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PubMedDate not supplied

[Prenatal diagnosis of spinal muscular atrophy (SMA) -- indications, restrictions, interpretation of results].

INTRODUCTION: Proximal spinal muscular atrophy of childhood and adolescence (SMA) is a genetic autosomal recessive disease. Caused in 96.5% by deletion in the SMN1 gene. Owing to the homogeneity of the molecular defect. Secondary prophylaxis can readily be offered to families at risk of SMA. PATIENTS: Prenatal diagnosis of SMA was carried out in a group of 50 families. Which were divided into two subgroups: with high and relatively low genetic risk of SMA. In all, 55 prenatal tests were performed in the period 1998-2003. RESULTS: In the first group including 45 families at high genetic risk, 9 of the 50 tests were positive (18%). The diagnosis of SMA was tentative in 7 cases from this group and it was based only on the clinical picture (the affected children are not alive, therefore DNA samples are not available). Prenatal examination in 1 of these 7 families showed the SMA genotype. In the second subgroup including 5 families with relatively low genetic risk of SMA in none of the studies was there a biallelic deletion of exon 7 in the SMNI gene. Mainly parents of children with a severe form of SMA and having no healthy offspring asked for prenatal examination (73% of the families). CONCLUSIONS: Prenatal diagnosis could be offered to families even if the diagnosis of SMA was not genetically verified. The negative result should he then interpreted individually. Until the carrier test will not he introduced to routine procedures. prenatal diagnosis can be also offered to families at relatively low risk of SMA.

Adult↗
PubMed1993

Dominant inherited distal spinal muscular atrophy with atrophic and hypertrophic calves.

The clinical, electrophysiological, radiological and morphological data of 3 members of a family with autosomal dominant distal spinal muscular atrophy (DSMA) are reported. One patient has the clinical picture of peroneal muscular atrophy with atrophic calves. His father and sister suffer from cramps and fasciculations of the calves with true neurogenic muscular hypertrophy of the calves. The electromyogram and the biopsy specimen are conclusive for motor neuron disease in this family. These findings suggest that the DSMA variant as described by D'Alessandro et al. (Arch. Neurol. (1982) 39: 657-660), concerning benign spinal muscular atrophy with hypertrophy of the calves, has to be considered as a mild manifestation of DSMA.

Adult↗
PubMed1976

Genetic investigations on chronic forms of infantile and juvenile spinal muscular atrophy.

A material of 247 cases selected from 260 cases of spinal muscular atrophy in the Warsaw Department of Neurology in 1960-1974 was analyzed. The size of sibships was established and calculations were made of the mean distribution of the age at onset, also according to sex, for the different clinical forms, genetical proportions by the method of siblings and of probands, and coefficient of sib-sib correlation for the material as a whole and separately for males, females and male-female pairs. The analysis shows the course of the disease to differ between the sexes and to be mild in males more often than in females, as is particularly noticeable in the higher age groups. Cases of Kugelberg-Welander's disease are predominantly male. The hypothesis is advanced that a proportion of male patients have a sex-linked modifying gene of a fairly high frequency (possibly of the range of 1 in 5 males, and 1 in 25, in the homozygous state, in females). Although it would not disprove conclusively the nosological distinctness of different forms of infantile and juvenile spinal muscular atrophy, the existence of the modifying gene, if proved, would tend rather to add to the likelihood of their constituting a single recessive autosomal disease.

Adolescent↗
PubMed2002

Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.

Animals↗
PubMed2002

Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is one of a group of progressive neurodegenerative diseases resulting from a polyglutamine repeat expansion. In SBMA the polymorphic trinucleotide CAG repeat in exon 1 of the androgen receptor (AR) gene is increased, resulting in expansion of a polyglutamine tract. Patient autopsy material reveals neuronal intranuclear inclusions (NII) in affected regions that contain only amino-terminal epitopes of the AR. Cell models have previously been unable to produce intranuclear inclusions containing only a portion of the AR. We report here the creation of an inducible cell model of SBMA that reproduces this important characteristic of disease pathology. PC12 cells expressing highly expanded AR form ubiquitinated intranuclear inclusions containing amino-terminal epitopes of the AR as well as heat shock proteins. Inclusions appear as distinct granular electron-dense structures in the nucleus by immunoelectron microscopy. Dihydrotestosterone treatment of mutant AR-expressing cells results in increased inclusion load. This model mimics the formation of ubiquitinated intranuclear inclusions containing the amino-terminal portion of AR observed in patient tissue and reveals a role for ligand in the pathogenesis of SBMA.

