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PubMed1998

The mutation properties of spinal and bulbar muscular atrophy disease alleles.

We studied the gene for the trinucleotide repeat disorder X-linked spinal and bulbar muscular atrophy (SBMA) to quantify the spectrum of mutations and gain insight into genetic anticipation. This analysis was performed using single sperm typing from an affected individual. This method allows the quantification of large numbers of meioses and therefore provides accurate information about genetic instability of the CAG repeat expansions which cause SBMA. Among 198 X chromosome-containing sperm cells, 20% had a CAG repeat number equal to the donor's somatic DNA of 49 CAG repeats, 56% were expansions, and 24% contractions. Most of the expansions (84%) and contractions (94%) were between 1 and 3 CAG repeats. These results are consistent with those obtained from one previously studied SBMA patient and reveal greater CAG repeat instability in sperm than in somatic tissue. Our results indicate that in SBMA, in contrast to sperm typing analysis of Huntington's disease, there is relative stability of the CAG repeat number during paternal transmissions and that the spectrum of mutations is narrow. These results are in agreement with the limited available clinical data and suggest that anticipation may not be a significant feature of this disease.

Adult↗
PubMed2004

Muscle MRI findings of X-linked spinal and bulbar muscular atrophy.

We report here muscle MRI findings of the lower limb in X-linked spinal and bulbar muscular atrophy (SBMA). T1-weighted imaging of muscle MRI disclosed that the thigh muscles, including the semimembranosus, biceps femoris longus and the vastus lateralis muscles, showed high intensity signals with atrophy. Contrarily, the sartorius, gracilis and rectus femoris muscles were comparably preserved. Not only the thigh muscles, but also the calf muscles including the gastrocnemius medialis and lateralis, and soleus muscles showed high intensity signals. In amyotrophic lateral sclerosis (ALS), the leg muscles are generally atrophic, but the selective pattern of fatty degeneration, seen in SBMA was not observed. Muscle MRI is a useful method of estimating the distribution and severity of SBMA in affected muscles.

Disease Progression↗
PubMed2005

X-linked spinal and bulbar muscular atrophy (Kennedy's disease) with long-term electrophysiological evaluation: case report.

X-linked spinal and bulbar muscular atrophy or Kennedy's disease is an adult-onset motor neuronopathy caused by a CAG repeat expansion within the first exon of an androgen receptor gene. We report the case of a 66-year-old man, previously diagnosed with motor neuron disease (MND), who presented acute and reversible left vocal fold (dysphonia) and pharyngeal paresis, followed by a slowly progressive weakness and also bouts of weakness, wasting and fasciculation on tongue, masseter, face, pharyngeal, and some proximal more than distal upper limb muscles, associated to bilateral hand tremor and mild gynecomastia. There were 5 electroneuromyography exams between 1989 and 2003 that revealed chronic reinnervation, some fasciculations (less than clinically observed) and rare fibrillation potentials, and slowly progressive sensory nerve action potentials (SNAP) abnormality, leading to absent/low amplitude potentials. PCR techniques of DNA analysis showed an abnormal number of CAG repeats, found to be 44 (normal 11-34). Our case revealed an acute and asymmetric clinical presentation related to bulbar motoneurons; low amplitude/absent SNAP with mild asymmetry; a sub-clinical or subtle involvement of proximal/distal muscles of both upper and lower limbs; and a probable evolution with bouts of acute dennervation, followed by an efficient reinnervation.

Aged↗
PubMed1981

Investigations on enzyme activity in the serum and CSF of patients with neuromuscular diseases.

