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Muelas N, Hackman P, Luque H, Suominen T, Espinós C, Garcés-Sánchez M, Sevilla T, Azorín I, Millán JM, Udd B, Vílchez JJ. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients. Laing myopathy is a distal myopathy caused by mutations in the tail of the slow beta-myosin heavy chain gene MYH7. A large cluster of patients belonging to different families, with Laing myopathy due to p.K1729del mutation, was found in the Safor region, Spain. The same mutation was previously reported in an American family with Italian ancestry. The possibility that p.K1729del in MYH7 might be a founder mutation in the Safor patients and the chance of a common origin with the Italian-American family mutation was investigated by haplotype analyses, mutation data origin estimation and historical inquiry. Our results show that the p.K1729del in MYH7 harboured by patients from the Safor indeed is a founder mutation. A common ancestral origin of this mutation in the Spanish and Italian families is also suggested because they all share a core SNP haplotype at locus MYH7. Data estimation yields the origin of the mutation in the Safor at the beginning of the XVII century, when the Moorish were spelt and the region was resettled with Italian families. [ABSTRACT FROM AUTHOR]

Background: Variant transthyretin amyloidosis (ATTRv) is a rare multisystemic disorder caused by mutations in the transthyretin (TTR) gene. The aim of the present work was to describe the clinical profile of asymptomatic carriers (AC) and Coutinho stage 1 ATTRv patients in Spain., Methods: National, multicentre, cross-sectional study that included 86 AC and 19 patients diagnosed in the previous 12 months to enrolment. Clinical and demographical data, TTR gene mutations, red flags anamnesis, neurological and cardiological assessments were collected., Results: The mean age of patients was 56.8 years at onset and 58.6 years at diagnosis; 53% of patients and 51% of AC were from non-endemic areas. Val50Met was the most frequent mutation in both groups. Neuropathy impairment score data (mean 17.7 ± 20.5) and small-fibre function in lower limbs assessed with SUDOSCAN revealed that patients were diagnosed at early stages of neurological impairment. Peripheral polyneuropathy (84.2%), autonomic neuropathy (73.7%), cardiac (63.2%) and gastrointestinal (47.4%) alterations were the most common symptoms in patients. Autonomic neuropathy, gastrointestinal impairment, carpal tunnel syndrome, cardiac and ocular alterations were potentially related to ATTRv in the AC group., Conclusions: The EMPATIa study provides a detailed description of AC and Coutinho stage 1 ATTRv patients across Spain, confirming the multisystemic clinical profile of the disease. This study reveals a diagnosis delay around 1.8 years, highlighting the importance of a profound disease awareness to reach a diagnose in earlier stages of neurological impairment., (© 2024. The Author(s).)

Background and Purpose: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients., Methods: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared., Results: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89)., Conclusions: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain., Methods: This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed., Results: 100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability., Conclusions: Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Background: The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain., Methods: Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals., Results: Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis ( p  < 0.001). Haplotype analysis revealed a common origin from an ancestor who lived ∼500 years ago in southeast Spain., Conclusions: Glu89Lys ATTRv is a TTR variant with a founder effect in Spain. It is associated with near complete penetrance, early onset and mixed cardiac and neurologic phenotype. Patients have poor prognosis, particularly if not treated with disease-modifying therapies.

