[Congenital muscular dystrophies in children]. / Distrofias musculares congénitas en el niño.

From the clinical and genetic point of view, congenital muscular dystrophies (CMD) are a heterogenic group of diseases within neuromuscular pathologies. The best known forms are: merosin deficiency CMD, collagen VI deficiency CMD, LMNA-related CMD, selenoprotein-related CMD (SEPN1) and alpha-dystroglycan-related CMD. They present with a broad spectrum of clinical phenotypes. Most of them are transmitted by recessive autosomal inheritance. The initial manifestations very often begin in infancy or in the neonatal period. There are clinical suspicions of the existence of hypotonia and paresis, and they are characterised by a dystrophic pattern in the muscular biopsy (muscle replaced by fibroadipose tissue, with necrosis and cell regeneration). Advances in the understanding of the molecular pathogenesis of CMD have made it possible to make further progress in the classification of the different subtypes. The aim of this review is to comment on the advances made in recent years as regards the classification of CMD in terms of genetics, the proteins involved and their clinical presentation.

TITLE: Distrofias musculares congenitas en el niño.Las distrofias musculares congenitas (DMC) representan desde el punto de vista clinico y genetico un grupo heterogeneo de enfermedades dentro de la patologia neuromuscular. Las formas mas conocidas son: DMC por deficit de merosina, DMC por deficit de colageno VI, DMC relacionada con LMNA, DMC relacionada con selenoproteina (SEPN1) y las DMC vinculadas a los alfa-distroglicanos. Se presentan con un amplio espectro de fenotipos clinicos. En su mayoria son de herencia autosomica recesiva. Con mucha frecuencia las manifestaciones iniciales comienzan en la infancia o en el periodo neonatal. Se sospechan clinicamente por la existencia de hipotonia y paresia y se caracterizan por la existencia de un patron distrofico en la biopsia muscular (sustitucion de musculo por tejido fibroadiposo, con necrosis y regeneracion celular). Avances en la comprension de la patogenesis molecular de las DMC han permitido profundizar en la clasificacion de los diferentes subtipos. El objetivo de esta revision es comentar los avances de los ultimos años en cuanto a la clasificacion de las DMC en relacion a la genetica, las proteinas involucradas y su presentacion clinica.

[Analysis of the interference pattern in patients with muscular dystrophy]. / Análisis del patrón de interferencia en pacientes con distrofia muscular.

INTRODUCTION: The conventional electromyography contribute to differentiation of myopatic and neuropatic patterns in neuromuscular disorders, however, the classical patterns related to myopatic changes can result in neurogenic components, this confusion could be due to denervation and reinervation changes involved at the different stages of those diseases. OBJECTIVE: Demonstrate the importance of quantitative electromyographic techniques, as the interference pattern analysis (IPA), for a better differentiation of muscular dystrophies. PATIENTS AND METHODS: IPA was done in 95 patients with 3 different muscular dystrophies: 52 Duchenne muscular dystrophy (DMD), 33 limb girdle muscular dystrophy (LGMD) and 10 myotonic muscular dystrophy (MD) individuals and in a control group of 25 individuals. The left braquial biceps and right anterior tibial muscles were evaluated; the variables analyzed were turns/seconds (t/s), amplitude/turns (a/t), ratio turns/amplitude mean and root squared mean (RSM). RESULTS: We found statistical significant differences in all variables in both braquial biceps and right anterior tibial muscles (p < 0.05) in DMD patients. In LGMD we only found differences in a/t in braquial biceps. In MD the differences were observed in a/t, ratio and RSM in braquial biceps, and in a/t (in anterior tibial). CONCLUSIONS: All the DMD patients show differences in IPA values in relation to control group, MD only in biceps, However there were not important changes in LGMD probably because the diversity and lack of homogeneity in affected muscles in this group.

The 10 autosomal recessive limb-girdle muscular dystrophies.

