Mitsuo Motobayashi

Neurodevelopmental features in 2q23.1 microdeletion syndrome: Report of a new patient with intractable seizures and review of literature

2q23.1 microdeletion syndrome is a recently characterized chromosomal aberration disorder uncovered through array comparative genomic hybridization (array CGH). Although the cardinal feature is intellectual disability (ID), neurodevelopmental features of the syndrome have not been systematically reviewed. We present a 5‐year‐old boy with severe psychomotor developmental delay/ID, progressive microcephaly with brain atrophy, growth retardation, and several external anomalies. He manifested intractable epilepsy, effectively treated with combined antiepileptic drug therapy including topiramate. Array CGH demonstrated a de novo interstitial deletion of approximately 1 Mb at 2q23.1–q23.2, involving four genes including MBD5. Nineteen patients have been reported to have the syndrome, including present patient. All patients whose data were available had ID, 17 patients (89%) had seizures, and microcephaly was evident in 9 of 18 patients (50%). Deletion sizes ranged from 200 kb to 5.5 Mb, comprising 1–15 genes. MBD5, the only gene deleted in all patients, is considered to be responsible for ID and epilepsy. Furthermore, the deletion junction was sequenced for the first time in a patient with the syndrome; and homology of three nucleotides, identified at the distal and proximal breakpoints, suggested that the deletion might have been mediated by recently‐delineated genomic rearrangement mechanism Fork Stalling and Template Switching (FoSTeS)/microhomology‐mediated break‐induced replication (MMBIR).

Successful treatment of fulminant Wilson's disease without liver transplantation

Fulminant Wilsons disease (WD) is life‐threatening. The revised WD prognostic index (RWPI) has been used to predict the severity of the disease, with a score ≥11 indicating fatal outcome without liver transplantation (LTx). We here report the case of a 10‐year‐old female patient with fulminant WD (RWPI, 16) who recovered fully after plasma exchange and continuous hemodiafiltration, followed by treatment with copper chelate agents. To the best of our knowledge, there have been five fulminant WD patients with RWPI ≥ 11 including the present patient, in whom LTx was not done. Based on the therapeutic modalities in these five cases, non‐surgical treatment (blood purification and copper chelate agents) may be able to avoid LTx in fulminant WD even with very high RWPI, although preparation for LTx is necessary.

Usefulness of allogeneic hematopoietic stem cell transplantation in first complete remission for pediatric blastic plasmacytoid dendritic cell neoplasm with skin involvement: a case report and review of literature.

No standard treatment has been established in childhood blastic plasmacytoid dendritic cell neoplasma (BPDCN) because of its rarity. We treated with acute lymphoblastic leukemia‐type regimen for a child with BPDCN with skin and leukemic involvement. She has been disease‐free for 4 years after allogeneic bone marrow transplantation in first complete remission. In 33 cases of pediatric BPDCN, the over survival was significantly lower in the patients with skin manifestation than those without cutaneous involvement. Accordingly, it is important to determine whether allogeneic hematopoietic stem cell transplantation should be applied to first complete remission in the patients with poor prognosis. Pediatr Blood Cancer 2013;60:E140–E142.

Hearing Loss Caused by a P2RX2 Mutation Identified in a MELAS Family With a Coexisting Mitochondrial 3243AG Mutation

Objectives: We present a family with a mitochondrial DNA 3243A>G mutation resulting in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), of which some members have hearing loss in which a novel mutation in the P2RX2 gene was identified. Methods: One hundred ninety-four (194) Japanese subjects from unrelated families were enrolled in the study. Targeted genomic enrichment and massively parallel sequencing of all known nonsyndromic hearing loss genes were performed to identify the genetic causes of hearing loss. Results: A novel mutation in the P2RX2 gene that corresponded to c.601G>A (p.Asp201Tyr) was identified. Two patients carried the mutation and had severe sensorineural hearing loss, while other members with MELAS (who did not carry the P2RX2 mutation) had normal hearing. Conclusion: This is the first case report of a diagnosis of hearing loss caused by P2RX2 mutation in patients with MELAS. A potential explanation is that a decrease in adenosine triphosphate (ATP) production due to MELAS with a mitochondrial 3243A>G mutation might suppress activation of P2X2 receptors. We also suggest that hearing loss caused by the P2RX2 mutation might be influenced by the decrease in ATP production due to MELAS.

Correlation Between White Matter Lesions and Intelligence Quotient in Patients With Congenital Cytomegalovirus Infection.

