A nationwide survey of Schaaf-Yang syndrome in Japan.

Schaaf-Yang syndrome (SYS) is a congenital disorder characterized by developmental delay, autism spectrum disorder and congenital joint contractures. In this study, a nationwide epidemiological questionnaire-based survey of SYS in the Japanese population was conducted to establish patient numbers, clinical features and genetic information. In the primary survey, we investigated the number of SYS patients. In the secondary survey, we obtained and analyzed detailed clinical and genetic information of SYS patients. This survey collected information on 25 genetically-confirmed patients. The major clinical symptoms included neonatal hypotonia (96% of the patients), poor suck in infancy (82%), developmental delay (100%) and joint contractures (83%). Other main symptoms and findings included characteristic facial features (100%), small hands (92%), eye abnormalities (92%) and short stature (79%). Based on the information collected on activities of daily living, 71% of patients were unable to walk, while 67%, 71%, and 81% of patients required full assistance with eating, toileting and bathing, respectively. Regarding inheritability, the genetic analysis of 21 patients revealed that 14 (67%) carried de novo truncating variants in the melanoma antigen L2 (MAGEL2) gene and seven (33%) had inherited truncating variants from their fathers who were carriers. This survey revealed the clinical and genetic features in Japanese SYS patients. The majority of SYS patients required assistance in many aspects of daily living, and there were a certain number of carriers of the imprinting disorder.

Proximal Junctional Kyphosis After Posterior Spinal Fusion for Severe Kyphoscoliosis in a Patient With PIEZO2-deficient Arthrogryposis Syndrome.

STUDY DESIGN: Case report. OBJECTIVE: Describe the clinical and radiological outcomes of a patient with a piezo-type mechanosensitive ion channel component 2 (PIEZO2)-deficient arthrogryposis receiving surgery for severe kyphoscoliosis. SUMMARY OF BACKGROUND DATA: Spinal deformity is a characteristic feature of arthrogryposis due to PIEZO2 gene deficiency, for which surgical correction is indicated when the deformity is progressive to avoid neurological deficits and respiratory impairment. However, there exist few reports on the surgical treatment of spinal deformity in PIEZO2-deficient arthrogryposis, and no therapeutic standards have been established. METHODS: We retrospectively reviewed a case of proximal junctional kyphosis after posterior spinal fusion for severe kyphoscoliosis in PIEZO2-deficient arthrogryposis. RESULTS: The patient was a 13-year-old girl with PIEZO2-deficient arthrogryposis who underwent posterior spinal fusion with an all-pedicle screw construct from T2 to L2 for a preoperative main thoracic curve Cobb angle of 78° and thoracic kyphotic angle of 83°. Postoperative Cobb angle of the main thoracic curve and thoracic kyphotic angle were improved at 11° and 34°, respectively. Although revision surgery was required for neurological deficits from proximal junctional kyphosis, she could walk with a crutch and improvements in clinical questionnaire scores were noted at 2 years and 3 months after surgery. CONCLUSION: Based on the present case, posterior spinal fusion represents a good treatment option for severe spinal deformity in PIEZO2-deficient arthrogryposis. Careful consideration of fusion level is needed to prevent proximal junctional kyphosis. LEVEL OF EVIDENCE: 5.

A novel PAK3 pathogenic variant identified in two siblings from a Japanese family with X-linked intellectual disability: case report and review of the literature.

Intellectual disability (ID) is a clinically and genetically heterogeneous developmental brain disorder. The present study describes two male siblings, aged 7 and 1 yr old, with severe ID, spastic quadriplegia, nystagmus, and brain atrophy with acquired microcephaly. We used the exome sequencing to identify the causative gene in the patients and identified a hemizygous missense variant, c.1282T>A (p.W428R), in the p21-activated serine/threonine kinase 3 gene (PAK3), which is associated with X-linked ID. p.W428R is located within the highly conserved kinase domain and was predicted to induce loss of enzymatic function by three mutation prediction tools (SIFT, PolyPhen-2, and MutationTaster). In addition, this variant has not been reported in public databases (as of the middle of December 2018) or in the data from 3275 individuals of the Japanese general population analyzed using high-depth whole-genome sequencing. To date, only 13 point mutations and deletions in PAK3 in ID have been reported. The literature review illustrated a phenotypic spectrum of PAK3 pathogenic variant, and our cases represented the most severe form of the PAK3-associated phenotypes. This is the first report of a PAK3 pathogenic variant in Japanese patients with X-linked ID.

Rigid Occipitocervical Instrumented Fusion for Atlantoaxial Instability in an 18-Month-Old Toddler With Brachytelephalangic Chondrodysplasia Punctata: A Case Report.

