Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano-like pattern.

Chromosomal triplications can be classified into recurrent and nonrecurrent triplications. Most of the nonrecurrent triplications are embedded in duplicated segments, and duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) has been established as one of the mechanisms of triplication. This study aimed to reveal the underlying mechanism of the TRP-DUP-TRP pattern of chromosomal aberrations, in which the appearance of moving averages obtained through array-based comparative genomic hybridization analysis is similar to the shadows of the caldera volcano-like pattern, which were first identified in two patients with neurodevelopmental disabilities. For this purpose, whole-genome sequencing using long-read Nanopore sequencing was carried out to confirm breakpoint junctions. Custom array analysis and Sanger sequencing were also used to detect all breakpoint junctions. As a result, the TRP-DUP-TRP pattern consisted of only two patterns of breakpoint junctions in both patients. In patient 1, microhomologies were identified in breakpoint junctions. In patient 2, more complex architectures with insertional segments were identified. Thus, replication-based mechanisms were considered as a mechanism of the TRP-DUP-TRP pattern.

A novel S269C mutation in fibroblast growth factor receptor 3 in a Japanese child with hypochondroplasia.

Functionally activating mutations in fibroblast growth factor receptor 3 (FGFR3) can cause four types of autosomal dominant skeletal dysplasia with short-limbed dwarfism that include the mildest phenotype, hypochondroplasia (HCH). A novel mutation (c.805A>T, p.S269C) was identified in a Japanese infant with HCH through direct sequencing of all FGFR3 exons and exon/intron boundaries. This mutation creates an additional cysteine residue in the extracellular region of FGFR3 that results in the functional activation of FGFR3.

A novel ZC4H2 gene mutation, K209N, in Japanese siblings with arthrogryposis multiplex congenita and intellectual disability: characterization of the K209N mutation and clinical findings.

OBJECTIVE: To reveal a molecular lesion in the ZC4H2 gene in a Japanese family with arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), and to characterize clinical features of patients with ZC4H2 gene mutations through a literature review. PATIENTS: The probands are male siblings. The elder brother is an 11-year-old boy who showed AMC and ID and frequent postprandial hypoglycemia since 3 years of age. The younger brother also showed AMC, ID, and subclinical postprandial hypoglycemia. The boys' mother also showed a minor malformation of the left toes. METHOD AND RESULT: Using Sanger sequencing, a hemizygous one base substitution designated c.627G > C, which is predicted to substitute asparagine for lysine at amino acid residue 209 (K209N), was identified in the siblings. The mother was heterozygous for this mutation. In silico analysis predicted K209N to be a constituent of a motif required for subcellular localization of the ZC4H2 protein in the nucleus. Transient expression studies of subcellular localization in COS-7 cells showed that compared to the wild-type protein, the transport of the mutant protein into the nucleus was inhibited, thus confirming K209N as a molecular lesion in this family. The literature reviews revealed postprandial hypoglycemia as a new clinical feature that should be considered in ZC4H2 gene-mutation disorders. CONCLUSION: A Japanese family with AMC and ID caused by a novel ZC4H2 gene mutation was reported. Hypoglycemia should be considered one of the features in this disorder.

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Loss-of-function mutations of STXBP1 in patients with epileptic encephalopathy.

Epileptic encephalopathy, which commences during early infancy, is a severe epileptic syndrome that manifests as age-dependent seizures and severe developmental delay. The syntaxin-binding protein 1 gene (STXBP1) is one of the genes responsible for epileptic encephalopathy. We conducted a cohort study to analyze STXBP1 in 42 patients with epileptic encephalopathy. We identified four novel mutations: two splicing mutations, a frameshift mutation, and a nonsense mutation. All of these mutations were predicted to cause loss-of-function. This result suggests loss-of-function is a common mechanism underlying STXBP1-related epileptic encephalopathy. The four patients showed epileptic features consistent with STXBP1-related epileptic encephalopathy, but showed variable radiological findings, including brain volume loss and myelination delay.

Alexander disease with mild dorsal brainstem atrophy and infantile spasms.

