RESUMEN
We report an African infant with Ellis-van Creveld (EVC) syndrome. EVC syndrome is a chondral and ectodermal dysplasia with autosomal recessive transmission. The baby presented with polydactyly, short limbs and atrioventricular septal defect, but was withdrawn from clinical follow up for the first year of life. Initial hematological abnormalities could not be explained and normalized later. EVC syndrome was confirmed by genetic analysis that showed two pathogenic mutations in the EVC2 gene, c.653_654del, p.Val218Glyfs*12 in exon 5, and c.2710C>T, p.Gln904* in exon 16. The variant c.653_654del; p.Val218Glyfs*12 in exon 5 has not been described before. Our review of medical literature suggested this is the first molecularly confirmed case of EVC syndrome in sub-Saharan Africa.
Asunto(s)
Síndrome de Ellis-Van Creveld/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Mano/diagnóstico por imagen , Humanos , Lactante , Masculino , Polidactilia/diagnóstico por imagen , Tanzanía , Tibia/diagnóstico por imagenRESUMEN
Obesity, mild intellectual disability, hypotonia, poor sucking, cryptorchidism in males, hypogonadism, and kyphoscoliosis are common features of Prader-Willi syndrome (PWS). We report a case who had severe respiratory complications due to extreme obesity and kyphoscoliosis, which are important causes of morbidity and mortality, and discuss management. Furthermore, this is the first molecularly confirmed PWS case in Sub-Saharan Africa outside South Africa.
RESUMEN
We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with ß-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.
Asunto(s)
Distrofina/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Eliminación de Secuencia , Adulto , Anciano , Emparejamiento Base , Células Cultivadas , Distroglicanos/genética , Exones , Sitios Genéticos , Genotipo , Humanos , Escala de Lod , Masculino , Distrofias Musculares/genética , Mutación , Linaje , Conformación Proteica , ARN Mensajero/genéticaRESUMEN
CONTEXT: Unbalanced subtelomeric chromosomal rearrangements are often associated with intellectual disability (ID) and malformation syndromes. The prevalence of such rearrangements has been reported to be 5-9% in ID populations. AIMS: To study the prevalence of subtelomeric rearrangements in the Indonesian ID population. MATERIALS AND METHODS: We tested 436 subjects with unexplained ID using multiplex ligation dependent probe amplification (MLPA) using the specific designed sets of probes to detect human subtelomeric chromosomal imbalances (SALSA P070 and P036D). If necessary, abnormal findings were confirmed by other MLPA probe kits, fluorescent in situ hybridization or Single Nucleotide Polymorphism array. RESULTS: A subtelomeric aberration was identified in 3.7% of patients (16/436). Details on subtelomeric aberrations and confirmation analyses are discussed. CONCLUSION: This is the first study describing the presence of subtelomeric rearrangements in individuals with ID in Indonesia. Furthermore, it shows that also in Indonesia such abnormalities are a prime cause of ID and that in developing countries with limited diagnostic services such as Indonesia, it is important and feasible to uncover the genetic etiology in a significant number of cases with ID.
RESUMEN
Apert syndrome (AS) is a rare autosomal dominant disorder characterised by craniosynostosis and limb malformations, and is associated with congenital heart disease and other systemic malformations, including intellectual disability. We report two Indonesian patients with AS, in whom molecular analysis detected p.Ser252Trp (c.755C>G) and p.Pro253Arg (c.758C>G) mutations in the fibroblast growth factor receptor 2 (FGFR2) gene, respectively. Although the syndrome has been frequently described, this is the first clinical report of AS confirmed by molecular analysis in Indonesia. The difference in severity of clinical features in the two patients may be consistent with a genotype-phenotype correlation of the FGFR2mutation. The management of individuals with AS is best achieved within a multidisciplinary setting. However, in most developing countries, early intervention may be delayed due to late diagnosis, a lack of facilities and financial constraints. This report underpins the benefits of early diagnosis for AS management.
