RESUMO
Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
Assuntos
Imunidade Adaptativa , Autofagia/imunologia , DNA/metabolismo , Endossomos/metabolismo , Imunidade Inata , Lisossomos/metabolismo , Proteínas/metabolismo , RNA/metabolismo , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/imunologia , Proteínas Relacionadas à Autofagia , Linfócitos B/imunologia , Transporte Biológico , Catarata/genética , Catarata/imunologia , Linhagem Celular , Humanos , Proteínas de Membrana Lisossomal , Mutação , Proteínas/genética , Receptor Toll-Like 9/metabolismo , Proteínas de Transporte VesicularRESUMO
DJ-1 mutations are associated to early-onset Parkinson's disease and accounts for about 1-2% of the genetic forms. The protein is involved in many biological processes and its role in mitochondrial regulation is gaining great interest, even if its function in mitochondria is still unclear. We describe a 47-year-old woman affected by a multisystem disorder characterized by progressive, early-onset parkinsonism plus distal spinal amyotrophy, cataracts and sensory-neural deafness associated with a novel homozygous c.461C>A [p.T154K] mutation in DJ-1. Patient's cultured fibroblasts showed low ATP synthesis, high ROS levels and reduced amount of some subunits of mitochondrial complex I; biomarkers of oxidative stress also resulted abnormal in patient's blood. The clinical pattern of multisystem involvement and the biochemical findings in our patient highlight the role for DJ-1 in modulating mitochondrial response against oxidative stress.
Assuntos
Fibroblastos/metabolismo , Estresse Oxidativo/genética , Doença de Parkinson/genética , Proteína Desglicase DJ-1/genética , Trifosfato de Adenosina/biossíntese , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Fibroblastos/patologia , Homozigoto , Humanos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
NDUFB11, a component of mitochondrial complex I, is a relatively small integral membrane protein, belonging to the "supernumerary" group of subunits, but proved to be absolutely essential for the assembly of an active complex I. Mutations in the X-linked nuclear-encoded NDUFB11 gene have recently been discovered in association with two distinct phenotypes, i.e. microphthalmia with linear skin defects and histiocytoid cardiomyopathy. We report on a male with complex I deficiency, caused by a de novo mutation in NDUFB11 and displaying early-onset sideroblastic anemia as the unique feature. This is the third report that describes a mutation in NDUFB11, but all are associated with a different phenotype. Our results further expand the molecular spectrum and associated clinical phenotype of NDUFB11 defects.
Assuntos
Acidose Láctica/genética , Anemia Sideroblástica/genética , Complexo I de Transporte de Elétrons/genética , Microftalmia/genética , Acidose Láctica/complicações , Acidose Láctica/fisiopatologia , Anemia Sideroblástica/complicações , Anemia Sideroblástica/fisiopatologia , Criança , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/deficiência , Predisposição Genética para Doença , Humanos , Masculino , Microftalmia/fisiopatologia , Mutação , Linhagem , Fenótipo , Tirosina-tRNA LigaseRESUMO
Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.
Assuntos
Cardiomiopatia Hipertrófica/genética , Lisina-tRNA Ligase/genética , Doenças Mitocondriais/genética , Transtornos Psicomotores/genética , Adolescente , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Transporte de Elétrons/genética , Feminino , Predisposição Genética para Doença , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Mutação , Fenótipo , Transtornos Psicomotores/complicações , Transtornos Psicomotores/patologiaRESUMO
BACKGROUND: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA. AIMS: To investigate the pathogenic nature of two homoplasmic mt-tRNA(Thr) deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts. RESULTS: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNA(Thr) levels or rates of mitochondrial protein synthesis. CONCLUSIONS: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.
Assuntos
DNA Mitocondrial/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Mutação , RNA de Transferência de Treonina/genética , RNA/genética , Adulto , Biópsia , Células Cultivadas , Criança , Análise Mutacional de DNA , Feminino , Fibroblastos , Humanos , Lactente , Masculino , Mitocôndrias Cardíacas/genética , Mitocôndrias Musculares/genética , Doenças Mitocondriais/fisiopatologia , Músculo Esquelético , Polimorfismo Genético , RNA Mitocondrial , Pele/citologiaRESUMO
Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.
Assuntos
DNA Mitocondrial/genética , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Especificidade de ÓrgãosRESUMO
Mucopolysaccharidosis IVA is an autosomal recessive disease caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS gene was performed for seven MPS IVA patients with attenuated phenotypes from three unrelated families. Four of 5 missense mutations identified in this study (p.F167V, p.R253W, p.R380S, p.P484S) and two reported (p.F97V, p.N204K), associated with attenuated phenotypes, were characterized using in vitro stable expression experiments, enzyme kinetic study, protein processing and structural analysis. The stably expressed mutant enzymes defining the attenuated phenotype exhibited a considerable residual activity (1.2-36.7% of the wild-type GALNS activity) except for p.R380S. Enzyme kinetic studies showed that p.F97V, p.F167V and p.N204K have lower affinity to the substrate compared with other mutants. The p.F97V enzyme was the most thermolabile at 55 degrees C. Immunoblot analyses indicated a rapid degradation and/or an insufficiency in processing in the mutant proteins. Tertiary structure analysis revealed that although there was a tendency for 'attenuated' mutant residues to be located on the surface of GALNS, they have a different effect on the protein including modification of the hydrophobic core and salt-bridge formation and different potential energy. This study demonstrates that 'attenuated' mutant enzymes are heterogeneous in molecular phenotypes, including biochemical properties and tertiary structure.
Assuntos
Condroitina Sulfatases/genética , Mucopolissacaridose IV/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Animais , Células CHO , Condroitina Sulfatases/química , Condroitina Sulfatases/deficiência , Condroitina Sulfatases/metabolismo , Cricetinae , Cricetulus , Análise Mutacional de DNA , Estabilidade Enzimática , Éxons , Feminino , Predisposição Genética para Doença , Temperatura Alta , Humanos , Interações Hidrofóbicas e Hidrofílicas , Itália , Japão , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mucopolissacaridose IV/enzimologia , Paquistão , Linhagem , Fenótipo , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Índice de Gravidade de Doença , Especificidade por Substrato , TransfecçãoRESUMO
Lysinuric protein intolerance (LPI) is a disorder of dibasic amino acid transport secondary to mutation of the SLC7A7 gene characterized by renal failure, pulmonary alveolar proteinosis, lupus-like autoimmune symptoms and usually increased plasma citrulline. In order to better understand the underlying mechanism, we studied the plasma and urinary nitrite/nitrate (NO2-/NO3-) concentrations in three LPI patients and the in vitro NO2- production in cultured fibroblasts. Our data show that NO3- levels are increased in the plasma of patients with LPI. Similarly, NO2- release in the medium of cultured fibroblasts was increased. On this basis, we hypothesize that some of the poorly understood clinical signs of LPI could be related to the activation of the NO-citrulline pathway.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Lisina/metabolismo , Óxido Nítrico/metabolismo , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/genética , Sistema y+L de Transporte de Aminoácidos , Células Cultivadas , Criança , Citrulina/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Humanos , Nitratos/sangue , Nitratos/urina , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Nitritos/sangue , Nitritos/urinaRESUMO
A multidisciplinary strategy was used to identify the molecular defect in a family with Leigh syndrome (LS). The propositus presented severe developmental delay, an ataxic-spastic gait and seizures. She died at 3.5 y of age from cardiorespiratory arrest. Postmortem examination disclosed pathological features typical of LS. A 12-y-old sister is affected with the same disease. Respiratory chain enzyme complex activities in skeletal muscle biopsy were normal. Adenosine triphosphate (ATP) synthesis during oxidative phosphorylation in skin fibroblasts mitochondria showed a severely hampered ATP production. Mitochondrial DNA sequencing revealed a new mutation in the ATPase 6 gene (T9176G). Site-directed mutagenesis in Escherichia coli strains was used to measure H+ pumping and ATP synthesis. Results were comparable to findings obtained in human cells. These data corroborate the use of E. coli strains as a feasible "animal" model for functional studies in pathogenic mutations of the ATPase 6 gene.