We present the case of a Japanese male infant with Alexander disease who developed infantile spasms at 8 months of age. The patient had a cluster of partial seizures at 4 months of age. He presented with mild general hypotonia and developmental delay. Macrocephaly was not observed. Brain magnetic resonance imaging (MRI) findings fulfilled all MRI-based criteria for the diagnosis of Alexander disease and revealed mild atrophy of the dorsal pons and medulla oblongata with abnormal intensities. DNA analysis disclosed a novel heterozygous missense mutation (c.1154 C>T, p.S385F) in the glial fibrillary acidic protein gene. At 8 months of age, tonic spasms occurred, and electroencephalography (EEG) revealed hypsarrhythmia. Lamotrigine effectively controlled the infantile spasms and improved the abnormal EEG findings. Although most patients with infantile Alexander disease have epilepsy, infantile spasms are rare. This comorbid condition may be associated with the distribution of the brain lesions and the age at onset of Alexander disease.

Nationwide survey (incidence, clinical course, prognosis) of Rasmussen's encephalitis.

PURPOSE: Rasmussen's encephalitis (RE) is a progressive and catastrophic epileptic disorder caused by chronic localized encephalitis. We performed a nationwide survey of RE to assess the clinical picture, treatment effect, and prognosis of Japanese RE patients. SUBJECTS & METHODS: The subjects were 27 patients (male:12; female:15) from 13 medical facilities. All of them satisfied the clinical and neuroimaging criteria for RE, including 14 pathologically proven cases. RESULTS: They were divided into the childhood-onset rapidly progressive type (CORP, n=19), and late-onset slowly progressive type (LOSP, n=8). The mean age at epilepsy onset was 4 years and 4 months in CORP, and 16 years in LOSP. The mean period between the onset age of epilepsy and development of frequent seizures was 1 year and 4 months in the former, and 3 years and 4 months in the latter. The immunomodulatory treatment including high-dose steroid (n=14) and high-dose intravenous immunoglobulin therapies (IVIgG, n=12) achieved more than a 50% reduction in the seizure frequency in 5 (36%) and 4 (33%) patients, respectively. Eight and seven patients underwent focal cortical resection and functional hemispherectomy, leading to significant improvement in 5 of the 8 patients and excellent seizure control in all 7 patients, respectively. CONCLUSION: Although the high-dose steroid and IVIG therapies may have alleviated the exacerbation of seizures in those with RE, they could not halt the disease progression. Functional hemispherectomy is still the only curative therapy for RE, despite the fact that the early introduction of this procedure remains controversial.

[Symptomatic hypersomnia due to orexin deficiency in hypothalamic lesions].

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and other abnormal manifestations of REM sleep. Recently, it was discovered that the pathophysiology of idiopathic narcolepsy-cataplexy is linked to orexin ligand deficiency in the brain and cerebrospinal fluid. Orexin neurons localize in the posterior hypothalamic area, which was previously described as "waking center" by von Economo in 1920s. Hypersomnia due to orexin ligand deficiency can also occur during the course of other neurological conditions, such as hypothalamic tumor, encephalopathy and demyelinating disorder (i.e. symptomatic hypersomnia). We experienced 8 pediatric cases with symptomatic hypersomnia. These cases were diagnosed as brain tumor (n = 2), head trauma (n = 1), encephalopathy (n = 1), demyelinating disorder (n = 3) and infarction (n = 1). Six pediatric cases with orexin measurements from the literatures were additionally included and total 14 cases were studied. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, a review of the case histories reveals numerous unquestionable cases of symptomatic hypersomnia. In these cases, the occurrences of the hypersomnia run parallel with the rise and fall of the causative diseases. Most of symptomatic hypersomnia cases show both extended nocturnal sleep time and EDS consisting of prolonged sleep episodes of NREM sleep. The features of nocturnal sleep and EDS in symptomatic hypersomnia are more similar to idiopathic hypersomnia than to narcolepsy.

A hippocampal lesion detected by high-field 3 tesla magnetic resonance imaging in a patient with temporal lobe epilepsy.

