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Background A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study. Methods Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case. Results Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia. Conclusions We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population.

Mutations in the ryanodine receptor-1 (RYR1) may cause disorders inherited in an autosomal dominant/recessive fashion. Sequencing of RYR1 in an infant of Ashkenazi Jewish descent with severe hypotonia, dislocation of hip, torticollis and scoliosis, and paternal family history of autosomal dominant mild disease. The child was compound heterozygote for a missense variant c.7042G > A inherited from her father associated with autosomal dominant disease, and a missense variant of unknown significance c.5309C > T inherited from an asymptomatic mother. This case raises the possibility of a dominant disease complicated by a second variant in the other allele serving as a modifier.

ObjectiveTo identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).MethodsClinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.ResultsA homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.ConclusionsOur findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.

Objective: To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings. Design: The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed. Clinical and laboratory data were retrospectively collected. Setting: University hospital. Patients: Seven patients (3 male) shared similar MRI abnormalities and clinical features. Main Outcome Measures: Pattern of MRI abnormalities and clinical and laboratory findings. Results: The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia, brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones. From the second year on, clinical improvement occurred. So far, no second episode of regression has happened. Lactate levels were elevated during clinical regression. Conclusion: These patients represent a single novel leukoencephalopathy, probably caused by a mitochondrial defect. Arch Neurol. 2012; 69(6): 718-722. Published online February 6, 2012. doi:10.1001/archneurol.2011.1048

The brain has a remarkable capacity for reorganization following injury, especially during the first years of life. Knowledge of structural reorganization and its consequences following perinatal injury is sparse. Here we studied changes in brain tissue volume, morphology, perfusion, and integrity in children with hemiplegia compared to typically developing children, using MRI. Children with hemiplegia demonstrated reduced total cerebral volume, with increased cerebrospinal fluid (CSF) and reduced total white matter volumes, with no differences in total gray matter volume, compared to typically developing children. An increase in cortical thickness at the hemisphere contralateral to the lesion (CLH) was detected in motor and language areas, which may reflect compensation for the gray matter loss in the lesion area or retention of ipsilateral pathways. In addition, reduced cortical thickness, perfusion, and surface area were detected in limbic areas. Increased CSF volume and precentral cortical thickness and reduced white matter volume were correlated with worse motor performance. Brain reorganization of the gray matter within the CLH, while not necessarily indicating better outcome, is suggested as a response to neuronal deficits following injury early in life. Guy’s and St Thomas’ Charity and the Marnie Kimelman Trust

Purpose To prospectively evaluate long-term effects of repeated botulinum toxin A (BTX-A) injections in children with cerebral palsy (CP). Methods Repeated injections of BTX-A were offered to children with CP, according to clinical indications, for a maximum of four injections within a period of two years. Injections were administered into lower extremity muscles of 26 consecutive children (age 3.7 ± 1.2 years, 16 boys) with hemiplegic or diplegic CP. Clinical assessments before and one month following each injection included a gross motor function measure (GMFM), a modified Ashworth scale, and range-of-motion of knee extension and ankle dorsiflexion. Results Twelve children received two injections, six received three injections, five received one injection, and three received four injections. The most common reason for discontinuing treatment was the need for orthopedic surgery ( n = 17). A long-term effect was demonstrated by a significant increase of the GMFM score before the first injection compared with the last injection for each patient ( P < 0.0001). There was no comparable change in the muscle tone or range-of-motion. The mean rate of GMFM change during the study was significantly higher than literature norms for CP children (13.2 vs. 5.37 per year, respectively, P < 0.01). The increase of the GMFM score before and one-month after injection (short-term effect) was significantly higher after the first injection than after the last injection ( P < 0.05). Similar results were found for the Ashworth scale and popliteal angle. Conclusions Botulinum toxin A injections have a long-term effect on gross motor function in children with CP even though the effect on muscle tone is short-term. The effect apparently declines with repeated injections, with most children benefitting from 2 to 3 injections.

Strehlow et al. describe the largest cohort to date of individuals with GRIN2A-related disorders. The results reveal two phenotypic subgroups associated with different classes of variants affecting distinct domains of the GluN2A protein with different functional consequences. The findings will help predict outcomes in newly diagnosed individuals., Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10−6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/− cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.