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Acrocefalosindactilia/diagnóstico , Acrocefalosindactilia/genética , Mutación , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Acrocefalosindactilia/etnología , Arginina/análisis , Análisis Mutacional de ADN , Resultado Fatal , Estudios de Asociación Genética , Humanos , Indonesia , Lactante , Recién Nacido , Masculino , Prolina/análisis , Serina/análisis , Triptófano/análisisRESUMEN
Ohdo syndrome comprises a heterogeneous group of disorders characterized by intellectual disability (ID) and typical facial features, including blepharophimosis. Clinically, these blepharophimosis-ID syndromes have been classified in five distinct subgroups, including the Maat-Kievit-Brunner (MKB) type, which, in contrast to the others, is characterized by X-linked inheritance and facial coarsening at older age. We performed exome sequencing in two families, each with two affected males with Ohdo syndrome MKB type. In the two families, MED12 missense mutations (c.3443G>A [p.Arg1148His] or c.3493T>C [p.Ser1165Pro]) segregating with the phenotype were identified. Upon subsequent analysis of an additional cohort of nine simplex male individuals with Ohdo syndrome, one additional de novo missense change (c.5185C>A [p.His1729Asn]) in MED12 was detected. The occurrence of three different hemizygous missense mutations in three unrelated families affected by Ohdo syndrome MKB type shows that mutations in MED12 are the underlying cause of this X-linked form of Ohdo syndrome. Together with the recently described KAT6B mutations resulting in Ohdo syndrome Say/Barber/Biesecker/Young/Simpson type, our findings point to aberrant chromatin modification as being central to the pathogenesis of Ohdo syndrome.
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Anomalías Múltiples/genética , Blefarofimosis/genética , Blefaroptosis/genética , Genes Ligados a X/genética , Cardiopatías Congénitas/genética , Discapacidad Intelectual/genética , Complejo Mediador/genética , Mutación Missense , Adolescente , Niño , Preescolar , Exoma , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Análisis de Secuencia de ADN/métodosRESUMEN
Mowat-Wilson syndrome (OMIM 235730) is a genetic condition characterized by moderate-to-severe intellectual disability, a recognizable facial phenotype, and multiple congenital anomalies. The striking facial phenotype in addition to other features such as severely impaired speech, hypotonia, microcephaly, short stature, seizures, corpus callosum agenesis, congenital heart defects, hypospadias, and Hirschsprung disease are particularly important clues for the initial clinical diagnosis. All molecularly confirmed cases with typical MWS have a heterozygous loss-of-function mutation in the zinc finger E-box protein 2 (ZEB2) gene, also called SIP1 (Smad-interacting protein 1) and ZFHX1B, suggesting that haploinsufficiency is the main pathological mechanism. Approximately 80% of mutations are nonsense and frameshift mutations (small insertions or deletions). About half of these mutations are located in exon eight. Here, we report the first Indonesian patient with Mowat-Wilson syndrome confirmed by molecular analysis.
RESUMEN
Pericentric inversions of chromosome 9 leading to unbalanced live-born offspring are relatively rare and so far only four cases have been reported. Here we present two sisters with an unbalanced recombinant chromosome 9 which resulted from a large maternal pericentric inversion inv(9)(p24.3q34.1). Further molecular characterisation of the aberrant chromosome 9 by 250k SNP array analysis showed a terminal 460 kb loss of 9p24.3 and a terminal 8.9 Mb gain of 9q34.11. We compared the clinical features of these two patients with the previous reported four cases as well as with patients with similar sized 9pter deletions or 9qter duplications. Based upon this study, we suggest that the recombinant chromosome 9 phenotype is mainly the result of duplication of a 3.4 Mb region of chromosome 9q34.11q34.13.
Asunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 9 , Monosomía , Hermanos , Trisomía , Adolescente , Adulto , Femenino , HumanosRESUMEN
BACKGROUND: DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome. AIM: To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations. METHODS: A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability. RESULTS: In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described. CONCLUSION: Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.
Asunto(s)
Anomalías Múltiples/genética , Movimiento Celular , Dineínas Citoplasmáticas/genética , Discapacidad Intelectual/genética , Mutación Missense , Neuronas/fisiología , Anomalías Múltiples/enzimología , Anomalías Múltiples/patología , Animales , Secuencia de Bases , Niño , Análisis Mutacional de ADN , Exoma , Femenino , Estudios de Asociación Genética , Humanos , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/patología , Masculino , Ratones , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
Cornelia de Lange syndrome is a dominantly inherited, genetically heterogeneous and clinically variable syndrome with multiple congenital anomalies and developmental delay. Gastrointestinal anomalies are common and an important cause of morbidity and mortality. We report on a newborn with a molecularly confirmed Cornelia de Lange syndrome who had an imperforate anus. This is the third report of Cornelia de Lange syndrome and imperforate anus.
