Identification of small-sized intrachromosomal segments at the ends of INV-DUP-DEL patterns.

The mechanism of chromosomal rearrangement associated with inverted-duplication-deletion (INV-DUP-DEL) pattern formation has been investigated by many researchers, and several possible mechanisms have been proposed. Currently, fold-back and subsequent dicentric chromosome formation has been established as non-recurrent INV-DUP-DEL pattern formation mechanisms. In the present study, we analyzed the breakpoint junctions of INV-DUP-DEL patterns in five patients using long-read whole-genome sequencing and detected 2.2-6.1 kb copy-neutral regions in all five patients. At the end of the INV-DUP-DEL, two patients exhibited chromosomal translocations, which are recognized as telomere capture, and one patient showed direct telomere healing. The remaining two patients had additional small-sized intrachromosomal segments at the end of the derivative chromosomes. These findings have not been previously reported but they may only be explained by the presence of telomere capture breakage. Further investigations are required to better understand the mechanisms underlying this finding.

PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.

Here we present four unrelated families with six individuals that have infantile-onset developmental delay/regression and epilepsy. Whole-exome sequencing revealed compound heterozygous mutations, c.[283G>A];[607G>A] in a gene encoding prolyl-tRNA synthetase (PARS2) in one family. Two pairs of compound heterozygous mutations, c.[151C>T];[1184T>G] and c.[707T>G];[594+1G>A], and a homozygous mutation, c.[500A>G];[500A>G], in a gene encoding asparaginyl-tRNA synthetase (NARS2) were also identified in the other three families. Mutations in genes encoding aminoacyl-tRNA synthetases cause gene-specific mitochondrial disorders. Biallelic PARS2 or NARS2 mutations are reported to cause Alpers' syndrome, which is an autosomal recessive neurodegenerative disorder characterized by psychomotor regression and epilepsy with variable degree of liver involvement. Moreover, it is known that NARS2 mutations cause various clinical phenotypes, including non-syndromic hearing loss, Leigh syndrome, intellectual disability with epilepsy and severe myopathy. The individuals with PARS2 and NARS2 mutations, we have reported here demonstrate similar neurological features as those previously reported, with diversity in clinical presentation such as hearing loss and seizure type. Our data broaden the clinical and mutational spectrum of PARS2- and NARS2-related disorders.

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.

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.

TRH therapy in a patient with juvenile Alexander disease.

Alexander disease is a rare disorder of the central nervous system caused by a de novo mutation in the glial fibrillary acidic protein (GFAP) gene. Unlike the much more common infantile form, the juvenile form is slowly progressive with bulbar, pyramidal and cerebellar signs. Herein, we report a 9-year old Japanese girl suffering from frequent vomiting, slurred speech and truncal ataxia. Juvenile Alexander disease was diagnosed by genetic analysis, which detected a novel GFAP mutation, D360V. We also describe our clinical success in treating this patient with thyrotropin releasing hormone (TRH).

[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.

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.

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.

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.

Asymptomatic hereditary Alexander's disease caused by a novel mutation in GFAP.

We report on a family with dominantly inherited asymptomatic Alexander's disease due to a novel Glial fibrillary acidic protein (GFAP) mutation. The proband, a 16-month-old boy, presented with megalocephaly and brain magnetic resonance imaging (MRI) showing the typical findings of Alexander's disease. Molecular analysis showed that he was a heterozygote of the L331P mutation of GFAP. His mother and sister, without megalocephaly or other neurological abnormalities, were also heterozygotes of the mutation and their brain magnetic resonance imaging showed mild changes in the caudates and deep frontal white matters. These results suggest the existence of a forme fruste of Alexander's disease. The L331P mutation may be associated with the mild phenotype of Alexander's disease. To elucidate the genotype-phenotype correlation in Alexander's disease, molecular diagnosis and MRI examination are required for many patients and their families.

Fluctuation of computed tomographic findings in white matter in Alexander's disease.

A Japanese boy developed febrile seizures and gait disturbance at 2 years of age and dysarthria a year later. He had generalized tonic-clonic seizures once or twice a year from the age of 4 years. Brain computed tomography (CT) showed symmetric low-density areas in the white matter of the frontal lobes. However, abnormal CT findings fluctuated occasionally, with no apparent change in clinical manifestations. Clinical evaluation at 9 years of age revealed hyper-reflexia, psychomotor retardation, megalencephaly, and slurred nasal speech. Magnetic resonance imaging showed white matter abnormalities, predominantly in the frontal lobes. He was a heterozygote of the Arg239Cys mutation of the glial fibrillary acidic protein gene and was diagnosed with Alexander's disease. Fluctuation of CT findings in white matter may reflect blood-brain barrier dysfunction in Alexander's disease.

Abnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards.

We report on two patients with congenital cytomegalovirus (CMV) infection asymptomatic at birth that was diagnosed retrospectively by polymerase chain reaction (PCR) of CMV DNA using blood stored on Guthrie cards. Neuroimaging studies showed abnormal myelination without any gray matter abnormalities. In the differential diagnosis of patients with abnormal white matter lesions and sensorineural hearing loss, one should consider congenital CMV infection. When investigating the etiology of patients with behavioral problems, migrational disorder, or white matter disease, PCR analysis of CMV DNA using blood stored on Guthrie cards might be helpful.

Trial of intraventricular ribavirin therapy for subacute sclerosing panencephalitis in Japan.

Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.

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.

A case of congenital axonal neuropathy associated with West syndrome.

We report the case of an 11-month-old girl with congenital axonal neuropathy and West syndrome. She had generalized hypotonia and an abnormal posture since birth, and apparently, her development was stalled. Deep tendon reflexes were absent, and at 5 months of age, she developed West syndrome followed by refractory seizures. Magnetic resonance imaging of the brain revealed mild cerebral and cerebellar atrophy, high-signal-intensity areas in the white matter, and hypoplasia of the corpus callosum. No action potentials were detected in both lower and upper extremities in motor and sensory conduction velocity analysis performed at 11 months of age. Sural nerve biopsy was performed, and analysis of the biopsied specimen revealed axonal degeneration. Originally designed resequencing analysis using microarray was carried out for the 27 genes associated with Charcot-Marie-Tooth disease, but no disease-causing mutations were identified. So far, there have been no reports on simultaneous development of congenital axonal neuropathy and West syndrome.

Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: clinical features and (99m)Tc-ECD brain perfusion SPECT findings.

Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervorden-Spatz syndrome (HSS), is an autosomal recessive neurodegenerative disorder characterized by iron accumulation in the brain. Mutations in the pantothenate kinase 2 (PANK2) gene are known to be responsible for PKAN. Several studies have revealed correlations between clinical phenotypes and particular PANK2 mutations. The adult-onset slowly progressive type of PKAN with PANK2 mutations is very rare. In this report, we describe siblings with the adult-onset slowly progressive type of PKAN with a novel mutation, Ile346Ser, in PANK2. The siblings had the same mutation in PANK2 and had common clinical signs such as misalignment of teeth, a high arched palate, hollow feet, a slight cognitive decline, and an apparent executive dysfunction, although they showed different patterns of movement disorders. Thus, even if PKAN patients have identical mutations, it is likely that they will present with different types of movement disorders. Brain perfusion single photon emission computed tomography in both patients showed decreased regional cerebral blood flow in the bilateral frontoparietal lobes, the globus pallidus, the striatum, and around the ventriculus quartus. Cardiac uptake of [(123)I] meta-iodobenzylguanidine was normal in both patients. Analysis of genotype-phenotype correlations and the elucidation of mutational effects on pantothenate kinase 2 function, expression, and structure are important for understanding the mechanisms of PKAN.