Two brothers with an IQSEC2 pathogenic variant presented with early onset intellectual disability, intractable epileptic seizures, autism spectrum disorders, postnatal microcephalus and slowly ...progressive rigid-spasticity. Their epileptic seizures were characterized by intractability, early onset epileptic spasms, and then clusters of tonic/tonic-clonic seizures, exacerbated by valproate. Electroencephalography showed periodic discharges, including periodic high voltage slow complexes and burst-suppression activity.
Whole exome sequencing, using DNA from peripheral blood of both brothers, identified a pathogenic variant, c.2776 C > T, p.(Arg 926*) in exon 9 of IQSEC2 (NM 001111125.3). Their parents and another brother did not have this variant, which may suggest that maternal gonadal mosaicism is the most likely mechanism.
Abstract Objective Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual ...disability, epilepsy, and characteristic craniofacial features. Method In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype–phenotype correlation among them was examined. Results We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. Conclusion The genotype–phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8–2.1 and 1.8–2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5 , located at 6.2 Mb away from the telomere. Although the genotype–phenotype correlation for the cardiac abnormalities is unclear, PRDM16 , PRKCZ , and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.
Abstract Objective The efficacy of pre-school health consultation in improving developmental and behavioral problems at 5-years of age with follow-up consecutive educational support before and after ...entrance into regular elementary school for 8 years in a rural city, Taketa, Oita prefecture, was evaluated. Methods This program involved a survey with a three-step method as follows. Step 1: interviews and checklists conducted by public health nurses and nursery/kindergarten teachers for all children. Step 2: medical screening for all children performed by a local/home-school doctor. Step 3: diagnosis in selected children carried out by child neurologists, special support education teachers and clinical/school psychologists. Subsequently, for 1–2 years until entrance into elementary school, these children and their parents were given speech, behavioral and mental support as well as group play therapy in nursery/kindergarten. Results During the 8-years study period, 56 children (5.4%) were diagnosed with developmental disorders and six children were diagnosed with maltreatment by their parents among 1165 eligible children. Of these subjects, 40 children received support consecutively after entrance into school, 38 of whom entered regular elementary school and 32 attended regular classes for 1–6 years. A total of 39 of 40 children have attended school without refusal. Moreover, the total number of students refusing to attend school in elementary school decreased for 3 years from 8 of 3246 children (0.25%) in 2006–2008 and 13 of 2889 children (0.45%) in 2009–2011 to only 1 of 2646 children (0.04%) in 2012–2014. Conclusions Pre-school developmental–behavioral screening and consecutive support programs in a rural city reduced the number of students refusing to attend school.
Human herpes virus 6 (HHV‐6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. ...HHV‐6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1 year and 3 months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV‐6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4–5‐fold increase in virus copy number of HHV‐6B compared to samples from other brain sites. Immunostaining indicated that HHV‐6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV‐6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV‐6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus‐oriented disorders, including mesial temporal lobe epilepsy.
Abstract Objective To elucidate the novel biological functions of heparan sulfate (HS) by clinic-pathologically studying a patient with paroxysmal atrioventricular (AV) block. Patient A ...long-surviving male patient with Sanfilippo syndrome type A presented with paroxysmal AV block at age 33 years. He then survived another 2.5 years after the onset of paroxysmal AV block and pacemaker implantation. Methods and results His cardiac histopathological examination at autopsy showed HS storage in the cardiac conduction system (CCS), especially in the atrioventricular node (AVN)-His bundle branches. Conclusion HS storage in the CCS might trigger AV block, arising from below the AVN-His bundle branches. This is the first description to indicate that HS might be an essential constituent of life-long CCS plasticity and that its storage in the CCS results in AV block.
Abstract Background: The clinical phenotypes and their severity in patients with tuberous sclerosis complex can be quite variable and are sometimes never determined simply by the primary mutation. ...These make clinically selecting appropriate treatments and predicting disease outcome difficult. In this report, the prognostic ominous sequence was evaluated in association with clinical manifestations and gene mutations. Methods: The patients were classified by each renal lesion of angiomyolipomas and polycystic disease. The other clinical manifestations and outcomes of epilepsy, mental retardation, facial angiofibromas, subependymal giant cell astrocytoma, cortical tubers were reviewed and each gene mutations were analyzed in seven unrelated patients. Results: Two patients with multiple and large proliferative renal angiomyolipoma showed poor clinical outcome than the patients with other renal lesions. These patients presented with progressively proliferative facial angiofibroma, West syndrome, Lennox–Gastaut syndrome, severe mental retardation, subependymal giant cell astrocytoma and they were affected by TSC2 gene mutations. Conclusion: The sequence of progressively proliferative renal angiomyolipoma, facial angiofibroma, West syndrome and TSC2 gene mutations might be prognostic ominous factors.
Cockayne syndrome presents senescence‐like changes starting in early infancy; however, the mechanism of premature aging remains unclear. In an autopsy of a 23‐year‐old woman with Cockayne syndrome, ...we evaluated the correlation between Cockayne pathology and the expression patterns of the senescence‐associated proteins p53 and Rb. Neuropathological findings in this case revealed basal ganglia calcification, tigroid leukodystrophy, bizarre reactive astrocytes, severe cerebellar atrophy with loss of Purkinje cells, and arteriolar/neuronal calcifications in the hypothalamus. Multiple arteriolar calcifications and sclerotic changes were seen in the central nervous system and kidney, but the endothelium of the aorta and coronary arteries remained intact appropriately for the individual's age without any finding of arteriosclerosis. Overexpression of p53 protein was confirmed in the cytoplasm of neurons in the basal ganglia, thalamus, hypothalamus, hippocampus and cerebellum, of arteriolar endothelial cells of the cerebrum and renal glomerular capillaries, and of cutaneous epithelial cells. The distribution of p53 overexpression was coincident with that of pathological alteration, such as neuronal loss, calcification and atrophy. High expression of p53 was localized in the cytoplasm, not in the nucleus. In contrast to p53, Rb was not expressed in any senescence lesion. In terms of senescence, distinct differences are found among organs in a patient with Cockayne syndrome. This segmental progeria differs from natural aging, and implicates p53 overexpression in the etiology of CS.
Abstract Background Barbiturates and benzodiazepines are the first-line anticonvulsants for neonatal seizures. However, in immature brains, those drugs may lead to paradoxical neuronal excitation. ...Patient A patient with benign familial neonatal epilepsy developed epileptic encephalopathy after massive doses of phenobarbital that were followed by a continuous infusion of midazolam on postnatal day 3. Electroencephalography revealed rhythmic delta activity in clusters with migrating epileptic foci. After discontinuation of both drugs, the patient's consciousness promptly improved and her electroencephalography normalized on postnatal day 5. Results This baby developed persistent electroencephalographic seizures due to massive doses of phenobarbital and midazolam. Conclusion Clinicians should be aware of this anticonvulsant-induced paradoxical neuronal excitation and the uncoupling phenomenon, especially in individuals with benign familial neonatal epilepsy, who have low seizure thresholds.
Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and ...frequent transfusion‐dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase‐liver and RBC (PK‐LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.