Animals↗
PubMed2002

Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is one of a growing number of neurodegenerative diseases caused by a polyglutamine-encoding CAG trinucleotide repeat expansion, and is caused by an expansion within exon 1 of the androgen receptor (AR) gene. The family of polyglutamine diseases is characterized by the presence of ubiquitinated, intranuclear inclusions associated with molecular chaperones and 26S proteasome components, although the role of these inclusions in the pathogenesis of polyglutamine diseases remains unclear. The over-expression of molecular chaperones of the Hsp70 and Hsp40 families has been shown to modulate inclusion frequency and cellular toxicity. We developed a cell culture system which enables the quantitative analysis of the effects of molecular chaperones on the biochemical properties of an expanded repeat AR. Using this approach, we demonstrate that Hsp70 and its co-chaperone Hsp40 not only increase expanded repeat AR solubility, but function to enhance the degradation of expanded repeat AR through the proteasome. Furthermore, our studies indicate that these molecular chaperones significantly decrease the half-life of an expanded repeat AR. Molecular chaperone enhancement of protein degradation points to the modulation of molecular chaperones as a potential therapeutic target for polyglutamine diseases.

Acetylcysteine↗
PubMed1998

Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the androgen receptor (AR). We have studied the mutant AR in an in vitro system, and find both aggregation and proteolytic processing of the AR protein to occur in a polyglutamine repeat length-dependent manner. In addition, we find the aberrant metabolism of expanded repeat AR to be coupled to cellular toxicity, indicating a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA.

Animals↗
PubMed2005

A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuroendocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Reported here is a detailed phenotypic study in a series of seven patients from the same family with SBMA with 50 to 54 CAG repeats, juvenile onset (mean age at onset 13 years [8 to 15 years]), and rapid progression leading to compromised ambulation in the mid-20s.

Adolescent↗
PubMed1999

[Transcriptional regulation and subcellular localization of mutant androgen receptor in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an adult form of motor neuronopathy with X-linked recessive hereditary trait, whose genetic mutation is an expansion of CAG repeats in the androgen receptor(AR) gene. The effect of the expansion of the polyglutamine stretch in AR protein has been investigated in several lines of experiments. The binding ability of androgen to AR is similar to control, but AR binding affinity to androgen responsive element(ARE) is increased in mutant AR, and AR-induced transcriptional activation decreases with increasing glutamine repeats. The subcellular localization of mutant AR may be variable among the tissues, but intranuclear inclusion of mutant AR occurs ubiquitously in neural and non-neural tissues. Therefore the expansion in the polyglutamine stretch may induce some pathological aberrations in transcriptional regulation and translocation of AR in SBMA.

Adult↗
PubMed1999

[In vitro aggregation and cellular toxicity of mutant androgen receptor protein in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor caused by expansion of a polyglutamine repeat within the androgen receptor(AR). We have studied the mutant AR in an in vitro system, and find aggregation of the AR protein to occur in a polyglutamine repeat length-dependent manner and the cellular toxicity to be coupled to aggregation. In addition we find intranuclear inclusions in nonneural tissues as well as affected neural tissues. These results indicate that the polyglutamine repeat length-dependent aggregation may be a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA. However, there is a recent report which suggests that inclusions did not correlate with cell death. Thus the mechanism of toxic gain of function remains to be elucidated.

Cell Death↗
PubMed1988

[Spinal muscular atrophy in adults].

Clinico-electromyographic characterization of 20 patients with different forms of the spinal muscular atrophy (bulbospinal in 8 patients, chronic proximal in 5, distal in 7) is reported. The patients displayed the characteristic clinical signs and neuronal changes in EMG. The latter data are specified for each form. The authors infer that the spinal muscular atrophy in adults, children and adolescents fall into one group, though differing in the onset age, type of inheritance, clinical features, severity and prognosis.

Adult↗
PubMed1999

Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype.