Assuntos
Escherichia coli/enzimologia , Doença de Leigh/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação , Criança , Pré-Escolar , Humanos , LinhagemAssuntos
Complexo I de Transporte de Elétrons/genética , Doença de Leigh/genética , Mitocôndrias/enzimologia , Mutação , Substituição de Aminoácidos , Encéfalo/patologia , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Humanos , Itália , Doença de Leigh/diagnóstico , Doença de Leigh/enzimologia , Imageamento por Ressonância Magnética , Masculino , Mitocôndrias/genética , Proteínas Mitocondriais , Subunidades Proteicas/genéticaRESUMO
Sixteen unrelated Southern European patients with the mitochondrial depletion syndrome (MDS) were analyzed for mutations in the TK2 and DGUOK genes. Three novel mutations were identified in TK2 (R183G, R254X, and 142insG). When we analyzed additional genes involved in the dNTPs pool, such as SLC25A19 (DNC) and NT5M (d-NT2), we did not detect mutations. The current study suggest that scanning the TK2, DGUOK, SLC25A19, and NT5M genes is likely to help about 10% of MDS families in terms of genetic counseling. Also, our findings indicate that genotype-phenotype correlations are not straightforward in MDS.
Assuntos
DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Doenças Mitocondriais/genética , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Europa (Continente) , Feminino , Humanos , Lactente , Masculino , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/mortalidade , Doenças Mitocondriais/patologia , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Estudos Retrospectivos , Síndrome , Timidina Quinase/genéticaRESUMO
OBJECTIVE: To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene. BACKGROUND: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. METHODS: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. RESULTS: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. CONCLUSION: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.
Assuntos
Córtex Cerebral , Coristoma/genética , Coristoma/patologia , Proteínas Contráteis/genética , Ventrículos Laterais/patologia , Proteínas dos Microfilamentos/genética , Mutação de Sentido Incorreto/genética , Aborto Espontâneo/genética , Aborto Espontâneo/patologia , Adolescente , Adulto , Sequência de Aminoácidos , Epilepsia/genética , Epilepsia/patologia , Feminino , Filaminas , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , LinhagemRESUMO
Cardiomyopathy associated with a mitochondrial DNA depletion syndrome is a rare condition. We report on a child with a hypertrophic cardiomyopathy and a mitochondrial depletion syndrome who was successfully treated by heart transplantation, given the tissue-specific nature of her mitochondrial disorder.
Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/cirurgia , DNA Mitocondrial/análise , Transplante de Coração , Complexo IV da Cadeia de Transporte de Elétrons/análise , Feminino , Humanos , Lactente , Músculo Esquelético/citologia , Miocárdio/enzimologia , Miocárdio/patologia , Succinato Desidrogenase/análiseRESUMO
BACKGROUND: Oxidative stress and mitochondrial dysfunction have long been considered to play a role in Friedreich's ataxia, a neurodegenerative disease due to a GAA expansion in a gene coding for a mitochondrial protein (frataxin), implicated in the regulation of iron metabolism. Since glutathione is an important antioxidant whose role has been recently proposed in the pathogenesis of some neurodegenerative diseases, we investigated glutathione metabolism in the blood of 14 patients with Friedreich's ataxia by measuring total, free and protein-bound glutathione concentrations. MATERIALS AND METHODS: Blood samples were obtained from 14 unrelated patients with Friedreich's ataxia (nine males, five females) and 20 age-matched healthy controls (10 males, 10 females). Total and free glutathione concentrations were determined by reverse-phase liquid chromatography with fluorescence detection; the glutathionyl-haemoglobin separation from healthy and pathological subjects was obtained by electrospray ionization-mass spectrometry. RESULTS: We consistently found a reduction of free glutathione levels (0.55 +/- 0.06 nmol mg(-1) haemoglobin, vs. 8.4 +/- 1.79 nmol mg(-1) haemoglobin, P < 0.001) in the blood of patients with Friedreich's ataxia, a total glutathione concentration comparable to the controls (15 +/- 2.6 nmol mg(-1) haemoglobin, vs. 15.4 +/- 1.4 nmol mg(-1) haemoglobin), and a significant increase of glutathione bound to haemoglobin (15 +/- 1.5 vs. 8 +/- 1.8%, P < 0.05) in erythrocytes. CONCLUSIONS: Our findings give evidence of an impairment in vivo of glutathione homeostasis in Friedreich's ataxia, suggesting a relevant role of free radical cytotoxicity in the pathophysiology of the disease; this study may also prove useful in the search for an oxidative stress marker in neurodegeneration.