Fifteen forms of limb-girdle muscular dystrophies (5 autosomal dominant and 10 autosomal recessive) have already been found. The 10 genes responsible for the autosomal recessive forms, which account for more than 90% of the cases, had their product identified. This review will focus on the most recent data on autosomal recessive-limb-girdle muscular dystrophy and on our own experience of more than 300 patients studied from 120 families who were classified (based on DNA, linkage and muscle protein analysis) in eight different forms of autosomal recessive-limb-girdle muscular dystrophy. Genotype-phenotype correlations in this highly heterogeneous group confirm that patients with mutations in different genes may be clinically indistinguishable. On the other hand, for most forms of autosomal recessive-limb-girdle muscular dystrophy a discordant phenotype, ranging from a relatively severe course to mildly affected or asymptomatic carriers may be seen in patients carrying the same mutation even within the same family. A gender difference in the severity of the phenotype might exist for some forms of autosomal recessive-limb-girdle muscular dystrophy, such as calpainopathy and telethoninopathy but not for others, such as dysferlinopathies or sarcoglycanopathies. Understanding similarities in patients affected by mutations in different genes, differences in patients carrying the same mutations or why some muscles are affected while others are spared remains a major challenge. It will depend on future knowledge of gene expression, gene and protein interactions and on identifying modifying genes and other factors underlying clinical variability.

myotilin Mutation found in second pedigree with LGMD1A.

Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant form of muscular dystrophy characterized by adult onset of proximal weakness progressing to distal muscle weakness. We have reported elsewhere a mutation in the myotilin gene in a large, North American family of German descent. Here, we report the mutation screening of an additional 86 families with a variety of neuromuscular pathologies. We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F). This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere. Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin. The identification of two independent pedigrees with the same disease, each bearing a different mutation in the same gene, has long been the gold standard for establishing a causal relationship between defects in a gene and the resultant disease. As a description of the second known pedigree with LGMD1A, this finding constitutes that gold standard of proof that mutations in the myotilin gene cause LGMD1A.

Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.

Walker-warburg syndrome: reports of two cases

The purpose of this study is to describe two infants that were diagnosed with Walker-Warburg syndrome (WWS), a rare form of congenital muscular dystrophy (CMD). They were studied in their clinical, laboratory, and neuroradiologic features. The index case had a brain magnetic resonance imaging (MRI) and the second patient had a head computerized tomography (CT). In addition, a literature review was performed to describe the main forms of CMD. The index case fulfilled all criteria for WWS. A brain MRI performed at age 4 months served to corroborate the clinical diagnosis, showing severe hydrocephalus, type II lissencephaly, cerebellar vermian aplasia, and a hypoplastic brain stem. The authors were able to establish a retrospective diagnosis of WWS in the index cases's older sister, based upon her clinical picture and head CT report.

Seven autosomal recessive limb-girdle muscular dystrophies in the Brazilian population: from LGMD2A to LGMD2G.

The autosomal recessive limb-girdle muscular dystrophies (AR-LGMDs) are a heterogeneous group of disorders of progressive weakness of the pelvic and shoulder girdle musculature. The clinical course is characterized by great variability, ranging from severe forms with onset in the first decade and rapid progression resembling clinically Xp21 Duchenne muscular dystrophy (DMD) to milder forms with later onset and slower course. Eight genes are mapped for the AR-LGMDs; they are: LGMD2A (CAPN3) at 15q, LGMD2B (dysferlin) at 2p, LGMD2C (gamma-SG) at 13q, LGMD2D (alpha-SG) at 17q, LGMD2E (beta-SG) at 4q, LGMD2F (6-SG) at 5q, LGMD2G at 17q, and more recently LGMD2H at 9q. The LGMD2F (delta-SG) and LGMD2G genes were mapped in Brazilian AR-LGMD families. Linkage analysis in two unlinked families excluded the eight AR-LGMD genes, indicating that there is at least one more gene responsible for AR-LGMD. We have analyzed 140 patients (from 40 families) affected with one of seven autosomal recessive LGMD loci, that is, from LGMD2A to LGMD2G. The main observations were: 1) all LGMD2E and LGMD2F patients had a severe condition, but considerable inter- and intra-familial clinical variability was observed among patients from all other groups; 2) serum CK activities showed the highest values in LGMD2D (alpha-SG) patients among sarcoglycanopathies and LGMD2B (dysferlin) patients among nonsarcoglycanopathies; 3) comparison between LGMD2A (CAPN3) and LGMD2B (dysferlin) showed that the first have on average a more severe course and have calf hypertrophy more frequently (86% versus 13%); and 4) inability to walk on toes was observed in approximately 70% of LGMD2B patients.