The CPK, aldolase, GOT, GPT, and LDH concentrations in the serum and lumbar CSF of 80 patients with neuromuscular diseases and 20 controls were measured. The value obtained in serum was essentially in agreement with the data in the literature. This is the first publications reporting on regular CSF enzyme examinations in different neuromuscular disorders, particularly the results obtained in neurogenic muscular atrophies, which have certain characteristic features. The LDH activity in CSF was decreased in peroneal muscular atrophy, the GPT concentration in CSF was elevated in spinal muscular atrophy, and the mean activity of CSF aldolase was increased in amyotrophic lateral sclerosis. The simultaneous determination of enzymes in serum and CSF can provide valuable information in the research of certain details of pathomechanisms and thus lead to further improvement of diagnosis.

Alanine Transaminase↗
PubMed2002

Abnormal nerve conduction velocity as a marker of immaturity in childhood muscle spinal atrophy.

Motor conduction velocity (CV) was tested in 117 infants and children with proximal spinal muscular atrophy (SMA), aged 1-53 months, and in 99 age-adjusted healthy controls. The children were classified into SMA forms 1 and 2 according to SMA International Consortium Criteria. In all children CV was tested in four nerves and the following parameters were taken into account: distal latency, conduction velocity, amplitude of muscle response. The electromyography of muscles revealed neurogenic changes. In all cases of severe form 1 motor CV was markedly slowed, with significantly prolonged distal latency and reduced amplitude of M response. In surviving children CV, although increasing with age, was always below the values of normal age-adjusted children. The slowing was particularly pronounced in the femoral nerve. In SMA2 children the values of all tested parameters were closer to the values of age-adjusted healthy children, nevertheless they were always below the edge of normal values, also the rate of maturation was much slower than in normal children. Sensory CV was normal in all tested groups. The findings are suggestive of delayed nerve maturation in childhood SMA.

Child, Preschool↗
PubMed2001

Death of motoneurons induced by trophic deprivation or by excitotoxicity is not prevented by overexpression of SMN.

The telomeric copy of the survival motor neuron gene (SMN1) is deleted or mutated in all spinal muscular atrophy (SMA) patients and these patients present mainly a loss in spinal motoneurons. Although studies performed in HeLa cells suggest that SMN may be involved in the biogenesis and possibly in recycling of spliceosomal small nuclear ribonucleoproteins (snRNPs), no link has been established between this function and the consequence of the absence of SMN in the specific loss of motoneurons. We attempted to answer the question of whether SMN plays a direct role in motoneuron survival by transducing cultured motoneurons with lentiviral vectors coding either for an antisense Smn mRNA or for full-length or truncated forms of SMN. We studied their effect on survival under different anti- or proapoptotic culture conditions. Our results show that increased levels of SMN are unable to protect motoneurons from death induced by trophic deprivation or by excitotoxicity. These results suggest that SMN is not a survival factor per se for motoneurons. In addition, overexpression of a truncated form of SMN shown to induce a modified subcellular localization and to exert a dominant-negative effect on snRNP biogenesis and RNA splicing in HeLa cells was ineffective in modifying both localization and survival in motoneurons.

Animals↗
PubMed1991

Recent advances in neuromuscular disorders in childhood.

This paper reviews recent advances in the molecular genetics of the muscular dystrophies and their implications for potential treatment. A brief review is also included of recent advances in locating the gene for the spinal muscular atrophies.

Animals↗
PubMed1996

Large scale deletions of the 5q13 region are specific to Werdnig-Hoffmann disease.

Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann disease), type II (intermediate form), and type III (Kugelberg-Welander disease). Recently, two genes have been found to be associated with SMA. The survival motor neurone gene (SMN) is an SMA determining gene as it is absent in 98.6% of patients. A second gene, XS2G3, or the highly homologous neuronal apoptosis inhibitory protein gene (NAIP) have been found to be more frequently deleted in type I than in the milder forms (types II and III). We investigated the correlation between the clinical phenotype and the genotype at this loci. A total of 106 patients were classified into type I (44), type II (31), and type III (31) and analysed using SMN, markers C212 and C272, and NAIP mapping upstream and downstream from SMN respectively. The combined analysis of all markers showed a large proportion of type I patients (43%) carried deletions of both SMN and its flanking markers (C212/272) and NAIP exon 5), as compared with none of the patients with type II or III SMA. The presence of large scale deletions involving these loci is specific to Werdnig-Hoffman disease (type I) and allows one to predict the severity of the disease in our series.

