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Background The MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients’ quality of life. Case A 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient’s clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient’s refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death. Conclusion The pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and β-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.

BackgroundVariants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear.MethodsWe examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.ResultsPathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.ConclusionsPrenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Mitochondrial complex I deficiency is caused by pathogenic variants in mitochondrial and nuclear genes associated with complex I structure and assembly. We report the case of a patient with NDUFA8-related mitochondrial disease. The patient presented with developmental delay, microcephaly, and epilepsy. His fibroblasts showed apparent biochemical defects in mitochondrial complex I. Whole-exome sequencing revealed that the patient carried a homozygous variant in NDUFA8. His fibroblasts showed a reduction in the protein expression level of not only NDUFA8, but also the other complex I subunits, consistent with assembly defects. The enzyme activity of complex I and oxygen consumption rate were restored by reintroducing wild-typeNDUFA8 cDNA into patient fibroblasts. The functional properties of the variant in NDUFA8 were also investigated using NDUFA8 knockout cells expressing wild-type or mutated NDUFA8 cDNA. These experiments further supported the pathogenicity of the variant in complex I assembly. This is the first report describing that the loss of NDUFA8, which has not previously been associated with mitochondrial disease, causes severe defect in the assembly of mitochondrial complex I, leading to progressive neurological and developmental abnormalities.

Objectives Quantitative or semiquantitative outcome measures for patients with Duchenne muscular dystrophy (DMD) are important, as they can be objective indicators of the natural history of DMD; these measures also aid in the evaluation of the efficacy of various treatments. However, the most widely used standard outcome measures in patients with DMD, such as the North Star Ambulatory Assessment and the 6-min walk test, cannot be applied after patients have become nonambulatory. We evaluated the utility and reliability of accelerometric analysis of motor activity in nonambulatory patients with DMD. Methods We measured the motor activity of the upper extremity in 7 nonambulatory patients with DMD, by using an accelerometer attached at the wrist of the dominant arm. To eliminate gravitational acceleration, we measured the changes in acceleration between measurements. The root of the sum of squared values of the changes per unit time in the 3 axes of the accelerometer was defined as a jerk. The total sum of the jerk values obtained at a measurement frequency of 15.625 Hz for 8 h was defined as the cumulative sum of jerks ( Cj ). Results The Cj values had significant and very strong or strong correlations with the Brooke Upper Extremity Scale ( r s = −0.973; p = 0.00023) and the arm function scores for the DMD Functional Ability Self-Assessment Tool ( r s = 0.810, p = 0.027). The values also had a very strong or strong correlation with the elbow flexion strength (nondominant arm: r = 0.931, p = 0.002; dominant arm: r = 0.750, p = 0.052). Conclusion Cj assessment is a useful method to evaluate motor activities in nonambulatory patients with DMD.

Background: Although the incidence of cerebral infarction is higher in Duchenne muscular dystrophy (.75 per 100) than in the general population (7.5-11.4 per 100 000), only 18 cases have been reported, and prevention and management guidelines for infarction in this disorder remain lacking. Patients and Methods: We encountered 2 cases of Duchenne muscular dystrophy with cerebral infarction. To clarify risk factors for such infarction in Duchenne muscular dystrophy, we reviewed 20 cases, including our 2 patients. Results: Age at onset of infarction ranged from 4 to 31 years (n = 19). Most patients were 16-21 years old (14 of 19; 73.7%). Eighteen patients (90%) had dilated cardiomyopathy (DCM), showing a higher frequency than in the age-matched general Duchenne muscular dystrophy population. Left ventricular ejection fraction (LVEF) ranged from 10.2% to 42% (median, 20%; n = 9). Detectable cardiac thrombus and atrial fibrillation were rare (2 of 17; 11.8%, and 1 of 17; 5.9%, respectively). Conclusions: Presence of DCM with low LVEF seems to be the strongest risk factor for cerebral infarction in Duchenne muscular dystrophy.

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent trabecular meshwork, and it is thought to result from arrest of the normal compaction process during embryogenesis. Patients with LVNC may be asymptomatic or have symptoms ranging from heart failure to stroke, life-threatening arrhythmias, or sudden death. The frequency of LVNC in children has increased with longer clinical courses. About 80% of patients with trisomy 13 have a congenital cardiac abnormality, but a clinical description of LVNC with trisomy 13 is lacking because of its poor prognosis and lack of awareness about LVNC. We described a patient with trisomy 13 who was diagnosed with LVNC-dilated phenotype and died suddenly, as well as two additional patients with LVNC. All three patients had chronic heart failure without congenital heart disease and were treated with diuretics. To manage trisomy 13 with or without congenital heart disease, cardiac disease such as LVNC may present at any ages, and therefore cardiac evaluation should be considered as a part of their appropriate management.