Walker-Warburg syndrome. Report of two cases.

The purpose of this study is to describe two infants that were diagnosed with Walker-Warburg syndrome (WWS), a rare form of congenital muscular dystrophy (CMD). They were studied in their clinical, laboratory, and neuroradiologic features. The index case had a brain magnetic resonance imaging (MRI) and the second patient had a head computerized tomography (CT). In addition, a literature review was performed to describe the main forms of CMD. The index case fulfilled all criteria for WWS. A brain MRI performed at age 4 months served to corroborate the clinical diagnosis, showing severe hydrocephalus, type II lissencephaly, cerebellar vermian aplasia, and a hypoplastic brain stem. The authors were able to establish a retrospective diagnosis of WWS in the index case's older sister, based upon her clinical picture and head CT report.

Deficiency of alpha-actinin-3 (ACTN3) occurs in different forms of muscular dystrophy.

The alpha-actinins belong to a superfamily of cytoskeletal proteins, and their role in human genetic diseases is still unclear. Therefore, they could be good candidates for muscular dystrophies of unknown etiology. We have analyzed alpha-actinin-3 (ACTN3) in muscle biopsies from a total of 54 patients. A complete deficiency was found in 9 patients: 2/12 with classical merosin-positive congenital MD (CMD), 1/12 with Severe Childhood Autosomal Recessive MD (DLMD), but with a positive IF pattern for the proteins of the sarcoglycan complex: 3/14 with mild limb-girdie MD (1LGMD2A and 2 yet unclassified), 1/10 with sarcoglycanopathies (LGMD2C), and 2/6 with Xp21 Duchenne MD (DMD). Patients within the same family, and with the same disease (DMD, LGMD2A, LGMD2C), were discordant for ACTN3 deficiency. Additionally, no correlation was found with the degree of muscle degeneration, nor with the clinical course. One ACTN3-deficient CMD patient showed no mRNA expression for the muscle ACTN3 gene, but the other ACTN3-deficient patients with different forms of muscular dystrophy showed very low or no mRNA expression as well. These results show that the deficiency of ACTN3 is a secondary effect in these dystrophies.

Linkage analysis in autosomal recessive limb-girdle muscular dystrophy (AR LGMD) maps a sixth form to 5q33-34 (LGMD2F) and indicates that there is at least one more subtype of AR LGMD.

Limb-girdle muscular dystrophies (LGMDs) represent a clinically heterogeneous group of genetic diseases characterised by progressive weakness of the pelvic and shoulder girdle muscles. An autosomal dominant form (LGMD1A) has been mapped at 5q22.3-31.3, while five genes responsible for the autosomal recessive forms were mapped respectively at: 15q15.1 (LGMD2A), 2p12-p16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D) and 4q12 (LGMD2E). Among 17 autosomal recessive (AR) LGMD Brazilian families with at least three affected sibs, we were able to exclude four families (one mild and three severe) from all these five known loci as well as from the dystroglycan and syntrophin genes. Therefore, we have performed a genome-wide search in two of the severely affected families, which are alpha-sarcoglycan negative. We demonstrate linkage of these two Duchenne muscular dystrophy-like families to 5q33-34, and propose to classify them as LGMD2F. In addition, linkage analysis in the other two genealogies that are alpha-sarcoglycan positive suggests that there is at least one other gene which causes AR LGMD.

