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Neuronal ceroid lipofuscinoses (NCLs) are relatively common storage diseases of childhood and early adolescence. Ultrastructural shape of storage cytosomes, type of disease gene, and age of onset serve to classify the different NCLs, some of which appear to cluster in Scandinavian countries. The CLN5 form usually presents as a classical epileptiform encephalopathy of late infancy but a more aggressive cognitive impairment has been described in a single family. We report two sibs harbouring a novel mutation (p.Tyr258Asp) in the CLN5 gene and displaying behaviour disturbances and mental deterioration, rather than epilepsy, as the dominant disease manifestation at onset.

Neuronal ceroid lipofuscinoses (NCLs) are characterized by epilepsy, visual failure, psychomotor deterioration, and accumulation of autofluorescent lipopigment. CLN8 mutations result in Northern epilepsy and Turkish variant late infantile NCL. We describe the clinical and neurophysiological findings of three patients with CLN8 mutations from Italy. In these patients, the onset of epilepsy occurred between 3 and 6 years of age, with myoclonic, tonic-clonic, and atypical absence seizures. Electroencephalograms revealed focal and/or generalized abnormalities. In all cases, blindness and progressive attenuation of the electroretinogram were observed. Magnetic resonance imaging revealed cerebral and cerebellar atrophy, thinning of the corpus callosum, deep white matter hyperintensity, and hyperintensity of the posterior limb of internal capsules. Skin biopsy revealed lysosomal storage in the cytoplasm of fibroblasts. The clinical picture of our cases resembles that of the Turkish patients and clearly differs from that of Northern epilepsy, which is marked by a prolonged course without myoclonus and visual loss. Definition of the clinical spectrum of this condition will aid in its recognition and have implications for diagnosis and genetic counseling.

Mutations in the EFHC1 gene have been reported in six juvenile myoclonic epilepsy (JME) families from Mexico and Belize. In this study, we screened 27 unrelated JME Italian families for mutations in the EFHC1 gene.Twenty-seven families (86 affected individuals, 52 women) with at least two affected members with JME were selected. DNA was isolated from peripheral blood lymphocytes by standard methods and each exon of the EFHC1 gene was amplified and sequenced using intronic primers.Two heterozygous mutations were identified in three unrelated families. One (R353 W) was a novel missense mutation, while the F229 L mutation was previously described (say which on of the two occurred in two families). Both mutations cosegregated with the disease. In a fourth family, the variant 545G-->A (resulting in the amino acid substitution R182 H) cosegregated with JME.The results of our study extend the distribution of EFHC1 mutations to the white population and confirm the high level of genetic heterogeneity associated with JME.

Mutations in the gene (GJB2) coding for Connexin 26 (Cx26) are responsible for genetic forms of sensorineural hearing loss. This article describes a family characterized by congenital profound hearing loss, inherited in an autosomal dominant fashion and associated to a R75Q substitution in Cx26. Cell transfection and fluorescence imaging, dye transfer experiments and dual patch clamp recording showed that the mutant completely prevents the formation of functional channels despite assembling into junctional plaques, in communication incompetent HeLa cells. The disease is not associated with palmar and plantar keratosis in any of the family members, suggesting that R75Q substitution is not sufficient for the development of the complete syndromic phenotype. The association of palmar and plantar keratosis with profound hearing loss may be dependent on genetic background, requiring a functional interaction between the mutated Cx26 and other epidermally expressed connexins.