Vanishing white matter disease (VWM) is an autosomal recessive leukodystrophy caused by mutations genes encoding the translational initiation factor 2B: EIF2B1-EIFB5. It is a heterogeneous neurological disorder with prominent cerebellar ataxia and spasticity in childhood-onset form and behavioural changes, dementia and seizures in adult-onset form (̴15% of cases). We present the case of a 60 years old patient, MTHFR homozygous, presenting white matter lesions and a subcortical vascular encephalopathy being diagnosed. To investigate a possible genetic cause, suspecting CADASIL, genetic and genomic analysis were performed.

Autism spectrum disorders (ASDs) constitute a set of heterogeneous neurodevelopmental conditions, characterized by a wide genetic variability that has led to hypothesize a polygenic origin. The metabolic profiles of patients with ASD suggest a possible implication of mitochondrial pathways. Although different physiological and biochemical studies reported deficits in mitochondrial oxidative phosphorylation in subjects with ASD, the role of mitochondrial DNA variations has remained relatively unexplored. In this review, we report and discuss very recent evidence to demonstrate the key role of mitochondrial disorders in the development of ASD.

BACKGROUND:Charcot-Marie-Tooth disease (CMT) constitutes a group of heterogeneous hereditary motor and sensor neuropathies. Mutations in the periaxin (PRX) gene cause CMT4F with an autosomal recessive early-onset demyelinating neuropathy and are extremely rare in a non-Romani white population.METHODS:We report on a 66-year-old Italian man presenting with slowly progressive and late-onset demyelinating CMT. The molecular analysis was performed using a custom panel containing 39 genes associated with the CMT phenotype.RESULTS:The patient harbored a homozygous PRX 71-nucleotide deletion (c.3286_3356del71, I1096fsX17).CONCLUSIONS:This is the first report that describes such a genetic mutation in a population of non-Romani origin.

BackgroundHyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases.Case presentationIn the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C>T or p.R299X inherited from the mother and c.587C>A or p.D98E inherited from the father.ConclusionsUntil now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

Amyotrophic Lateral Sclerosis and CHARGE syndrome are complex neurological disorders, which never occurred together in the same family and, to date, no putative correlation between them has been described on PubMed Central. Due to our aim was to evaluate the presence of different genetic variants involved in these pathologies, we reported a clinical and genetic description of two sisters affected by these two different disorders. In the CHARGE patient, molecular analysis of the CHD7 gene revealed the c.8016G>A de novo variant in exon 37. The ALS patient had been screened negative for mutations in SOD1, TARDBP, FUS/TLS, C9orf72 and KIF5A genes. Anyway, targeted next generation sequencing analysis identified known and unknown genetic variations in 39 ALS-related genes: a total of 380 variants were reported, of which 194 in the ALS patient and 186 in the CHARGE patient. To date, although the results suggest that the occurrence of the two syndromes in the same family is co-incidental rather than based on a causative genetic variant, we could hypothesize that other factors might act as modulators in the pathogenesis of these different phenotypes.

Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body and their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10). We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy.

Background: Neurological disorders are a highly heterogeneous group of pathological conditions that affect both the peripheral and the central nervous system. These pathologies are characterized by a complex and multifactorial etiology involving numerous environmental agents and genetic susceptibility factors. For this reason, the investigation of their pathogenetic basis by means of traditional methodological approaches is rather arduous. High-throughput genotyping technologies, including the microarray-based comparative genomic hybridization (aCGH), are currently replacing classical detection methods, providing powerful molecular tools to identify genomic unbalanced structural rearrangements and explore their role in the pathogenesis of many complex human diseases. Methods: In this report, we comprehensively describe the design method, the procedures, validation, and implementation of an exon-centric customized aCGH (NeuroArray 1.0), tailored to detect both single and multi-exon deletions or duplications in a large set of multi-and monogenic neurological diseases. This focused platform enables a targeted measurement of structural imbalances across the human genome, targeting the clinically relevant genes at exon-level resolution. Conclusion: An increasing use of the NeuroArray platform may offer new insights in investigating potential overlapping gene signatures among neurological conditions and defining genotypephenotype relationships.

The association between multiple sclerosis (MS) and hereditary and sporadic demyelinating disorders of the peripheral nervous system is extremely rare. We herein report a case of Charcot-Marie-Tooth disease type 1B with p.Val102fs mutation in the MPZ gene that developed relapsing remitting MS.

Autosomal recessive spastic paraplegia form 35 (SPG35) is a rare form of Hereditary Spastic Paraplegia (HSP, MIM 18260) characterized by childhood onset of spasticity, cognitive decline and leukodystrophy [ [1] Dick K.J. Al-Mjeni R. Baskir W. et al. A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23. Neurology. 2008; 71: 248-252 Crossref PubMed Scopus (43) Google Scholar ]. Additional clinical features such as seizures, dysphagia, dysarthria, dystonia, neuropathy and brain iron accumulation were also observed [ [2] Kruer M.C. Paisan-Ruiz C. Boddaert N. Yoon M.Y. Hama H. Gregory A. et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann. Neurol. 2010; 68: 611-618 Crossref PubMed Scopus (186) Google Scholar ]. Mutations in the fatty acid 2-hydroxylase (FA2H) gene have been associated to the SPG35 form. FA2H encodes a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent monooxygenase, involved in the synthesis of 2-hydroxy fatty acid galactolipids, that are the major component of myelin sheath [ [3] Maldonado E.N. Alderson N.L. Monje P.V. et al. FA2H is responsible for the formation of 2-hydroxy galactolipids in peripheral nervous system myelin. J. Lipid Res. 2008 Jan; 49 (Epub 2007 Sep 27): 153-161 Crossref PubMed Scopus (36) Google Scholar ].

