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Abstract: Background: Hypomyelination and congenital cataract (HCC) is a rare autosomal recessive white matter disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system, caused by mutations in the FAM126A gene. Aims: To report three patients of two unrelated families segregating novel mutations. Methods: clinical, neurophysiological, neuroradiologic and molecular investigations were carried out. Results: All patients show bilateral congenital cataract and progressive neurological impairment with peripheral neuropathy. The clinical phenotype is consistent with the severe form of HCC. Brain magnetic resonance imaging show the combination of a diffuse hypomyelination with superimposed periventricular white matter signal abnormalities. Conclusions: this study describes three additional HCC patients indicating that this recently defined leukoencephalopathy should be included in the differential diagnosis of hypomyelination in childhood. The peculiar clinical and neuroradiologic findings are useful to properly address molecular investigations and allow the differential diagnosis between HCC and other hypomyelinating forms. [Copyright &y& Elsevier]

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND , CHAT , GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ , RAPSN , and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected. [ABSTRACT FROM AUTHOR]

Summary: Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function. [Copyright &y& Elsevier]

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination. [ABSTRACT FROM AUTHOR]

The neuronal ceroid lipofuscinoses are a group of dominant neurodegenerative, progressive, and fatal disorders characterized clinically by myoclonic epilepsy, in variable association with dementia, ataxia, and visual loss. Neuronal ceroid lipofuscinoses were classified into several phenotypes according to their age of onset: infantile, late infantile, juvenile, and adult. A specific phenotype was named “northern epilepsy,” and its onset of signs occurs between ages 5-10 years. Deficiencies in the lysosomal activity of two specific enzymes were found in several types of neuronal ceroid lipofuscinosis: palmitoyl-protein thioesterase 1, encoded by the CLN1 gene, and tripeptidyl-peptidase 1, encoded by the CLN2 gene. Several mutations in CLN2 were described previously. We describe a novel mutation in two siblings of Israeli-Arab origin, with a clinical picture compatible with late infantile neuronal ceroid lipofuscinosis. Both siblings were found to be homozygous for a deletion of a C nucleotide at position 775 in exon 7 of the CLN2 gene. These findings have implications for the worldwide epidemiology of neuronal ceroid lipofuscinosis. [Copyright &y& Elsevier]