Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease

[EN] Mutations in the ganglioside-induced-differentiation-associated protein 1 gene (GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A) or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive inheritance, but few autosomal dominant GDAP1 mutations have also been reported. We performed a GDAP1 gene screening in a clinically well-characterized series of 81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to 4 unrelated families in whom the heterozygous p.R120W was found to be the only disease-causing mutation. The main objective was to fully characterize the neuropathy caused by this mutation. The clinical picture included a mild-moderate phenotype with onset around adolescence, but great variability. Consistently, ankle dorsiflexion and plantar flexion were impaired to a similar degree. Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic resonance imaging studies demonstrated selective involvement of intrinsic foot muscles in all patients and a uniform pattern of fatty infiltration in the calf, with distal and superficial posterior predominance. Pathological abnormalities included depletion of myelinated fibers, regenerative clusters and features of axonal degeneration with mitochondrial aggregates. Our findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene mutations which can cause an axonal CMT with a wide clinical profile.We are grateful to the propositi and their relatives for their kind collaboration. We also want to thank I. Llopis and M. Escutia for their help with sample management. This work was supported by the Instituto de Salud Carlos III [PI08/90857, PI08/0889, CP08/00053 and PS09/00095], the Fundacion para la Investigacion del Hospital Universitari La Fe [CM06/00154], the Spanish Ministry Science and Innovation [grant number SAF2006-01047], and the Generalitat Valenciana [grant no. Prometeo/2009/05]. Dr. C. Espinos has a "Miguel Servet'' contract funded by the Fondo de Investigacion Sanitaria. Both Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) and Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED) are initiatives from the Instituto de Salud Carlos III.Sivera, R.; Espinós-Armero, CÁ.; Vílchez, JJ.; Mas, F.; Martínez-Rubio, D.; Chumillas, MJ.; Mayordomo, F.... (2010). Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease. Journal of the Peripheral Nervous System. 15(4):334-344. https://doi.org/10.1111/j.1529-8027.2010.00286.x33434415

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease

[EN] Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p. R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p. R190W mutation and another patient that harboured a MORC2 p. S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.This collaborative joint project is awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R+D+I Plan (IR11/TREAT-CMT to T.S., S.I.P.P., F.P. and C.E.; PI12/00453 to C.E.; and PI12/0946 to T.S.), co-funded with FEDER funds. Additional support was provided by the Ramon Areces Foundation and by the ISCIII and the Centro de Investigacion Principe Felipe (CPII14/00002) to C.E.Sevilla, T.; Lupo, V.; Martínez-Rubio, D.; Sancho, P.; Sivera, R.; Chumillas, MJ.; García-Romero, M.... (2016). Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. Brain. 139:62-72. https://doi.org/10.1093/brain/awv311627213

Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

[EN] Background Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. Methods We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. Results We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. Conclusion MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.The authors thank the patients and healthy relatives for having participated in this project. We are grateful to the Eurobiobank CIBERER and the Biobank La Fe for their participation in the collection and processing of patient samples. We also thank the technicians at the Department of Genomics and Translational Genetics (CIPF) who participated in the quality control and processing of DNA samples (Virginia Rejas and Laura Ramírez), and the Bachelor¿s thesis student Andrea Ballester who helped with some clinical data collection. This project was funded by the Instituto de Salud Carlos III (ISCIII), FEDER (Grants no. PI12/00946 and PI16/00403 to TS, PI15/00187 to CE). MF holds a grant funded by the IIS La Fe (Grant no. 2015/0085). AS-M holds a grant funded by the Fundació Per Amor a l'Art (FPAA). JFV-C holds a ' Rio Hortega' contract funded by the ISCIII.Lupo, V.; Frasquet, M.; Sánchez-Monteagudo, A.; Pelayo-Negro, A.; García-Sobrino, T.; Sedano, MJ.; Pardo, J.... (2018). Characterizing the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. Journal of Medical Genetics. 55(12):814-823. https://doi.org/10.1136/jmedgenet-2018-105650814823551

Transferrin Isoforms, Old but New Biomarkers in Hereditary Fructose Intolerance

Hereditary Fructose Intolerance (HFI) is an autosomal recessive inborn error of metabolism characterised by the deficiency of the hepatic enzyme aldolase B. Its treatment consists in adopting a fructose-, sucrose-, and sorbitol (FSS)-restrictive diet for life. Untreated HFI patients present an abnormal transferrin (Tf) glycosylation pattern due to the inhibition of mannose-6-phosphate isomerase by fructose-1-phosphate. Hence, elevated serum carbohydrate-deficient Tf (CDT) may allow the prompt detection of HFI. The CDT values improve when an FSS-restrictive diet is followed; however, previous data on CDT and fructose intake correlation are inconsistent. Therefore, we examined the complete serum sialoTf profile and correlated it with FSS dietary intake and with hepatic parameters in a cohort of paediatric and adult fructosemic patients. To do so, the profiles of serum sialoTf from genetically diagnosed HFI patients on an FSS-restricted diet (n = 37) and their age-, sex- and body mass index-paired controls (n = 32) were analysed by capillary zone electrophoresis. We found that in HFI patients, asialoTf correlated with dietary intake of sucrose (R = 0.575, p < 0.001) and FSS (R = 0.475, p = 0.008), and that pentasialoTf+hexasialoTf negatively correlated with dietary intake of fructose (R = −0.386, p = 0.024) and FSS (R = −0.400, p = 0.019). In addition, the tetrasialoTf/disialoTf ratio truthfully differentiated treated HFI patients from healthy controls, with an area under the ROC curve (AUROC) of 0.97, 92% sensitivity, 94% specificity and 93% accuracy.This work was supported by Exp. No. 2018111095, Basque Government, Health Department to J.D.H., and by FEDER; Federación Española de Enfermedades Raras (FI18053)

