RESUMEN
Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.
Asunto(s)
Encéfalo/patología , Conexina 43/genética , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Anomalías del Ojo/genética , Anomalías del Ojo/patología , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/patología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Sindactilia/genética , Sindactilia/patología , Anomalías Dentarias/genética , Anomalías Dentarias/patología , Adolescente , Adulto , Anomalías Craneofaciales/complicaciones , Anomalías del Ojo/complicaciones , Femenino , Deformidades Congénitas del Pie/complicaciones , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Sindactilia/complicaciones , Anomalías Dentarias/complicacionesRESUMEN
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.
Asunto(s)
Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/patología , Adulto , Femenino , Francia , Humanos , Leucoencefalopatías/genética , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroimagen/métodosRESUMEN
Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an ironsulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein.
Asunto(s)
Fibroblastos/metabolismo , Proteínas Hierro-Azufre/genética , Proteínas Mitocondriales/genética , Mutación , Ácido Tióctico/biosíntesis , Aciltransferasas/genética , Adolescente , Vías Biosintéticas/genética , Proteínas Portadoras/genética , Niño , Preescolar , Femenino , Fibroblastos/química , Humanos , Lactante , Masculino , Mitocondrias/metabolismo , Fosforilación Oxidativa , Estrés Oxidativo , Fenotipo , Proteínas/genética , Ácido Tióctico/genéticaRESUMEN
In vertebrates, 14-3-3 proteins form a family of seven highly conserved isoforms with chaperone activity, which bind phosphorylated substrates mostly involved in regulatory and checkpoint pathways. 14-3-3 proteins are the most abundant protein in the brain and are abundantly found in the cerebrospinal fluid in neurodegenerative diseases, suggesting a critical role in neuron physiology and death. Here we show that 14-3-3eta-deficient mice displayed auditory impairment accompanied by cochlear hair cells' degeneration. We show that 14-3-3eta is highly expressed in the outer and inner hair cells, spiral ganglion neurons of cochlea and retinal ganglion cells. Screening of YWHAH, the gene encoding the 14-3-3eta isoform, in non-syndromic and syndromic deafness, revealed seven non-synonymous variants never reported before. Among them, two were predicted to be damaging in families with syndromic deafness. In vitro, variants of YWHAH induce mild mitochondrial fragmentation and severe susceptibility to apoptosis, in agreement with a reduced capacity of mutated 14-3-3eta to bind the pro-apoptotic Bad protein. This study demonstrates that YWHAH variants can have a substantial effect on 14-3-3eta function and that 14-3-3eta could be a critical factor in the survival of outer hair cells.
RESUMEN
Etiologic diagnosis of adulthood leukodystrophy is challenging in neurologic practice. We describe here the clinico-radiological features of a novel autosomal dominant leukodystrophy in a single family. Clinical and MRI features were recorded in a three generation family. Exome sequencing was performed in two affected relatives and one healthy member. Four total relatives (3 women and 1 man, mean age at onset: 45, range 32-59) were followed: 2 for migraine and 2 for cognitive loss. MRI features were homogeneous in the four affected relatives: extensive and symmetrical white matter hyperintensities on T2-weighted images, with a posterior predominance, involvement of the middle cerebellar peduncles, corpus callosum and the posterior limb of the internal capsules. An extensive metabolic screening was negative. In addition, sequencing of pathogenic genes involved in dominant leukodystrophies (NOTCH3, LMNB1, GFAP, CSF1R) was negative. No mutation has been identified yet with exome sequencing. This report is peculiar because of dominant inheritance, adult onset, highly homogeneous white matter hyperintensities on T2-weighted MR images, predominant in the middle cerebellar peduncles and posterior part of internal capsule and absence of mutation of the genes involved in dominant leukodystrophies.
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Encéfalo/patología , Leucoencefalopatías/diagnóstico , Imagen por Resonancia Magnética , Adulto , Exoma , Salud de la Familia , Femenino , Pruebas Genéticas , Proteína Ácida Fibrilar de la Glía/genética , Humanos , Lamina Tipo B/genética , Leucoencefalopatías/líquido cefalorraquídeo , Leucoencefalopatías/genética , Masculino , Persona de Mediana Edad , Mutación , Receptor Notch3 , Receptores Notch/genéticaRESUMEN
Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.
