RESUMEN
Friedreich ataxia and ataxia with selective vitamin E deficiency (AVED) share very similar clinical phenotypes. We have mapped the AVED locus to proximal 8q with only three large consanguinous Tunisian families, representing to our knowledge the first use of homozygosity mapping for primary linkage analysis. Subsequently, three additional families showed linkage with the same markers. A maximum lod score of 17.9 was obtained at theta = 0 for the haplotype D8S260-D8S510, consisting of the two closest markers. With only 6 families, the AVED locus is therefore mapped precisely as illustrated by the lod-1 confidence interval of 2.4 cM on either side of D8S260-D8S510. Isolation of a yeast artificial chromosome contig > 800 kilobases (kb) showed that D8S260 and D8S510 are less than 400 kb apart.
Asunto(s)
Cromosomas Humanos Par 8 , Ataxia de Friedreich/genética , Homocigoto , Deficiencia de Vitamina E/genética , Adulto , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Femenino , Ligamiento Genético , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , TúnezRESUMEN
Autosomal recessive Duchenne-like muscular dystrophy (DLMD) is a severe dystrophic myopathy. The incidence is unknown because of its clinical similarity to Duchenne muscular dystrophy (DMD). Three highly inbred DLMD families from Tunisia were analysed for chromosomal linkage using 135 polymorphic microsatellite markers. A significant lod score of z = 9.15 at theta = 0.03 was found with the 13q12 locus D13S115. Two additional 13q12 markers, D13S143 and D13S120, also gave significant lod scores. Therefore, the primary DLMD defect gene lies in the pericentrometric region of chromosome 13q.
Asunto(s)
Cromosomas Humanos Par 13 , Ligamiento Genético , Distrofias Musculares/genética , Centrómero/ultraestructura , Mapeo Cromosómico , Cromosomas Humanos Par 13/ultraestructura , Consanguinidad , ADN Satélite/genética , Femenino , Genes Recesivos , Marcadores Genéticos , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo Genético , TúnezRESUMEN
Amyotrophic lateral sclerosis (ALS) usually presents as a sporadic disorder of motor neurons. However, familial forms of ALS have been described--autosomal dominant forms (ALS1, ALS3), clinically indistinguishable from the sporadic form, and autosomal recessive forms with early onset and slower progression of symptoms (ALS2). To localize the gene for one of the autosomal recessive forms of ALS, we applied linkage analysis to a large inbred family from Tunisia. A lod score maximum of Zmax = 8.2 at theta = 0.00 was obtained with marker D2S72 located on chromosome 2q33-q35. The fine mapping of this region suggested that the ALS2 locus lies in the 8 cM segment flanked by D2S155 and D2S115.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Cromosomas Humanos Par 2/genética , Genes Recesivos , Adolescente , Adulto , Esclerosis Amiotrófica Lateral/clasificación , Niño , Preescolar , Mapeo Cromosómico , Consanguinidad , Femenino , Marcadores Genéticos , Haplotipos/genética , Humanos , Escala de Lod , Masculino , Linaje , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Secuencias Repetitivas de Ácidos Nucleicos , Túnez/epidemiologíaRESUMEN
Disorganization of the neurofilament network is a prominent feature of several neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy and axonal Charcot-Marie-Tooth disease. Giant axonal neuropathy (GAN, MIM 256850), a severe, autosomal recessive sensorimotor neuropathy affecting both the peripheral nerves and the central nervous system, is characterized by neurofilament accumulation, leading to segmental distension of the axons. GAN corresponds to a generalized disorganization of the cytoskeletal intermediate filaments (IFs), to which neurofilaments belong, as abnormal aggregation of multiple tissue-specific IFs has been reported: vimentin in endothelial cells, Schwann cells and cultured skin fibroblasts, and glial fibrillary acidic protein (GFAP) in astrocytes. Keratin IFs also seem to be alterated, as most patients present characteristic curly or kinky hairs. We report here identification of the gene GAN, which encodes a novel, ubiquitously expressed protein we have named gigaxonin. We found one frameshift, four nonsense and nine missense mutations in GAN of GAN patients. Gigaxonin is composed of an amino-terminal BTB (for Broad-Complex, Tramtrack and Bric a brac) domain followed by a six kelch repeats, which are predicted to adopt a beta-propeller shape. Distantly related proteins sharing a similar domain organization have various functions associated with the cytoskeleton, predicting that gigaxonin is a novel and distinct cytoskeletal protein that may represent a general pathological target for other neurodegenerative disorders with alterations in the neurofilament network.
