Brain & Development最新文献

Purpose

We investigated the volumetric differences in cortical and subcortical structures between patients with complex febrile seizure (FS) and recurrent simple FS. We aimed to identify the brain morphological patterns of children with complex FS.

Methods

Twenty-five patients with complex FS and age- and sex-matched 25 patients with recurrent simple FS with structural magnetic resonance imaging (MRI) scans were studied. Cortical volumetric analysis was performed using a voxel-based morphometry method with the CAT12 toolbox within SPM12. FSL-FIRST was used to obtain volume measures of subcortical deep grey matter structures (amygdala, caudate nucleus, thalamus, nucleus accumbens, putamen, globus pallidus, and hippocampus). The volumetric asymmetry index (AI) and laterality index (LI) were calculated for each subcortical structure.

Results

Compared with recurrent simple FS, complex FS demonstrated lower volume in the left putamen (p = .003) and right nucleus accumbens (p = .001). Additionally, patients with complex FS presented a higher magnitude of AI of the nucleus accumbens (p < .001) compared with recurrent simple FS.

Conclusions

The findings indicate that volumetric analysis may be a useful marker for the detection of FS-induced changes that reflect microstructural alterations. This study is the first to report on alterations in the putamen and nucleus accumbens in FS.

Background

Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD.

Case Report

The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M.

Conclusions

In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

Background

There are no established biomarkers for diagnosing acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) in the early acute phase, called “the 1st seizure phase”. Based on our clinical experience, we hypothesized that serial examinations of blood levels of aspartate aminotransferase (AST) in children with febrile convulsive status epilepticus (FCSE) revealed higher levels in patients with AESD in the 1st seizure phase than in those with prolonged febrile seizures (PFs).

Methods

To test our presented hypothesis, we retrospectively investigated changes in serum AST in patients with FCSE due to AESD (n = 11) or PFs (n = 27) who were serially examined within 48 h of the onset of convulsions.

Results

The rate of increase in AST was significantly higher in patients with AESD than in those with PFs. The rate of increase in AST correlated with previously reported scoring systems, i.e., Yokochi and Tottori scores, for the prediction of AESD. A positive correlation between the rate of increase in AST and creatinine levels in the first examination were observed; however, creatinine levels did not significantly differ between the AESD and PFs groups in the first or second examination. Blood levels of pH, ammonia, and sugar in the first examination and C-reactive protein in the second examination were significantly higher in the AESD group than in the PFs group.

Conclusions

The present study revealed that the rate of increase in AST was significantly higher in patients with AESD than in those with PFs. A novel predictive scoring system needs to be established in combination with the rate of increase in AST and reported clinical parameters, which will improve the prognosis of patients with FCSE.

Background

Autism spectrum disorder is a major neurodevelopmental disorder. Temtamy syndrome is a rare syndromic intellectual developmental disorder that presents with global developmental delay, autism, seizures, and agenesis/dysgenesis of the corpus callosum.

Methods

We report a case of a male child who presented with global developmental delay, and autism. Additional clinical features in the child were prominent eyes, long palpebral fissures with eversion of lateral third of the lower eyelid, hypoplastic nipples, and persistent fetal fingertip pads. The clinical features were in favor of Kabuki-like syndrome. MRI brain revealed corpus callosal dysgenesis, mild cerebellar para-vermian, and vermian atrophy.

Results

Trio exome sequencing has revealed a novel pathogenic compound heterozygous variant c.145A >T (p.Lys49Ter) and c.224_242del (p.Val85GlufsTer88) in exon 2 of the C12orf57 gene.

Conclusion

This is the first case of Temtamy syndrome reported from India with additional novel phenotypic features not reported previously and broadens the phenotypic spectrum of the disorder. In addition, it expands the spectrum of pathogenic variants in the C12orf57 gene.

Introduction

Although the whole-exome sequencing (WES) approach has been widely used in clinic, many rare diseases with syndromic and nonsyndromic neurological manifestations remain undiagnosed. Coffin-Siris syndrome (CSS) is a rare autosomal dominant genetic disease characterized by neurodevelopmental delay. A suspected diagnosis can be made based on the typical CSS clinical features; however, molecular genetic testing is necessary for a confirmed diagnosis.

