Ryuta Tanaka

Abnormal brain MRI signal in 18q-syndrome not due to dysmyelination

BACKGROUND 18q-Syndrome is a chromosomal disorder exhibiting various symptoms arising from the central nervous system. Brain magnetic resonance imaging (MRI) of patients with this syndrome usually demonstrates abnormal white matter intensities. This is widely believed to be due to impaired myelin formation because this syndrome involves the deletion of the myelin basic protein (MBP) gene in 18q23. However, this hypothesis has not been confirmed by actual pathology because early death is unusual and autopsy rarely performed. PATIENT A 6-year-old boy with ring chromosome 18 syndrome was examined by genetic analysis for the MBP gene, brain MRI, and autopsy. RESULTS Haploinsufficiency of the MBP gene was confirmed. T(2)-weighted MRI revealed diffuse high intensities throughout the cerebral white matter. Pathological examination showed the cerebral white matter to be uniformly stained by Klüver-Barrera and MBP immunohistochemical staining. Oligodendrocytes were immunoreactive for proteolipid protein and ferritin but not MBP. Electron microscopy revealed clusters of axons wrapped in compact myelin sheaths with distinct major dense lines. Holzer and immunohistochemical staining for glial fibrillary acidic protein showed extensive staining of the white matter and an increased number of glial filaments. CONCLUSIONS This pathological study demonstrated that in this disorder, the brain was well myelinated, contrary to established hypotheses about this disorder. The MRI signal abnormalities in 18q-syndrome could be attributed to gliosis and not to dysmyelination.

Novel compound heterozygous LIAS mutations cause glycine encephalopathy.

Glycine encephalopathy (GCE) is a rare autosomal recessive disorder caused by defects in the glycine cleavage complex. Here we report a patient with GCE and elevated level of glycine in both the serum and the cerebrospinal fluid. Trio-based whole-exome sequencing identified novel compound heterozygous mutations (c.738-2A>G and c.929T>C (p.Met310Thr)) in LIAS. To date, three homozygous mutations have been reported in LIAS. All previously reported GCE patients also show elevated level of serum glycine. Our data further supports LIAS mutations as a genetic cause for GCE.

Neurochemistry in shiverer mouse depicted on MR spectroscopy.

To evaluate the neurochemical changes associated with hypomyelination, especially to clarify whether increased total N‐acetylaspartate (tNAA) with decreased choline (Cho) observed in the thalamus of msd mice with the plp1 mutation is a common finding for hypomyelinating disorders.

Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts

Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively.

A novel homozygous mutation of GJC2 derived from maternal uniparental disomy in a female patient with Pelizaeus–Merzbacher-like disease

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, motor developmental delay, ataxia, and progressive spasticity. The gap junction protein gamma-2 gene (GJC2), encoding the gap junction protein connexin 47, is one of the genes responsible for this condition. In this study, a novel homozygous mutation in GJC2 (c.746C>G; p.P249R) was identified in a 21-year-old female patient with PMLD. Although her mother was a carrier of this mutation, the Mendelian inheritance pattern could not be determined because the paternal sample was unavailable. Alternatively, chromosomal microarray testing together with single nucleotide polymorphism typing (CGH+SNP) was performed to determine the gene copy number and analyze the haplotype in the 1q42.13 region in which GJC2 is located. The result showed no deletion, but the GJC2 region was involved in the loss-of-heterozygosity region. Furthermore, haplotype of chromosome 1, in which GJC2 is located, revealed that both copies of chromosome 1 were derived from the patients mother, indicating maternal uniparental disomy of chromosome 1. This study showed the advantage of the SNP genotyping microarray for detecting the origin of the mutation.

Tigroid pattern of the white matter: a previously unrecognized MR finding in lissencephaly with cerebellar hypoplasia

Brain MR images of a 14-month-old boy with lissencephaly and cerebellar hypoplasia showed numerous radiating linear structures in the white matter. This finding was identical to the tigroid or leopard-skin pattern that is seen in Pelizaeus-Merzbacher disease or metachromatic leukodystrophy and represents the perivascular white matter spared from demyelination. We speculate that mutations of the reelin gene, expressed both in the cortex and in the white matter, may play an important role in its development.

A pediatric case of critical illness polyneuropathy : clinical and pathological findings

Critical illness polyneuropathy (CIP) is a sensorimotor polyneuropathy recognized in adult intensive care patients with sepsis and multiple organ dysfunction and only a few cases have been reported in children. Here we report a 13-year-old Japanese boy with CIP that developed during the course of encephalopathy. Two months after the onset of encephalopathy, he developed tetraplegia although consciousness had already recovered. Deep tendon reflex was absent. MRI of the brain and spinal cord was normal and no abnormality in the cerebrospinal fluid was detected. Motor and sensory nerve conduction velocities of the lower limbs and somatosensory evoked potential could not be detected. The motor activity subsequently showed gradual recovery, although standing and walking could not be achieved. Sural nerve biopsy performed 3 years after the onset showed severe reduction of the number of myelinated large-diameter fibers, thin myelin in almost all fibers and cluster formation of myelinated small-diameter fibers, indicating primary axonal degeneration with regeneration. We report here for the first time the neuropathological changes in peripheral nerves during the chronic stage of CIP in children.

Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly.

Middle interhemispheric variant of holoprosencephaly (MIH) is a rare brain malformation; hemispheric fusion does not occur at the rostral forebrain, but rather across the posterior frontal region. Barkovich and Quint1 first described and proposed MIH as part of the holoprosencephaly (HPE) spectrum in 1993. Although classic HPE and MIH share several similarities, they are related to different embryological mechanisms: classic HPE is caused by a defect in the formation of the embryonic floor plate, whereas MIH occurs after a disturbance to the roof plate formation.2 The gene ZIC2 is important for the differentiation of the roof plate in the dorsal midline of the neural tube of the developing embryo. In humans, ZIC2 mutations have been identified in 3%–4% of HPE cases, including individuals with MIH, thus confirming that MIH is a variant of HPE.3

Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A

Wiedemann‐Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down‐slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co‐workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12‐year‐old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.

Cyclic vomiting syndrome after acute autonomic and sensory neuropathy

1 Nakanishi K, Yoshikawa N. Immunoglobulin A nephropathies in children (includes HSP). In: Avner ED, Harmon WE, Niaudet P, Yoshikawa N, Emma F, Goldstein SL (eds). Pediatric Nephrology, 7th edn. Springer-Verlag, Berlin, 2016; 983–1033. 2 Yoshikawa N, Ito H, Sakai T et al. A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. J. Am. Soc. Nephrol. 1999; 10: 101–9. 3 Yata N, Nakanishi K, Shima Y et al. Improved renal survival in Japanese children with IgA nephropathy. Pediatr. Nephrol. 2008; 23: 905–12. 4 Kamei K, Nakanishi K, Ito S et al. Long-term results of a randomized controlled trial in childhood IgA nephropathy. Clin. J. Am. Soc. Nephrol. 2011; 6: 1301–7. 5 Russo D, Minutolo R, Pisani A et al. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. Am. J. Kidney Dis. 2001; 38: 18–25.