Objective: To describe the clinical characteristics and outcomes in patients with refractory myasthenia gravis (MG) and to determine the effectiveness and side effects of the drugs used for their treatment., Methods: This observational retrospective cross-sectional multicenter study was based on data from the Spanish MG Registry (NMD-ES). Patients were considered refractory when their MG Foundation of America post-interventional status (MGFA-PIS) was unchanged or worse after corticosteroids and two or more other immunosuppressive agents. Clinical and immunologic characteristics of drug-refractory patients, efficiency and toxicity of drugs used, and outcome (MGFA-PIS) at end of follow-up were studied., Results: We included 990 patients from 15 hospitals. Eighty-four patients (68 of 842 anti-acetylcholine receptor [AChR], 5 of 26 anti-muscle-specific tyrosine kinase [MusK], 10 of 120 seronegative, and 1 of 2 double-seropositive patients) were drug refractory. Drug-refractory patients were more frequently women (p < 0.0001), younger at onset (p < 0.0001), and anti-MuSK positive (p = 0.037). Moreover, they more frequently presented a generalized form of the disease, bulbar symptoms, and life-threatening events (p < 0.0001; p = 0.018; and p = 0.002, respectively) than non-drug-refractory patients. Mean follow-up was 9.8 years (SD 4.5). Twenty-four (50%) refractory patients had side effects to one or more of the drugs. At the end of follow-up, 42.9% of drug-refractory patients (42.6% of anti-AChR, 100% of anti-MuSK, and 10% of seronegative patients) and 79.8% of non-drug-refractory patients (p < 0.0001) achieved remission or had minimal manifestations. Eighty percent of drug-refractory-seronegative patients did not respond to any drug tested., Interpretation: In this study, 8.5% of MG patients were drug-refractory. New more specific drugs are needed to treat drug-refractory MG patients., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs)., Methods: Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS)., Results: From 86 families with IPNs, 99 patients (59 males) were identified, 85 with sensorimotor neuropathy or CMT (2/3 demyelinating form) and 14 with distal hereditary motor neuropathy (dHMN). Genetic diagnosis was achieved in 79.5% families, with a similar mutation detection rate in the demyelinating (88.7%) and axonal (89.5%) forms, significantly higher than in the dHMN families (27.3%). CMT1A was the most common subtype, followed by those carrying heterozygous mutations in either the GDAP1 or GJB1 genes. Mutations in 15 other genes were identified, including a new pathogenic variant in the ATP1A gene. The CMTPedS detected significant disease progression in all genetic subtypes of CMT, at a rate of 1.84 (±3.7) over 1 year (p < 0.0005, n = 62) and a 2-year rate of 3.6 (±4.4: p < 0.0005, n = 45). Significant disease worsening was also detected for CMT1A over 1 (1.7 ± 3.6, p < 0.05) and 2 years (4.2 ± 4.3, p < 0.0005)., Conclusions: This study highlights the unique spectrum of IPN gene frequencies among pediatric patients in this specific geographic region, identifying the CMTPedS as a sensitive tool to detect significant disease worsening over 1 year that could help optimize the design of clinical trials., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: MORC2 mutations have been described as a rare cause of axonal Charcot-Marie-Tooth disease (CMT2Z). The aim of this work was to determine the frequency and distribution of these mutations throughout Spain, to provide a comprehensive phenotypical description and, if possible, to establish a genotype-phenotype correlation., Methods: Retrospectively, data on patients diagnosed with CMT2Z in Spain were collected and clinical, electrophysiological and muscle imaging information were analysed., Results: Fifteen patients with CMT2Z were identified throughout Spain, seven of them belonging to a single kindred, whilst the rest were sporadic. The most common mutation was p.R252W, and four new mutations were identified. Eleven patients were categorized as having a scapuloperoneal phenotype, with asymmetric muscle weakness, early proximal upper limb involvement and frequent spontaneous muscular activity with distal sensory impairment and pes cavus, whilst two presented with a more classic length dependent sensory motor phenotype. This distinction was corroborated by the distribution of muscle fatty infiltration in muscle imaging. Two other patients were classified as having a neurodevelopmental phenotype consisting in congenital or early onset, delay in motor milestones, and global developmental delay in one of them. Nerve conduction studies revealed an unequivocally axonal neuropathy with frequent spontaneous activity, and serum creatine kinase levels were increased in 50% of the patients., Conclusions: MORC2 mutations are a rare cause of CMT in Spain, but in-depth phenotyping reveals a recognizable phenotypic spectrum that will be clinically relevant for future identification of this disease., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Bicuspid aortic valve (BAV) is the most common congenital heart disease. This study aimed to determine the prevalence rate of BAV in first-degree relatives (FDR) and the inheritance pattern according to different morphotypes and aortic dilation., Methods: BAV probands were consecutively studied at eight tertiary referral centres. After sequential screening, FDR were included in the study. The BAV morphotype, aortic dilation and aortic phenotype were assessed by transthoracic echocardiography., Results: Seven hundred and twenty-four FDR of 256 BAV probands agreed to undergo family screening. The prevalence of BAV was 6.4% in FDR (9.2% in men, 3.5% in women, p=0.002). Aortic dilation was diagnosed in 9.6% of FRD with tricuspid aortic valves (TAV), with a root phenotype in 2.7% and tubular in 6.9% and more frequently in the presence of arterial hypertension (OR 4.48; CI 95% 2.51 to 7.99; p=0.0001) and valvular regurgitation (OR 5.87, CI 95% 1.37 to 25.16; p=0.025). The heritability ( h 2 ) of BAV was highly significant (0.47; p=0.002); however, no concordance was observed among valve morphotypes. Aortic dilation heritability was not significant., Conclusions: The BAV prevalence rate in FDR was low (6.4%) but aortic dilation was observed in 9.6% of FDR with TAV. The heritability of BAV was high without concordance in valve morphotypes, and aortic dilation heritability was not observed. Patients with BAV should be made aware of its familial pattern., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa and Cataracts) (MIM# 612674) is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene. We evaluated two Spanish siblings affected with pes cavus, sensorimotor neuropathy, hearing loss, retinitis pigmentosa and juvenile cataracts in whom the genetic test of ABHD12 revealed a novel homozygous frameshift mutation, c.211&#95;223del (p.Arg71Tyrfs*26). The earliest clinical manifestation in these patients was a demyelinating neuropathy manifested with a Charcot-Marie-Tooth phenotype over three decades. Progressive hearing loss, cataracts and retinitis pigmentosa appeared after the age of 30. We herein describe the complete clinical picture of these two patients, and focus particularly on neuropathy characteristics. This study supports the fact that although PHARC is rare, its phenotype is very characteristic and we should include its study in patients affected with demyelinating polyneuropathy, hearing loss and retinopathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.