SUMMARY Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

A. Magariello*, L. Citrigno*, S. Zuchner, M. Gonzalez, A. Patitucci, V. Sofia, F. L. Conforti, I. Pappalardo, R. Mazzei, C. Ungaro, M. Zappia and M. Muglia Institute of Neurological Sciences, National Research Council, Mangone (CS), Italy; Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA; and Dipartimento G.F. Ingrassia Sezione di Neuroscienze Universit a di Catania, Catania, Italy

Hereditary spastic paraplegia (HSP) includes a group of diseases characterized by progressive spastic weakness of the lower limbs (pure forms) with possible additional signs (complicated forms). The SPG10 form is due to alteration in the kinesin1A gene (KIF5A) that encodes the neuronal kinesin heavy chain, a protein required for the anterograde axonal transport. We performed clinical, neurophysiological and molecular studies in two siblings affected by AD-HSP complicated by deafness. The screening of the KIF5A gene revealed the novel mutation p.Leu259Gln in two affected siblings and in their father with a pure form of HSP.

Charcot–Marie–Tooth (CMT) diseases include a group of clinically heterogeneous inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and intermediate CMT forms. CMTs are associated with different genes, although mutations in some of these genes may cause both clinical pictures. To date, more than 50 CMT genes have been identified, but more than half of the cases are due to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate the frequency of disease mutations of these four genes in the axonal form of CMT in order to evaluate their effectiveness in the molecular diagnosis of CMT2 patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel: 11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in PMP22. No mutations were found in GJB1. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus usually not tested in CMT2 patients. By including this gene in the analysis, we reached a molecular diagnosis rate of 39.5 %, which is one of the highest reported in the literature. Our findings confirm the MFN2 gene as the most common cause of CMT2 and suggest that PMP22 rearrangements should be considered in the molecular diagnosis of CMT2 patients.

Spinal neurofibromatosis (SNF) is a related form of neurofibromatosis 1 (NF1), characterized by bilateral neurofibromas (histologically proven) of all spinal roots (and, eventually, of all the major peripheral nerve branches) with or without other manifestations of classical NF1. By rigorous application of these criteria to the 98 SNF cases published, we developed: (i) a cohort of 49 SNF patients (21 males and 28 females; aged 4–74 years]: 9 SNF families (21/49), 1 mixed SNF/NF1 family (1/49) and 27 of 49 sporadic SNF patients (including 5 unpublished patients in this report); and (ii) a group of 49 non‐SNF patients including: (a) 32 patients with neurofibromas of multiple but not all spinal roots (MNFSR): 4 mixed SNF/MNFSR families (6/32); (b) 14 patients with NF1 manifestations without spinal neurofibromas, belonging to SNF (8/49) or MNFSR families (6/32); (c) 3 patients with neurofibromas in one spinal root. In addition to reduced incidence of café‐au‐lait spots (67% in SNF vs 56% in MNFSR), other NF1 manifestations were less frequent in either cohort. Molecular testing showed common NF1 gene abnormalities in both groups. The risk of developing SNF vs NF1 was increased for missense mutations [p = 0.0001; odds ratio (OR) = 6.16; confidence interval (CI) = 3.14–13.11], which were more frequent in SNF vs MNFSR (p = 0.0271).

Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into 'no anxiety' and 'subclinical anxiety' groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.

European Journal of NeurologyVolume 20, Issue 1 p. e22-e23 Letter to the Editor First mutation in the nuclear localization signal sequence of spastin protein identified in a patient with hereditary spastic paraplegia A. Magariello, A. Magariello Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorC. Tortorella, C. Tortorella Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorA. Patitucci, A. Patitucci Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorR. Tortelli, R. Tortelli Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorM. Liguori, M. Liguori Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorR. Mazzei, R. Mazzei Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorF. L. Conforti, F. L. Conforti Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorL. Citrigno, L. Citrigno Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorC. Ungaro, C. Ungaro Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorI. L. Simone, I. L. Simone Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorM. Muglia, Corresponding Author M. Muglia Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalyCorrespondence: M. Muglia, National Research Council, Institute of Neurological Sciences, 87050 Mangone, Cosenza, Italy (tel.: +3909849801228; fax: +390984969306; e-mail: [email protected]).Search for more papers by this author A. Magariello, A. Magariello Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorC. Tortorella, C. Tortorella Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorA. Patitucci, A. Patitucci Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorR. Tortelli, R. Tortelli Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorM. Liguori, M. Liguori Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorR. Mazzei, R. Mazzei Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorF. L. Conforti, F. L. Conforti Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorL. Citrigno, L. Citrigno Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorC. Ungaro, C. Ungaro Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalySearch for more papers by this authorI. L. Simone, I. L. Simone Department of Neurological and Psychiatric Sciences, Institute of Neurology, University of Bari, Bari, ItalySearch for more papers by this authorM. Muglia, Corresponding Author M. Muglia Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, ItalyCorrespondence: M. Muglia, National Research Council, Institute of Neurological Sciences, 87050 Mangone, Cosenza, Italy (tel.: +3909849801228; fax: +390984969306; e-mail: [email protected]).Search for more papers by this author First published: 22 December 2012 https://doi.org/10.1111/ene.12000Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume20, Issue1January 2013Pages e22-e23 RelatedInformation

Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3'-untranslated region [UTR] variant, c.*41G>A; c.523+3ins[GAGGTG]; c.335-15del[TTTT]; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes.