村松 一洋

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.

Corona virus infectious disease, emerged in 2019(COVID-19)は、流行の主体が感染性の高いオミクロン変異株に置き換わり小児の感染者数が増加し、けいれん、意識障害、脳炎・脳症例も増加し、重症化する症例や後遺症を残す症例も報告されている。われわれが経験した小児COVID-19の出血性ショック脳症症候群や、片側けいれん・片麻痺・てんかん症候群を含む3症例の急性脳症を提示する。小児COVID-19の急性脳症はインフルエンザ脳症と同様、さまざまな臨床病型・重症度、そして予後をとりうる。(著者抄録)

BACKGROUND: Fabry disease (FD) is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A (α-Gal A) encoded by the GLA gene. The symptoms of FD occur as a result of the accumulation of globotriaosylceramide (Gb3), comprising a substrate of α-Gal A, in the organs. Adeno-associated virus (AAV)-mediated gene therapy is a promising treatment for FD. METHODS: α-Gal A knockout (GLAko) mice were injected intravenously with AAV2 (1 × 1011 viral genomes [vg]) or AAV9 (1 × 1011 or 2 × 1012 vg) vectors carrying human GLA (AAV-hGLA), and plasma, brain, heart, liver and kidney were tested for α-Gal A activity. The vector genome copy numbers (VGCNs) and Gb3 content in each organ were also examined. RESULTS: The plasma α-Gal A enzymatic activity was three-fold higher in the AAV9 2 × 1012 vg group than wild-type (WT) controls, which was maintained for up to 8 weeks after injection. In the AAV9 2 × 1012 vg group, the level of α-Gal A expression was high in the heart and liver, intermediate in the kidney, and low in the brain. VGCNs in the all organs of the AAV9 2 × 1012 vg group significantly increased compared to the phosphate-buffered-saline (PBS) group. Although Gb3 in the heart, liver and kidney of the AAV9 2 × 1012 vg was reduced compared to PBS group and AAV2 group, and the amount of Gb3 in the brain was not reduced. CONCLUSIONS: Systemic injection of AAV9-hGLA resulted in α-Gal A expression and Gb3 reduction in the organs of GLAko mice. To expect a higher expression of α-Gal A in the brain, the injection dosage, administration route and the timing of injection should be reconsidered.

Background and objectives To clarify whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection cause acute encephalopathy in children and which are the most common syndromes that cause them and what are the outcomes. Methods A nationwide web-based survey among all members of the Japanese Society of Child Neurology to identify pediatric patients aged < 18 years who developed acute encephalopathy in Japan between 1 January 2020 and 31 May 2022 associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by polymerase chain reaction or antigen tests using pharyngeal swabs. Acute encephalopathy was defined as acute onset of impaired consciousness lasting > 24 h or an altered mental state; neurological symptoms arising within 2 weeks of onset of COVID-19 or multisystem inflammatory syndrome in children (MIS-C)/pediatric inflammatory multisystem syndrome (PIMS); evidence of SARS-CoV-2 infection; and reasonable exclusion of other diseases. Patients were divided into the known clinico-radiological acute encephalopathy syndrome group and unexplained or unclassifiable acute encephalopathy group. Outcomes were assessed by pediatric cerebral performance category (PCPC) score at hospital discharge. Results Of the 3,802 society members, 217 representing institutions responded, and 39 patients with suspected acute encephalopathy were reported, of which 31 met inclusion criteria. Of these patients, 14 were diagnosed with known clinico-radiological acute encephalopathy syndromes, with acute encephalopathy with biphasic seizures and late reduced diffusion (five patients) being the most common. Five developed acute encephalopathy associated with MIS-C/PIMS. Among 31 patients, 9 (29.0%) had severe sequelae or died (PCPC ≥ 4). Two of three patients with encephalopathy with acute fulminant cerebral edema and two with hemorrhagic shock and encephalopathy syndrome died. The PCPC scores were higher in the known clinico-radiological acute encephalopathy syndrome group than in the unexplained or unclassifiable acute encephalopathy group (P < 0.01). Discussion Acute encephalopathy related to SARS-CoV-2 infection was demonstrated to be more severe than that caused by other viruses in Japan. Acute encephalopathy syndromes characterized by specific neuroradiological findings was associated with poor clinical outcomes.

PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.

Abstract Static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WIPI4. However, the pathophysiology of the disease, particularly the function of WDR45/WIPI4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WIPI4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e., ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron‒containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood/β-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications.

BACKGROUND: Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM. METHODS: We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy. RESULTS: Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells. CONCLUSION: Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.

INTRODUCTION: Methyl-CpG binding protein 2 gene (MECP2) is located on the X chromosome (Xq28) and is important for nervous and immune system functioning. Patients with MECP2 duplication syndrome (MDS) have recurrent respiratory infections (RRIs). Although RRIs often occur with MDS because some patients with MDS also have hypoimmunoglobulinemia and duplication of the interleukin-1-receptor-associated kinase-1 gene (IRAK1), which is also located on Xq28, the phenotype of IRAK1 duplication in patients with MDS remains unclear. METHODS: The clinical course of three patients with MDS who underwent laryngotracheal separation (LTS) at two institutions was summarized. RESULTS: Three patients with MDS were identified to have recurrent pneumonia characteristic of aspiration pneumonia, sometimes requiring artificial ventilation therapy; they had no other bacterial infections. After LTS, they rarely had pneumonia. In MDS, MECP2 expression increased two-fold naturally, while IRAK-1 expression showed no difference compared with a healthy subject. CONCLUSIONS: Since RRIs in MDS are thought to be caused by aspiration and not susceptibility to infection previously estimated to be major complication, the evaluation of aspiration is recommended for RRIs for better management of MDS.

Previous studies have reported that hypothyroidism can lead to sick sinus syndrome (SSS) or other rhythm disturbances. Variants in the alpha subunit of the cardiac sodium channel (SCN5A) are known to be among the genetic causes of SSS. We encountered an adolescent patient with SSS and hypothyroidism who also harbored an SCN5A variant. The patient was a 13-year-old girl who was referred to our hospital because of bradycardia identified during a school electrocardiography screening. Clinical examination revealed severe hypothyroidism due to Hashimoto thyroiditis and SSS. After levothyroxine supplementation, her symptoms of hypothyroidism improved; however, the SSS did not. Genetic testing revealed a heterozygous variant (c.1066 G>A, p.Asp356Asn) in SCN5A. This is the first report of the coexistence of SSS due to an SCN5A variant and severe hypothyroidism in an adolescent patient. While patients with SCN5A variants exhibit phenotypic heterogeneity due to the presence of various modifiers, the presence of severe hypothyroidism may affect the development of SSS. This case highlights the importance of genetic analysis, including testing for SCN5A variants, in patients with hypothyroidism complicated by SSS or cardiac conduction disorders.

2018年以降に日本小児神経学会が公表した以下の3つの提言を紹介した。1)脳波等神経生理検査時の鎮静における医療安全に関する提言・指針、2)小児頭部外傷時のCT撮像基準の提言・指針、3)West症候群に対するACTH療法を安全に施行するための手引き。この提言内容は、小児と小児に関わる全ての医療関係者の医療安全につながるものであり、広く周知されるべきものである。

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.

<jats:title>ABSTRACT</jats:title> <jats:p>A 7-week-old girl with a normal birth history suddenly developed respiratory distress while feeding. Cardiopulmonary resuscitation was initiated at home after she had a cardiac arrest and was continued in the emergency room but all efforts at resuscitation proved unsuccessful and she died 2 h after presentation. Investigations performed in the emergency room revealed that she had a significantly high white blood cell count and severe anaemia. The cause of death was identified as KMT2A-rearranged infantile acute lymphoblastic leukaemia based on cytogenetic tests. She had no abnormalities at the 4-week check-up; however, she developed a skin nodule on her abdomen thereafter, and the family did not consult a doctor for fear of contracting COVID-19. Early detection and diagnosis could have changed the prognosis of the patient. The present case highlights the negative impact of the reduction of outpatient consultations during the COVID-19 pandemic.</jats:p>