RESUMEN
Genetic factors play a significant role in the etiology of intellectual disability (ID). The goal of this study was to identify microscopically visible chromosomal abnormalities in an Indonesian ID population and to determine their frequency, pattern, and clinical features. A total of 527 intellectually disabled individuals from special schools and institutions in 4 different areas on Java Island, Indonesia, were screened for cytogenetic abnormalities. Additional analyses were carried out for verification or further characterization by using fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, or analysis of the FMR1 promoter CGG(n) repeat. Of the 527 individuals with ID, chromosomal abnormalities were found in 87 (16.5%). Trisomy 21 was the major chromosomal abnormality, identified in 74 patients (14%). Other chromosome abnormalities included 8 X-chromosomal and 5 autosomal aberrations. Details on chromosome aberrations and confirmation analyses are discussed. This study shows that chromosomal abnormalities are an important cause of ID in Indonesia. Cytogenetic analysis is important for an adequate diagnosis in patients and subsequent genetic counseling for their families, especially in developing countries with limited facilities, such as Indonesia.
Asunto(s)
Trastornos de los Cromosomas , Análisis Citogenético/métodos , Adolescente , Adulto , Niño , Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/genética , Cromosomas Humanos X/genética , Países en Desarrollo , Síndrome de Down/diagnóstico , Síndrome de Down/epidemiología , Síndrome de Down/genética , Femenino , Asesoramiento Genético , Humanos , Hibridación Fluorescente in Situ , Indonesia , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/genética , Masculino , Técnicas de Amplificación de Ácido Nucleico , Adulto JovenRESUMEN
A subset of ciliopathies, including Sensenbrenner, Jeune, and short-rib polydactyly syndromes are characterized by skeletal anomalies accompanied by multiorgan defects such as chronic renal failure and retinitis pigmentosa. Through exome sequencing we identified compound heterozygous mutations in WDR19 in a Norwegian family with Sensenbrenner syndrome. In a Dutch family with the clinically overlapping Jeune syndrome, a homozygous missense mutation in the same gene was found. Both families displayed a nephronophthisis-like nephropathy. Independently, we also identified compound heterozygous WDR19 mutations by exome sequencing in a Moroccan family with isolated nephronophthisis. WDR19 encodes IFT144, a member of the intraflagellar transport (IFT) complex A that drives retrograde ciliary transport. We show that IFT144 is absent from the cilia of fibroblasts from one of the Sensenbrenner patients and that ciliary abundance and morphology is perturbed, demonstrating the ciliary pathogenesis. Our results suggest that isolated nephronophthisis, Jeune, and Sensenbrenner syndromes are clinically overlapping disorders that can result from a similar molecular cause.
Asunto(s)
Cilios , Displasia Ectodérmica/genética , Mutación Missense , Enfermedades Renales Poliquísticas/genética , Proteínas/genética , Síndrome de Costilla Pequeña y Polidactilia/genética , Enfermedades Torácicas/genética , Adolescente , Adulto , Niño , Cilios/genética , Cilios/patología , Anomalías Craneofaciales/genética , Proteínas del Citoesqueleto , Exoma/genética , Femenino , Fibroblastos/metabolismo , Flagelos/genética , Flagelos/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Datos de Secuencia Molecular , Marruecos , Países Bajos , Noruega , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Enfermedades Renales Poliquísticas/congénito , Adulto JovenRESUMEN
BACKGROUND: MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions. METHODS AND RESULTS: In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery. CONCLUSIONS: This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.
Asunto(s)
Deleción Cromosómica , Discapacidad Intelectual/genética , MicroARNs/genética , Adolescente , Adulto , Animales , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 1/metabolismo , Variaciones en el Número de Copia de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Dihidrouracilo Deshidrogenasa (NADP)/genética , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Femenino , Dosificación de Gen , Regulación de la Expresión Génica , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , MicroARNs/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Complejo Represivo Polycomb 2 , Polimorfismo de Nucleótido Simple , Cultivo Primario de Células , Ratas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , TransfecciónRESUMEN
Deletions of the distal 3q22.3 region encompassing the gene forkhead transcription factor FOXL2 (FOXL2) usually result in intellectual disability (ID) and the highly recognizable blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). We encountered three patients with molecularly defined interstitial deletions distal to the FOXL2 gene. They present with remarkably similar manifestations comprising variable ID, a coarse facial appearance, including prominent nose and eyebrows, hypogonadism and skin pigmentation abnormalities, and they share an approximately 8.8 Mb overlapping 3q24q25 deletion. Interestingly, one of the present patients was described previously in a clinical report with emphasis on her clinical similarity to the Wisconsin syndrome, suggesting that Wisconsin syndrome might be caused by a (micro) deletion within the 3q24q25 region.
