A p.Arg499His Mutation in SPAST Is Associated with Infantile Onset Ascending Spastic Paralysis Complicated with Dysarthria and Anarthria.

The complication of anarthria in hereditary spastic paraplegia (HSP) patients has been reported to result from mutations in either ALS2 or FA2H. Here, we present a case of a 12-year-old boy with hereditary spastic paralysis and anarthria associated with a SPAST mutation. Initial presentation was at 14 months of age, when the patient experienced leg stiffness. At 3 years of age, he could speak well using sentences. At 9 years of age, he was found to have dysarthria and had difficulty writing. At 12 years of age, the ability to speak was lost. The patient could not vocalize any words, despite contraction of his neck and respiratory muscles during attempted vocalization. Additionally, the patient has never walked independently in his life. Considering these symptoms, we diagnosed him as having infantile onset ascending hereditary spastic paralysis (IAHSP) complicated with anarthria. By whole-exome sequencing, we discovered a heterozygous SPAST mutation c.1496G > A (p.Arg499His), which was not found in the parents and is probably de novo. This mutation was already repeatedly described with similar phenotype. Our results suggest that the p.Arg499His mutation in SPAST should be considered as a differential diagnosis in IAHSP.

Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation.

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences].

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus.

HCN1 is one of four genes encoding hyperpolarization-activated cyclic nucleotide-gated channels. The phenotypic spectrum associated with HCN1 variants ranges from neonatal developmental and epileptic encephalopathy to idiopathic generalized epilepsy. We report a Japanese patient with repetitive focal seizures and super-refractory status epilepticus since early infancy caused by a de novo HCN1 variant, NM_021072.4, c.1195T>C, p.(Ser399Pro). This variant might have a dominant-negative effect on channel function, leading to severe epileptic encephalopathy.

West syndrome associated with mosaic duplication of FOXG1 in a patient with maternal uniparental disomy of chromosome 14.

FOXG1 on chromosome 14 has recently been suggested as a dosage-sensitive gene. Duplication of this gene could cause severe epilepsy and developmental delay, including infantile spasms. Here, we report on a female patient diagnosed with maternal uniparental disomy of chromosome 14 and West syndrome who carried a small supernumerary marker chromosome. A chromosomal analysis revealed mosaicism of 47,XX, + mar[8]/46,XX[18]. Spectral karyotyping multicolor fluorescence in situ hybridization analysis confirmed that the marker chromosome was derived from chromosome 14. A DNA methylation test at MEG3 in 14q32.2 and microsatellite analysis using polymorphic markers on chromosome 14 confirmed that the patient had maternal uniparental disomy 14 as well as a mosaic small marker chromosome of paternal origin containing the proximal long arm of chromosome 14. Microarray-based comparative genomic hybridization analysis conclusively defined the region of the gain of genomic copy numbers at 14q11.2-q12, encompassing FOXG1. The results of the analyses of our patient provide further evidence that not only duplication but also a small increase in the dosage of FOXG1 could cause infantile spasms.

Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient.

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.

Temporal changes in brain MRI findings in Rasmussen syndrome.

INTRODUCTION: MRI data is essential for early diagnosis and evaluation of surgical indication in patients with Rasmussen syndrome (RS). In the present study, we examined the status and evolutionary changes in MRI lesions to identify the MRI characteristics of RS. METHODS: MRI of 15 RS patients was examined regarding frequency and distribution of atrophic lesions on T1-weighted images and high intensity lesions on FLAIR or T2-weighted images. RESULTS: In 13 patients, atrophic lesions were observed predominantly in the frontal lobes with various extent of involvement. High intensity lesions were also observed in 13 patients. High intensity lesions were significantly more prevalent in the cortex of patients with later onset and were present in the insula in 37.5% of epilepsia partialis continua (EPC) type patients and in 57.1% of non-EPC type. Early MRI showed various combinations of atrophic lesions or high intensity lesions in seven of nine patients who underwent MRI examinations within one year of their first seizure. Serial MRI revealed high intensity lesions with characteristic features of regression (20.0% of patients), fluctuation (regression followed by reappearance; 33.3%) and expansion (46.7%). Appearance and reappearance of high intensity lesions in the cortex and/or subcortical white matter were associated with aggravation of seizures. Bilateral high intensity lesions were observed in three patients with unilateral epileptogenic foci, who were successfully treated by surgical intervention. CONCLUSION: Dynamic evolutionary changes in lesions (regression, fluctuation and expansion of high intensity lesions), as observed on MRI, may be a diagnostic feature of Rasmussen syndrome.

Early-onset absence epilepsy at eight months of age.