PURPOSE: Forced normalization (FN) indicates psychotic episodes associated with seizure remission and disappearance of epileptiform activity on EEG. FN is likely to occur when frequent seizures are abruptly terminated by anti-epileptic drugs (AEDs) or epilepsy surgery. METHODS: We describe an atypical case of a patient with FN induced by lacosamide (LCM). RESULTS: A 23-year-old female patient with Lennox-Gastaut syndrome (LGS) was administered AEDs for LGS and hospitalised with weight loss and abnormal behaviour. Her condition fulfilled the FN criteria, which was considered to be induced by LCM. After a reduction in LCM dose, her abnormal behaviour and appetite improved. During LCM use, the patient developed no seizures, and the high amplitude diffuse sharp and slow wave complexes that were frequently observed before LCM disappeared on EEG. The LCM dose was tapered to 150 mg per day, and she became calmer with socially appropriate behaviours, although a few mild focal seizures relapsed. CONCLUSION: LCM was effective for treating LGS in this patient and induced FN. Initially, it was difficult to recognise FN in cases of psychiatric disorders, especially in patients with intellectual disability. Patients with FN induced by LCM are rare, and only four patients have been previously reported who were treated by antipsychotic drug for psychosis.

INTRODUCTION: Metachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder. Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer. CASE REPORT: The patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range. DISCUSSION: Rapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.

<title>Abstract</title><sec> <title>Background</title> Congenital central hypoventilation syndrome (CCHS) is a rare disease characterized by sleep apnea. Anoxia often occurs soon after birth, and it is important to prevent anoxia-mediated central nervous system complications; however, data on the relationship between respiratory management and the prognosis for intellectual development of patients with CCHS is not well yet investigate. </sec><sec> <title>Methods</title> We performed a retrospective chart review cohort study of patients with CCHS in Japan. We investigated the risk and prognostic factors for developmental outcomes and examined the disease in terms of its symptoms, diagnosis, complications, and treatment. </sec><sec> <title>Results</title> Of the 123 patients with CCHS included in the survey, 88 patients were 6 years old and older. They were divided into two group based on their intelligence quotient. Those treated using positive-pressure ventilation via tracheostomy in the first three months of life had a better developmental prognosis than those managed via tracheostomy after three months of age and those treated by ventilation using mask (OR = 3.80; 95% CI: 1.00–14.37, OR = 4.65; 95% CI: 1.11–19.37). There was no significant difference in physical development (<italic>P</italic> = 0.64). </sec><sec> <title>Conclusions</title> The best respiratory treatment for patients with CCHS is ventilation via tracheostomy, initiated ideally before the age of three months. </sec>

Niemann-Pick disease type C1 (NPC1) is a fatal congenital neurodegenerative disorder caused by mutations in the NPC1 gene, which is involved in cholesterol transport in lysosomes. Broad clinical manifestations of NPC1 include liver failure, pulmonary disorder, neurological deficits, and psychiatric symptoms. The main cause of death in NPC1 patients involves central nervous system (CNS) dysfunction; there is no essential treatment. We generated a tyrosine-mutant adeno-associated virus (AAV) 9/3 vector that expresses human NPC1 under a cytomegalovirus (CMV) promoter (AAV-CMV-hNPC1) and injected it into the left lateral ventricle (5 μL) and cisterna magna (10 μL) of Npc1 homo-knockout (Npc1-/-) mice. Each mouse received total 1.35 × 1011 vector genome on days 4 or 5 of life. AAV-treated Npc1-/- mice (n = 11) had an average survival of >28 weeks, while all saline-treated Npc1-/- mice (n = 11) and untreated Npc1-/- mice (n = 6) died within 16 weeks. Saline-treated and untreated Npc1-/- mice lost body weight from 7 weeks until death. However, the average body weight of AAV-treated Npc1-/- mice increased until 15 weeks. AAV-treated Npc1-/- mice also showed a significant improvement in the rotarod test performance. A pathological analysis at 11 weeks showed that cerebellar Purkinje cells were preserved in AAV-treated Npc1-/- mice. In contrast, untreated Npc1-/- mice showed an almost total loss of cerebellar Purkinje cells. Combined injection into both the lateral ventricle and cisterna magna achieved broader delivery of the vector to the CNS, leading to better outcomes than noted in previous reports, with injection into the lateral ventricles or veins alone. In AAV-treated Npc1-/- mice, vector genome DNA was detected widely in the CNS and liver. Human NPC1 RNA was detected in the brain, liver, lung, and heart. Accumulated unesterified cholesterol in the liver was reduced in the AAV-treated Npc1-/- mice. Our results suggest the feasibility of gene therapy for patients with NPC1.

