CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we ...previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired demyelinating disease of the peripheral nervous system with unknown etiology. Alopecia universalis, an advanced form of ...alopecia areata (AA), is a condition characterized by complete hair loss. Here we report the first case of childhood CIDP associated with AA who was successfully treated with a combination of intravenous immunoglobulin (IVIg) and corticosteroids.
This case describes a nine-year-old Japanese girl who developed alopecia, progressive muscle weakness, and eventually loss of walking ability (at ages 2, 4, and 7, respectively). She was treated with IVIg and prednisolone combination therapy, which improved muscle weakness and alopecia. She was positive for serum IgG-GM2 type anti-glycolipid antibodies, which may be associated with this rare combination of diseases.
Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, ...cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images. We detected compound heterozygous mutation in LONP1. One allele contained a paternally inherited frameshift mutation (p.Ser100Glnfs*46). The other allele contained a maternally inherited missense mutation (p.Arg786Trp), which was predicted to be pathogenic by web-based prediction tools. The two mutations were not found in Exome Variant Server or our 575 in-house control exomes. Some features were not consistent with CODAS syndrome but overlapped with Marinesco-Sjögren syndrome, a multisystem disorder caused by a mutation in SIL1. An atypical mutation site may result in atypical presentation of the LONP1 mutation.
Recently, de novo KIF1A mutations were identified in patients with intellectual disability, spasticity and cerebellar atrophy and/or optic nerve atrophy. In this study, we analyzed a total of 62 ...families, including 68 patients with genetically unsolved childhood cerebellar atrophy, by whole-exome sequencing (WES). We identified five de novo missense KIF1A mutations, including only one previously reported mutation (p.Arg316Trp). All the mutations are located in the motor domain of KIF1A. In all patients, initial symptom onset was during the infantile period, and included developmental delay in three patients and gait disturbance in two. Thereafter, they showed gait disturbances, exaggerated deep tendon reflexes, cerebellar symptoms and cerebellar atrophy on brain magnetic resonance imaging. Four patients showed lower limb spasticity, upper limb clumsiness and visual disturbances. Nerve conduction study revealed peripheral neuropathy in three patients. This study further delineates clinical features of de novo KIF1A mutations. Genetic testing of KIF1A should be considered in children with developmental delay, cerebellar atrophy and pyramidal features.
Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases ...and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.1741C>T;2158C>T p.(Arg581*);(Arg720*). The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.
Summary
Objective
GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In ...addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations.
Methods
In total, 526 and 145 patients with infantile epilepsy were analyzed by whole‐exome sequencing and GABRA1‐targeted resequencing, respectively.
Results
We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N‐terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously.
Significance
Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.
The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, ...p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.
Human metapneumovirus (hMPV) is a common cause of upper and lower respiratory tract infections in children. A few case reports have described hMPV encephalitis or encephalopathy. Neuroimaging data on ...patients with hMPV encephalitis are scarce. We report a patient with trisomy 13 who developed severe hMPV pneumonia, multifocal cerebral and cerebellar hemorrhagic infarctions and extensive cerebral white matter demyelination. Although adult respiratory distress syndrome and disseminated intravascular coagulation contributed to the devastating central nervous system (CNS) lesions, endothelial dysfunction of the CNS caused by hMPV infection probably also played a pathophysiological role in this case.
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