Asunto(s)
Anomalías Múltiples/genética , Axones/patología , Cromosomas Humanos Par 16/genética , Proteínas del Citoesqueleto/genética , Cabello/patología , Neuropatía Hereditaria Motora y Sensorial/genética , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/genética , Alelos , Secuencia de Aminoácidos , Enfermedad de Charcot-Marie-Tooth/clasificación , Enfermedad de Charcot-Marie-Tooth/genética , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/fisiología , Análisis Mutacional de ADN , ADN Complementario/genética , Exones/genética , Mutación del Sistema de Lectura , Heterogeneidad Genética , Genotipo , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/veterinaria , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Proteínas del Tejido Nervioso/deficiencia , Enfermedades Neurodegenerativas/patología , Proteínas de Neurofilamentos/deficiencia , Proteínas de Neurofilamentos/genética , Mutación Puntual , Estructura Terciaria de Proteína , Secuencias Repetitivas de Aminoácido , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
INTRODUCTION: The objective of this work was to review current data about the pathophysiology, clinical features, and treatment of thrombotic microangiopathies. CURRENT KNOWLEDGE: Thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. In thrombotic thrombocytopenic purpura, systemic microvascular aggregation of platelets causes ischemia in the brain and other organs. In the hemolytic-uremic syndrome, platelet-fibrin thrombi occlude predominantly the renal circulation. Thrombotic microangiopathy is a rare disorder whose varied clinical manifestations result from the formation of platelet-rich thrombi within the microvasculature and consequent tissue ischemia. The clinical features are acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. This diagnosis is of considerable importance because of the possible fulminant clinical course. Some atypical forms may be unrecognized. Plasma exchange is the current reference treatment of thrombotic thrombocytopenic purpura. However, in the light of recent publications, either infusions of concentrates of purified enzyme or more intensive immunosuppressive therapy would be more specific.
Asunto(s)
Microcirculación/fisiología , Trombosis/epidemiología , Fibrinolíticos/uso terapéutico , Heparina/uso terapéutico , Humanos , Incidencia , Pronóstico , Trombosis/diagnóstico , Trombosis/fisiopatología , Trombosis/terapiaRESUMEN
AIM: Our aim was to study the susceptibility of Streptococcus pneumoniae to antibiotics in patients with pneumococcal meningitis and to search for the prognosis factors in those patients. METHODS: We have studied retrospectively 31 cases of pneumococcal meningitis. Comparaisons were performed with univariate analysis. RESULTS: The mean age was 36.7 +/- 20.5 years (ranged: 9 and 78 years). The sex ratio was 3,4. The susceptibility of Streptococcus pneumoniae to penicillin G was affected in 10 cases (33% of isolated pneumococcus. The MIC to penicillin G was > or =2 in only one case. The hospital mortality was 26% (8/31). With univariate analysis, factors associated with death were: age > or =55 years (Ss p= 0,006, OR: 17.2 IC95%: 2.3-134), albuminorachie > or = 7 g/l (p = 0.002, OR: 22; IC95%: 1.9-2.51), shock (p = 0.031, OR: 6.7; IC95%: 1.05-42) and Glasgow Coma Score (GCS) < or =8 (p = 0.001, OR: 20; IC95%: 2.68-149). CONCLUSION: No susceptibility to penicillin G is not associated with a worse outcome in patients with pneumococcal meningitis. An age > or =55 years, albuminorachie > or =7 g/l shock and Glasgow Coma Score < or =8 at admission were determinant of the prognosis in our study.
Asunto(s)
Meningitis Neumocócica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
Post traumatic renal artery thrombosis is rarely described in the literature. This pathology can result from stretch injury to inelastic intima of the renal artery, or by the direct flow to the abdomen causing compression injury to the renal artery against the vertebral column. However, the association of this pathology with hematologic diseases (in particular protein C deficit) was never described. We report an observation of a 28-year-old man with an uneventful history who was admitted to the intensive care unit for traumatic head injury associated with post traumatic renal artery thrombosis requiring nephrectomy. The etiologic investigation of this thrombo-embolic complication reveals a protein C deficit. Our patient was improved under treatment. This original observation confirms that post traumatic renal artery thrombosis can be associated with hematologic diseases (in particular protein C deficit).
Asunto(s)
Traumatismos Craneocerebrales/complicaciones , Deficiencia de Proteína C/diagnóstico , Arteria Renal , Trombosis/genética , Accidentes de Tránsito , Adulto , Humanos , Masculino , Radiografía , Arteria Renal/diagnóstico por imagen , Trombosis/diagnóstico por imagenRESUMEN
OBJECTIVE: To report the clinical experience, biochemical findings, complications and maternal outcome in patients with acute fatty liver of pregnancy (AFLP). PATIENTS AND METHODS: Retrospective study over a period of 11 years (1993-2003). The diagnosis of AFLP was confirmed by liver biopsy in 15 women. However, in 7 women a medical committee that took into account clinical symptoms, and laboratory findings assessed the diagnosis. RESULTS: Were included in this study, 22 women with a mean age of 30+/-5.4 years. Only 22.7% of cases were primigravid. The mean gestational age was 36+/-2.76 weeks (range 31-41 weeks). The fetus was a male infant in 75% of cases. Ten women were admitted in the hospital without jaundice. However 15 women had developed an icterus since their hospital admission or during ICU stay. The mean SAPS II on the ICU admission was of 24.86+/-11.2 points. Biological disturbances observed were mainly: liver cytolysis in 91% of cases, a trend to hypoglycaemia in 86%, a hypoprotidemia in 66.7% and CIVD in 32%. During their ICU stay, 19 women (86.4%) developed one or several organ failures associated to the hepatic failure and 18 women required blood transfusion. After an average stay of 7.5 days, evolution was marked by the death of seven patients (31.8%). Factors correlated with a poor prognosis were: the delay of medical consultation, the development of jaundice, the development of encephalopathy, respiratory or a circulatory failure. DISCUSSION AND CONCLUSION: AFLP is a rare but life-threatening complication. Furthermore AFLP shares features with other more common and less perilous illnesses. An early diagnosis and appropriate therapy of this pathology should improve the poor prognosis in our country.
Asunto(s)
Hígado Graso/diagnóstico , Complicaciones del Embarazo/diagnóstico , Enfermedad Aguda , Adulto , Transfusión Sanguínea , Cuidados Críticos , Hígado Graso/mortalidad , Hígado Graso/terapia , Femenino , Edad Gestacional , Humanos , Fallo Hepático/complicaciones , Masculino , Insuficiencia Multiorgánica/epidemiología , Insuficiencia Multiorgánica/etiología , Embarazo , Complicaciones del Embarazo/mortalidad , Complicaciones del Embarazo/terapia , Resultado del Embarazo , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: To analyze the clinico-biological manifestations, identify the causes and evaluate the outcome of patients with severe thrombotic microangiopathies admitted in a Tunisian intensive care unit. METHODS: Retrospective study over a period of 10 years (1995-2004) in an intensive care unit. RESULTS: Were included in this study 9 cases with a mean age of 29.2+/-9 years (range 15-44 years). Fever was observed in 5 patients, neurological impairment in 5 and digestive manifestations in 6. Haemolytic anaemia, thrombocytopenia and acute renal failure were observed in 100% of the cases. In our study, the aetiologies of thrombotic microangiopathies were: complicated pregnancy in 6 cases, systemic lupus erythematosus in 1 case. In contrast, no aetiology was found in 2 patients. Plasma exchange was performed in 5 patients, while 4 patients received only plasma infusion. After an average stay of 18+/-12.5 days, evolution was marked by the death 3 patients. CONCLUSION: The incidence of severe thrombotic microangiopathies is rare in Tunisian ICU. The clinical manifestations are not specific. Despite the improvement in the outcome by exogenous plasma supply, thrombotic microangiopathies with severe organ dysfunctions leading to hospitalization in the intensive care unit are associated with a high mortality rate.
