Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this ...incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10
) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.
X-linked lymphoproliferative disease type 1 (XLP1) is a rare monogenic immune dysregulation disorder caused by a deficiency of a signaling lymphocyte activation molecule-associated protein (SAP). ...While many patients with XLP1 present with fatal hemophagocytic lymphohistiocytosis upon Epstein Barr virus (EBV) infection, a small fraction present with limbic encephalitis in the absence of EBV infection. It is poorly understood why SAP deficiency may cause limbic encephalitis in XLP1.
A 12-year-old boy presented with seizures, changes in personality, memory loss, and cognitive deficits during treatment for interstitial pneumonia. A diagnosis of limbic encephalitis was made. Despite treatment against CD8+ T cell-mediated autoimmunity with intravenous methylprednisolone, dexamethasone, intravenous immunoglobulin, plasma exchange, cyclosporine, weekly etoposide, mycophenolate mofetil, and adalimumab, encephalitis progressed until the patient died after one month of treatment intitiation. Post-mortem genetic testing revealed a de novo SH2D1A truncating mutation. Tests for EBV infection were negative. Initial spinal fluid revealed markedly elevated protein levels, mild pleocytosis, and elevation of two chemokines (C-X-C motif chemokine ligand CXCL 10 and CXCL 13). Moreover, initial spinal fluid was tested positive for anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) autoantibody.
In XLP1-associated limbic encephalitis, anti-AMPAR autoantibody production by the dysregulated immune system due to SAP deficiency might be a pathogenic mechanism of central nervous system manifestations. In addition to the standard treatment for XLP1, targeted treatment against B-cell-mediated immunity might be indicated for patients with XLP1-associated limbic encephalitis.
Current assessment of patients with cerebellar disorders is based on conventional neurological examination that is dependent on subjective judgements. Quantitative measurement of cerebellar ataxias ...(CAs) is essential for assessment of evidence-based treatments and the monitoring of the progress or recovery of diseases. It may provide us a useful tool to navigate future treatments for ataxia. We developed a Kinect v2. sensor system with a novel algorithm to measure and evaluate movements for two tests of Scale for the Assessment and Rating of Ataxia (SARA): the nose-finger test and gait. For the nose-finger test, we evaluated and compared accuracy, regularities and smoothness in the movements of the index finger and the proximal limbs between cerebellar patients and control subjects. For the task of walking, we evaluated and compared stability between the two groups. The precision of the system for evaluation of movements was smaller than 2 mm. For the nose-finger test, the mildly affected patients tended to show more instability than the control subjects. For a severely affected patient, our system quantified the instability of movements of the index finger using kinematic parameters, such as fluctuations and average speed. The average speed appears to be the most sensitive parameter that contrasts between patients with CAs and control subjects. Furthermore, our system also detected the adventitious movements of more proximal body parts, such as the elbow, shoulder and head. Assessment of walking was possible only in patients with mild CAs. They demonstrated large sways and compensatory wide stances. These parameters appeared to show higher accuracy than SARA. This examiner-independent device measures movements of the points of interest of SARA more accurately than eye and further provides additional information about the ataxic movements (e.g., the adventitious movements of the elbow, shoulder and head in the nose-finger test and the wide-based walking with large oscillation in the gait task), which is out of the scope of SARA. Our new system enables more accurate scoring of SARA and further provides additional information that is not currently evaluated with SARA. Therefore, it provides an easier, more accurate and more systematic description of CAs.
Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired ...by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia.
Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period.
Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases.
Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.
Coffin-Lowry syndrome is a rare X-linked disease, caused by loss-of-function mutations in the RPS6KA3 gene. Patients exhibit severe intellectual disability with characteristic dysmorphism. As there ...are no specific laboratory findings to support the diagnosis of Coffin-Lowry syndrome, it may be difficult to diagnose—especially in young children, where the characteristic craniofacial features are less discernible.
Here we report on a 2-year-old boy with Coffin-Lowry syndrome with a novel missense mutation in the RPS6KA3 gene. On magnetic resonance imaging, his brain exhibited periventricular signal abnormalities with multiple small cystic lesions. These findings may aid in diagnosis of Coffin-Lowry syndrome.
We present a boy with KMT2B‐related dystonia (DYT‐KMT2B), a recently identified early‐onset generalized dystonia. He manifested prominent asterixis, which improved following bilateral globus pallidus ...interna deep brain stimulation (GPi‐DBS). Although variable involuntary movements, including myoclonus and tremor, can be seen in patients with DYT‐KMT2B, asterixis has not been reported. This is also the first report which shows the beneficial effect of bilateral GPi‐DBS for asterixis, suggesting that dysfunction of the cortico‐basal ganglia‐thalamo‐cortical circuit may be involved in its pathomechanism.
Objective
To elucidate the genetic background and genotype‐phenotype correlations for epilepsy with myoclonic‐atonic seizures, also known as myoclonic‐astatic epilepsy (MAE) or Doose syndrome.
...Methods
We collected clinical information and blood samples from 29 patients with MAE. We performed whole‐exome sequencing for all except one MAE case in whom custom capture sequencing identified a variant.
Results
We newly identified four variants: SLC6A1 and HNRNPU missense variants and microdeletions at 2q24.2 involving SCN1A and Xp22.31 involving STS. Febrile seizures preceded epileptic or afebrile seizures in four patients, of which two patients had gene variants. Myoclonic‐atonic seizures occurred at onset in four patients, of which two had variants, and during the course of disease in three patients. Variants were more commonly identified in patients with a developmental delay or intellectual disability (DD/ID), but genetic status was not associated with the severity of DD/ID. Attention‐deficit/hyperactivity disorder and autistic spectrum disorder were less frequently observed in patients with variants than in those with unknown etiology.
Significance
MAE patients had genetic heterogeneity, and HNRNPU and STS emerged as possible candidate causative genes. Febrile seizures prior to epileptic seizures and myoclonic‐atonic seizure at onset indicate a genetic predisposition to MAE. Comorbid conditions were not related to genetic predisposition to MAE.
The aim of this study was to report a case of Peters plus-like syndrome, which revealed to have an 8q21.11 microdeletion by copy number variation analysis using exome data.
A 6-month-old Japanese boy ...presented with bilateral corneal opacity since birth. The right eye maintained central corneal transparency with slightly inferior nasal and superior peripheral corneal opacities. The entire cornea was opacified in the left eye, particularly in the superior quadrants with vascularization, suggesting Peters anomaly. Identification of intraocular structures in the left eye was difficult; however, hypoplasia of the circumferential anterior iris stroma appeared bilaterally present, and no abnormalities were present in the posterior segment on funduscopic examination of the right eye and ultrasonography in the left eye. He had several facial malformations in addition to corneal opacity, but no other external abnormalities. General examination, including biochemical tests of blood and urine, physiological and imaging tests including abdominal echo, auditory brain stem response, brain computed tomography, and magnetic resonance imaging, showed no abnormalities. However, the patient showed intellectual disability and delayed motor development.
Although his karyotype was normal, copy number variation analysis using exome data and subsequent quantitative polymerase chain reaction identified a de novo 4.6-Mb deletion at 8q21.11q21.13; thus, the patient was diagnosed with 8q21.11 microdeletion syndrome.
We identified a de novo 4.6-Mb deletion at 8q21.11q21.13 in a patient with ophthalmic anterior segment dysgenesis and systemic complications, clinically diagnosed as Peters plus-like syndrome. Clinically, the 8q21.11 microdeletion syndrome shows a phenotype similar to that of Peters plus syndrome, and a genetic diagnosis is required.
Variants in the type IV collagen gene (
) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with
variants remain ...unclear.
We examined
in 218 individuals with suspected
/2-related brain defects. Among those arising from
variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail.
Pathogenic
variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with
variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly.
Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and
gene testing should be considered when pathogenic variants are strongly suspected.
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