Early infancy-onset stimulation-induced myoclonic seizures in three siblings with inherited glycosylphosphatidylinositol (GPI) anchor deficiency.

Inherited glycosylphosphatidylinositol anchor deficiency causes a variety of clinical symptoms, including epilepsy, however, little information is available regarding seizures as a symptom. We report three siblings with inherited glycosylphosphatidylinositol anchor deficiency with PIGL gene mutations. The phenotypes of the subjects were not consistent with CHIME syndrome or Mabry syndrome, as reported in previous studies. All shared some clinical manifestations, including transient apnoea as neonates, dysmorphic facial features, and intellectual disability. Between one week and 3 months of life, all patients developed myoclonic seizures. Myoclonic jerks were easily evoked by sudden unexpected acoustic or tactile stimuli. None showed elevation of serum alkaline phosphatase. Vitamin B6 was given to one of the three siblings, but failed to suppress seizures. The presence of early infancy-onset stimulation-induced myoclonic seizures combined with dysmorphic facial features should lead physicians to consider the possibility of inherited glycosylphosphatidylinositol anchor deficiency.

Acute Bilateral Photoreceptor Degeneration in an Infant After Vaccination Against Measles and Rubella.

Importance: Ocular inflammation is occasionally observed after vaccinations, and most of them resolve without permanent visual disturbances. However, there are some rare cases of severe ocular complications following vaccinations. Objective: To report the findings in an infant boy who developed an acute loss of vision bilaterally after Haemophilus influenzae type b, Pneumococcal conjugate vaccination, and measles and rubella vaccination. His vision did not recover. Design, Setting, and Participant: A retrospective review of the medical records of a 13-month-old Japanese boy. Main Outcomes and Measures: Fundus and fluorescein angiographic findings, ultrasonographic and optical coherence tomographic images, and electroretinographic findings. Results: A healthy 13-month-old boy had an acute loss of vision in both eyes 31 days after Haemophilus influenzae type b and Pneumococcal conjugate vaccinations and 24 days after a measles and rubella vaccination. He also developed a common cold 10 days before the vision loss. Ultrasonography showed an exudative retinal detachment 1 day after the onset of the visual reduction; however, his fundi appeared normal 4 days later. His eyes did not pursue objects, and pupillary light reflexes were not present. No signs of anterior uveitis were noted. He was treated with corticosteroids, but his vision did not improve. The retinal vessels gradually attenuated, and diffuse small white punctate lesions appeared in the deep retina. Optical coherence tomography showed a thinner outer nuclear layer and an absent ellipsoid zone. The electroretinograms were nonrecordable. These findings suggested a severe impairment of the photoreceptors, especially their outer segments. Western blot analysis of the patient's sera detected an antibody against recoverin, a calcium-binding protein of photoreceptors. Conclusions and Relevance: We hypothesize that an infection induced severe chorioretinitis with an exudative retinal detachment, which then produced an autoantibody against recoverin. The autoantibody then altered the function of the photoreceptors very rapidly. The initial infection may have been caused by the measles and rubella vaccination. However, because to our knowledge this has not been reported previously, the visual loss after the vaccinations may have been an extremely rare event that was coincidental or may have been related to the vaccination.

Neurological manifestations of 2q31 microdeletion syndrome.

Microdeletion of 2q31 involving the HOXD gene cluster is a rare syndrome. The deletion of the HOXD gene cluster is thought to result in skeletal anomalies in these patients. HOX genes encode highly conserved transcription factors that control cell fate and the regional identities along the primary body and limb axes. We experienced a new patient with 2q31 microdeletion encompassing the HOXD gene cluster and some neighboring genes including the ZNF385B. The patient showed digital anomalies, growth failure, epileptic seizures, and intellectual disability. Magnetic resonance imaging showed delayed myelination and low signal intensity in the basal ganglia. The ZNF385B is a zinc finger protein expressed in brain. Disruption of ZNF385B was suspected to be responsible for the neurological features of this syndrome.