Assuntos
Ataxia de Friedreich/sangue , Glutationa/sangue , Adolescente , Adulto , Criança , Cromatografia Líquida de Alta Pressão , Feminino , Ataxia de Friedreich/fisiopatologia , Hemoglobinas/análise , Humanos , Masculino , Estresse Oxidativo/fisiologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
We review here those malformations of the cerebral cortex which are most often observed in epilepsy patients, for which a genetic basis has been elucidated or is suspected and give indications for genetic testing. There are three forms of lissencephaly (agyria-pachygyria) resulting from mutations of known genes, which can be distinguished because of their distinctive imaging features. They account for about 85% of all lissencephalies. Lissencephaly with posteriorly predominant gyral abnormality is caused by mutations of the LIS1 gene on chromosome 17. Anteriorly predominant lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females are caused by mutations of the XLIS(or DCX) gene. Mutations of the coding region of XLIS were found in all reported pedigrees, and in most sporadic female patients with SBH. Missense mutations of both LIS1 and XLIS genes have been observed in some of the rare male patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia has been associated with mutations of the reelin gene. With few exceptions, children with lissencephaly have severe developmental delay and infantile spasms early in life. Patients with SBH have a mild to severe mental retardation with epilepsy of variable severity and type. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with focal epilepsy in females and prenatal lethality in males. About 88% of patients have focal epilepsy. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. Additional, possibly autosomal recessive gene(s) are likely to be involved in causing BPNH non-linked to FLN1. Tuberous sclerosis (TS) is a dominant disorder caused by mutations in at lest two genes, TSC1 and TSC2. 75% of cases are sporadic. Most patients with TS have epilepsy. Infantile spasms are a frequent early manifestation of TS. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene have been reported in some patients. However, at present, there is no clear indication on the possible pattern of inheritance and on the practical usefulness that mutation detection in an individual with schizencephaly would carry in terms of genetic counselling. Amongst several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on several occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheritance and association to 22q11.2 deletions. FISH analysis for 22q11.2 is advisable in all patients with perisylvian polymicrogyria. Parents of an affected child with normal karyotype should be given up to a 25% recurrence risk.
Assuntos
Encéfalo/anormalidades , Epilepsia/diagnóstico , Epilepsia/genética , 1-Alquil-2-acetilglicerofosfocolina Esterase , Encéfalo/metabolismo , Cromossomos Humanos Par 17/genética , Análise Mutacional de DNA , Epilepsia/epidemiologia , Testes Genéticos , Humanos , Imageamento por Ressonância Magnética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Proteína Reelina , Cromossomo X/genéticaRESUMO
We describe a pedigree in which eight individuals presented with a non-progressive disorder with onset between the ages of 12 and 50 years. It was characterized by predominantly distal, semi-continuous rhythmic myoclonus (all patients), generalized tonic-clonic seizures (all patients) and complex partial seizures (three patients). Most individuals had rarely suffered seizures and had a normal cognitive level, but three individuals with intractable seizures had mild mental retardation. The pattern of inheritance was autosomal dominant with high penetrance. We defined this disorder as autosomal dominant cortical myoclonus and epilepsy (ADCME). All patients had frontotemporal as well as generalized interictal EEG abnormalities. A neurophysiological study of the myoclonus suggested a cortical origin. Back-averaging of the data generated a series of waves with a frequency that mirrored the frequency of EMG bursts. Frequency analysis identified significant peaks with coherence between EMG and EEG, which were recorded over the contralateral rolandic area in five patients. The frequency of coherence was 8-25 Hz and phase spectra confirmed that EEG activity preceded EMG activity by 8-15 ms. In two individuals there was also significant coherence between the ipsilateral EEG and EMG, consistent with the transcallosal spread of myoclonic activity. The C-reflex at rest was enhanced and somatosensory and visual evoked potentials were of high amplitude. The resting motor threshold intensity to transcranial magnetic stimulation was significantly reduced (38%; SD +/- 7; P = 0.01) and the post-motor evoked potential silent period (101 ms; SEM +/- 10) was significantly shortened compared with the controls (137 ms; SEM +/- 18). These clinical and neuro- physiological characteristics suggest diffuse cortical hyperexcitability and high propensity for intra-hemispheric and inter-hemispheric cortical spread, as well as rhythmic myoclonic activity. Genome-wide linkage analysis identified a critical region spanning 12.4 cM between markers D2S2161 and D2S1897 in 2p11.1-q12.2, with a maximum two-point LOD score of 3.46 at Theta 0.0 for marker D2S2175. Multipoint LOD score values, reaching 3.74 around D2S2175, localize the ADCME gene to the centromeric region of chromosome 2. The exclusion of the locus for familial adult myoclonic epilepsy on chromosome 8q23.3-q24 from linkage to our family and the new localization of the responsible gene to chromosome 2cen, together with the different phenotype, define a new epilepsy syndrome. We hypothesize that the responsible gene causes cortical hyperexcitability that is widespread but particularly involves the frontotemporal circuits.