Asunto(s)
Enfermedades Vasculares Periféricas/etiología , Púrpura Trombocitopénica Idiopática/complicaciones , Lesión Renal Aguda/complicaciones , Adolescente , Adulto , Argelia/epidemiología , Anemia Hemolítica/complicaciones , Anemia Hemolítica/diagnóstico , Reanimación Cardiopulmonar , Femenino , Fiebre/etiología , Humanos , Unidades de Cuidados Intensivos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/fisiopatología , Enfermedades Vasculares Periféricas/epidemiología , Enfermedades Vasculares Periféricas/terapia , Intercambio Plasmático , Embarazo , Complicaciones Cardiovasculares del Embarazo/fisiopatología , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: Celiac disease is a pathology which is rarely associated with thrombosis complications. Cerebral vascular thrombosis has never been described in patients with a celiac disease. OBSERVATION: We report an observation of a 21-year-old girl with a history of celiac disease who was hospitalized in the intensive care unit for convulsive status epilepticus secondary to a cerebral venous thrombosis. The etiologic investigation of this thrombo-embolic complication revealed protein S deficit. Our patient improved under symptomatic treatment. COMMENT: This original observation confirms that celiac disease can be associated with cerebral venous thrombosis.
Asunto(s)
Enfermedad Celíaca/complicaciones , Venas Cerebrales , Deficiencia de Proteína S/complicaciones , Trombosis de la Vena/complicaciones , Adulto , Femenino , Humanos , Trombosis de la Vena/terapiaRESUMEN
PURPOSE: To estimate the consumption of antibiotics in our hospital and to determine the points at which will be targeted the recommendations of good practice of antibiotherapy. PATIENTS AND METHODS: Our study is a one day prevalence study where antibiotic's prescriptions are analyzed by a group of 6 doctors referents in antibiotherapy. RESULTS: During the study day, 443 patients were studied. Means age was 44.2 +/- 23.3 years (range: 1 and 102 years). 101 infections were diagnosed in 48 patients (10.8%). 192 patients (43.3%) received antibiotics. Antibiotherapy was curative in 44% of cases. The most prescribed antibiotics were gentamicin (85.2 DDD/1000 patients), metronidazole (79 DDD/1000 patients), and cefotaxime (73.9 DDD/1000 patients). According to the evaluation group, 30.7% of the antibiotic's prescription was considered unjustified. The antibioprophylaxis represents the category most often unjustified (49%). The molecules in which prescription was frequently considered unjustified are the ciprofloxacin (67%), the amoxicilline-clavulanate (40%) and the cefotaxime (40%). CONCLUSION: Our results suggest that an action of good practice should be targeted at the antibioprophylaxis and should concern especially molecules in which prescription was frequently unjustified.
Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Hospitales Universitarios/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Farmacorresistencia Microbiana , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , TúnezRESUMEN
We describe a large kindred of 6 patients with a slowly progressive autosomal recessive form of giant axonal neuropathy (GAN). The propositus presented with progressive infantile onset of distal amyotrophy of 4 limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in both lower limbs. The EMG and nerve biopsy showed typical hypertrophic neuritis. In 4 patients, there were giant axons filled with neurofilaments, with normal conduction velocity. In the youngest boy, the neurologic deficit was less severe, and the nerve biopsy revealed only a few unmyelinated axons filled with neurofilaments. These cases appear to represent a different genetic defect from other reported cases of GAN.
Asunto(s)
Axones/ultraestructura , Neuronas Motoras/ultraestructura , Enfermedades Neuromusculares/genética , Enfermedades del Sistema Nervioso Periférico/genética , Adulto , Niño , Preescolar , Femenino , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Hipertrofia , Masculino , Persona de Mediana Edad , Fibras Nerviosas Mielínicas/ultraestructura , Enfermedades Neuromusculares/patología , Linaje , Enfermedades del Sistema Nervioso Periférico/patologíaRESUMEN
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, the disease locus (FRDA) of which has been assigned to 9q13-q21.1 by genetic linkage analysis in affected families. We report two large inbred Tunisian families with FA manifestations that did not show the expected linkage. The disease locus could be excluded from a large (12 cMo) region around FRDA. This is the first report providing evidence for nonallelic genetic heterogeneity for the FA clinical phenotype. On subsequent analysis, all patients had very low levels of serum vitamin E whereas the parents and healthy sibs had normal vitamin E levels. This establishes that the selective vitamin E deficiency with normal fat absorption is an autosomal recessive trait, which is associated in the two families reported here with the FA phenotype.