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Anoftalmos/genética , Heterogeneidad Genética , Microftalmía/genética , Mutación Puntual/genética , Adolescente , Adulto , Anoftalmos/diagnóstico , Anoftalmos/patología , Niño , Preescolar , Proteínas del Ojo/genética , Femenino , Factores de Transcripción Forkhead/genética , Factor 6 de Diferenciación de Crecimiento/genética , Proteínas de Homeodominio/genética , Humanos , Lactante , Masculino , Microftalmía/diagnóstico , Microftalmía/patología , Factores de Transcripción Otx/genética , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Factores de Transcripción SOXB1/genética , Factores de Transcripción/genéticaRESUMEN
INTRODUCTION: Cavitary white matter changes are mainly described in leukodystrophies and especially in vanishing white matter disease. Large cavitary lesions are not typical for multiple sclerosis (MS). METHODS: We studied MS patients with large cavitary brain lesions. Patient characteristics, disease onset/duration/subtype, expanded disability status scale (EDSS), mini mental state (MMS), vanishing white matter disease genetic analysis, and MRI characteristics of the cavitary lesions were analyzed. RESULTS: Twenty patients were analyzed (6 men and 14 women). Mean age at disease onset was 37.6 (range 17-58). Mean disease duration was 10 years (range 2-20). Five patients had initial relapsing-remitting MS and nine patients had primary-progressive MS. Mean EDSS was 5.5 (range 2-8). Mean MMS was 20/30. Vanishing white matter disease genetic analysis was performed and negative in seven patients. Inferior corpus callosum lesions were seen in all patients with available sagittal FLAIR sequences. Cavitary lesions were strictly supratentorial, and located inside the diffuse leukoencephalopathy, with often a posterior predominance. CONCLUSION: MS patients with large cavitary lesions seem to represent a MS subgroup, predominantly women, with relatively late disease onset, predominantly primary-progressive type, relatively high EDSS scores, and severe cognitive dysfunction.
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Esclerosis Múltiple/patología , Sustancia Blanca/patología , Adolescente , Adulto , Edad de Inicio , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/psicología , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.
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Distrofina/genética , Estudios de Asociación Genética , Heterogeneidad Genética , Distrofia Muscular de Duchenne/genética , Adolescente , Edad de Inicio , Niño , Preescolar , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Francia/epidemiología , Técnicas Genéticas , Humanos , Masculino , Actividad Motora , Distrofia Muscular de Duchenne/epidemiología , FenotipoRESUMEN
INTRODUCTION: The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.
Asunto(s)
Factor 2B Eucariótico de Iniciación/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/epidemiología , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/patología , Adolescente , Adulto , Edad de Inicio , Niño , Estudios de Cohortes , Recolección de Datos , Progresión de la Enfermedad , Femenino , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Mutación/fisiología , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: It is known from postnatal diagnosis that imbalances of the subtelomeric regions contribute significantly to idiopathic mental retardation. PATIENT AND METHODS: We report a case of a 4-year-old child with growth retardation, minor physical abnormalities, hypotonia and developmental delay associated with a derivative chromosome 4. Molecular cytogenetic investigations were performed to characterize the chromosomal rearrangement. RESULTS: Multi fluorescence in situ hybridization revealed the presence of chromosome 2 material on the derivative chromosome 4. Metaphase comparative genomic hybridization detected a terminal 4q34 deletion. Array CGH analysis could precise breakpoints with duplication 2q36 â qter. The clinical phenotype was similar to those described in cases with a trisomy 2qter. CONCLUSION: This study emphasizes the value of array CGH to detect or characterize chromosome rearrangements in mentally retarded patients. Unlike metaphase CGH, the high resolution of array CGH in subtelomeric regions allows an accurate description of chromosomal aberrations.