Early-onset absence epilepsy refers to patients with absence seizures beginning before age four and comprises a heterogeneous group of epilepsies. Onset of absence seizures in the first year of life is very rare. We report a girl with intractable absence seizures with onset at age eight months. Her seizures were characterised by loss of responsiveness, with eyes drifting upwards and some myoclonic jerks of the upper and lower limbs. These symptoms were accompanied by bilaterally symmetric high-amplitude 2-2.5 Hz generalised spike-and-wave discharges on the electroencephalogram. Her seizures were refractory to conventional antiepileptic drugs; treatment with adrenocorticotropic hormone was transiently effective. Comprehensive metabolic screening, cytogenetic, and genetic analysis did not determine an underlying cause of her condition. Patients with intractable, very early-onset absence epilepsy with a myoclonic component have an unfavourable outcome and may be classified under a new epileptic syndrome, such as "early infantile absence epilepsy".

ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H+-ATPases is essential for brain development in humans and mice.

Vacuolar H+-ATPases (V-ATPases) transport protons across cellular membranes to acidify various organelles. ATP6V0A1 encodes the a1-subunit of the V0 domain of V-ATPases, which is strongly expressed in neurons. However, its role in brain development is unknown. Here we report four individuals with developmental and epileptic encephalopathy with ATP6V0A1 variants: two individuals with a de novo missense variant (R741Q) and the other two individuals with biallelic variants comprising one almost complete loss-of-function variant and one missense variant (A512P and N534D). Lysosomal acidification is significantly impaired in cell lines expressing three missense ATP6V0A1 mutants. Homozygous mutant mice harboring human R741Q (Atp6v0a1R741Q) and A512P (Atp6v0a1A512P) variants show embryonic lethality and early postnatal mortality, respectively, suggesting that R741Q affects V-ATPase function more severely. Lysosomal dysfunction resulting in cell death, accumulated autophagosomes and lysosomes, reduced mTORC1 signaling and synaptic connectivity, and lowered neurotransmitter contents of synaptic vesicles are observed in the brains of Atp6v0a1A512P/A512P mice. These findings demonstrate the essential roles of ATP6V0A1/Atp6v0a1 in neuronal development in terms of integrity and connectivity of neurons in both humans and mice.

Early onset West syndrome with cerebral hypomyelination and reduced cerebral white matter.

Numerous numbers of pre-, peri- and postnatal damages cause West syndrome in early infancy, however, etiology in many cases are not still elucidated despite intensive biochemical and neuroradiologic investigations. We described four patients having early onset epileptic encephalopathy with severe hypomyelination and reduction in cerebral white matter. The clinical symptoms of these patients are impaired visual attention, acquired microcephaly, spastic tetraplegia, profound psychomotor delay and infantile spasms since early infancy. All patients had striking hypomyelination of cerebrum, reduced volume of white matter and cortical atrophy on MRI. Serial MRI investigations in three patients showed absence of myelination of the white matter. On EEG, one patient revealed suppression-burst and other three had hypsarrhythmia. Despite having intractable seizures, no patient showed deterioration of neurological development. The group of these findings is mimicking to clinical manifestations of 3-phosphoglycerate dehydrogenase deficiency, and has some overlap with progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy (PEHO) like syndrome, however it is not compatible with these two conditions. The findings observed in our patients can be regarded as a new clinical condition associated with early onset West syndrome.

Brain maturation-related spike localization in Panayiotopoulos syndrome: magnetoencephalographic study.

Focal spike activities in Panayiotopoulos syndrome involve all brain regions in electroencephalography, and commonly reveal multiple foci, often through occipital predominance. To investigate correlations between developmental brain maturation and spike origin in Panayiotopoulos syndrome, we evaluated age-related or duration-related magnetoencephalographic spike localization in 25 patients with Panayiotopoulos syndrome. Regarding age at examination, patients with frontal spikes were significantly older than patients with spikes on rolandic, parieto-occipital, or calcarine sulci. Occipital spikes were classified into two subgroups, located at the calcarine sulcus and parieto-occipital sulcus. Both calcarine and parieto-occipital localizations were seen in patients around the same age. Follow-up magnetoencephalography was performed on three patients, and demonstrated shifting localization or disappearance of magnetoencephalographic spikes. These results suggest that the location of spike discharges is not directly related to seizure symptoms, but instead indicates maturation-related cortical hyperexcitability in patients with Panayiotopoulos syndrome.

Megalencephaly and polymicrogyria with polydactyly syndrome.