Nearly 80% of patients with temporal lobe epilepsy have some types of lesion identified by conventional 1.5 tesla (T) magnetic resonance imaging (MRI). We performed high-field 3 T MRI in a 5-year-old patient with recurrent complex partial seizures who was diagnosed as having right temporal lobe epilepsy based on the results of single photon emission computed tomography and ictal video-electroencephalogram monitoring, because 1.5 T MRI failed to detect any abnormalities in the suspected region. High-field 3 T MRI revealed a small high-intensity lesion on fast spin-echo short inversion time inversion-recovery images of the hippocampus, possibly responsible for the seizures. This is the first report detecting a hippocampal lesion by 3 T MRI, which could not be found by conventional 1.5 T MRI.

Leukoencephalopathy around a tumor cyst following intracystic methotrexate injection.

A 4-year-old female with choroid plexus carcinoma developed progressive disturbance of consciousness 2 years after postoperative treatment with radiotherapy, chemotherapy, and focal methotrexate injection into a residual tumor cyst. Magnetic resonance imaging revealed white matter lesions localized around the expanding large cyst. A malignant recurrence of choroid plexus carcinoma with a propensity of cerebrospinal fluid overproduction was suspected. However, daily drainage of cerebrospinal fluid from the cyst and treatment with glycerol and dexamethasone achieved improvement. Diffuse hypoperfusion over the lesions on single-photon emission computed tomography denied the possibility of residual tumor aggravation and together with subsequent atrophic changes confirmed that the lesions reflect localized leukoencephalopathy, possibly associated with methotrexate forced into the parenchyma as a result of the expanding intracystic high pressure.

Choroid plexus carcinoma presented with spinal dysfunction caused by a drop metastasis: a case report.

A 2-year-old girl demonstrating gait disturbance and dysuria was evaluated and showed two large remote tumors at the left lateral ventricle and lower spinal canal. Pathological analysis demonstrated both of the tumors to be choroid plexus carcinoma (CPC) with high MIB-1 labeling index. The enhanced mitotic propensity would have contributed to an early stage of drop metastasis from the primary site to the sacral sac and following accelerated formation of a longitudinal tumor, which had grown in the subarachnoid space conforming to the spinal canal and finally caused the presenting symptoms of spinal dysfunction. This report shows that CPC can develop exophytically in the subarachnoid space as well as in the ventricle simultaneously before appearance of clinical symptoms and confirms the importance of extensive neuroimaging in its evaluation.

Hypocretin-1 (orexin-A) levels in human lumbar CSF in different age groups: infants to elderly persons.

STUDY OBJECTIVES: Recent CSF and postmortem brain hypocretin measurements in human narcolepsy suggest that hypocretin deficiency is involved in the pathophysiology of the disease. In this study, we measured CSF hypocretin-1 levels in various age ranges from infants to elder people to investigate the age-dependent change of hypocretin concentrations. DESIGN: CSF hypocretin levels were compared by age groups and gender. ANOVA was used to examine the influences of these two parameters on CSF hypocretin levels. SETTING: University-based sleep and biology laboratory. PATIENTS OR PARTICIPANTS: Two hundred seventy two patients were included in this study, with 157 males and 115 females (0-79 years old). INTERVENTIONS: CSF samples were obtained by lumber punctures with informed consents. MEASUREMENTS AND RESULTS: Hypocretin-1 levels are not different in respect to gender or age, although our samples constitute a heterogeneous group with various disease conditions. CSF hypocretin-1 levels in infants under 4 months are similar to those in adults. CONCLUSIONS: Early maturation of hypocretin transmission is suggested. No age- or gender-dependent changes in CSF hypocretin is observed.

Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene.

Early-onset (infantile) Alexander disease is associated with mutations in the glial fibrillary acidic protein (GFAP) gene and two hot spots correlate to the severe phenotype. No molecular mechanisms have been elucidated in late-onset (juvenile) Alexander disease. The authors report a novel GFAP mutation in a patient with juvenile Alexander disease. The authors discuss similar molecular mechanisms in another intermediate filament disease and propose a possible molecular pathogenesis in juvenile Alexander disease.

Lidocaine-dependent early infantile status epilepticus with highly suppressed EEG.

We report an early infantile patient characterized by intractable hyponatremia, progressive megalencephaly, and epileptic seizures with an EEG pattern that alternated between interictal low-voltage background and ictal burst activity. Repeatedly all the abnormal findings improved in a lidocaine-dependent manner. Given the pharmacologic mechanisms of lidocaine as a sodium channel blocker, we speculate that our patient had a sodium channel dysfunction.