Spastic paraplegia type 10 (SPG10) is an autosomal dominant form of hereditary spastic paraplegia (HSP) due to mutations in KIF5A, a gene encoding the neuronal kinesin heavy chain implicated in anterograde axonal transport. KIF5A mutations were found in both pure and complicated forms of the disease; a single KIF5A mutation was also detected in a CMT2 patient belonging to an SPG10 mutant family. To confirm the involvement of the KIF5A gene in both CMT2 and SPG10 phenotypes and to define the frequency of KIF5A mutations in an Italian HSP patient population, we performed a genetic screening of this gene in a series of 139 HSP and 36 CMT2 affected subjects. We identified five missense changes, four in five HSP patients and one in a CMT2 subject. All mutations, including the one segregating in the CMT2 patient, are localized in the kinesin motor domain except for one, falling within the stalk domain and predicted to generate protein structure destabilization. The results obtained indicate a KIF5A mutation frequency of 8.8% in the Italian HSP population and identify a region of the kinesin protein, the stalk domain, as a novel target for mutation. In addition, the mutation found in the CMT2 patient strengthens the hypothesis that CMT2 and SPG10 are the extreme phenotypes resulting from mutations in the same gene.

Alternating hemiplegia of childhood (AHC, MIM 104290) is a rare syndrome, characterised by early onset of episodic hemi- or quadriplegia lasting minutes to days. The majority of patients are sporadic. Only a few familial cases are reported in the literature. Here we describe a new familial case from a Greek island with four affected members in two generations, the mother and three out of four children. All patients share a normal karyotype. Due to the partial clinical overlap of familial hemiplegic migraine (FHM) with AHC, we screened the ATP1A2 gene coding for the α2 subunit of the Na,K pump, associated with FHM type 2. We found a novel heterozygous mutation segregating with the disease and causing a threonine to asparagine replacement (T378N). This missense mutation localises to the ATPases phosphorylation site of the hydrolase domain. The affected residue is highly conserved in all the known α subunits of the Na,K and Na,H pumps from vertebrates to invertebrates. Functional data suggest that loss of function of the mutated ATP1A2 isoform is involved in generating the disease phenotype. This is the first mutation associated with AHC identified so far

Mutations in the SPG7 gene encoding a mitochondrial protein termed paraplegin, are responsible for a recessive form of hereditary spastic paraparesis. Only few studies have so far been performed in large groups of hereditary spastic paraplegia (HSP) patients to determine the frequency of SPG7 mutations. Here, we report the result of a mutation screening conducted in a large cohort of 135 Italian HSP patients with the identification of six novel point mutations and one large intragenic deletion. Sequence analysis of the deletion breakpoint, together with secondary structure predictions of the deleted region, indicate that a complex rearrangement, likely caused by extensive secondary structure formation mediated by the short interspersed nuclear element (SINE) retrotransposons, is responsible for the deletion event. Biochemical studies performed on fibroblasts from three mutant patients revealed mild and heterogeneous mitochondrial dysfunctions that would exclude a specific association of a complex I defect with the pathology at the fibroblast level. Overall, our data confirm that SPG7 point mutations are rare causes of HSP, in both sporadic and familial forms, while underlying the puzzling and intriguing aspects of histological and biochemical consequences of paraplegin loss.

This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding a-and b-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G > C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open-lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine-rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the b-tubulin gene TUBB2B, supporting its critical role in migration ⁄ organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly.A spectrum of neurological disorders characterized by abnormal neuronal migration, differentiation, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding the a-tubulin and b-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. Defects in any of the genes encoding any of these isotypes generate a large spectrum of brain malformations including dysmorphism of the basal ganglia and brainstem, partial or complete agenesis of the corpus callosum (ACC), cerebellar vermis hypoplasia, and different types of cortical malformations.1,2 Various grades of lissencephaly, ranging from the complete loss of gyri and sulci (agyria) to the brain with simplified abnormally thick convolutions (pachygyria) and perisylvian polymicrogyria (PMG), have been associated with mutations of the a-tubulin gene TUBA1A. 3-5Bilateral asymmetrical PMG has been observed in association with mutations in the b-tubulin gene TUBB2B, 6 whereas cortical defects (PMG and gyral disorganization) and axon guidance disorders (hypoplasia of the oculomotor nerves) have been found in individuals displaying defects of the b-tubulin gene TUBB3. 7,8 Finally, a mutation in the a-tubulin gene TUBA8 has been described in individuals with generalized PMG and optic nerve hypoplasia.9 These findings suggest a crucial role of tubulin genes in neuronal microtubules coassembly. 10 Microtubules play a key role in cellular processes that are crucial for cortical development during neuronal migration and differentiation, but also in cortical laminar organization (involving both pyramidal neurons and interneurons), in the regulation of neuronal cell proliferation, and in neuronal guidance of the radial glia (axon outgrowth and maintenance). 6,10 In this study we report the case of a female with microcephaly, comple...