A 71-nucleotide deletion in the periaxin gene in an Italian patient with late-onset slowly progressive demyelinating Charcot-Marie-Tooth disease.

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.

Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia.

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.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies.

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.

The natural history of spinal neurofibromatosis: a critical review of clinical and genetic features.

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).

A novel KIF5A mutation in an Italian family marked by spastic paraparesis and congenital deafness.

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.

Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia.

BACKGROUND AND PURPOSE: Adult-onset dystonia may be related, amongst other factors, to abnormal neuronal plasticity in cortical and subcortical structures. Brain-derived neurotrophic factor is a major modulator of synaptic efficiency and neuronal plasticity. Recent works documented that a single nucleotide polymorphism (SNP) of the BDNF gene, the Val66Met SNP, modulates short-term plastic changes within motor cortical circuits. In this study we aimed at exploring the effect of this SNP upon the risk of developing common forms of primary adult-onset dystonia. METHODS: We explored the influence of the Val66Met SNP of the BDNF gene on the risk of cranial and cervical dystonia in a cohort of 156 Italian patients and 170 age- and gender-matched healthy control subjects drawn from the same population. RESULTS: The presence of the rare Met allele was not significantly associated with the diagnosis of dystonia (age- and gender-adjusted odds ratios of 1.22, P = 0.38). The study had a >90% power to detect a 50% change in the risk of developing cranial-cervical dystonia associated with the presence of the Met allele. Moreover, there was no relationship between Val66Met SNP and age at dystonia onset or type of dystonia. CONCLUSION: Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor shared by the various forms of primary adult-onset dystonia.

A novel mutation in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene associated with a severe Rett phenotype.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

CADASIL: extended polymorphisms and mutational analysis of the NOTCH3 gene.

CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. Most mutations result in a gain or loss of cysteine residue in one of the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein, thus sparing the number of cysteine residues. To date, more than 130 different mutations in the NOTCH3 gene have been reported in CADASIL patients, of which 95% are missense point mutations. Many polymorphisms have also been identified in the NOTCH3 coding sequence, some of them leading to amino acid substitutions. The aim of the present study was to analyze the NOTCH3 gene in a large group of patients affected by leukoencephalopathy and to investigate the presence of genetic variants. The molecular analysis revealed several nucleotide alterations. In particular, we identified 20 different mutations, 22 polymorphisms, and 8 genetic variants of unknown pathological significance never reported previously. We hope that this NOTCH3 gene mutational analysis, performed in such a significant number of unrelated and related patients affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 gene, thus contributing to enlargement of the NOTCH3 gene variation database.

Charcot-Marie-Tooth type X: unusual phenotype of a novel CX32 mutation.

BACKGROUND: X-linked Charcot-Marie-Tooth disease (CMTX), caused by mutations in the gene encoding connexin32, is the second most common form of inherited demyelinating neuropathy, next to CMT 1A, and accounts for 10-20% of all hereditary demyelinating neuropathies. AIMS OF THE STUDY: To describe clinical and electrophysiological data of an Italian family carrying a novel mutation in the Cx32 gene. PATIENTS AND METHODS: Clinical, electrophysiological, and genetic findings of three patients carrying the Ser128Leu mutation in the intracellular domain of the Cx32 gene were reported. Brain MRI studies were also performed. RESULTS: In our family the disease was characterized by a moderate-to-severe polyneuropathy affecting similarly males as well females. In the proband the phenotype was quite unusual in terms of late-onset, rapidity of evolution and severity. Abnormal brain MRI in association with CNS symptoms were also observed. Both sons had also clinical evidence of CNS involvement. CONCLUSIONS: The Ser128Leu mutation in the Cx-32 gene is a novel substitution, which has not been reported so far. This novel mutation could be added to the group of Cx-32 mutations with CNS phenotypes. The identification of new CMTX causing mutations is a crucial step for carrier detection and pre-symptomatic diagnosis.

Charcot-Marie-Tooth disease type 1B: marked phenotypic variation of the Ser78Leu mutation in five Italian families.

OBJECTIVES: To describe clinical, electrophysiological and genetic data of five unrelated Sicilian pedigrees harbouring a heterozygous Ser78Leu mutation in the myelin protein zero (MPZ) extracellular domain. MATERIALS AND METHODS: Clinical, electrophysiological and genetic findings of 16 patients were reported. Polymorphic markers flanking the coding sequence of MPZ gene were also analysed. RESULTS: A wide range of age at onset was observed in families 1 and 3, with a clinical heterogeneity, in terms of severity of the disease, within the same family (families 1 and 3), and among families. A markedly unsteady gait was a distinctive feature of many members of family 1. All patients in family 2 complained of severe cramps and painful paresthesia. Molecular genetic analysis showed that all affected subjects shared a common haplotype at three microsatellite loci D1S2858, D1S2624 and D1S484. CONCLUSIONS: Our study provides further evidence that phenotypic features of MPZ mutations can vary within and among different families. High frequency of Ser78Leu mutation in Sicily as well as the results of haplotype analyses suggest that the mutation may have been inherited from a common ancestor.

A novel locus for dHMN with pyramidal features maps to chromosome 4q34.3-q35.2.

The distal hereditary motor neuropathy (dHMN) is a rare genetically and clinically heterogeneous disorder characterized by weakness and wasting of distal limb muscles in absence of overt sensory abnormalities. Recently, pyramidal signs have been also described in some patients with dominant or recessive dHMN, and two different loci have been identified in families affected by dHMN complicated with pyramidal dysfunction. We investigated an Italian family affected by an autosomal dominant dHMN complicated by pyramidal signs in order to map a new gene locus. The disease maps to a novel locus in a 26-cM region flanked by D4S1552 and D4S2930 on chromosome 4q34.3-35.2. Three candidate genes (SNX25, CASP3 and TUBB4Q) located in the critical region were screened for the presence of mutations by heteroduplex analysis. No mutations have been detected in the analyzed genes. In conclusion, the new private genetic locus we reported further confirms the wide heterogeneity of dHMN.

A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy.

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.