Objectives

Three CSS-like patients with negative results in the WES and chromosomal microarray analysis (CMA) were recruited in this study.

Methods

We used whole-genome sequencing (WGS) technology to sequence the peripheral blood of the three families. To further explore the possible pathogenesis of CSS, we performed RNA-sequencing (RNA-seq).

Results

WGS identified the three CSS patients were carrying de novo copy number variants of the ARID1B gene, which have not been reported before. RNA-seq identified 184 differentially expressed genes (DEGs), with 116 up-regulated and 68 down-regulated. Functional annotation of DEGs showed that two biological processes (immune response, chemokine activity) and two signaling pathways (cytokine-cytokine receptor interaction, chemokine activity) were highlighted. We speculated that ARID1B deficiency might trigger abnormal immune responses, which may be involved in the pathophysiologic mechanisms of CSS.

Conclusion

Our research provided further support for WGS application in CSS diagnosis and made an investigational approach for the underlying mechanisms of CSS.

Background

Hyperphenylalaninemia is a biomarker for several monogenic neurotransmitter disorders where the body cannot metabolise phenylalanine to tyrosine. Biallelic pathogenic variants in DNAJC12, co-chaperone of phenylalanine, tyrosine, and tryptophan hydroxylases, leads to hyperphenylalaninemia and biogenic amines deficiency.

Methods and Results

A male firstborn to non-consanguineous Sudanese parents had hyperphenylalaninemia 247 µmol/L [reference interval (RI) < 200 µmol/L] at newborn screening. Dried blood spot dihydropteridine reductase (DHPR) assay and urine pterins were normal. He had severe developmental delay and autism spectrum disorder without a notable movement disorder. A low phenylalanine diet was introduced at two years without any clinical improvements. Cerebrospinal fluid (CSF) neurotransmitters at five years demonstrated low homovanillic acid (HVA) 0.259 µmol/L (reference interval (RI) 0.345–0.716) and 5-hydroxyindoleaetic acid (5HIAA) levels 0.024 µmol/L (reference interval (RI) 0.100–0.245). Targeted neurotransmitter gene panel analysis identified a homozygous c.78 + 1del variant in DNAJC12. At six years, he was commenced on 5-hydroxytryptophan 20 mg daily, and his protein-restricted diet was liberalised, with continued good control of phenylalanine levels. Sapropterin dihydrochloride 7.2 mg/kg/day was added the following year with no observable clinical benefits. He remains globally delayed with severe autistic traits.

Conclusions

Urine, CSF neurotransmitter studies, and genetic testing will differentiate between phenylketonuria, tetrahydrobiopterin or DNAJC12 deficiency, with the latter characterised by a clinical spectrum ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and movement disorder, normal DHPR, reduced CSF HIAA and HVA. DNAJC12 deficiency should be considered early in the differential workup of hyperphenylalaninemia identified from newborn screening, with its genotyping performed once deficiencies of phenylalanine hydroxylase (PAH) and tetrahydrobiopterin (BH4) have been biochemically or genetically excluded.

Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome.

Case report

We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia.

Conclusion

Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype–genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.

Background

Pericytes play a role in the maintenance of the blood–brain barrier and neuroinflammation, attracting attention as to whether they are also involved in the pathogenesis of epilepsy. This study aimed to explore the relationship between West syndrome and pericytes.

Methods

Eighteen Japanese pediatric West syndrome patients and nine controls aged 2 years or younger were retrospectively enrolled in this study. We assessed the serum levels of pericyte markers, serum PDGFRβ (platelet-derived growth factor receptor β), CD13 (aminopeptidase N), and 27 cytokines in 17 pediatric patients with West syndrome and the control group.

Results

Patients with West syndrome exhibited significantly increased CD13 and decreased PDGFRβ levels, compared with controls but not serum cytokine levels. These values did not differ significantly between symptomatic and idiopathic West syndrome.

Conclusion

Pericytes might be implicated in the pathogenesis of West syndrome.