Quinidine therapy for West syndrome with KCNTI mutation: A case report.

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.

Clinical characteristics of seizures associated with viral gastroenteritis in children.

OBJECTIVE: We analyzed the clinical features of seizures during gastroenteritis in children by comparing the norovirus and rotavirus pathogen, and the impact of fever, if present, during the seizure episodes. METHODS: Retrospective analysis was performed on 293 consecutive pediatric patients admitted with viral gastroenteritis to Osaka General Hospital between November 2007 and May 2009. Eighteen patients developed seizures, 12 of whom were positive for norovirus and six for rotavirus, as revealed by antigen detection. Of these 18 seizure patients, eight presented without fever (the aFS group) and 10 presented with febrile episodes (FS group). RESULTS: Seizure patients in the rotavirus group (83%) were more likely to be febrile than those in the norovirus group (58%). Compared with the aFS group, 90% of patients in the FS group presented seizures at an early stage of gastroenteritis. The frequency of clustered seizures in the FS group was considerably higher than that of febrile seizures in general and was also as high as that of "convulsions with mild gastroenteritis (CwG)". All seizure patients, whether febrile or afebrile, presented with generalized tonic clonic seizures (GTCS), complex partial seizures (CPS), or both. Diazepam (DZP) was less effective and carbamazepine (CBZ) was completely effective for the cessation of seizures in the FS group, similar to the drug response observed in CwG. CONCLUSIONS: The causative pathogen (norovirus or rotavirus) affected the frequency of febrile episodes during gastroenteritis, but fever had little effect on the clinical features of seizures. However, seizures occurred earlier during gastroenteritis in the FS group. On the whole, the clinical features of febrile seizures during viral gastroenteritis may closely resemble those of "convulsions with mild gastroenteritis" (CwG) than those of febrile seizures in general with respect to the frequency of clustered seizures and the antiepileptic drug responses and may have a pathogenic mechanism distinct from those of febrile seizures due to other causes.

Ictal 99mTc-Ethyl Cysteinate Dimer SPECT Findings of a Girl With Refractory Localization-Related Epilepsy Who Developed Transient Ictal Bradycardia.

Ictal bradycardia, which is considered to be one of the causes of sudden unexplained death in epilepsy, is rare. A 10-year-old girl with focal cortical dysplasia in her right centroparietal region developed transient ictal bradycardia during cluster seizures. Brain magnetic resonance imaging demonstrated a high signal intensity lesion adjacent to the focal cortical dysplasia lesion. Ictal 99mTc-ethyl cysteinate dimer single-photon emission computed tomography (SPECT) detected hyperperfusion in an area containing the high signal intensity lesion, which was located close to the insular cortex. Since the hyperperfusion zone observed on SPECT was considered to reflect seizure propagation, it is possible that the ictal bradycardia experienced in the present case was caused by the following mechanism: The repetitive seizure activity caused the high-intensity lesion seen on MRI to expand into the right insular cortex, which controls cardiac rhythm, resulting in ictal bradycardia.

Benign neonatal sleep myoclonus: our experience of 15 Japanese cases.

