A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8.

Pontocerebellar hypoplasia (PCH) is currently classified into 16 subgroups. Using mostly next-generation sequencing, pathogenic variants have been identified in as many as 24 PCH-associated genes. PCH type 8 (PCH8) is a rare heterogeneous disorder. Its clinical presentation includes severe development delay, increased muscle tone, microcephaly, and magnetic resonance imaging (MRI) abnormalities such as reduced cerebral white matter, a thin corpus callosum, and brainstem and cerebellar hypoplasia. To date, only two variants in the CHMP1A gene (MIM: 164010), NM_002768.5: c.88 C > T (p.Glu30*) and c.28-13 G > A, have been identified homozygously in seven patients with PCH8 from four families (MIM: 614961). CHMP1A is a subunit of the endosomal sorting complex required for transport III (ESCRT-III), which regulates the formation and release of extracellular vesicles. Biallelic CHMP1A loss of function impairs the ESCRT-III-mediated release of extracellular vesicles, which causes impaired progenitor proliferation in the developing brain. Herein, we report a patient with PCH8 who had a homozygous CHMP1A variant, c.122delA (p.Asn41Metfs*2), which arose from segmental uniparental disomy. Although our patient had similar MRI findings to those of previously reported patients, with no progression, we report some novel neurological and developmental findings that expand our knowledge of the clinical consequences associated with CHMP1A variants.

[The effect of noninvasive positive pressure ventilation in children with severe motor and intellectual disabilities with respiratory insufficiency].

We investigated the clinical course of 20 children (persons) with severe motor and intellectual disabilities (SMID) who were treated with noninvasive positive pressure ventilation (NPPV) for respiratory insufficiency. NPPV was effective in 10 of 11 patients treated for acute respiratory failure, and in 7 of 9 patients treated for chronic respiratory failure. Twelve patients were treated with NPPV for more than one year. There were no complications associated with NPPV in any of the patients. NPPV improved ventilation impairment soon after ventilation was started, and avoided the need for the endtracheal intubation by adjusting airway management and the choice of mask in all but one of the patients with acute respiratory failure. NPPV in combination with wearing a chin strap was highly effective in patients with open state or upper airway obstruction. Five patients were successfully weaned off the ventilator soon after recovery from acute respiratory failure using NPPV, whereas 5 patients who continued NPPV during the chronic phase after recovery did not experience recurrent episodes of acute respiratory failure. We conclude that NPPV may be an effective treatment for SMID with respiratory insufficiency.

Two unrelated patients with MRE11A mutations and Nijmegen breakage syndrome-like severe microcephaly.

MRE11 and NBS1 function together as components of a MRE11/RAD50/NBS1 protein complex, however deficiency of either protein does not result in the same clinical features. Mutations in the NBN gene underlie Nijmegen breakage syndrome (NBS), a chromosomal instability syndrome characterized by microcephaly, bird-like faces, growth and mental retardation, and cellular radiosensitivity. Additionally, mutations in the MRE11A gene are known to lead to an ataxia-telangiectasia-like disorder (ATLD), a late-onset, slowly progressive variant of ataxia-telangiectasia without microcephaly. Here we describe two unrelated patients with NBS-like severe microcephaly (head circumference -10.2 SD and -12.8 SD) and mutations in the MRE11A gene. Both patients were compound heterozygotes for a truncating or missense mutation and carried a translationally silent mutation. The truncating and missense mutations were assumed to be functionally debilitating. The translationally silent mutation common to both patients had an effect on splicing efficiency resulting in reduced but normal MRE11 protein. Their levels of radiation-induced activation of ATM were higher than those in ATLD cells.

Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A.

Charcot-Marie-Tooth disease (CMT) has been classified into two types, CMT1 and CMT2, demyelinating and axonal forms, respectively. CMT2 has been further subdivided into eight groups by linkage studies. CMT2A is linked to chromosome 1p35-p36 and mutation in the kinesin family member 1B-beta (KIF1B) gene had been reported in one pedigree. However, no mutation in KIF1B was detected in other pedigrees with CMT2A and the mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) gene were recently detected in those pedigrees. MFN2, a mitochondrial transmembrane GTPase, regulates the mitochondrial network architecture by fusion of mitochondria. We studied MFN2 in 81 Japanese patients with axonal or unclassified CMT and detected seven mutations in seven unrelated patients. Six of them were novel and one of them was a de novo mutation. Most mutations locate within or immediately upstream of the GTPase domain or within two coiled-coil domains, which are critical for the functioning or mitochondrial targeting of MFN2. Formation of a mitochondrial network would be required to maintain the functional peripheral nerve axon.

Potentially harmful sleep habits of 3-year-old children in Japan.

To examine the sleep habits of 3-year-old children, we questioned guardians during a routine health examination for 3-year-old children at a public health center. According to the 1105 questionnaires analyzed, the proportion of children who fell asleep at 10 p.m. or later was 49.6%. The nocturnal sleep onset time was significantly correlated with the wake-up time in the morning and was significantly negatively correlated with the nocturnal sleep duration. The average daily total sleep duration (nocturnal sleep duration + nap duration) of regular nap-takers showed a significant negative correlation with the nocturnal sleep onset time. The average values for height, weight, and body mass index (BMI) were not correlated with the nocturnal sleep onset time. Children who went to sleep later got less sleep than those who went to sleep earlier. Because sleep debt has a harmful impact on older children and adults, late sleep onset may have adverse health consequences in young children.