BACKGROUND It is well known that congenital cytomegalovirus infection exhibits white matter and other types of lesions in magnetic resonance imaging (MRI), but little is known on the clinical significance of white matter lesions because they are also present in asymptomatic congenital cytomegalovirus infection. We investigated for relationships among white matter lesions, intelligence quotient, and other neurodevelopmental features. METHODS Nine children (five boys and four girls; mean age: 87.4 months, range: 63-127 months) with sensorineural hearing loss (five bilateral and four unilateral) had been diagnosed as having congenital cytomegalovirus infection by positive polymerase chain reaction findings of dried umbilical cords. They were evaluated for the presence of autistic features, tested using Wechsler Intelligence Scale for Children-Fourth Edition for intelligence quotient, and underwent brain MRI to measure white matter lesion localization and volume. RESULTS At the time of MRI examination (mean age: 69.4 months, range: 19-92 months), white matter lesions were detected in eight of nine patients. Five subjects were diagnosed as having autism spectrum disorders. We observed increased white matter lesion volume was associated with lower intelligence quotient scores (R(2) = 0.533, P = 0.026) but not with autism spectrum disorders. CONCLUSIONS In individuals with congenital cytomegalovirus, an increased white matter lesion volume is associated with lower intelligence quotient scores but not with an increased likelihood of autistic behavior.

Evaluation of Mucorales DNA load in cerebrospinal fluid in a patient with possible cerebral mucormycosis treated with intravenous liposomal amphotericin B

We report the case of a 19-year-old male with possible cerebral mucormycosis following chemotherapy. We detected a Lichtheimia DNA load of 2.0×10(4) copies/ml in cerebrospinal fluid (CSF), although a CSF culture showed no growth. After treatment with intravenous liposomal amphotericin B, the Lichtheimia DNA load fell below the detection limit, and at the same time the patients headache and imaging findings improved. The quantification of Mucorales DNA in CSF may be useful for evaluating cerebral mucormycosis.

Viral load and ganciclovir (GCV) concentration in cerebrospinal fluid of patients successfully treated with GCV or valGCV for human herpesvirus 6 encephalitis/myelitis following umbilical cord blood transplantation

We describe successful treatment of 3 cases of human herpesvirus 6 (HHV‐6) encephalitis/myelitis following cord blood transplantation (CBT). Ganciclovir (GCV) (10 mg/kg/day) reduced HHV‐6 load to undetectable levels in cerebrospinal fluid (CSF). Early dose reduction in the presence of HHV‐6 detectable in CSF resulted in an increased HHV‐6 load. GCV was capably shifted to valganciclovir (VGCV) with an almost equivalent concentration. GCV/VGCV may be effective for HHV‐6 encephalitis/myelitis after CBT, although HHV‐6 load in CSF should be monitored.

Clinical features of a female with WDR45 mutation complicated by infantile spasms: a case report and literature review

We present a 3-year-old girl with beta-propeller protein-associated neurodegeneration (BPAN) who had a de novo heterozygous splice-site mutation of c.831-1G>C in WDR45 and developed infantile spasms; her onset age of infantile spasms was relatively late. Her infantile spasms and hypsarrhythmia disappeared promptly by adrenocorticotropic hormone therapy (CORTROSYN®Z, 0.0125mg/kg/day daily for 2weeks intramuscularly), though the administration of pyridoxal phosphate and valproic acid had poor efficacy. BPAN is known to be associated with various types of seizures, but there are few reports on infantile spasms, especially in females. To date, only 5 patients with BPAN have been reported to develop infantile spasms, and our patient is the second case in females. In this report, we showed that female patients with BPAN had milder phenotypic features than males: males developed intractable infantile spasms in early infancy, while females had treatable infantile spasms in late infancy.

Successful treatment for West syndrome with severe combined immunodeficiency

Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T-B+NK- severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04-0.09 to 0.20-1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T-B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient.

A rational approach to identifying newborns with hearing loss caused by congenital cytomegalovirus infection by dried blood spot screening

Abstract Objective: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection, with the majority of infected newborns having no detectable signs. The aim of this study was to examine the accuracy of our newly developed DBS-based assay as an appropriate mass screening method for cCMV infection. Methods: Between May 2011 and October 2016, newborns delivered at six hospitals in Nagano Prefecture, Japan were enrolled prospectively. We employed dried blood spot (DBS)-based assays with real-time quantitative PCR (qPCR). Results: Prior to the clinical study, confirmation analysis was carried out using positive and negative controls. The sensitivity and specificity of this DBS-based qPCR assay for the detection of CMV DNA were 83 and 97%, respectively. During the study period, 9675 newborns were enrolled. The total recovery rate of DBS was 99.92% (9,667/9,675). From our analysis of the 9,667 samples, 47 DBS samples were found positive by the qPCR test (0.48%), and 9620 (99.5%) DBS samples were CMV-negative. Conclusions: The risk of neural disorders associated with cCMV infection is thought likely to increase with CMV viral load in the blood. DBS screening for cCMV may be sufficient in a clinical setting, and offers a realistic and feasible option for universal mass screening.