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Trastorno Dismórfico Corporal/genética , Cromosomas Humanos Par 2 , Cromosomas Humanos Par 4 , Hibridación Genómica Comparativa/métodos , Discapacidad Intelectual/genética , Translocación Genética , Trastorno Dismórfico Corporal/complicaciones , Preescolar , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 4/genética , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Metafase/genética , Análisis por Micromatrices/métodos , Translocación Genética/genéticaAsunto(s)
Convulsiones Febriles/diagnóstico , Anticonvulsivantes/uso terapéutico , Preescolar , Diagnóstico Diferencial , Diazepam/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Relaciones Profesional-Familia , Derivación y Consulta , Factores de Riesgo , Prevención Secundaria , Convulsiones Febriles/clasificación , Convulsiones Febriles/etiología , Convulsiones Febriles/terapiaRESUMEN
The human myelin proteolipid protein 1 gene (hPLP1), which encodes the major structural myelin proteins of the central nervous system (CNS), is classically described as expressed in the oligodendrocytes, the CNS myelinating cells. We identified two new exons in the intron 1 of the hPLP1 gene that lead to the expression of additional mRNA and protein isoforms mainly expressed in neurons instead of oligodendrocytes. Those novel neuronal PLP isoforms are detected as soon as human fetal development and their concomitant expression is specific of the human species. As classical PLP proteins, the novel protein isoforms seem to be addressed to the plasma membrane. These results suggest for the first time that PLP may have functions in humans not only in oligodendrocytes but also in neurons and could be implicated in axono-glial communication. Moreover, this neuronal expression of the hPLP1 gene might explain the neuronal dysfunctions in patients carrying hPLP1 gene mutations.
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Membrana Celular/metabolismo , Proteína Proteolipídica de la Mielina/metabolismo , Neuronas/metabolismo , Comunicación Celular/fisiología , Exones , Regulación del Desarrollo de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Hibridación in Situ , Proteína Proteolipídica de la Mielina/genética , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations. METHODS: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family. RESULTS: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1). CONCLUSIONS: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.
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Predisposición Genética a la Enfermedad/genética , Cabeza/anomalías , Microcefalia/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Pruebas Genéticas , Genotipo , Cabeza/diagnóstico por imagen , Cabeza/patología , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Imagen por Resonancia Magnética , Masculino , Microcefalia/diagnóstico por imagen , Microcefalia/patología , Fenotipo , Tractos Piramidales/fisiopatología , Radiografía , Convulsiones/genética , Convulsiones/fisiopatología , Cráneo/anomalías , Cráneo/diagnóstico por imagen , Cráneo/patología , Adulto JovenRESUMEN
OBJECTIVE: This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy. METHODS: CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy. RESULTS: All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%). CONCLUSION: Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.
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Asialoglicoproteínas/líquido cefalorraquídeo , Asialoglicoproteínas/genética , Factor 2B Eucariótico de Iniciación/genética , Transferrina/análogos & derivados , Adulto , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Demencia Vascular/líquido cefalorraquídeo , Demencia Vascular/diagnóstico , Demencia Vascular/genética , Humanos , Lactante , Leucodistrofia de Células Globoides/líquido cefalorraquídeo , Leucodistrofia de Células Globoides/diagnóstico , Leucodistrofia de Células Globoides/genética , Mutación , Sensibilidad y Especificidad , Transferrina/líquido cefalorraquídeo , Transferrina/genéticaRESUMEN
The CACH/VWM syndrome is an autosomal recessive leukodystrophy characterized by a broad spectrum of clinical presentations and by diffuse cavitary degeneration of the white matter on MRI. Mutations responsible for this disorder are missense or frameshift mutations occurring in the five genes (EIF2B1-5) that encode the translation eukaryotic initiation factor eIF2B. We found that a patient with infantile CACH/VWM carries a mutation in the acceptor splice site of EIF2B5 exon 6. In lymphoblastoid cells of the patient, we detected an abnormal EIF2B5 transcript in which exon 6 was absent, however, the predicted protein product lacking part of the non-catalytic domain encoded by exon 6 was not detected. The eIF2B GEF activity was severely decreased. These data support the importance of the non-catalytic domain of the eIF2Bepsilon subunit in the eIF2B complex formation and activity.