Vitamin C and folate status in hereditary fructose intolerance

Background Hereditary fructose intolerance (HFI) is a rare inborn error of fructose metabolism caused by the deficiency of aldolase B. Since treatment consists of a fructose-, sucrose- and sorbitol-restrictive diet for life, patients are at risk of presenting vitamin deficiencies. Although there is no published data on the status of these vitamins in HFI patients, supplementation with vitamin C and folic acid is common. Therefore, the aim of this study was to assess vitamin C and folate status and supplementation practices in a nationwide cohort of HFI patients. Methods Vitamin C and folic acid dietary intake, supplementation and circulating levels were assessed in 32 HFI patients and 32 age- and sex-matched healthy controls. Results Most of the HFI participants presented vitamin C (96.7%) and folate (90%) dietary intake below the recommended population reference intake. Up to 69% received vitamin C and 50% folic acid supplementation. Among HFI patients, 15.6% presented vitamin C and 3.1% folate deficiency. The amount of vitamin C supplementation and plasma levels correlated positively (R = 0.443; p = 0.011). Interestingly, a higher percentage of non-supplemented HFI patients were vitamin C deficient when compared to supplemented HFI patients (30% vs. 9.1%; p = 0.01) and to healthy controls (30% vs. 3.1%; p < 0.001). Conclusions Our results provide evidence for the first time supporting vitamin C supplementation in HFI. There is great heterogeneity in vitamin supplementation practices and, despite follow-up at specialised centres, vitamin C deficiency is common. Further research is warranted to establish optimal doses of vitamin C and the need for folic acid supplementation in HFI.This work was supported by Exp. No. 2018111095, Basque Government, Health Department; FEDER, the Spanish Federation for Rare Diseases (FI18053); and Danone-Nutricia-Metabolics, which was not involved in the study hypothesis/design, execution, analysis, or interpretation

Literatura en familia : cuento lo que sé

La valoración general del proyecto por parte del asesor del CPR es muy buena.- No consta su publicación.Un grupo de diez profesores de secundaria de un instituto de Alcantarilla (Murcia) ha realizado este proyecto consistente en la creación de una herramienta didáctica para el aprendizaje de los contenidos curriculares del área de lengua y literatura bajo el enfoque metodológico del trabajo por proyectos, que desarrolla competencias y conocimientos conceptuales que integran el conocimiento del pasado histórico de dos configuraciones histórico-políticas integradas: el pasado histórico de España y el pasado histórico de la Comunidad Autónoma de la Región de Murcia. Los alumnos trabajan sobre su propia historia, creando personajes y haciendo intervenir otros basados en la investigación y documentación histórica sobre sus antepasados, miembros de las familias de los alumnos. La investigación sobre fuentes históricas ha permitido la construcción de las genealogías familiares de los alumnos, elaborando los contenidos digitales en soporte electrónico, lo que permite que sean usados en la implantación didáctica del proyecto, diseñando y elaborando guías didácticas de investigación y documentación histórica y de creación literaria..Consejería de Educación, Ciencia e Investigación. Dirección General de Formación Profesional e Innovación EducativaMurciaConsejería de Educación, Ciencia e Investigación. Servicio de Publicaciones y Estadística; Avda. La Fama, 15; 30006 Murcia; Tel. +34968278685; Fax +34968279835; [email protected]

Vidas que cuentan : literatura en familia para educación secundaria

A partir del proyecto educativo 'Cuento lo que sé. Literatura en familia', alumnos de tercero y cuarto de enseñanza secundaria del Instituto 'Francisco Salzillo' de Alcantarilla (Murcia), reflejan a través de relatos el tiempo, la vida, las costumbres y lugares que forman parte de su pasado familiar y, por tanto, de sus propias vidas. Esta tarea investigadora, genealógica e histórica, documental y literaria, ha permitido reforzar sus conocimientos y fortalecido su formación en valores.MurciaConsejería de Educación, Formación y Empleo. Biblioteca; Avda. de la Fama, 15 ; 30006 Murcia; +34968279685; +34968279835; [email protected]

Espacios y destinos turísticos en tiempos de globalización y crisis

2 volúmenesXII Coloquio de Geografía del Turismo, Ocio y Recreación de la Asociación de Geógrafos Españoles. Colmenarejo (Madrid), del 17 al 19 de junio de 2010.Este libro ha sido editado con la colaboración económica del Ministerio de Ciencia e Innovación (ref. CS02010-10416-E)