Background: Bicuspid aortic valve is the most common cardiovascular congenital malformation affecting 2% of the general population. The incidence of life-threatening complications, the high heritability, and familial clustering rates support the interest in identifying risk or protective genetic factors. The main objective of the present study was to identify population-based genetic variation associated with bicuspid aortic valve and concomitant ascending aortic dilation., Materials and Methods: A cross-sectional exome-wide association study was conducted in 565 Spanish cases and 484 controls. Single-marker and gene-based association analyses enriched for low frequency and rare genetic variants were performed on this discovery stage cohort and for the subsets of cases with and without ascending aortic dilation. Discovery-stage association signals and additional markers indirectly associated with bicuspid aortic valve, were genotyped in a replication cohort that comprised 895 Caucasian cases and 1483 controls., Results: Although none of the association signals were consistent across series, the involvement of HMCN2 in calcium metabolism and valve degeneration caused by calcium deposit, and a nominal but not genome-wide significant association, supported it as an interesting gene for follow-up studies on the genetic susceptibility to bicuspid aortic valve., Conclusions: The absence of a genome-wide significant association signal shows this valvular malformation may be more genetically complex than previously believed. Exhaustive phenotypic characterization, even larger datasets, and collaborative efforts are needed to detect the combination of rare variants conferring risk which, along with specific environmental factors, could be causing the development of this disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

To describe the profile of left-sided polymicrobial endocarditis (PE) and to compare it with monomicrobial endocarditis (ME).Among 1011 episodes of left-sided endocarditis consecutively diagnosed in 3 tertiary centers, between January 1, 1996 and December 31, 2014, 60 were polymicrobial (5.9%), 821 monomicrobial (81.7%), and in 123 no microorganism was detected (12.2%). Seven patients (0.7%) were excluded from the analysis because contamination of biologic tissue could not be discarded. The authors described the clinical, microbiologic, echocardiographic, and outcome of patients with PE and compared it with ME.Mean age was 64 years SD 16 years, 67% were men and 30% nosocomial. Diabetes mellitus (35%) were the most frequent comorbidities, fever (67%) and heart failure (43%) the most common symptoms at admission. Prosthetic valves (50%) were the most frequent infection location and coagulase-negative Staphylococci (48%) and enterococci (37%) the leading etiologies. The most repeated combination was coagulase-negative Staphylococci with enterococci (n = 9). Polymicrobial endocarditis appeared more frequently in patients with underlying disease (70% versus 56%, P = 0.036), mostly diabetics (35% versus 24%, P = 0.044) with previous cardiac surgery (15% versus 8% P = 0.049) and prosthetic valves (50% versus 37%, P = 0.038). Coagulase-negative Staphylococci, enterococci, Gram-negative bacilli, anaerobes, and fungi were more frequent in PE. No differences on age, sex, symptoms, need of surgery, and in-hospital mortality were detected.Polymicrobial endocarditis represents 5.9% of episodes of left-sided endocarditis in our series. Despite relevant demographic and microbiologic differences between PE and ME, short-term outcome is similar., Competing Interests: The authors have no conflicts of interest to disclose.

Objectives: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area., Methods: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups., Results: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically., Conclusions: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region.

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737&#95;P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range., (© 2012 John Wiley & Sons A/S.)

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes., (© 2012 Wiley Periodicals, Inc.)

Introduction: Early identification of prognostic factors is essential to improve the grim prognosis associated with left-sided infective endocarditis. This group identified three independent risk factors obtained within 72 h of admission, (Staphylococcus aureus, heart failure and periannular complications) for inhospital mortality or urgent surgery in a series of 317 patients diagnosed at five tertiary centres (derivation sample). A stratification score was constructed for the test cohort by a simple arithmetic sum of the number of variables present. The goal was to validate this model internally and externally in a prospective manner with two different cohorts of patients., Methods: The appropriateness of the model was tested prospectively on predicting events in two cohorts of patients with left-sided endocarditis: internally with the 263 consecutive patients diagnosed at the same centres where the model was derived (internal validation sample), and externally with 264 patients admitted at another hospital (external validation sample)., Results: The discriminatory power of the model, expressed as the area under the receiver operating characteristic curve was similar between derivation and both validation samples (internal 0.67 vs 0.68, p=0.79; external 0.67 vs p=0.74, p=0.09). There was a progressive, significant pattern of increasing event rates as the risk stratification score increased in both validation cohorts (p<0.001 by χ² for trend)., Conclusions: The early risk stratification model derived, based on variables obtained within 72 h of admission, is applicable to different populations with left-sided endocarditis. A simple bedside assessment tool is provided to clinicians that identifies patients at high risk of having an adverse event.