Main clinical features of the three mapped autosomal recessive limb-girdle muscular dystrophies and estimated proportion of each form in 13 Brazilian families.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a group of muscle diseases with a wide spectrum of clinical signs, varying from very severe to mild. Four different loci that when mutated cause the AR LGMD phenotype have been mapped or cloned or both: in two of them the linked families seem to have a relatively mild phenotype (LGMD2a and LGMD2b), in the third one the reported linked families show a more severe clinical course (LGMD2c), while mutations in the fourth locus may cause severe or mild phenotypes (LGMD2d). The relative proportion of each of these genetic forms among the LGMD families and whether there are other genes that when mutated cause this phenotype is unknown. The closest available informative markers for each of the mapped AR LGMD genes have been tested in 13 Brazilian families with at least three affected patients. The findings from the present report confirm non-allelic heterogeneity for LGMD and suggest that in our population about 33% of the LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed.

Distrofia muscular de duchenne: A propósito de un caso

Se revisa bibliográficamente y se reporta un caso de Distrofia muscular de Duchenne, por consideralo una patología qu eno es frecuente pero tampoco rara, a pesar de que en nuyestro país no se sabe realmente cual es su incidencia. Se trata de un paciente de sexo masculino de 12 años de edad quien ingreso al sevicio de pediatría del Hospital Enrique Garcés en el mes de junio de 1995, que consulto por disbasia y dolor de columna lumbar. Se señala que es una enfermedad recesiva de la niñez ligada al cromosoma X, y de que afecta a uno de cas 3300 varones que nacen vivos: la anomalía genética se localiza en el cromosoma Xp21...

A common missense mutation in the adhalin gene in three unrelated Brazilian families with a relatively mild form of autosomal recessive limb-girdle muscular dystrophy.

Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a heterogeneous group of diseases with a wide spectrum of clinical variability, classified phenotypically into two main groups, the most severe forms (Duchenne-like muscular dystrophy, DLMD, or severe childhood autosomal recessive muscular dystrophy, SCARMD) and the milder forms. Four genes causing AR LGMD have been mapped: the 15q (LGMD2a), the 2p (LGMD2b), the 13q locus (LGMD2c) and the adhalin gene on chromosome 17q (LGMD2d). In the present report we have performed linkage analysis with 17q markers in three mild AR LGMD and in four DLMD families with adhalin deficiency and unlinked to 2p, 15q or 13q genes. Linkage was observed only among the mild cases. Patients from these three 17q-linked families showed near or total deficiency of adhalin in muscle biopsies. An identical missense mutation was identified in all three 17q-linked unrelated families. These results indicate that AR LGMD with a mild phenotype is caused by mutations in the adhalin gene. In addition, they demonstrate that there is at least one other locus for DLMD associated with adhalin deficiency.

Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region.

The mild autosomal recessive limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of muscle diseases. The first gene to be mapped and associated with this phenotype was a locus on 15q based on linkage analysis in families from a French geographic isolate. These results have been confirmed in other populations, but it was shown that there is genetic heterogeneity for this form of LGMD. Recently, a second locus has been mapped to chromosome 2p. The confirmation of the mapping of this second locus in LGMD families from different populations is of utmost importance for the positional cloning of this gene (HGMW-approved symbol LGMD2B). In this publication, haplotypes generated from five chromosome 2 markers from all of the known large families linked to chromosome 2p are reported together with the recombinants that show the current most likely location of the LGMD 2B gene.

Why is the reproductive performance lower in Becker (BMD) as compared to limb girdle (LGMD) muscular dystrophy male patients?

We had previously reported that patients affected with BMD have a significantly reduced reproductive performance (f = 0.12) as compared to male LGMD patients of similar age and physical impairment (f = 0.98). In the present study parameters such as the socio-economic level, as well as psychosocial, intellectual, and psychiatric functionings could not explain the low fitness of BMD patients. The effect of genetic counseling, a greater difficulty in coping with the disease, and relating to women and/or a potential malfunction of reproductive physiology are discussed as possible causes.

