclonic epilepsy; PSW = 3–6 Hz polyspike and slow wave complexes; SW = single spike and slow wave complex.

A comparative study of high-dose and low-dose ACTH therapy for West syndrome

PURPOSE A prospective randomized controlled study was conducted for the purpose of identifying the lowest effective ACTH dose, with the fewest adverse effects, for the treatment of West syndrome (WS). SUBJECTS AND METHODS Twenty-five subjects with cryptogenic (CWS, n = 9) or symptomatic (SWS, n = 16) WS were enrolled in this study. They were randomly assigned to receive either low-dose (0.005 mg/kg per day = 0.2 IU/kg per day) or high-dose (0.025 mg/kg per day = 1 IU/kg per day) synthetic ACTH therapy. ACTH was administered every morning for 2 weeks and tapered to zero over the subsequent 2 weeks. Both effectiveness and adverse effects were compared between the two treatment regimens in each type of WS. RESULT After completion of the treatment protocol in the CWS group, spasms and hypsarrhythmia were completely suppressed in 3/4 (75%) given the low-dose and 5/5 (100%) given the high-dose treatment. In the SWS group, the spasms and hypsarrhythmia disappeared in 6/8 (75%) in each dose group. There were no significant differences in initial responses between the low-dose and high-dose treatments for either type of WS (P > 0.05). Long-term seizure and developmental outcomes, assessed in the 17 responders who were followed up for longer than 1 year after the completion of ACTH therapy, were also essentially the same. We did not recognize differences in side effect profiles between the two treatment regimens with the exceptions of sleepiness and brain shrinkage estimated by CT scan, both of which were significantly milder in the low-dose than in the high-dose group (P < 0.05). CONCLUSION Unexpectedly, this prospective randomized controlled study demonstrated the dose of ACTH required for spasm cessation and disappearance of the hypsarrhythmic EEG pattern to be lower than previously believed. A low-dose regimen should thus be considered for CWS, and for SWS associated with significant cerebral atrophy.