Most childhood cases of acute necrotizing encephalopathy (ANE) involve neither family history nor recurrence. ANE occasionally occurs, however, as a familial disorder or recurs in Caucasian patients. A mutation of RAN-binding protein 2 (RANBP2) has been discovered in more than one half of familial or recurrent ANE patients. In contrast, there has been no report of this mutation in East Asia. Here, we report the first sibling cases of typical ANE in Japan, with poor outcome. DNA analysis of genes associated with ANE or other encephalopathies, including RANBP2 and carnitine palmitoyl transferase II (CPT2), indicated neither mutations nor disease-related polymorphisms. On literature review, recurrent or familial ANE without the RANBP2 mutation has a more severe outcome and greater predilection for male sex than that with the RANBP2 mutation. This suggests that there are unknown gene mutations linked to ANE.

Cutis laxa (CL) syndromes are connective tissue disorders characterized by redundant, sagging, inelastic and wrinkled skin, with organ involvement. Here, we describe a patient with ALDH18A1-related CL who developed cyclic vomiting. The patient was a 12-year-old boy who presented with poor postnatal growth, hypotonia, short stature, joint hyperlaxity, microcephaly, strabismus, bilateral cataracts, facial dysmorphism and severe mental retardation. Bone radiographs showed osteopenia and osteoporosis, and magnetic resonance angiography showed marked kinking and tortuosity of the brain vessels. These findings were clinically compatible with ALDH18A1-related CL. Molecular analysis revealed a de novo heterozygous mutation (p.R138Q) in ALDH18A1. No mutations were found in PYCR1 gene. The patient developed cyclic vomiting with decreased blood levels of ornithine, citrulline, arginine and proline without hyperammonemia and other hypoaminoacidemias were also found. ALDH18A1 encodes Δ(1)-pyrroline-5-carboxylate synthase, which is related to the biosynthesis of ornithine, citrulline, arginine, and proline. Cyclic vomiting has never been reported in other ALDH18A1-related CL patients. This is the first case report of ALDH18A1-related CL with cyclic vomiting associated with amino acid abnormalities.

SummaryObjective Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. Methods Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. Significance Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders.

Meckel's diverticulum (MD) is the most prevalent congenital anomaly of the gastrointestinal tract and often presents a diagnostic challenge. Patients with trisomy 18 frequently have MD, but the poor prognosis and lack of consensus regarding management for neonates has meant that precise information on the clinical manifestations in infants and children with MD is lacking. We describe the cases of three children with trisomy 18 who developed symptomatic MD. Intussusception was diagnosed in Patient 1, intestinal volvulus in Patient 2, and gastrointestinal bleeding in Patient 3. All three patients underwent surgical treatment and only the Patient 1 died due to pulmonary hypertensive crisis. The other two patients experienced no further episodes of abdominal symptoms. In patients with trisomy 18, although consideration of postoperative complications and prognosis after surgical treatment is necessary, symptomatic MD should carry a high index of suspicion in patients presenting with acute abdomen.

Background Disorders of oxidative phosphorylation (OXPHOS) cause an increase in the NADH/NAD + ratio, which impairs the glycolysis pathway. Treatment with pyruvate is expected to decrease the ratio and thereby restore glycolysis. There are some case reports on the efficacy of pyruvate treatment for mitochondrial diseases. However, few of these reports assessed their results using a standardized scale. Methods We monitored 4 bedridden patients with OXPHOS disorders who continued therapies of 0.5–1.0g/kg/day of sodium pyruvate for more than 12months. The efficacies of these treatments were evaluated with the Newcastle Pediatric Mitochondrial Disease Scale and the Gross Motor Function Measure with 88 items. Results The ages of the patients at the treatment initiation ranged from 8–100months. Of the 4 patients, 3 exhibited improvements within 1–3months from the initiation of treatment. Among these 3 patients, one maintained the improvement for over 2years. The remaining 2 regressed 3–6months after the initiation of treatment. The blood lactate/pyruvate ratios did not correlate with the efficacy of treatment. Conclusion Pyruvate was effective even in bedridden patients with OXPHOS disorders, at least in the short term. Clinical trials with more patients and less severe disabilities are necessary to evaluate the long-term efficacy of this treatment. Biomarkers other than lactate and pyruvate need to be identified to biochemically monitor the efficacy of this treatment.

Febrile infection-related epilepsy syndrome (FIRES) is a severe epileptic syndrome that manifests with refractory seizures or status epilepticus in previously healthy children after banal febrile illness. The neuroimaging findings in the acute phase of FIRES are nonspecific or normal. We report the case of a 7-year-old boy with FIRES who presented with a reversible lesion in the splenium of the corpus callosum on brain magnetic resonance imaging (MRI). The patient developed clusters of clonic seizures with a deviation of the eyes after a 3-day history of fever. A reversible splenial lesion was observed on brain MRI and, therefore, the initial diagnosis was mild encephalitis/encephalopathy with a reversible splenial lesion (MERS). However, the intractable complex partial seizures necessitated a long-term midazolam infusion, indicating that FIRES was a more likely diagnosis than MERS. All other findings of this patient met the diagnostic criteria for FIRES. With this diagnosis, a high-dose phenobarbital was administrated, and the seizures were successfully controlled. This case indicated that FIRES should be considered even in patients with a reversible splenial lesion associated with encephalitis/encephalopathy.