Charcot-Marie-Tooth (CMT) disease type 4 (CMT4) is the name given to autosomal recessive forms of hereditary motor and sensory neuropathy (HMSN). When we began this study, three genes or loci associated with inherited peripheral neuropathies had already been identified in the European Gypsy population: HMSN-Lom (MIM 601455), HMSN-Russe (MIM 605285) and the congenital cataracts facial dysmorphism neuropathy syndrome (MIM 604168). We have carried out genetic analyses in a series of 20 Spanish Gypsy families diagnosed with a demyelinating CMT disease compatible with an autosomal recessive trait. We found the p.R148X mutation in the N-myc downstream-regulated gene 1 gene to be responsible for the HMSN-Lom in four families and also possible linkage to the HMSN-Russe locus in three others. We have also studied the CMT4C locus because of the clinical similarities and showed that in 10 families, the disease is caused by mutations located on the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene: p.R1109X in 20 out of 21 chromosomes and p.C737&#95;P738delinsX in only one chromosome. Moreover, the SH3TC2 p.R1109X mutation is associated with a conserved haplotype and, therefore, may be a private founder mutation for the Gypsy population. Estimation of the allelic age revealed that the SH3TC2 p.R1109X mutation may have arisen about 225 years ago, probably as the consequence of a bottleneck.

Background: Several hypotheses have been postulated to explain the etiopathogenesis of chronic fatigue syndrome (CFS). Among these, immunologic dysfunction has been proposed. Up to 30 % of these patients have a history of allergic disease. The aim of this study was to investigate whether allergic sensitization is higher in patients with CFS than in the general population., Methods: Twenty-five patients with CFS and 20 controls were evaluated. A clinical history for allergy was taken and immediate hypersensitivity tests were performed., Results: Twelve patients (48 %) and eight controls (40 %) had a family history of atopy. Personal histories of atopy were as follows: rhinoconjunctivitis: 12 patients (48 %), seven controls (35 %); asthma: five patients (20 %), two controls (10 %); food allergy: three patients (12 %); atopic dermatitis: two patients; contact dermatitis: two patients. No statistically significant differences were found between the groups in any of the variables (p > 0.05). In the CSF group, 3.4 % (15/441) of the inhalant prick tests were positive, and in the control group 3.8 % (16/420) were positive. None of the tests for hypersensitivity to food or latex were positive., Conclusions: In our study atopy was not more prevalent in patients with CFS than in healthy controls, although the CSF group tended to report more respiratory symptoms and drug allergies.

We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.

Epidemiological studies performed directly on the population show a prevalence of Friedreich's ataxia (FA) from 1 to 4.7 cases/100,000 inhabitants. An indirect epidemiological approach can be achieved using genetic methods like consanguinity studies to determine the frequency of a mutated gene and the incidence of certain diseases in the population. We obtained consanguinity data of a series of FA patients in Valencia, Spain and the figures on consanguinity in the general population that were estimated according to the Archive of Dispensations given by the Catholic church for consanguineous marriages. From these data, the frequency of the FA gene was calculated as 1/127. From these data, applying the Hardy-Weinberg principle, the frequency of the carriers was 1/64 and the incidence was 6.18/100,000 live births. Assuming a life expectancy of FA of 45 years, the prevalence was 3.83/100,000 inhabitants. These figures are in the same range as those obtained in population studies.

In a prospective study of community-acquired pneumonias, 30 patients were diagnosed with Legionnaires' disease in 15 months. Clinical, laboratory and radiologic features of these patients are reviewed and compared with those who have pneumococcal pneumonia. Alcoholism, history of smoking, previous antimicrobial therapy, gastrointestinal and neurologic manifestations, elevations of serum transaminases, alkaline phosphatase and creatinine levels were more frequent in pneumonia due to Legionella pneumophila than in pneumococcal pneumonia. The presence of respiratory failure and radiologic progression were common findings that suggested L pneumophila as the etiologic agent of a community-acquired pneumonia. Development of respiratory failure was associated with involvement of several lobes and isolation of L pneumophila in any specimen. In 21 of 30 patients with Legionnaires' disease, L pneumophila was isolated from respiratory specimens. Overall mortality was 10 percent, but it increased to 27 percent in patients not treated with erythromycin initially.