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Blefarofimosis/genética , Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Fenotipo , Adolescente , Blefarofimosis/patología , Femenino , Proteína Forkhead Box L2 , Humanos , Discapacidad Intelectual/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple/genética , SíndromeRESUMEN
The most common mutations found in FBN1 are missense mutations (56%), mainly substituting or creating a cysteine in a cbEGF domain. Other mutations are frameshift, splice and nonsense mutations. There are only a few reports of patients with marfanoid features and a molecularly proven complete deletion of a FBN1 allele. We describe the clinical features of 10 patients with a complete FBN1 gene deletion. Seven patients fulfilled the Ghent criteria for Marfan syndrome (MFS). The other three patients were examined at a young age and did not (yet) present the full clinical picture of MFS yet. Ectopia lentis was present in at least two patients. Aortic root dilatation was present in 6 of the 10 patients. In three patients, the aortic root diameter was on the 95th percentile and in one patient, the diameter of the aortic root was normal, the cross-section, however, had a cloverleaf appearance. Two patients underwent aortic root surgery at a relatively young age (27 and 34 years). Mitral valve prolapse was present in 4 of the 10 patients, and billowing of the mitral valve in 1. All patients had facial and skeletal features of MFS. Two patients with a large deletion extending beyond the FBN1 gene had an extended phenotype. We conclude that complete loss of one FBN1 allele does not predict a mild phenotype, and these findings support the hypothesis that true haploinsufficiency can lead to the classical phenotype of Marfan syndrome.
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Alelos , Síndrome de Marfan/genética , Proteínas de Microfilamentos/genética , Mutación , Adolescente , Adulto , Niño , Preescolar , Cisteína/metabolismo , Desplazamiento del Cristalino/genética , Desplazamiento del Cristalino/patología , Femenino , Fibrilina-1 , Fibrilinas , Haploinsuficiencia , Humanos , Masculino , Prolapso de la Válvula Mitral/genética , Fenotipo , Eliminación de Secuencia , Adulto JovenRESUMEN
ZNF630 is a member of the primate-specific Xp11 zinc finger gene cluster that consists of six closely related genes, of which ZNF41, ZNF81, and ZNF674 have been shown to be involved in mental retardation. This suggests that mutations of ZNF630 might influence cognitive function. Here, we detected 12 ZNF630 deletions in a total of 1,562 male patients with mental retardation from Brazil, USA, Australia, and Europe. The breakpoints were analyzed in 10 families, and in all cases they were located within two segmental duplications that share more than 99% sequence identity, indicating that the deletions resulted from non-allelic homologous recombination. In 2,121 healthy male controls, 10 ZNF630 deletions were identified. In total, there was a 1.6-fold higher frequency of this deletion in males with mental retardation as compared to controls, but this increase was not statistically significant (P-value = 0.174). Conversely, a 1.9-fold lower frequency of ZNF630 duplications was observed in patients, which was not significant either (P-value = 0.163). These data do not show that ZNF630 deletions or duplications are associated with mental retardation.
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Cromosomas Humanos X/genética , Eliminación de Gen , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Estudios de Casos y Controles , Mapeo Cromosómico , Estudios de Cohortes , Hibridación Genómica Comparativa , Femenino , Dosificación de Gen , Duplicación de Gen , Humanos , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/genética , Linaje , Fenotipo , Recombinación GenéticaRESUMEN
Duplications in Xq28 involving the methyl CpG binding protein 2 gene (MECP2) have been described in male patients with severe mental disability, delayed milestones, absence of language, hypotonia replaced by spasticity and retractions, and recurrent and often severe infections. In a study involving five patients in two families, multiplex ligation-dependent probe amplification was used to screen the Xq28 region that includes MECP2, focusing on the presence of gene duplications. Some manifestations of the disease observed in these patients may occur less regularly than the classical abnormalities. Epilepsy with frequent seizures of the myoclonic-astatic type was observed in these patients and was associated with a slowing of the background electroencephalographic activity, rather than the generalized spike-waves or polyspike-waves usually observed in this type of seizure. In addition, cerebral abnormalities were observed with magnetic resonance imaging that were inconstant and nonspecific but that could nonetheless assist in diagnosis of this genetic pathology.