Toothbrushing-induced seizures are rare reflex seizures triggered by the brushing of one's own teeth. We encountered an 11-year-old girl with severe mental retardation, hypotonic cerebral palsy and epilepsy who presented with toothbrushing-induced seizures. She had had spontaneous brief tonic seizures several times a day since the age of 1 year and 2 months and started presenting with the same type of seizures induced by toothbrushing from the age of 8 years. As she could not brush her teeth by herself due to her disabilities, her mother brushed her teeth daily for her. The interictal EEG showed spike-and-wave complexes in the frontal regions bilaterally. The [Tc-99m]HMPAO-SPECT at the time of the seizure induced by toothbrushing suggested that the seizures originated from the left perisylvian cortex. This is the first report of toothbrushing-induced seizures triggered by the brushing of the patient's teeth by another person ('passive toothbrushing').

Compared to cerebral radiation-induced cavernous hemangiomas (RICHs), little is known about intraspinal RICHs. A 13-year-old male suddenly developed symptomatic spinal hemorrhage eight years after hematopoietic stem cell transplantation using a total body irradiation (TBI) based myeloablative regimen. A solitary small hemangioma was detected on follow-up T2 star weighted magnetic resonance imaging of the spine. His neurological symptoms gradually improved with supportive treatment and rehabilitation, although he experienced rebleeding 2 years later. Intraspinal RICH is very rare but should be recognized as a possible late adverse effect in pediatric patients who received TBI.

Background Valproate-induced Fanconi syndrome is a rare adverse effect of valproate. Severely disabled patients who require tube feeding are reported to be susceptible to valproate-induced Fanconi syndrome. Although most patients with valproate-induced Fanconi syndrome are asymptomatic and detected incidentally with findings such as hypophosphatemia, hypouricemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, clinical symptoms such as bone fracture, fever, tachypnea, and edema have been reported. Patient description This 15-year-old, severely disabled, tube-fed, male patient with cytochrome oxidase deficiency had taken valproate for 3 years when he developed fever for 3 weeks. Hypophosphatemia, hypouricemia, hypokalemia, increased urinary β2-microglobulin, and generalized hyperaminoaciduria, as well as hypocarnitinemia, were found, indicating that he had Fanconi syndrome. Valproate was the most likely cause of Fanconi syndrome in this patient. After discontinuation of valproate, the fever resolved immediately, and the laboratory findings normalized. Conclusion Valproate-induced Fanconi syndrome should be considered when individuals taking valproate develop fever of unknown origin.

We introduced a low glycemic index treatment using Japanese ethnic foods to a 13-year-old girl with Lennox-Gastaut syndrome caused by tuberous sclerosis complex. She had previously refused the modified Atkins diet within 2 weeks of diet treatment because of its restrictiveness. The low glycemic index treatment was implemented by limiting the daily carbohydrate intake to 50 g of foods with a glycemic index of less than 50 relative to that of glucose, which included udon, soba, and unpolished Japonica rice with natto. One month after the initiation of the diet therapy, the clusters of tonic seizures for 30 to 60 minutes during sleep were reduced from two or three times per week to once or twice per month, and the frequent myoclonic seizures in the awake state disappeared. She has been on the diet therapy for more than 1 year, and the efficacy of the diet has been sustained. Low glycemic index treatment should be considered for patients with medication-resistant epilepsy who cannot tolerate restrictive diet therapies. Japanese ethnic foods can be used for this diet therapy.

Grisel syndrome is a non-traumatic atlantoaxial subluxation and a rare complication of any inflammatory condition of the upper neck and otolaryngological procedures. Delayed diagnosis causes neurological impairment, ranging from radiculopathy to paralysis and death. Kawasaki disease is a very frequent and important acute febrile vasculitis of childhood that is seen worldwide, and upper neck involvement (cervical lymphadenopathy) is one of the common symptoms of Kawasaki disease. A case of Grisel syndrome that occurred as a complication of Kawasaki disease is reported. This is the first case report, in English, of Grisel syndrome as a complication of Kawasaki disease. Conclusion: Pediatricians should be aware of Grisel syndrome as a possible complication of Kawasaki disease.

Compared to the classical ketogenic diet (KD), the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT) are more liberal and less restrictive diet therapies for the treatment of medication-resistant epilepsy. The MAD was first reported by Kossoff et al. in 2003, and gained global popularity with sufficient evidence in its efficacy reported recently in a controlled study. The LGIT was first reported by Pfeifer et al. in 2005, and its use has also become widespread. We reviewed the efficacy of both diet therapies in the treatment of medication-resistant epilepsy based on the evidence from previous literatures and our own clinical experience. From our experience, the LGIT was more liberal, tolerable, and dietetically balanced than the MAD. To find out which of these diets is most appropriate in different epilepsies and different patients, future controlled comparative studies on the efficacy, tolerability, and dietetic advantages between the MAD and the LGIT are necessary.