STUDY DESIGN: Case report. OBJECTIVE: We report here on an 18-month-old boy with brachytelephalangic chondrodysplasia punctata (BCDP), whose atlantoaxial instability was successfully managed with occipitocervical instrumented fusion (OCF) using screw and rod instrumentations. SUMMARY OF BACKGROUND DATA: Recently, there have been a number of reports on BCDP with early onset of cervical myelopathy. Surgical OCF is a vital intervention to salvage affected individuals from the life-threatening morbidity. Despite recent advancement of instrumentation techniques, however, rigid OCF is technically demanding in very young children with small and fragile osseous elements. To our best knowledge, this is the first report on application of the instrumentation technique to a toddler patient with BCDP. METHODS: A 16-month-old boy with BCDP presented with tetraplegia and swallow obstacle. Hypoplasia of the odontoid process and atlantoaxial instability were present in lateral radiographs. T2-weighted magnetic resonance (MR) images revealed a high signal region in the spinal cord at the C1-2 and C7-T1 levels. Cervical computed tomography (CT) showed that the pedicles and lateral masses in the cervical spine were small and immature, but the laminae were comparatively thick. RESULTS: One week before surgery, the patient was fitted with a Halo-body jacket. We performed plate-rod placement with occipital cortical screws and C2/C3 interlaminar screws, and added an autogenous bone graft using the right 8 and 9 ribs. Rigid fixation of the occipito-cervical spine was completed successfully without major complications. Postoperative halo-body jacket immobilization was continued for 3 months, after which Aspen collar was fitted. CT confirmed occipitocervical bone fusion at 6 months after surgery. Mild clinical improvements in motor power of the affected muscles and swallowing were witnessed at 1 year postoperatively. CONCLUSION: Rigid fixation using screw, rod, and occipital plate instrumentation was successful in an 18-month-old toddler with BCDP and atlantoaxial instability. Bone fusion was achieved at postoperative 6 months. LEVEL OF EVIDENCE: 5.

Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature.

Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN is caused by mutations in an X-linked gene WDR45 that is involved in autophagy. BPAN is characterized by developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. Brain magnetic resonance imaging (MRI) shows iron deposition in the bilateral globus pallidus (GP) and substantia nigra (SN). Clinical manifestations and laboratory findings in early childhood are limited. We report a 3-year-old girl with BPAN who presented with severe developmental delay and characteristic facial features. In addition to chronic elevation of serum aspartate transaminase, lactate dehydrogenase, creatine kinase, and soluble interleukin-2 receptor, she had persistent elevation of neuron specific enolase (NSE) in serum and cerebrospinal fluid. MRI using susceptibility-weighted imaging (SWI) demonstrated iron accumulation in the GP and SN bilaterally. Targeted next-generation sequencing identified a de novo splice-site mutation, c.831-1G>C in WDR45, which resulted in aberrant splicing evidenced by reverse transcriptase-PCR. Persistent elevation of NSE and iron deposition on SWI may provide clues for diagnosis of BPAN in early childhood.

Application of magnetoencephalography in epilepsy patients with widespread spike or slow-wave activity.

PURPOSE: To examine whether magnetoencephalography (MEG) can be used to determine patterns of brain activity underlying widespread paroxysms of epilepsy patients, thereby extending the applicability of MEG to a larger population of epilepsy patients. METHODS: We studied two children with symptomatic localization-related epilepsy. Case 1 had widespread spikes in EEG with an operation scar from a resection of a brain tumor; Case 2 had hemispheric slow-wave activity in EEG with sensory auras. MEG was collected with a 204-channel helmet-shaped sensor array. Dynamic statistical parametric maps (dSPMs) were constructed to estimate the cortical distribution of interictal discharges for these patients. Equivalent current dipoles (ECDs) also were calculated for comparison with the results of dSPM. RESULTS: In case 1 with widespread spikes, dSPM presented the major activity at the vicinity of the operation scar in the left frontal lobe at the peak of the spikes, and some activities were detected in the left temporal lobe just before the peak in some spikes. In case 2 with hemispheric slow waves, the most active area was located in the left parietal lobe, and additional activity was seen at the ipsilateral temporal and frontal lobes in dSPM. The source estimates correlated well with the ictal manifestation and interictal single-photon emission computed tomography (SPECT) findings for this patient. In comparison with the results of ECDs, ECDs could not express a prior activity at the left temporal lobe in case 1 and did not model well the MEG data in case 2. CONCLUSIONS: We suggest that by means of dSPM, MEG is useful for presurgical evaluation of patients, not only with localized epileptiform activity, but also with widespread spikes or slow waves, because it requires no selections of channels and no time-point selection.

High uptake on 11C-methionine positron emission tomographic scan of basal ganglia germinoma with cerebral hemiatrophy.

We herein describe a 12-year-old male patient with a germinoma of the basal ganglia who presented with progressive hemiparesis. MR imaging showed ipsilateral cerebral hemiatrophy predominantly in the left basal ganglia, whereas no mass or enhancement was depicted. Single photon emission CT revealed no significant uptake of thallium, whereas (11)C-methionine positron emission tomography showed clearly discernible uptake in the left putamen. Stereotactic biopsy, referencing the results of (11)C-methionine positron emission tomography, was performed, allowing histologic verification of germinoma to be established. (11)C-methionine positron emission tomography was the only technique that indicated the precise localization of the tumor in our patient and enabled biopsy-based final diagnosis of the basal ganglia germinoma without any overt mass formation.