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An adult female patient was diagnosed with arginase 1 deficiency (ARG1-D) at 4 years of age, and had been managed with protein restriction combined with sodium benzoate therapy. Though the treatment was successful in ameliorating hyperammonemia, hyperargininemia persisted. After being under control with a strict restriction of dietary protein, severe fall of serum albumin levels appeared and her condition became strikingly worsened. However, after sodium phenylbutyrate (NaPB) therapy was initiated, the clinical condition and metabolic stability was greatly improved. Current management of ARG1-D is aimed at lowering plasma arginine levels. The nitrogen scavengers, such as NaPB can excrete the waste nitrogen not through the urea cycle but via the alternative pathway. The removal of nitrogen via alternative pathway lowers the flux of arginine in the urea cycle. Thereby, the clinical complications due to insufficient amount of protein intake can be prevented. Thus, NaPB therapy can be expected as a useful therapeutic option, particularly in patients with ARG1-D.

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs.

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation.

Background Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the lysosomal enzyme, aspartylglucosaminidase (AGA). This disorder is rare in the general population except in Finland. Since the most characteristic feature of this disorder is a progressive developmental regression, patients often show no specific symptoms in the initial stages, and thus early diagnosis is often challenging. Case report We encountered a 16-year-old boy who began to show difficulties in his speech at the age of 6years. Due to a mild regression in his development, he gradually lost common daily abilities. His diagnosis was first obtained through exome sequencing that identified a novel homozygous mutation in the AGA gene. This result was reasonable because of parental consanguinity. Reduced enzymatic activity of AGA was then confirmed. His urine was retrospectively screened by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and a specific pattern of abnormal metabolites was identified. Conclusions Because both exome sequencing and MALDI-TOF-MS screening are adaptable and comprehensive, future combinatory use of these methods would be useful for diagnosis of rare inborn errors of metabolism such as AGU.

A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene (MAP2K2), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones. Some of these findings overlapped to that of the patients with 16p13.11 microduplications and CFC syndrome. Although craniosynostosis was occasionally observed in patients with dominant-negative mutations in RAS/MAP kinase signaling genes (RASopathies) related to CFC syndrome, it was also reported in two patients with 16p13.11 microduplications. Genetic contributions of both chromosomal aberrations were discussed.

PURPOSE The level of residual cognitive function in patients with early brain injury is a key factor limiting rehabilitation and the quality of life. Although understanding residual function is necessary for appropriate rehabilitation, the extent of its effects on cognitive improvement remains unknown. This study evaluated cognitive function in patients with severe motor and intellectual disabilities after early brain injuries due to cerebral hemorrhage or periventricular leukomalacia. We focused on neural responses to hearing the subject's own name (SON). According to previous studies, differences in response to SON are associated with several types of cognitive dysfunction. METHODS We examined healthy subjects (aged 21.4 ± 1.10 years; control) and patients with a previous brain injury (aged 13-27 years at the time of our analysis) resulting in periventricular leukomalacia or a cerebral hemorrhage during the perinatal period or childhood. We recorded EEG responses to the SON and to other Japanese words, obtaining EEG-evoked potentials with wavelet transformations. RESULTS Compared with healthy controls, beta power (not alpha power) revealed differences in response to SON by patients with brain injury, especially those with cerebral hemorrhage. CONCLUSIONS We suggest that alpha and beta power differences reflect different cognitive functions and that the SON response reveals more than one process. Beta powers may reflect the intellectual disability of cognitive function in response to self-relevant stimuli, especially in patients with cerebral hemorrhage. Meanwhile, alpha powers did not differ from those of the healthy controls, suggesting that the patients perhaps paid attention to their own names.

Background Proteolipid protein 1 gene ( PLP1 ) mutations result in a continuum of neurological findings characterized by X-linked hypomyelinating leukodystrophies of the central nervous system, from mild spastic paraplegia type 2 to severe Pelizaeus–Merzbacher disease. Patients We report spastic paraplegia type 2 in three individuals in one family. A 29-year-old man developed progressive spastic quadriplegia from early childhood with dysarthria, ataxia, dysphagia, and intellectual delay, but he displayed no nystagmus. His mother developed adult-onset mild spastic diplegia with dementia developing in later life, whereas his sister exhibited spastic diplegia from childhood, complicated by motor developmental delay and dysphagia. All three individuals had initially mild but progressive neurological phenotypes, no nystagmus, normal brainstem auditory-evoked potentials, and demyelinating peripheral neuropathy, but with varying clinical severity. Results A 33-kb deletion encompassing exon 2 to 7 of PLP1 was identified in all three patients. Cloning of the junction fragment of the genomic recombination revealed a short palindromic sequence at the distal breakpoint, potentially facilitating a double-strand deoxyribonucleic acid break, followed by nonhomologous end joining. X-inactivation study and sequencing of the undeleted PLP1 alleles failed to explain the differences in severity between the two female patients. Conclusions PLP1 partial deletion is a rare cause of spastic paraplegia type 2 and exhibits X-linked dominant inheritance with variable expressivity.