The classical form of severe spinal muscular atrophy (SMA type 1; Werdnig-Hoffmann disease) has a very consistent clinical phenotype that is well recognized by paediatricians. It usually presents at birth or within the first few months of life. There is general hypotonia, with axial and limb weakness; the legs are affected more than the arms and proximal muscles more than distal, leaving residual spontaneous activity in the feet and in the forearms and hands. Facial muscles are spared so that the infant usually has a bright normal expression. The intercostal muscles are always affected, whereas the diaphragm is spared, allowing adequate spontaneous respiratory activity until the infants are precipitated into respiratory failure by an incidental respiratory infection, or aspiration. With rare exception they die by 2 years of age with a median around 7 months and with about 80% of the children dying by the time they are 1 year old. There is a consistent homozygous deletion in exons 7 and 8 of the telomeric copy of the survival motor neuron (SMN) gene. In the current issue of the journal, MacLeod and her colleagues have documented five cases of more severe spinal muscular atrophy, with a history of diminished fetal movements in utero and presenting at birth with asphyxia and severe weakness.

Cell Survival↗
PubMed1987

Cardiorespiratory responses to exercise in patients with spinal muscular atrophy and limb-girdle dystrophy.

Maximum oxygen consumption, maximum heart rate and maximum ventilation during cycle ergometer exercise were studied in individuals with spinal muscular atrophy (N = 8) and limb-girdle dystrophy (N = 8). The limiting factors in aerobic power may be related to loss of functional muscular mass rather than to changes in the oxygen transport system. There was no correlation between VO2 max values and muscle strength as determined by a manual test of the affected muscles recruited for bicycle exercise. The results, therefore, do not support the possibility of a correlation between these indices previously proposed on the basis of clinical evidence.

Adolescent↗
PubMedDate not supplied

[F-wave studies in spinal muscular atrophy].

For checking the hypothesis on increased excitability of the spinal motor neurons in patients with spinal muscular atrophy the F wave was analysed in 12 patients. The hypothesis has been confirmed, but increased excitability of motor neurons is not equally pronounced in all motor nuclei of the spine.

Adolescent↗
PubMed1994

Autosomal recessive proximal spinal muscular atrophy in 101 sibs out of 48 families: clinical picture, influence of gender, and genetic implications.

We analysed the clinical picture of 101 sibs (43 sib pairs, 5 triplets) with autosomal recessive proximal spinal muscular atrophy (SMA). Linkage data of 20 sibships, which were available for analysis, were in agreement with chromosome 5q linkage. The patients were classified according to the motor development into SMA I (never sat), SMA II (sitting without support), and SMA III (walking without aids). Three sibs with adult onset (> 30 years = SMA IV) were discussed as a separate entity. Age-of-onset of the 101 patients showed a wide spectrum (prenatal to 47 years). Among sib pairs with SMA I and SMA II the ages-of-onset appeared to be very similar except of one atypically discordant sib pair. With regard to SMA III, 3 out of 13 sibships (23%) showed a marked variation in age-of-onset ranging from 5-15 years within a family. Concerning acquired motor development (ability to sit and walk), 7 sibships (15%) belonged to different SMA types. Ages of death in 29 sib pairs in whom at least one sib had died before the age of 20 years were strikingly discordant. Neither the degree of disability nor the respiratory deficits are reliable predictors of life expectancy. Although a predominance of males can be observed, no significant effect of gender has been established in familial cases. The existence of multiple allelism seems to be the most suitable explanation for the high interfamilial variability considering the clinical concordance in most affected sib pairs.

Adolescent↗
PubMed2004

[Neuromuscular diseases (NME). I. Spinal muscular atrophy, peripheral nerve diseases, congenital myasthenia gravis].

Among the group of clinically and genetically heterogeneous spinal muscular atrophies(SMA), the autosomal recessive proximal types I-III are the most frequent. They are caused by mutations of the telomeric copy of the survival motor neuron gene (SMN1) on chromosome sq while loss of the centromeric copy (SMN2) does not lead to SMA. The conservation of exon 7 in the SMN2 copy seems to be crucial for possible causal therapy options. The genetic defect is also known for spinal muscular atrophy with respiratory distress. Hereditary polyneuropathies are caused by mutations in several genes on different chromosomes. Genetic and phenotypic heterogeneity must be considered. Data on clinical symptoms, inheritance, and neurophysiology are obligatory for the most effective molecular analysis. Hereditary congenital myasthenic syndromes are clinically, genetically, and pathogenetically heterogeneous. The diagnostic significance of molecular genetic analyses is still increasing. Therapeutic options include oral medication and assisted ventilation as needed.

Humans↗