Epilepsy and episodic ataxia type 2: family study and review of the literature.

Episodic ataxia type 2 (EA2) is a hereditary disorder characterized by paroxysmal attacks of ataxia, vertigo and nausea, due to mutations in the CACNA1A gene, which encodes for α1 subunit of the P/Q-type voltage-gated Ca2+ channel (CaV2.1). Other manifestations may be associated to CACNA1A mutations, such as migraine and epilepsy. The correlation between episodic ataxia and epilepsy is often underestimated and misdiagnosed. Clinical presentation of EA2 varies among patients and within the same family, and the same genetic mutation can lead to different clinical phenotypes. We herewith describe an Italian family presenting with typical EA2 and, in two of the family members (patients II.3 and III.1), epileptic seizures. The sequencing revealed a heterozygous deletion of 6 nucleotides in exon 28 of CACNA1A gene, present in all affected patients. Evidence suggests that mutations of CACNA1A, conferring a loss/reduction of CaV2.1 function, lead to an increase of thalamocortical excitation that contributes to epileptiform discharges. Our description highlights intra-family variability of EA2 phenotype and suggests that mutations in the CACNA1A gene should be suspected in individuals with focal or generalized epilepsy, associated with a family history of episodic ataxia.

Amplifying the spectrum of SPAST gene mutations.

Hereditary spastic paraplegias (HSPs) include a group of neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities, caused by axon degeneration of corticospinal tracts. Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant form of HSP and is caused by mutations in the SPAST gene. SPAST gene encodes for the protein spastin, a member of the ATPases Associated with a variety of cellular Activity (AAA) family.We describe a newly variant in SPAST gene, within an Italian family affected by pure HSP. In particular, we found a heterozygous intragenic microdeletion of 3T in exon 13 of SPG4 gene. The 3T deletion results in a mutated protein with a unique leucine residues deletion at the protein position 508, in the AAA ATPase domain. This variant is not registered in any public database either as rare normal variant nor as mutation in SPAST gene and the importance of this aminoacid is confirmed by the absolute conservation in multiple alignments with diverse species. We conclude that the novel SPAST gene variant identified is probably pathogenic and destabilizes the precise arrangement of the nucleotide binding domain, with a consequent loss-of-function of the mutated spastin protein.

Evaluating the SERCA2 and VEGF mRNAs as Potential Molecular Biomarkers of the Onset and Progression in Huntington's Disease.

Abnormalities of intracellular Ca2+ homeostasis and signalling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of Huntington's disease (HD). As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, we adopted a multiplex real-time PCR approach to analyse the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose we recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provides evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. Our results provide a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD.

Quick MLPA test for quantification of SMN1 and SMN2 copy numbers.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused in about 95% of SMA patients by homozygous deletion of the survival motor neuron 1 (SMN1) gene or its conversion to the highly homologous SMN2 gene. In the majority of cases, disease severity correlates inversely with increased SMN2 copy number. Because of the comparatively high incidence of healthy carriers and severity of the disease, detection of sequence alterations and quantification of SMN1 and SMN2 copy numbers are essential for exact diagnosis and genetic counselling. Several assays have been developed for this purpose. Multiplex ligation-dependent probe amplification (MLPA) is a versatile technique for relative quantification of different nucleic acid sequences in a single reaction. Here, we establish a quick MLPA-based assay for the detection of SMN1 and SMN2 copy numbers with high specificity and low complexity.

Myelin protein zero Val102fs mutation manifesting with isolated spinal root hypertrophy.

The Val102fs mutation of the myelin protein zero gene (MPZ) has been associated with Charcot-Marie-Tooth disease type 1B (CMT1B). Here we describe an unusual presentation of the Val102fs mutation characterized by symptoms of spinal root hypertrophy with no overt peroneal muscular atrophy. Two sisters aged 41 and 35 years complained of neck pain and presented only pes cavus or deep-tendon hyporeflexia. In both of them magnetic resonance imaging revealed non-enhancing hypertrophy of spinal roots misdiagnosed as neurofibromatosis; neurophysiology disclosed a demyelinating neuropathy and addressed the correct molecular diagnosis. This report adds new data concerning the clinical presentations of MPZ mutations.