Assuntos
Cromossomos Humanos Par 2 , Epilepsias Mioclônicas/genética , Epilepsia Parcial Complexa/genética , Epilepsia Tônico-Clônica/genética , Ligação Genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estimulação Elétrica , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsia Parcial Complexa/diagnóstico , Epilepsia Tônico-Clônica/diagnóstico , Potenciais Somatossensoriais Evocados , Potenciais Evocados Visuais , Saúde da Família , Feminino , Genes Dominantes , Humanos , Magnetismo , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Linhagem , ReflexoRESUMO
Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Here we review those malformations for which a genetic basis has been elucidated or is suspected and the types of associated epilepsy. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including partial epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene were reported in 13 patients. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with epilepsy in females and prenatal lethality in males. About 88% of patients have partial epilepsy. Filamin A mutations, all leading to a truncated protein, have been reported in three families and in sporadic patients. The most frequent forms of lissencephaly (agyria-pachygyria) are caused by mutations of LIS1. XLIS mutations cause classical lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females. The thickness of the heterotopic band and the degree of pachygyria correlate with the likelihood of developing Lennox-Gastaut syndrome. Mutations of the coding region of XLIS were found in all reported pedigrees and in 38-91% of sporadic female patients with SBH. With few exceptions, children with LIS1 mutations have isolated lissencephaly, with severe developmental delay and infantile spasms. Autosomal recessive lissencephaly with cerebellar hypoplasia, accompanied by severe developmental delay, seizures, and hypotonia has been associated with mutations of the reelin gene. Fukuyama congenital muscular dystrophy is due to mutations of the fukutin gene and is accompanied by polymicrogyria. Febrile seizures and epilepsy with generalized tonic-convulsions appear in about 50% of children but are usually not severe. Tuberous sclerosis (TS) is caused by mutations in at least two genes, TSC1 and TSC2; 75% of cases are sporadic; 60% of patients have epilepsy, manifested in 50% of them as infantile spasms. TSC1 mutations seem to cause a milder disease with fewer cortical tubers and lower frequency of seizures. Among several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on several occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheritance, and association with 22q11.2 deletions. About 65% of patients have severe epilepsy, often Lennox-Gastaut syndrome.
Assuntos
Córtex Cerebral/anormalidades , Epilepsia/genética , Epilepsia/patologia , 1-Alquil-2-acetilglicerofosfocolina Esterase , Movimento Celular , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Mapeamento Cromossômico , Proteínas Contráteis/genética , Proteínas Contráteis/metabolismo , Epilepsia/fisiopatologia , Filaminas , Humanos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Distrofias Musculares/genética , Mutação Puntual/genética , Proteína Reelina , Esclerose Tuberosa/genéticaRESUMO
Hereditary Spastic Paraplegias (HSPs) are heterogeneous neurodegenerative disorders whose etiopathogenesis is still unclear. The identification of pathogenic mutations in a gene (SPG7) encoding a mitochondrial metalloprotease suggested that oxidative phosphorylation (OXPHOS) alterations might underlie HSP in a subgroup of patients. We performed clinical, morphological, biochemical, and molecular genetic studies in six HSP patients and in six sporadic patients to investigate OXPHOS in muscle biopsies. Complicated and pure forms were included in our study. Morphological alterations of the type seen in OXPHOS-related disorders were found in three patients. Five patients showed an isolated defect of complex I activity. No mutations in the SPG7 gene were detected. Our results suggest that OXPHOS defects in HSP patients are more common than previously believed.