We report the clinical manifestations of a 26-month-old Japanese girl with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. She was born to healthy, nonconsanguineous parents at 37 weeks by caesarian section after prenatal ultrasonography suggested hydrocephalus. Macrocephaly and polydactyly of both lower extremities were noted at birth. At 3 months of age, epileptic seizures developed. The patient displayed impaired vision and profound global developmental delay. Magnetic resonance imaging of the brain revealed dilatation of the lateral and third ventricles with cavum septi pellucidi et vergae and generalized polymicrogyria, most prominent in both perisylvian regions and the right frontal region. Despite ventriculomegaly, radionuclide cisternography indicated normal cerebrospinal circulation, suggesting that pathogenesis of the megalencephaly was unrelated to obstructive hydrocephalus. Decreased white matter volume and abnormal signal intensity in the occipital lobes were also noted. Visual disturbance due to white matter abnormality appears to represent a significant characteristic of this syndrome. The genetic background of the syndrome remains unclear.

Magnetoencephalographic findings of Panayiotopoulos syndrome with frontal epileptic discharges.

We previously reported the results of a magnetoencephalographic study in patients with Panayiotopoulos syndrome manifesting occipital epileptic discharges, in which the equivalent current dipoles of spike discharges were clustered alongside the major cortical sulci, such as parieto-occipital and calcarine. This report is the result of a magnetoencephalographic study of three patients with Panayiotopoulos syndrome exhibiting equivalent current dipoles clustering in the frontal area. Patient 1, a 13-year-old male, exhibited clustering equivalent current dipoles alongside right inferior frontal sulcus, but the orientations were irregular. Patient 2 is an 11-year-old younger brother of Patient 1, whose magnetoencephalograph revealed equivalent current dipoles clustering alongside right prefrontal sulcus and regular orientations. Patient 3 is a 10-year-old female who had equivalent current dipoles clustering alongside right superior frontal sulcus and extremely regular orientations. The locations of clustering equivalent current dipoles of frontal spike discharges were not restricted to one specific frontal sulcus but were present in various locations over the convexity of the prefrontal area. In conclusion, these findings suggest that it is inappropriate to classify Panayiotopoulos syndrome as occipital epilepsy. In addition, the result of this study, that frontal spike discharges seem to occur in relatively older patients, may suggest a correlation between brain maturation and spike occurrence.

[An infant with multiple cavernous angiomas presenting with frequent epileptic seizures - detection of epileptic focus by magnetoencephalography].

We report on a six-year-old girl with frequent partial seizures secondary to multiple cavernous angiomas (CAs) since the age of 17 months. MRI showed two CAs in the left parietal and right frontal lobes. Ictal scalp video EEG demonstrated complex partial seizures of left hemispheric origin, indicating that the left parietal CA was the epileptogenic lesion. Ictal SPECT showed extensive hyper-perfusion in the left frontal and parietal lobes, indicating the left hemispheric focus. Magnetoencephalography (MEG) showed clustered equivalent current dipoles of interictal spikes in the left parietal cortex adjacent to the left parietal CA. We performed lesionectomy of the left parietal CA at 19 months old. The patient became seizure-free for four years. Postoperative MEG yielded no residual interictal spikes. Our study suggests that early surgical intervention of CA may prevent from further development of epileptic seizures. MEG can identify both the epileptogenic zone and lesion underlying the multiple CAs in the infants with catastrophic partial seizures.

Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency.

Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable.

High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders.

OBJECTIVE: Recent studies have elucidated causative roles for genetic abnormalities in early-onset epileptic encephalopathies (EOEE). Accompanying characteristic features, in addition to seizures, have also been suggested to provide important clues for an early and accurate genetic diagnosis of affected patients. In this study, we investigated the underlying genetic causes in patients with EOEE associated with infantile movement disorders. METHODS: We examined 11 patients with EOEE and involuntary movements (nine with West syndrome and two with nonsyndromic epileptic encephalopathy). All showed severe developmental delay, cognitive impairment, and involuntary movements such as chorea, ballism, dyskinesia or myoclonus, and hand stereotypies. We performed whole-exome sequencing of 10 patients, while the other patient underwent high-resolution melting analysis of candidate EOEE genes. RESULTS: We identified mutations in CDKL5, SCN2A, SETD5, ALG13, and TBL1XR1 in seven patients with West syndrome, and in SCN1A and GRIN1 in the two patients with unclassified epileptic encephalopathy. All mutations were validated as de novo events. The genetic cause was undetermined in the remaining two patients. CONCLUSIONS: We found pathogenic mutations in seven genes, in nine of 11 patients with EOEE and involuntary movements. Although the results of our study are preliminary because of the small number of patients, they nevertheless suggest that specific accompanying phenotypes such as hyperkinetic movements or hand stereotypies could be important in narrowing the disease spectrum and identifying causative genetic abnormalities.

Multi-institutional study on the correlation between chromosomal abnormalities and epilepsy.