Distrofia muscular de duchenne. Estudio de corte de pacientes del servicio de rehabilitación del Hospital de niños Baca Ortíz (HBO)

En el presente trabajo se realiza una revisión retrospectiva de la Distrofia Muscular de Duchenne, con pacientes tratados en la consulta externa del servicio de rehabilitación del Hospital de Niños Baca Ortíz, durante un período de 18 años- comprendido entre los años 1975 y 1993- tiempo en el cual se diagnostica a 18 pacientes con esta enfermedad, de un total de 40 nipos con distrofia muscular progresiva, equivalente al 0.9 por ciento de todos los niños tratados, en rehabilitación, en la época señalada. Se analizan varios parámetros como: sexo, lugar de procedencia, motivo de consulta (lo más consultado constituyó la dificultad para deambular -en un 56 por ciento de los pacientes-) La característica clínica (la más frecuente fue el aumento de volumen de gemelos en un 100 por ciento y en igual porcentaje la disminución de la potencia muscular, especialmente de miembros inferiores). El diagnóstico: se basó en el examen clínico ( en el 100 por ciento) y se confirmó en algunos pacientes con valores de CPK, aldolasa, electromiograma biopsia. El tratamiento en un 61 por ciento fue netamente fisiátrico, 39 por ciento acudieron en forma irregular, 32 por ciento en forma regular. En la actualidad, se logró encontrar a 11 por ciento de los pacientes, los mismos que se hallan confinados a silla de ruedas, pero sin mayores complicaciones en su estado general de salud...

Distrofia muscular estudio genético clínico de 4 pacientes

En el presente estudio se presenta un grupo de pacientes afectados por la devastadora DISTROFIA MUSCULAR, enfermedad determinada geneticamente y caracterizada por una paulatina degeneración de la fibra muscular esquelética sin presentar alteraciones en el sistema nervioso central o nervios periféricos; los probandos corresponden respectivamente a las 4 principales formas de distrofia, que caracterizan a los distintos modos de transmisión hereditaria: de Duchenne y Becker como ligados al cromosoma X, Fascio escápulo humeral como autosonancia dominante y de las cinturas como autosómica recesiva. El estudio comprende historia clínica, examen físico, hallazgos clínicos, exámenes de laboratorio y aspectos genéticos donde, a partir de la discusión con la literatura existente se incluye la conducta tomada en cada caso.

[Duchenne and Becker muscular dystrophy in Chile]. / Distrofia muscular de Duchenne y Becker en Chile.

Duchenne muscular dystrophy is one of the best known forms of muscular dystrophy. The incidence in different countries varies from 130 to 390 per million male live births. Becker variety may be considered a mild form of Duchenne dystrophy, with an incidence 10 times lower. A sex linked recessive inheritance is involved in both forms, the affected gene is placed at locus X21. The incidence of both forms in Chile is similar to that reported worldwide, and has been increasing since 1950. Increased CK and LDH levels are confirmed in patients, and overall, they are also higher in female carriers. However only 26% of carriers have increased CK levels and 21% increased LDH levels, compared to normal subjects. Electromyograms show myopathic characteristics in all carrier women. The scope of a prospective clinical, genetic and epidemiologic study currently underway is discussed.

Exclusion of the gene responsible for facioscapulohumeral muscular dystrophy (FSH) at 6q23-q27.

Facioscapulohumeral muscular dystrophy (FSH) is an autosomal dominant condition with variable expressivity and age dependent penetrance. Linkage studies still did not exclude regions 11, 2q, 6q, 7p, 8p, 10q, 12p and 14p as possible locations for the FSH gene. In the present study we have analysed 80 individuals (36 patients and 44 normals) belonging to 8 unrelated Brazilian families with 3 probes located on the long arm of chromosome 6:MHB(6q22-q23), ESR(6q24-q27) and TCP1(6q25-q27). Results of linkage analysis suggest that the gene responsible for FSH muscular dystrophy is not in the region 6q23-q27.