Several patients with beta-propeller protein-associated neurodegeneration (BPAN)/static encephalopathy with neurodegeneration in adulthood have been reported to present Rett syndrome (RTT)-like features. This report presents an individual with BPAN showing clinical features of RTT. Psychomotor delay and epilepsy onset were noted at 1 year, and regression began at 4 years. Screening of the methyl-CpG binding protein 2 (MECP2) did not show variants. At 22 years, basal ganglia iron deposits were found on magnetic resonance imaging (MRI), and the WD-domain repeat 45 gene (WDR45) variant was identified. Review of the literature showed that BPAN with RTT-like features is associated with more epileptic seizures and less deceleration of head growth, breathing irregularities, and cold extremities than classic RTT with MECP2 variants. These clinical presentations may provide clues for differentiating between these two disorders. However, both WDR45 and MECP2 should be screened in patients presenting a clinical picture of RTT without specific MRI findings of BPAN.

OBJECTIVE: The early diagnosis of beta-propeller protein-associated neurodegeneration (BPAN) before distinct brain magnetic resonance imaging (MRI) findings of iron deposition occur remains challenging. This study examined whether children with BPAN have characteristic high-amplitude (>50 μV) fast activity (HAFA) on electroencephalography (EEG). METHODS: We conducted a retrospective analysis of EEG performed during childhood in five patients with BPAN. We also examined 143 EEGs from 59 patients with different etiologies, including epilepsy (n = 33), acute encephalopathy (n = 6), neurodevelopmental disorders (n = 5), non-epileptic events (n = 4), and others (n = 11). Trained electroencephalographers reviewed all of the EEGs. When excessive fast activity was observed, the amplitude, frequency, and locality were assessed. RESULTS: All five patients with BPAN underwent initial EEGs at 12-21 months old, and diffuse continuous HAFA (range 20-50 Hz) was observed on both awake and sleep EEGs. In the awake records, there was no clear posterior dominant rhythm in 4 of the 5 patients. Although 28% of the 143 EEGs had continuous excessive fast activity, mainly in the sleep records, only two (1.4%) exhibited HAFA when asleep, and their awake EEGs had clear posterior dominant rhythm. CONCLUSIONS: The EEGs of children with BPAN showed diffuse HAFA continuously when both awake and asleep, which is uncommon in children with other etiologies. SIGNIFICANCE: This study provides an important clue for the early diagnosis of BPAN.

Ring chromosome 20 syndrome is an epileptic and neurodevelopmental encephalopathy that occurs in children, characterised by a triad of refractory frontal lobe seizures, recurrent non-convulsive status epilepticus and frontal lobe-dominant paroxysmal discharges. However, details of other clinical features associated with ring chromosome 20 syndrome remain unknown. Here, we report two patients with ring chromosome 20 syndrome who had praxis-induced reflex seizures. Case 1 was an 11-year-old girl who presented with seizures triggered by specific activities such as mental and written calculations, writing, decision-making, recall, sudden changes in routine or ambient temperature and bathing. During calculations, left frontal lobe-dominant, 3-Hz slow-wave bursts were observed on EEG. Lacosamide effectively suppressed her tonic seizures. Case 2 was a six-year-old boy who presented with seizures triggered by specific activities such as calculations, recall and bathing. During calculations, frontal lobe-dominant, 3-Hz spike and slow-wave bursts were observed on EEG. Although his epilepsy was refractory, gabapentin reduced the frequency of focal seizures. In both cases, the hyperexcitability in the frontal lobe may have spread to the motor cortex and precipitated praxis-induced seizures. Therefore, in addition to the known characteristic triad, praxis-induced reflex seizures may also be a feature of ring chromosome 20 syndrome.