Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

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.

Autopsy Report of a Woman with Infantile Alexander Disease Who Survived 39 Years.

Patients with infantile Alexander disease (AxD) usually do not survive beyond their early teens without life support care because of progressive central hypoventilation. We present the autopsy report of a woman with infantile AxD carrying an R239C mutation in the glial fibrillary acidic protein gene, who survived 39 years. She presented with psychomotor retardation in infancy and regressed after age 5. Brain computed tomography scans showed bilateral low frontal white matter density. She became quadriplegic with bulbar palsy and was intellectually handicapped after a measles infection at age 7. Tube feeding was introduced because of dysphagia at age 15. Noninvasive positive pressure ventilation was required due to central hypoventilation in her early thirties. She died of neurogenic respiratory failure at 39 years. Autopsy findings revealed a markedly atrophic brain (709 g, -6.0 standard deviation), especially in the frontal lobe, cerebellum, and brainstem portions. We found demyelination, gliosis, and cystic lesions throughout the brain, and we saw Rosenthal fibers accumulating in the perivascular spaces. We also identified a variety of abnormalities in other organs such as pancreatic necrosis, completely desquamated epithelium in the lower esophagus and stomach, foreign-body giant cells in the colon submucosa, glomerular sclerosis, and multiple bladder stones. This is the first autopsied case report of a patient with infantile AxD with long survival, who showed not only central nervous system characteristic findings, but also unexpected pathological changes in other organs.

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy.

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

Discordant phenotype caused by CASK mutation in siblings with NF1.

With the advent of next-generation sequencing (NGS), a blended phenotype has been shown to be caused by multilocus molecular diagnosis. Here, we present siblings of neurofibromatosis type 1 (NF1) with discordant phenotypes. Further genetic investigation revealed that the younger sister had trisomy 8 mosaicism with a low ratio and a known pathogenic mutation in the CASK gene. This is the first report of a blended phenotype caused by NF1, CASK disorder, and trisomy 8 mosaicism.

Peripheral nerve pathology at fixed stage in spinal muscular atrophy with respiratory distress type 1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is characterized by severe respiratory failure due to diaphragmatic paralysis and distal muscular weakness in early infancy. After an initial decline in respiratory state and motor function until 1-2years of age, residual capabilities reach a plateau. We report the peripheral neuropathological findings of a patient with SMARD1 at 1year and 1month of age, when his muscle strength and respiratory symptoms had deteriorated and then stabilized for several months. Peripheral nerve biopsy revealed severely progressed axonal degeneration. This finding suggests the rapid progression of peripheral axonal neuropathy in SMARD1 that leads to its characteristic clinical course of respiratory failure and paralysis in the early infantile period.

Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia.

PURPOSE: Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations. MATERIALS AND METHODS: Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations). RESULTS: In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP). CONCLUSION: The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS.

[Irreversible cerebral ischemia caused by febrile status epilepticus in Sturge-Weber syndrome type III].

We report a 9-year-old girl with Sturge-Weber syndrome (SWS) type III, whose motor function deteriorated after an episode of febrile status epilepticus. The patient had leptomeningeal angiomas in the left temporal, occipital, and parietal lobes. Complex partial seizures, which started at 8 months, were controlled by antiepileptic medications. At 9 years of age, she developed irreversible ischemic lesions in the left temporal and occipital regions after the febrile status epilepticus and her motor function deteriorated. In addition to antiepileptic medications, aspirin therapy was started.SWS type III is a rare disorder characterized by leptomeningeal angiomatosis without facial nevus. In addition to the chronic ischemia in the affected cortex, epileptic seizures result in a phased progression of ischemia in SWS. Although the patient's complex partial seizures had been well-controlled, a single episode of febrile status epilepticus resulted in permanent brain lesions. The impairment of appropriate hemodynamic response to status epilepticus, together with venous hypertension in the affected side in SWS may have caused the cerebral infarction in our case. Seizure control is crucial to improving the neurological prognosis of SWS.

A missense mutation in domain III in HSPG2 in Schwartz-Jampel syndrome compromises secretion of perlecan into the extracellular space.

Schwartz-Jampel syndrome (SJS) type 1 is characterized by short stature, myotonia, and chondrodysplasia, and is caused by partial loss-of-function mutations in HSPG2 encoding perlecan. Six missense mutations have been reported in SJS to date and only one has been characterized using a recombinant protein. We report an 11-year-old Japanese boy with SJS, who shows "rigid" walking with less flexion of knees/ankles and protruded mouth. His intelligence is normal. We identified by whole genome resequencing a heterozygous missense p.Leu1088Pro in domain III-2 and a heterozygous nonsense p.Gln3061Ter in domain IV of perlecan. Expression studies revealed that p.Leu1088Pro markedly reduces the cellular expression of domain III-2 and almost nullifies its secretion into the culture medium. As five of the seven missense mutations in SJS affect domain III of perlecan, domain III is likely to be essential for secretion of perlecan into the extracellular space.

ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus.

OBJECTIVE: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor (ADORA2A), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD. METHODS: We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes. RESULTS: Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls (p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32-4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain (p = 0.003 and 0.002, respectively) and lymphoblasts (p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression (p = 0.024), as well as cellular cAMP production (p = 0.0006), was significantly higher in AA than BB diplotype. CONCLUSIONS: AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.

Small heat shock protein 27 mutation in a Japanese patient with distal hereditary motor neuropathy.

Heat shock protein 27 (HSP27) belongs to a family of small heat shock proteins that play significant roles in the cellular stress response and are also involved in the control of protein-protein interactions as chaperons. Mutation in HSP27 has been identified as the cause of axonal Charcot-Marie-Tooth disease (CMT) and distal hereditary motor neuropathy (HMN). Heat shock protein 22 (HSP22) is a molecular counterpart of HSP27, and its mutation is another cause of distal HMN. We screened the mutation of HSP27 and HSP22 in 68 Japanese patients with axonal CMT or unclassified CMT and six Japanese patients with distal HMN. We detected a heterozygous P182S mutation of HSP27 in a patient with distal HMN, but we found no mutations in HSP22. Mutation in HSP27 may impair the formation of the stable neurofilament network that is indispensable for the maintenance of peripheral nerves.

Leptomeningeal angiomatosis with infantile spasms.

We describe a 7-month-old female with leptomeningeal angiomatosis who developed infantile spasms. She did not manifest facial nevus or ocular choroidal angioma. Leptomeningeal angiomatosis is characterized by venous angiomas of leptomeninges and usually accompanied by facial nevus, a condition known as Sturge-Weber syndrome. In Sturge-Weber syndrome, leptomeningeal angiomas can cause infantile spasms but much less frequently than in other neurocutaneous syndromes, such as tuberous sclerosis. This patient is the first reported case of leptomeningeal angiomatosis without facial nevus who developed infantile spasms. Leptomeningeal angiomas should be taken into consideration as a cause of infantile spasms, even in the absence of facial nevus. We suggest that this case is clinically within the spectrum of Sturge-Weber syndrome, and that the embryologic origin of this case is similar to that of Sturge-Weber syndrome.

Large fontanelles are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB.

CBFB at 16q22 heterodimerizes with either RUNX2 (also known as CBFA1) or RUNX1 (CBFA2) to activate the transcription of downstream molecules. RUNX2 regulates osteoblast differentiation and chondrocyte maturation and its haploinsufficiency leads to cleidocranial dysplasia, characterized large fontanelles, hypoplasia or aplasia of the clavicles, hypoplasia of the distal phalanges, and a wide pubic symphysis. Complete loss of Runx1 or Cbfb in mice is lethal because of the absence of fetal liver hematopoiesis. Fetal rescue in Cbfb(-/-) mice by providing the Cbfb functions in the hematopoietic progenitors leads to wide fontanelle and delayed chondrocyte maturation, presumably resulting from the incomplete function of the transcriptional pathway mediated by the Cbfb-Runx2 heterodimer. The present report describes a patient with a small deletion of chromosome 16q22.1 encompassing CBFB. Skeletal abnormalities included a widely open fontanelle, multiple wormian bones along the sagittal suture, hypoplasia of the distal phalanges, and mildly shortened clavicles. G-banding analysis revealed a shortening of the 16q22.1 band. A fluorescence in situ hybridization analysis, using the BAC probe spanning the CBFB locus at 16q22.1, revealed that the CBFB probe hybridized to only one of the two homologous chromosome 16 regions. Array-comparative genomic hybridization analysis revealed that the deletion spans 1.2 megabases. In reviewing eight previously reported cases of 16q interstitial deletions involving band q22, large cranial sutures were noted in all but one case. Considering the phenotypic similarity of the 16q22 deletion case and Cbfb(-/-) mice rescued for hematopoiesis and the consistency of the phenotype among 16q22 deletion cases, we suggest that the common phenotypic feature of the 16q22 deletion, large fontanelles, can be attributed to a haploinsufficiency of CBFB.

Altered patterns of neuron production in the p27 knockout mouse.

The number and distribution of neurons in the murine neocortex are altered by loss of function of p27Kip1, a cyclin-dependent kinase inhibitor that regulates cell cycle progression at the G1 phase. We show that a temporary decline in the production of non-GABAergic projection neurons occurs in the dorsomedial neopallium of the p27Kip1 knockout mouse during the mid-term of neuronogenesis. It is followed by an augmentation of neuron production later in neuronogenesis leading to an increased production of projection neurons for the upper layers of the neocortex (layers II-IV). p27Kip1 is likely to play a critical role in cell internal regulatory mechanisms of proliferation/differentiation behavior of neural progenitor cells and may be directly involved in the control of neuron number during the period when non-GABAergic projection neurons for layers II-IV are being produced.