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Encéfalo/anomalías , Encéfalo/fisiopatología , Epilepsia/genética , Epilepsia/fisiopatología , Duplicación de Gen , Proteína 2 de Unión a Metil-CpG/genética , Adolescente , Adulto , Encéfalo/patología , Niño , Epilepsia/patología , Familia , Humanos , Imagen por Resonancia Magnética , Masculino , Técnicas de Amplificación de Ácido Nucleico , Convulsiones/genética , Convulsiones/patología , Convulsiones/fisiopatología , Adulto JovenRESUMEN
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
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Encefalopatías Metabólicas Innatas/genética , Inmunidad Innata , Proteínas de Unión al GTP Monoméricas/genética , Sustitución de Aminoácidos , Encefalopatías Metabólicas Innatas/inmunología , Humanos , Proteínas de Unión al GTP Monoméricas/inmunología , Proteína 1 que Contiene Dominios SAM y HDRESUMEN
OBJECTIVE: Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. We designed a cross-sectional study to find out whether neuromuscular features are part of EDS. METHODS: Standardized questionnaires, physical examination, nerve conduction studies, electromyography, muscle ultrasound, and muscle biopsy were performed in 40 EDS patients with the vascular, classic, tenascin-X (TNX)-deficient type EDS, and hypermobility type of EDS caused by TNXB haploinsufficiency. RESULTS: Muscle weakness, myalgia, and easy fatigability were reported by the majority of patients. Mild-to-moderate muscle weakness (85%) and reduction of vibration sense (60%) were common. Nerve conduction studies demonstrated axonal polyneuropathy in five patients (13%). Needle electromyography myopathic features in nine patients (26%) and a mixed neurogenic-myopathic pattern in most (60%). Muscle ultrasound showed increased echo-intensity (48%) and atrophy (50%). Mild myopathic features were seen on muscle biopsy of five patients (28%). Overall, patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected. INTERPRETATION: Mild-to-moderate neuromuscular involvement is common in various types of EDS, with a remarkable relation between residual TNX level and degree of neuromuscular involvement, compatible with a dose-effect relation. The findings of this study should increase awareness of neuromuscular symptoms in EDS patients and improve clinical care. They also point to a role of the extracellular matrix in muscle and peripheral nerve function.
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Síndrome de Ehlers-Danlos/clasificación , Síndrome de Ehlers-Danlos/fisiopatología , Músculo Esquelético/patología , Unión Neuromuscular/patología , Adolescente , Adulto , Estudios Transversales , Síndrome de Ehlers-Danlos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular/fisiología , Debilidad Muscular/patología , Músculo Esquelético/fisiología , Conducción Nerviosa/fisiología , Unión Neuromuscular/fisiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
We recently demonstrated aberrant staining of fibrillin-1 in lung tissue specimens with emphysematous lesions. In this study, we have extended this observation by an elaborate analysis of the elastic fibre. Using domain-specific antibodies to fibrillin-1, and to other elastin fibre-associated molecules, lung tissue derived from patients without obvious clinical emphysema, but harbouring various degrees of microscopical emphysematous lesions, was analysed. In addition, the fibrillin-regulated growth factor TGF-beta was studied. Electron microscopy and biochemical analysis of desmosine (a marker for elastin) were also performed. Results were compared with lung tissue derived from patients with clinical emphysema. Domain-specific antibodies recognizing the C-terminal, N-terminal, and middle part of fibrillin-1 showed aberrant staining patterns associated with increasing degrees of microscopical emphysema. Staining for elastin, emilin-1, and fibulin-2 was, however, not aberrant. TGF-beta staining was markedly increased. On the electron microscopic, but not light microscopical, level, initial elastic fibre degradation was noticed in specimens with microscopical emphysema. Lung specimens from patients with clinical emphysema also displayed fragmented fibrillin-1 staining and, in addition, displayed extensive degradation of the elastic fibre. The results suggest that fibrillin-1 anomalies and TGF-beta overexpression are associated with initial events occurring during the emphysematous process. Based on these and other data, a mechanism for emphysematogenesis is proposed.