Objective To determine the morphological characteristics and pathogenic factors of cerebellar injury in extremely low birth weight infants (ELBWI). Subjects and methods Neuroimaging examination was performed on 17 eligible surviving ELBWI. Their MR images were assessed and classified its pattern of cerebellar injuries. Brain pathology was examined on 15 patients, who isolated this neuroimaging subjects. The trend of brain pathologies was revealed. Results Four types of morphological pattern were recognized: (i) the absence of major portions in the cerebellum (6/17 cases); (ii) focal cerebellar tissue loss (2/17); (iii) unilateral cerebellar atrophy/hypoplasia (3/17); (iv) small cerebellum with entrapped fourth ventricle (6/17). In cerebellar pathology, the most common findings were focal or widespread cerebellar subarachnoid hemorrhage (12/15) and olivocerebellar degeneration (12/15). In addition, one-third of the cases indicated remote cerebellar parenchymal hemorrhage. Conclusion In MRI-defined lesions, the absence of major portions or focal tissue loss was associated with cerebellar parenchymal hemorrhage and/or hemorrhagic infarction, that is destructive lesion. On the other hand, small cerebellum or unilateral atrophy/hypoplasia, that is impaired development, may be related to the cerebellar neuron loss due to hemosiderin deposits in the surface of the cerebellum. The cerebellar injury in ELBWI is probably caused by not only environmental factors such as hemorrhage, hypoxia-ischemia, or other deleterious effect, but also immaturity of the rapidly growing cerebellum in particular gestational age.

Background: In order to clarify the correlation between morphological characteristics and clinical features in epilepsy patients with unilateral hippocampal abnormality, morphological and morphometric magnetic resonance imaging studies were performed. Methods: We selected a series of childhood-onset epilepsy patients with unilateral hippocampal abnormality. The volume of hippocampal formation and anterior temporal lobe were measured, and the hippocampal morphology was compared with their clinical features. The morphological characteristics of the hippocampal formation were classified into three groups: group I, diffuse and severe volume reduction of the hippocampal formation and anterior temporal lobe with abnormal signal; group II, focal atrophy or focal abnormal signal in the hippocampal formation; and group III, no significant volume reduction but an enlargement of the temporal horn. Results: All of the patients in group I had a history of status epilepticus in infancy. Temporal lobe epilepsy (TLE) was found in three of four patients. Group II contained TLE in three and frontal lobe epilepsy in one. One patient with intractable TLE had a history of status epilepticus in infancy. Group III contained miscellaneous epilepsies, including benign partial epilepsy with centro-temporal spikes in three of seven patients. Five patients in group III showed some characteristic features of hippocampal malrotation, which refers to incomplete hippocampal infolding. Conclusions: Diffuse and severe volume reduction of the hippocampal formation and anterior temporal lobe with unilateral hippocampal sclerosis was strongly associated with status epilepticus in infancy. Both hippocampal sclerosis and hippocampal malrotation suggest significant roles in the pathogenesis of epilepsy.

Neuropathology and neuroimaging of long-term survival cases of arginase deficiency are rarely reported. The magnetic resonance imaging (MRI) of our case showed severe multicystic white matter lesions with cortical atrophy, which were more severe compared with previous reports. In this patient, low-protein diet successfully reduced hyperammonemia, but hyperargininemia persisted. These severe neurological and MRI findings may be explained by a compound heterozygote, inheriting both of severe mutant alleles from her parents.

Background Severe motor and intellectual disability (SMID) patients cannot express their feelings with language. Understanding what they are thinking about or how they feel is thus difficult. This study focused on brain responses to hearing their own names to clarify the situation in these patients. Methods We performed and analyzed electroencephalography (EEG) for six patients with SMID and eleven healthy subjects. All subjects were presented with auditory stimuli including calling the subject’s own name (SON) and reading words. EEG was analyzed by time–frequency analysis, event-related spectral perturbation (ERSP) to detect EEG power changes caused by EEG amplitude, and inter-trial coherence (ITC) to investigate phase-locked changes. Results ERSP results from healthy subjects showed significant theta power increases as a specific response to SON. While we could not identify a similar pattern in the responses of patients with SMID, analysis of ITC revealed that theta phase-locked activity increased in response to SON not only in all healthy subjects, but also in four patients. Discussion These results indicate that theta phase-locked activity in some patients with SMID was strongly associated with SON, as in healthy subjects. Our study suggests the existence of specific neural markers that signal an attentional shift in patients upon hearing SON.

SummaryObjective De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs). Methods A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples). Results We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic–clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability. Significance Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.