While there is an abundance of literature describing the association of chromosome aberrations with epilepsy, only a few refer to the detailed features of epilepsy. It is important to investigate the associations between specific chromosome abnormalities and features of epilepsy to identify genes involved in epilepsy and treat them more effectively. We investigated the correlation between specific chromosome aberrations and epilepsy by sending questionnaires to the members of Kyoto Multi-institutional Study Group of Pediatric Neurology. Seventy-six patients were collected from 10 institutions. Chromosome abnormalities included: Down syndrome (n = 19); Angelman syndrome (n = 8); Prader-Willi syndrome (n = 4); 4p- syndrome (n = 3); 1q- syndrome (n = 2); 5p- syndrome (n = 2); Miller-Dieker syndrome (n = 2); 18q- syndrome; (n = 2); Klinefelter syndrome; (n = 2); and 32 other individual chromosomal aberrations. Overall, the severity of mental retardation correlated with the severity of epilepsy. We could abstract characteristic features of epilepsy in some syndromes. In Angelman and Prader-Willi syndromes, febrile seizures occurred frequently, the onset of epilepsy was in early childhood and seizure phenotype was multiple. Paroxysmal discharge of the occipital region and diffuse high voltage slow wave on electroencephalography were characteristic in Angelman syndrome. In Down syndrome, West syndrome and focal epilepsy were common and the prognosis of epilepsy in West syndrome with Down syndrome was good. In 4p- syndrome, febrile seizures were often seen, and unilateral or generalized clonic or tonic-clonic status epilepticus were characteristic. For the other chromosomal aberrations investigated here, the patient numbers were too small to abstract common features of epilepsy.

Gómez-López-Hernández syndrome in a Japanese patient: a case report.

Gómez-López-Hernández syndrome (GLHS) is a rare neurocutaneous syndrome characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parieto-occipital alopecia. We herein describe the first Japanese patient with GLHS characterized by the standard triad with typical craniofacial anomaly including hypertelorism, brachyturricephaly and midface retrusion, and a short stature. This female patient had also exhibited fever-induced convulsive seizures and psychomotor developmental delay since infancy. Brain magnetic resonance imaging showed severe rhombencephalosynapsis, supratentorial abnormalities (aplasia of the septum pellucidum, severe ventricular enlargement, and hypoplasia of the corpus callosum), and hippocampus atrophy. Bilateral ectopic cerebellums were also observed. This report describes the long-term clinical outcome of GLHS and a new neuroradiological finding regarding rhombencephalosynapsis.

Rub epilepsy in an infant with Turner syndrome.

We report a case of infantile refractory epilepsy associated with Turner syndrome (TS), showing very frequent, focal clonic seizures of the left upper extremity. Characteristically, in addition to spontaneous fits, her seizure was inducible by rubbing her left hand and forearm for a few seconds. Accordingly, she was diagnosed with a rare form of reflex epilepsy, "rub epilepsy". Neuroradiological investigation indicated the existence of cortical abnormalities, such as focal cortical dysplasia of the right parietal lobe. Patients with TS are reported to have neuroanatomical abnormalities, especially of the parietal lobe. Thus, our case may imply a causal relationship between potential cortical hyperexcitability of the parietal lobe and epilepsy in TS. This is the first reported infantile case of rub epilepsy, and more generally, reflex epilepsy associated with TS.

[A case of bilateral paramedian thalamic infarction in childhood with the sensory disturbance and the sensory loss of taste].

Bilateral paramedian thalamic infarcts are characterized by disturbance of consciousness, followed by persisting dementia, decreased spontaneity, apathy, amnesia and paralysis of eye movement. We report a 15-year-old boy with this syndrome, who exhibited transient coma at the onset. In addition to the typical symptoms, he complained of sensory disturbance in the lower extremities and face and the loss of taste sense. MRI showed symmetric paramedian thalamic infarction. There was no lesion in the midbrain. The etiology of infarct in this boy remained unknown despite extensive laboratory and neuroradiological examination. His sensory disturbance in the extremities and face may be due to extensive involvement of the inferolateral area of the thalamus by infarction of the paramedian thalamic artery. This patient illustrates that bilateral paramedian thalamic infarction can occur in a previously healthy child.

[Serial MEG change in a boy with Landau-Kleffner syndrome].

We report a 7-year-old boy with Landau-Kleffner syndrome (LKS), with emphasis on the effect of therapy and serial MEG. The equivalent current dipoles (ECDs) of spike discharges accumulated in the bilateral Heschl gyri, predominantly on the right. Although spike discharges on the scalp EEGs disappeared by treatment with clonazepam and sodium valproate, the auditory agnosia did not improve. Therapeutic trials with conventional antiepileptic drugs were unsuccessful. A high-dose corticosteroid was effective, with disappearance of ECDs, appearance of auditory evoked fields (AEF) in the bilateral Heschl gyri on MEG, and improvement of behavioral problems and amelioration of acquired aphasia. The clinical course of this patient suggests that MEG findings are useful not only in making precise diagnosis of LKS but also in assessing and predicting the effects of treatment.