PURPOSE: Benign neonatal sleep myoclonus is a non-epileptic movement disorder that may mimic neonatal seizures. The aim of this study was to clarify the clinical manifestations and outcomes in Japanese infants with benign neonatal sleep myoclonus. METHODS: We reviewed the clinical manifestations and outcomes in 15 consecutive patients with benign neonatal sleep myoclonus (males: 10), including three paired familial cases, referred to our center between 1996 and 2011. The diagnosis of benign neonatal sleep myoclonus was based on a neonatal onset, characteristic myoclonic jerks that occurred during sleep, and normal electroencephalogram findings. RESULTS: All were healthy full-term neonates at birth. The age at onset ranged from 1 to 18 days (median: 7 days). Prior to referral to our center (3-8 weeks), two infants had been placed on antiepileptic drugs, without effects. During the clinical course, the myoclonic jerks resolved by 6 months in 14 of the 15 patients. On follow-up (final evaluation, mean: 38 months), all but one patient (speech delay) showed normal development. None developed epilepsy. Of note, migraine occurred after 5 years of age in three children, including one who developed cyclic vomiting syndrome, evolving to migraine. Another boy developed cyclic vomiting syndrome, a precursor of migraine, before 1 year, and was being followed. A high incidence of migraine was observed in five (42%) of 12 parents whose detailed family history was available. CONCLUSION: Our study suggests that benign neonatal sleep myoclonus is related to migraine. With the high rate of familial cases, further genetic study, including migraine-related gene analysis, is necessary to determine the underlying mechanism responsible for benign neonatal sleep myoclonus.

[Successful treatment with intravenous steroid pulse therapy of a boy with recurrent idiopathic sixth nerve palsy].

A 3-year-old boy developed left-sided convergent strabismus one week after upper respiratory infection. All examinations, including analysis of cerebrospinal fluid, a tensilon test, and brain MRI, were negative. He was diagnosed with idiopathic sixth nerve palsy. His symptom resolved gradually with vitamin B12, and remitted completely three months after onset. At the age of 6 years, he experienced recurrence of left-sided sixth nerve palsy. After vitamin B12 failed, his symptom responded markedly to intravenous steroid pulse therapy starting on day 26 after relapse. He has been symptom-free for three years since the second remission. Steroid therapy might be effective, and should be considered in children with idiopathic sixth nerve palsy who do not show spontaneous remission.

Predictive value of EEG findings at control of epileptic spasms for seizure relapse in patients with West syndrome.

PURPOSE: To evaluate the prognostic importance of electroencephalography (EEG) findings at cessation of epileptic spasms for seizure outcome. METHODS: We reviewed 71 children with West syndrome (cryptogenic 14) who had obtained control of epileptic spasms with initial treatment (adrenocorticotropic hormone (ACTH) 37, high-dose vitamin B6 2, and antiepileptic drugs 32). According to the EEG findings at control of epileptic spasms, the subjects were divided into three groups: normal group (no epileptic activity, n=12), abnormal group (residual epileptic activity without hypsarrhythmia, n=53), and hypsarrhythmic group (persisting hypsarrhythmia, n=6). RESULTS: Overall, 47 (66%) of the 71 patients (cryptogenic 4) had experienced relapses of seizures (epileptic spasms 23 and focal seizure 24) after initial control of epileptic spasms. Within symptomatic cases, seizure relapse rate varied widely from 0% (Down syndrome) to 100% (tuberous sclerosis), depending on underlying causes. Seizure relapse depended on the EEG findings at control of epileptic spasms. The normal group had a significantly lower seizure relapse rate (17%) in comparison with the abnormal group (75%), the hypsarrhythmic group (83%), and the epileptiform (abnormal plus hypsarrhythmic, 76%) group. No significant difference in seizure relapse rate was observed between non-hypsarrhythmic (normal plus abnormal, 65%) and hypsarrhythmic groups. At the last follow-up, normal group children also showed a favorable seizure prognosis (seizure control 100%). CONCLUSIONS: A favorable seizure prognosis is associated with the disappearance of epileptic activity, but not the resolution of hypsarrhythmic pattern on EEG at control of epileptic spasms. We suggest that effective treatment for West syndrome should produce both cessation of epileptic spasms and disappearance of epileptic activity on EEG.

Genotype-phenotype correlations in alternating hemiplegia of childhood.

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.

[Evaluation of six cases with hypothalamic hamartoma: the relationship between MRI findings and clinical features].

