Clinical phenotypes, genotypes and treatment in Chinese dystonia patients with KMT2B variants.

BACKGROUND: KMT2B-related dystonia is a recently discovered hereditary dystonia that mostly occurs in childhood. This dystonia usually progresses to generalized dystonia with cervical, cranial, pharynx and larynx involvement. Our study summarizes genotype-phenotype features and deep brain stimulation (DBS) efficacy observed with KMT2B-related dystonia patients in China. METHODS: We identified 20 patients with KMT2B variations from dystonia samples with a gene panel and whole exome sequencing. Genetic, clinical and treatment analyses of these patients with KMT2B mutations were further conducted. RESULTS: We summarized the genotype and phenotypic characteristics of KMT2B-related patients in China, including 16 sporadic patients and 3 pedigrees (including 4 patients). Thirty-five percent (7/20) of patients had been published previously. The age of onset was between 1 month and 24 years (average 6.90 ± 5.72 years). Sixty-five percent (13/20) of patients had onset from lower limbs. Upper limbs or larynx accounted for 15% (3/20) and 20% (4/20) of patients, respectively. In the same family, male patients tended to have more severe symptoms than female patients. Carriers of KMT2B variants may present with nonmotor symptoms without dystonia. Abnormal endocrine metabolism could also be seen in our patients, including advanced bone age that had never been reported previously. Nine of our patients underwent DBS surgery. The mean follow-up time was 4.9 (range 1.3-16) months after DBS, and perceptible improvement of clinical symptoms were observed. CONCLUSIONS: The genotypic and phenotypic spectra of Chinese KMT2B-related dystonia patients were further expanded. DBS surgery might be the preferred option for severe KMT2B-related dystonia patients till now.

Modeling vanishing white matter disease with patient-derived induced pluripotent stem cells reveals astrocytic dysfunction.

AIMS: Vanishing white matter disease (VWM) is an inherited leukoencephalopathy in children attributed to mutations in EIF2B1-5, encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B). Although the defects are in the housekeeping genes, glial cells are selectively involved in VWM. Several studies have suggested that astrocytes are central in the pathogenesis of VWM. However, the exact pathomechanism remains unknown, and no model for VWM induced pluripotent stem cells (iPSCs) has been established. METHODS: Fibroblasts from two VWM children were reprogrammed into iPSCs by using a virus-free nonintegrating episomal vector system. Control and VWM iPSCs were sequentially differentiated into neural stem cells (NSCs) and then into neural cells, including neurons, oligodendrocytes (OLs), and astrocytes. RESULTS: Vanishing white matter disease iPSC-derived NSCs can normally differentiate into neurons, oligodendrocytes precursor cells (OPCs), and oligodendrocytes in vitro. By contrast, VWM astrocytes were dysmorphic and characterized by shorter processes. Moreover, δ-GFAP and αB-Crystalline were significantly increased in addition to increased early and total apoptosis. CONCLUSION: The results provided further evidence supporting the central role of astrocytic dysfunction. The establishment of VWM-specific iPSC models provides a platform for exploring the pathogenesis of VWM and future drug screening.

The value of preoperative magnetic resonance imaging in predicting postoperative recovery in patients with cervical spondylosis myelopathy: a meta-analysis.

This meta-analysis was designed to elucidate whether preoperative signal intensity changes could predict the surgical outcomes of patients with cervical spondylosis myelopathy on the basis of T1-weighted and T2-weighted magnetic resonance imaging images. We searched the Medline database and the Cochrane Central Register of Controlled Trials for this purpose and 10 studies meeting our inclusion criteria were identified. In total, 650 cervical spondylosis myelopathy patients with (+) or without (-) intramedullary signal changes on their T2-weighted images were examined. Weighted mean differences and 95% confidence intervals were used to summarize the data. Patients with focal and faint border changes in the intramedullary signal on T2 magnetic resonance imaging had similar Japanese Orthopaedic Association recovery ratios as those with no signal changes on the magnetic resonance imaging images of the spinal cord did. The surgical outcomes were poorer in the patients with both T2 intramedullary signal changes, especially when the signal changes were multisegmental and had a well-defined border and T1 intramedullary signal changes compared with those without intramedullary signal changes. Preoperative magnetic resonance imaging including T1 and T2 imaging can thus be used to predict postoperative recovery in cervical spondylosis myelopathy patients.

The value of preoperative magnetic resonance imaging in predicting postoperative recovery in patients with cervical spondylosis myelopathy: a meta-analysis

This meta-analysis was designed to elucidate whether preoperative signal intensity changes could predict the surgical outcomes of patients with cervical spondylosis myelopathy on the basis of T1-weighted and T2-weighted magnetic resonance imaging images. We searched the Medline database and the Cochrane Central Register of Controlled Trials for this purpose and 10 studies meeting our inclusion criteria were identified. In total, 650 cervical spondylosis myelopathy patients with (+) or without (-) intramedullary signal changes on their T2-weighted images were examined. Weighted mean differences and 95g% confidence intervals were used to summarize the data. Patients with focal and faint border changes in the intramedullary signal on T2 magnetic resonance imaging had similar Japanese Orthopaedic Association recovery ratios as those with no signal changes on the magnetic resonance imaging images of the spinal cord did. The surgical outcomes were poorer in the patients with both T2 intramedullary signal changes, especially when the signal changes were multisegmental and had a well-defined border and T1 intramedullary signal changes compared with those without intramedullary signal changes. Preoperative magnetic resonance imaging including T1 and T2 imaging can thus be used to predict postoperative recovery in cervical spondylosis myelopathy patients.