SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain.

BACKGROUND: Inherited and de novo mutations in sodium channel genes underlie a variety of channelopathies. Mutations in SCN2A, encoding the brain sodium channel Na(V)1.2, have previously been reported to be associated with benign familial neonatal infantile seizures, febrile seizures plus, and intractable epilepsy of infancy. METHODS: We evaluated the clinical characteristics in a patient with a neonatal-onset complex episodic neurologic phenotype. We screened SCN2A for mutations and carried out in vitro electrophysiologic analyses to study the consequences of the identified mutation. We studied the developmental expression of Na(V)1.2 in cerebellum by immunohistochemical analysis. RESULTS: The patient presented with neonatal-onset seizures and variable episodes of ataxia, myoclonia, headache, and back pain after 18 months of age. The patient carries a de novo missense mutation (p.Ala263Val) in SCN2A, which leads to a pronounced gain-of-function, in particular an increased persistent Na(+) current. Immunohistochemical studies suggest a developmentally increasing expression of Na(V)1.2 in granule cell axons projecting to Purkinje neurons. CONCLUSIONS: These results can explain a neuronal hyperexcitability resulting in seizures and other episodic symptoms extending the spectrum of SCN2A-associated phenotypes. The developmentally increasing expression of Na(V)1.2 in cerebellum may be responsible for the later onset of episodic ataxia.

A deletion/inversion rearrangement of the beta-globin gene cluster in a Turkish family with delta beta zero-thalassemia intermedia.

The most common forms of hereditary persistence of fetal hemoglobin synthesis (HPFH) and delta beta zero-thalassemia result from simple deletions of the beta-globin gene cluster or from point mutations in the gamma-globin gene promoters. These naturally occurring mutants extend our understanding of globin gene regulation and hemoglobin switching. Furthermore, they provide the opportunity to test in vivo hypothetical switching models that are based on the experimental approach. We report here a family with delta beta zero-thalassemia from Turkey with a complex rearrangement of the beta-globin gene cluster that involves two deletions of 11.5 kb and 1.6 kb, and an inversion of 7.6 kb. The larger deletion removes both the delta-and the beta-globin genes with 3' flanking sequences, whereas the smaller deletion affects DNA of unknown function. The inversion contains the entire L1 repeat 3' of the beta-globin gene. There are structural motifs near the breakpoints (introduction of an "orphan" nucleotide, multiple direct and inverted repeats) suggesting a nonhomologous type of recombination event. The hematologic phenotype and the molecular structure of the rearranged beta-globin gene cluster are consistent with a competitive relationship between the fetal and the adult globin genes and/or with the translocation of enhancer sequences into the gamma-globin gene region.

The proximal element of the beta globin locus control region is not functionally required in vivo.

In addition to local sequence elements the regulation of the high-level, development- and tissue-specific expression of the human beta globin gene cluster appears to require distant regulatory sequences which have been termed locus control region. In the chromatin of erythroid cells the locus control region is characterized by four DNaseI hypersensitive sites that are located 6-18 kb 5' of the epsilon globin gene. The definition of the sequences minimally required for locus control region activity is likely to further the understanding of its physiology and will be of interest for the development of somatic gene therapy strategies of the hemoglobinopathies. We present here the analysis of a family with a 3,030-bp deletion of sequences upstream of the epsilon globin gene including the most 3' locus control region element and cosegregating beta(0) thalassemia. The deletion is linked in cis to a structurally and functionally normal beta globin gene. The proximal element of the locus control region does not therefore appear to be necessary for beta globin gene activity in vivo.

Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element.

A patient with homozygous beta thalassemia of German/Italian descent was found to be doubly heterozygous for the common IVS1-110 G----A mutation of the beta globin gene and for a novel C----T mutation of the proximal CACCC-box of the beta globin gene promoter at position -87 relative to the transcription start site (cap). Transcription analysis in an HeLa cell transfection assay indicated a 45% to 51% residual activity of the gene with the -87 C----T mutation relative to normal, further underlining the physiologic role of the affected promoter element. The finding of an only moderately reduced transcriptional activity of the beta globin gene with the -87 C----T mutation corresponds well with the clinical phenotype of the reported patient, which is characterized by a late onset of symptoms, moderate anemia, and normal physical development. The ethnically German mother of the propositus has minimal anemia with only slightly changed red blood cell indices, which can also be explained by the relatively high residual activity of the gene with the -87 C----T mutation.