Asunto(s)
Cromosomas Humanos Par 9 , Ataxia de Friedreich/genética , Deficiencia de Vitamina E/genética , Adulto , Consanguinidad , Femenino , Ataxia de Friedreich/complicaciones , Ligamiento Genético , Humanos , Escala de Lod , Masculino , Fenotipo , Túnez , Deficiencia de Vitamina E/complicacionesRESUMEN
Autosomal dominant cerebellar ataxias (ADCA) type 1 are a clinically and genetically heterogeneous group of neurodegenerative disorders. We report a large Tunisian ADCA type 1 family in which 17 patients (mean age at onset +/- SD = 35.6 +/- 15.3 years) were examined. There was mean anticipation of 10.3 +/- 15.4 years in this family; anticipation was greater in paternal (28 +/- 8.2 years) than in maternal (2.7 +/- 10.9 years) transmission. Linkage analysis performed with microsatellite markers linked to the spinal cerebellar ataxia 1 (SCA1) locus on chromosome 6p and the SCA2 locus on chromosome 12q excluded linkage to SCA1, but there was close linkage with marker D12S105 (Zmax = 2.51 at theta = 0.00). This result was confirmed by multipoint analysis, which generated a maximal lod score of 3.46 at this locus. Multipoint analysis and haplotype reconstruction reduced the interval containing the SCA2 locus to 6.4 cM, a narrowing of the 35-cM interval in a previously described Cuban SCA2 family with a clinical picture similar to that of our family, including a high frequency of postural and action tremor.
Asunto(s)
Degeneraciones Espinocerebelosas/genética , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , TúnezRESUMEN
Miyoshi myopathy (MM) is a young-adult-onset, autosomal recessive distal muscular dystrophy initially affecting the plantar flexors. We analyzed 12 MM families, five with consanguineous marriage, for chromosomal linkage using polymorphic microsatellite DNA markers to map the MM gene. A significant lod score was obtained with the 2p12-14 locus D2S291 (Zmax = 15.3 at theta = 0). Two additional 2p12-14 markers, D2S286 (Z = 10.7 at theta = 0) and D2S292 (Z = 7.2 at theta = 0.05), also gave significant lod scores. These markers will be useful for diagnosis of symptomatic and presymptomatic patients, prenatal and carrier diagnosis of family members carrying MM, and ultimately identification of a gene responsible for MM.
Asunto(s)
Cromosomas Humanos Par 2 , Ligamiento Genético , Distrofias Musculares/genética , Adolescente , Adulto , Niño , Mapeo Cromosómico , Humanos , Escala de Lod , LinajeRESUMEN
We describe the histomorphometric changes in the superficial peroneal nerve biopsy from 13 patients with xeroderma pigmentosum (XP). The mean age at time of biopsy was 15 yr (range 2.5-24 yr). The clinical examination was normal in the two youngest patients and showed absence of the deep tendon reflexes, with choreo-athetosis in ten patients. In addition, in the three oldest patients there were cerebellar signs, ataxia and Babinski signs. The nerve biopsy showed an age-dependent decrease of myelinated fibres, which was mild in the youngest and severe in the oldest patients. This was associated with rare acute axonal degeneration, sparse axonal regeneration, rare axonal atrophy and few onion bulb formations. These findings suggest a neuropathic process. This neuronal degeneration seems to be a progressive and stereotyped phenomenon in XP.