OBJECTIVE: We evaluated the relationship between MRI findings and clinical features in patients with hypothalamic hamartoma (HH). METHODS: We retrospectively reviewed MRI and clinical data (mental retardation, precocious puberty, behavioral problems, and epilepsy) in six patients (3 males and 3 females, ages 12 to 26) with HH. Based on the MRI classification by Arita, HH was classified into two types: parahypothalamic (P) and intrahypothalamic (I). RESULTS: Only one patient was classified as having P-type HH and five were classified as having I-type HH. The patient with P-type HH (diameter 21 mm) showed precocious puberty and mild behavioral problems, but did not developed epilepsy. On the other hand, all patients with I-type HH (diameter 10-32 mm, median 17 mm) developed epilepsy and behavioral problems. Except for one patient, who had the smallest sized HH, I-type four patients developed mental retardation and precocious puberty. Among patients with I-type HH, the size of the tumor was inversely correlated with the age at epilepsy onset and with the degree of mental retardation (DQ/IQ). CONCLUSION: Our data suggested that the MRI classification by Arita, when combined with tumor size, might be helpful in predicting the clinical manifestations in patients with HH.

Identification of ATP1A3 mutations by exome sequencing as the cause of alternating hemiplegia of childhood in Japanese patients.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described ATP1A3 mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis. PRINCIPAL FINDINGS: A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of ATP1A3, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of ATP1A3. They were de novo mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other ATP1A3 mutations. INTERPRETATION: Heterozygous de novo mutations of ATP1A3 were identified in all Japanese patients with AHC examined in this study, confirming that ATP1A3 mutation is the cause of AHC.

A Five-Year-Old Boy with Marked Hypergastrinemia Associated with H. pylori Infection.

A 5-year-old boy was referred to our department for persistent epigastric discomfort. Serum gastrin level was 635 pg/ml with a pepsinogen (PG) I level of 102.7 ng/ml and a PG I/II ratio of 23.2, indicating a hyperacidic state. Upper gastrointestinal endoscopy showed normal gastric mucosal folds and no abnormalities including no gastric mucosal atrophy. To investigate the cause of hypergastrinemia, a Ca injection test was performed and the patient showed no definitive response to a large load of Ca. Contrast-enhanced dynamic CT revealed no space-occupying lesions. The results from these two studies were not consistent with the presence of gastrinoma. A urea breath test showed 2.8%, and a test for the fecal H. pylori antigen was positive. Since H. pylori infection was considered to be a possible cause of hypergastrinemia, eradication therapy was introduced. The therapy was shown to be successful by using a repeated urea breath test that showed a normalization to 0.6%. 7 months after the therapy blood examination showed a gastrin level of 191 pg/ml, a PG I level of 36.7 ng/ml, and a PG I/II ratio of 7.3. An immunostaining study of the gastric mucosa suggested that a decrease in somatostatin secretion due to a reduction in D cell population might have induced hypergastrinemia in this case. In children with H. pylori infection showing marked hypergastrinemia, immunohistochemical examination and therapeutic diagnosis by eradication may be helpful in the differential diagnosis of gastrinoma.

A case of pediatric virilizing adrenocortical tumor resulting in hypothalamic-pituitary activation and central precocious puberty following surgical removal.

We present a 6-year-old boy with a virilizing adrenocortical tumor who initially presented with peripheral precocious puberty. Development of facial acne, pubic hair and a growth spurt were noted at the age of five. A low-pitched voice as well as maturation of external genitalia was noted at the age of six. Both serum and urinary levels of adrenal androgens were elevated. Abdominal computed tomography revealed a large right suprarenal mass and he underwent surgical resection without any complications. The histological diagnosis was adrenocortical carcinoma according to the criteria of Weiss. Following surgical removal of the androgen-producing tumor, the patient subsequently developed hypothalamic-pituitary activation and demonstrated central precocious puberty. He was treated with a gonadotropin-releasing hormone agonist in order to delay further pubertal progression. Clinical follow-up of potential secondary effects of excess hormone secretion after removal is important in some pediatric patients with virilizing adrenocortical tumor.