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Ataxia/genética , Dominio Catalítico , Factor 2B Eucariótico de Iniciación/química , Factor 2B Eucariótico de Iniciación/genética , Exones/genética , Sitios de Empalme de ARN/genética , Eliminación de Secuencia , Adolescente , Adulto , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Resultado Fatal , Femenino , Regulación de la Expresión Génica , Genoma Humano/genética , Humanos , Lactante , Imagen por Resonancia Magnética , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Mutations in the eukaryotic translation initiation factor 2B (eIF2B) represent a heterogenous group of autosomal recessive leucodystrophy characterized by a diffuse CSF-like aspect of the white matter at MRI designed as vanishing white matter (VWM) and episodes of acute deterioration after stresses. The mild juvenile and adult forms are often associated with primary ovarian failure, a syndrome referred to as ovarioleukodystrophy (OLD). We reported case of a woman with OLD who successfully underwent in vitro fertilization with donated oocytes and embryo transfer. Pregnancy was complicated by a non-convulsive epileptic status leading to the identification of compound heterozygous EIF2B5 mutation (p.Arg113His and p.Arg299His). The patient gave birth to a healthy child by Caesarean section. In conclusion, we report for the first time that in vitro fertilization and embryo transfer can lead to a successful procreation in patients with OLD related to EIF2B mutations. However this procedure must be considered with cautiousness, because of its potential neurological risks.
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Factor 2B Eucariótico de Iniciación/genética , Fertilización In Vitro/efectos adversos , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/metabolismo , Mutación/genética , Complicaciones del Embarazo/fisiopatología , Enfermedad Aguda , Adulto , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Transferencia de Embrión/efectos adversos , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/fisiopatología , Humanos , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/patología , Donación de Oocito/efectos adversos , Enfermedades del Ovario/genética , Enfermedades del Ovario/metabolismo , Enfermedades del Ovario/fisiopatología , Embarazo , Estrés Fisiológico/genética , Estrés Fisiológico/metabolismo , Estrés Fisiológico/fisiopatologíaRESUMEN
BACKGROUND: Pelizaeus-Merzbacher-like disease (PMLD) is a genetically heterogeneous disorder within the group of hypomyelinating leukoencephalopathies. Mutations of the gap junction protein alpha 12 (GJA12) gene are known to cause one autosomal recessive PMLD form. Few patients with GJA12 mutated PMLD have been reported, and to date, the frequency as well as the genotypic and phenotypic spectrum of GJA12 related PMLD is unclear. METHODS: We report mutation analysis of the GJA12 gene in a clinical and radiologic well-characterized multiethnic cohort of 193 patients with PMLD from 182 families. RESULTS AND CONCLUSIONS: Only 16 patients (8.3%) from 14 families (7.7%) carry GJA12 mutations including five families where we detected only one mutated allele. Among those, we identified 11 novel alterations. Thus, GJA12 mutations are a rather rare cause for Pelizaeus-Merzbacher-like disease. The clinical phenotype of patients with a GJA12 mutation was evaluated and is overall comparable to the clinical features seen in mild forms of proteolipid protein 1 (PLP1) related disorder but with better cognition and earlier signs of axonal degeneration.
Asunto(s)
Conexinas/genética , Uniones Comunicantes/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Enfermedad de Pelizaeus-Merzbacher/genética , Adolescente , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Marcadores Genéticos/genética , Pruebas Genéticas , Genotipo , Humanos , Lactante , Masculino , Proteínas de la Membrana/genética , Proteína Proteolipídica de la Mielina/genética , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Enfermedad de Pelizaeus-Merzbacher/metabolismo , Enfermedad de Pelizaeus-Merzbacher/fisiopatología , Fenotipo , Degeneración Walleriana/genética , Degeneración Walleriana/metabolismo , Degeneración Walleriana/fisiopatologíaRESUMEN
A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes "foamy" aspect. A total of 148 cases have been reported so far. This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stresses. Clinical symptoms are variable, from fatale infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behaviour dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies. Prevalence of these remains unknown. Diagnosis lays on the detection of EIF2B mutations, affecting predominantly the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress. No specific treatment exists except the "prevention" of cellular stress. Corticosteroids sometimes proved to be useful in acute phases. Prognosis seems to correlate with the age of onset, the earliest forms being more severe.