Asunto(s)
Envejecimiento/patología , Axones/patología , Xerodermia Pigmentosa/patología , Adolescente , Adulto , Niño , Preescolar , Humanos , Degeneración Nerviosa , Fibras Nerviosas/ultraestructura , Fibras Nerviosas Mielínicas/patología , Regeneración Nerviosa , Nervio Peroneo/patologíaRESUMEN
We report the clinical and genetic linkage analysis of a large Tunisian family with thirteen affected patients suffering from Charcot-Marie-Tooth disease with pyramidal involvement. The inheritance is autosomal recessive. The clinical phenotype is consistent in all patients. It is characterized by onset during the first decade, a progressive course and distal atrophy in all four limbs, associated with a mild pyramidal syndrome. Nerve biopsy in two patients showed severe axonal neuropathy. Genetic linkage excluded known loci of different genetic forms of Charcot-Marie-Tooth disease, familial spastic paraplegia and familial amyotrophic lateral sclerosis. A significant lod score was obtained with marker D8S286, confirming linkage to chromosome 8q21.3. The clinical syndrome observed in this family seems to correspond to a new genetic form of autosomal recessive Charcot-Marie-Tooth disease.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 8/genética , Genes Recesivos/genética , Ligamiento Genético/genética , Enfermedades del Sistema Nervioso Periférico/genética , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Mapeo Cromosómico , Femenino , Marcadores Genéticos/genética , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Tractos Piramidales/fisiopatología , TúnezRESUMEN
The LGMD2C linked to chromosome 13q and related to a 35 KDa dystrophin-associated glycoprotein deficiency, is very similar to Duchenne muscular dystrophy with an autosomal recessive inheritance. It is characterized by a variability of the age of onset, the severity of the evolution and the severity of myopathic changes at the muscle biopsy. This variability was also present in the expression of the alpha-sarcoglycan between the same sibships and between different families.
Asunto(s)
Cromosomas Humanos Par 13 , Genes Recesivos , Músculo Esquelético/fisiopatología , Distrofias Musculares/genética , Edad de Inicio , Extremidades , HumanosRESUMEN
Four of the currently recognized autosomal recessive limb-girdle muscular dystrophies (LGMD type 2C-F) are caused by mutations in the genes encoding components of the sarcoglycan complex. LGMD 2C, caused by mutations in gamma-sarcoglycan, is prevalent in northern Africa, especially in Tunisia, where this type of muscular dystrophy was originally described. Although the disease initially was assumed to be genetically homogeneous in this region, linkage to the alpha-sarcoglycan locus (LGMD 2D) has also been found. We have now identified the first Tunisian family with beta-sarcoglycanopathy (LGMD 2E), further adding to the genetic heterogeneity of autosomal recessive LGMD in this population. Direct sequencing of the beta-sarcoglycan gene revealed a homozygous mutation (G272-->T, Arg91Leu) in exon 3. This change affects the same arginine residue in the immediate extracellular domain of the protein that was mutated to a proline (G272-->C, Arg91Pro) in a Brazilian family with a severe form of the disease. Immunohistochemical analysis for the sarcoglycan complex demonstrates absence of the known components of the complex in both of these families. We postulate that the immediate extracellular domain of beta-sarcoglycan may be important for the assembly and/or maintenance of this complex, potentially mediated by disulfide-bond formation to another sarcoglycan via the single cysteine residue in that domain.
Asunto(s)
Proteínas del Citoesqueleto/genética , Exones/genética , Homocigoto , Glicoproteínas de Membrana/genética , Distrofias Musculares/clasificación , Distrofias Musculares/genética , Mutación/genética , Adolescente , Adulto , Mapeo Cromosómico , Distroglicanos , Ligamiento Genético/genética , Humanos , Linaje , TúnezRESUMEN
Limb-girdle muscular dystrophy type 2C is an autosomal recessive muscular disorder caused by mutations in the gene encoding the gamma-sarcoglycan subunit. This gamma-sarcoglycanopathy is prevalent in Tunisia where only one homozygous mutation a 521-T deletion has been identified. The aim of this study was to carry out a comparative clinical and immunocytochemical analysis of Tunisian patients sharing the same gamma-sarcoglycan gene mutation. One hundred and thirty-two patients were classified as severe, moderate or mild according to a calculated severity score. Heterogeneous phenotypes between siblings were encountered in 75% of the families. The severity of the disease was not found to be related to the age of onset. Immunohistochemical studies of muscle biopsy showed a total absence of gamma-sarcoglycan, a normal or slightly reduced alpha and delta-sarcoglycans whereas the expression of beta-sarcoglycan was variable. The residual sarcoglycan expression was not related to the clinical phenotype. In conclusion, the phenotypic variability in sarcoglycanopathies in Tunisia seems to involve a modifying gene controlling the course of the disease.