Nuria Raguer

Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: Should all sporadic ALS cases also be screened for SOD1?

BACKGROUND SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia. OBJECTIVE To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis. RESULTS Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant. CONCLUSIONS The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered.

Phenotypic variability in a Spanish family with MNGIE

Abstract—Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset.

Cellular transplants in amyotrophic lateral sclerosis patients: an observational study.

BACKGROUND AIMS Cytotherapy is a promising option for neurodegenerative disease treatment. Because of the fatal prognosis and imperative need for effective treatment, amyotrophic lateral sclerosis (ALS) patients request this therapy before its effectiveness has been verified. The increase in clinics offering cytotherapies but providing little scientific information has prompted considerable medical tourism. We present an observational study of Spanish ALS patients receiving cytotherapy, analyzing the experiences arising from the treatment (TX) and considering two progression markers, FVC and ALSFRS-R. METHODS Twelve ALS patients with a mean age of 48.6 years (SD 12.8) received cytotherapy 26.9 months (SD 15.8) after clinical onset. ALSFRS-R and FVC at TX were 32.3 (SD 6.8) and 63.4% (SD 15.3), respectively. TX involved transplants of olfactory ensheathing cells in three patients, and autologous mesenchymal stromal cells in the remainder. RESULTS One patient died 33 months post-TX after surviving for 49 months. Five required mechanical non-invasive home ventilation 7.4 months post-TX. Two required invasive ventilation 13 months post-TX. Five patients needed gastrostomy feeding 23.3 months post-TX. Survival between clinical onset and the study end date was 50 months (SD 17.2). No significant adverse events or changes in the decline of FVC and ALSFRS-R compared with the diseases natural history were observed. CONCLUSIONS Our observations suggest that these therapies do not halt the course of the disease. Cytotherapy cannot yet be considered a curative treatment for ALS.

A novel thymidine phosphorylase mutation in a Spanish MNGIE patient.

A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE.

Late-onset metachromatic leukodystrophy clinically presenting as isolated peripheral neuropathy: compound heterozygosity for the IVS2+1G-->A mutation and a newly identified missense mutation (Thr408Ile) in a Spanish family.

We report the case of a 50‐year‐old woman and her 32‐year‐old daughter, both of whom are affected with adult‐onset metachromatic leukodystrophy (MLD) clinically presenting as peripheral neuropathy. Arylsulfatase A (ARSA) activities were markedly reduced, and electrophysiology showed a severe demyelinating neuropathy with features of chronic acquired demyelinating polyneuropathy. Molecular genetic studies of the family revealed that the proband and her affected daughter are compound heterozygotes for the common IVS2+1G→A mutation and a newly identified missense mutation, Thr408Ile. This case indicates that adult metachromatic leukodystrophy should be considered in adult patients with demyelinating peripheral neuropathy of unknown etiology.

A New Method for Measuring Motor Evoked Potentials in the Awake Rat: Effects of Anesthetics

The goal of this investigation was to develop a method to study the neurophysiological integrity of the central motor tract using motor evoked potentials in the awake rat and assess the effects of different anesthetics in this model. Rats were implanted with six subcutaneous electrodes (pediatric myocardial pacing leads) and one cranial screw. Motor evoked potentials of the hind limb were elicited after cranial and sciatic nerve stimulation. Experiments were repeated on different days during three weeks studying the effect of three different anesthetics (propofol, ketamine/xylazine, pentobarbital) at three different doses. Stimulation of motor evoked potentials in the awake rat was well tolerated with no effects on behavior. The electrodes could be kept chronically in place without signs of infection. The repeated recordings on different days showed high reproducibility after the fourth day following implantation of the electrodes. All three anesthetics induced an increase in the latency and a decrease in the amplitude of the motor evoked potentials which were dose dependent. Propofol (up to 1 mg/kg x min(1)) affected motor evoked potentials to a lesser extent than the other anesthetics. Based upon these findings, we believe that our approach provides a new method of chronically implanting electrodes in the rat to assess the neurophysiological function of the motor tract without the need of anesthetics. This model may prove useful in the investigation of various diseases that affect the motor pathways without the confounding effects of anesthesia.

Investigation of the role of SMN1 and SMN2 haploinsufficiency as a risk factor for Hirayama's disease: Clinical, neurophysiological and genetic characteristics in a Spanish series of 13 patients

OBJECTIVE The effect of the number of copies in the SMN1 and SMN2 genes - the most extensively studied susceptibility and modifying genetic factors in adult onset motor neuron diseases - as a genetic risk factor for Hirayamas disease (HirD) has never been studied. The purpose of this study was to investigate the influence of the number of copies of the SMN1/SMN2 genes on the resulting phenotype in 13 HirD Spanish patients. PATIENTS AND METHODS We performed a qualitative and quantitative SMN1/SMN2 gene analysis in 13 unrelated HirD patients. The phenotype-genotype correlation was investigated, paying particular attention to the effect of the SMN1/SMN2 copy number on the diseases phenotype. RESULTS No patient had a homozygous deletion of the SMN1 or SMN2. No differences were found when comparing the SMN1 and SMN2 copy number distributions of the healthy population and HirD patients, and they do not therefore appear to be a susceptibility factor. There was also no correlation found between the number of copies of the SMN1 and SMN2 and the severity of the resulting phenotype. CONCLUSION Our results suggest that SMN1 and SMN2 are not predisposing factors for HirD and therefore support a lack of association between these genes and the resulting phenotype.

Study of the prevalence of familial autoimmune myasthenia gravis in a Spanish cohort

BACKGROUND Myasthenia gravis (MG) is an autoimmune disease caused by a failure of neuromuscular transmission. Familial clustering has been reported despiteMG usually manifesting as a sporadic condition presumed not to be inherited. Our study investigated the prevalence of FAMG in a Spanish cohort, characterizing their phenotype,antibody titres and thymus findings. MATERIAL/METHODS We investigated the presence of familial cases in 462 MG patients, characterizing by age and MGFA class at debut, quantitative MG score, antibody titres, MGFA post-intervention status and thymus pathology. RESULTS Sixteen cases from8 unrelated pedigrees were identified. The prevalence of FAMG caseswas 3.46%.Mean age at onset was 57.8 ± 17.4 years (range=23–82). Distribution at debut was: 6 ocular, 4 IIa, 4IIb, 1 IIIa and 1 IIIb. Thymoma was identified in two of the 7 thymectomized individuals. CONCLUSIONS The prevalence of FAMG in Spain is similar to other populations. Post-intervention status did not differ from sporadic autoimmune MG. As in other neuromuscular disorders, phenotype and inheritance heterogeneity are present in FAMG. In addition to the interfamilial heterogeneity observed, members of the same family affected with FAMG may even present different ages of onset, severity and thymus involvement. Further studies are necessary to clarify the role of genetic risk factors in this form of autoimmune MG.

SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

Myasthenia gravis following alemtuzumab therapy for multiple sclerosis

Alemtuzumab, indicated for active relapsing-remitting multiple sclerosis (MS), produces lymphocyte depletion followed by a different pattern of T- and B-cell repopulation, increasing the risk of secondary autoimmune diseases.1 According to the published long-term safety data, thyroid disorders are the most common autoimmune adverse event.2 Myasthenia gravis (MG), an autoimmune antibody-mediated disorder, rarely coexists in patients with MS.3,4 To date, MG has not been reported in patients with MS exposed to alemtuzumab.