Adult↗
PubMed1999

Diagnostic challenges in ALS.

Although the essential requirements for diagnosis of amyotrophic lateral sclerosis (ALS) are clearly defined by the El Escorial criteria, many physicians, including neurologists, still miss the diagnosis. Physician misdiagnosis of ALS relates to lack of knowledge about ALS and skill and to diagnostic difficulty. The differential diagnosis must exclude nonmotor neuron diseases and other adult-onset motor neuron diseases with restricted presentations, e.g., progressive bulbar palsy (pure bulbar), progressive muscular atrophy (pure lower motor neuron) and primary lateral sclerosis (pure upper motor neuron), ALS-like syndromes and ALS variants, and adult-onset spinal muscular atrophies. Although the diagnosis of ALS remains a clinical one, laboratory testing can be used to exclude other diseases and to confirm the diagnosis. Such tests include EMG and nerve conduction studies, MRI and CT of the spine and brain, identification of biochemical markers in blood and CSF, and muscle or nerve biopsy. Genetic testing can identify gene defects in some types of familial ALS and in certain other inherited motor neuron diseases that mimic ALS. At present there is no widely accepted protocol for laboratory testing in cases of suspected ALS, but it is hoped that laboratory tests will improve in the future to facilitate earlier confirmation of a diagnosis of ALS. However, correct and early diagnosis of ALS can only be achieved when the first, second, or third physician who sees the patient knows about ALS and includes it in a differential diagnosis.

Adult↗
PubMed1996

Structure and organization of the human survival motor neurone (SMN) gene.

Spinal muscular atrophies (SMA) are characterized by degeneration of the anterior horn cells of the spinal cord and represent the second most common fatal autosomal-recessive disorder after cystic fibrosis. We have previously identified the survival motor neurone gene (SMN), a SMA-determining gene in the 5q13 region encoding a hitherto unknown protein. In this report, we describe the organization and structure of SMN. The gene is approximately equal to 20 kb in length and consists of nine exons. Sequence data of the 5' end of the gene show that the dinucleotide repeat C272 is close to several putative binding sites for transcription factors, which will help to characterize the regulation of the SMN and CBCD541 gene expression. The availability of the human SMN and its highly homologous counterpart (CBCD541) gene structures and exon-intron boundaries will hopefully speed up the characterization of SMN gene mutations in SMA.

Amino Acid Sequence↗
PubMed2004

Progressive and selective degeneration of motoneurons in a mouse model of SMA.

Spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by the degeneration of motoneurons of the spinal cord and brainstem, results from loss-of-function mutations in the survival motor neuron gene (smn). The goal of these experiments was to analyse axons and cell bodies of motoneurons in different regions of the CNS during disease progression in a mouse model of SMA carrying a deletion of the exon 7 directed to neurons. These experiments demonstrate a progressive loss of motor axons and of motoneurons in the CNS. This is the first study that describes a selective neurodegeneration in this line of mice and underlines the importance of exon 7 in some populations of motoneurons for survival in vivo.

Animals↗
PubMed1992

[Cervical root avulsion presenting proximal segmental muscular atrophy of unilateral upper extremity].

A 56-year-old woman noticed non-progressive weakness in the proximal part of the right upper extremity from her childhood. At the age of 37 years, she was diagnosed as "spinal muscular atrophy" by an orthopedic surgeon. At the age of 56, neurological examinations revealed muscular atrophy and weakness confined to the right deltoid, biceps brachii and brachioradialis together with minor sensory disturbance in the lateral side of the right shoulder and forearm without pyramidal sign in the lower extremities. The neurological features of this case differed from those of juvenile type of distal and segmental muscular atrophy of upper extremities in distribution of muscular atrophy, and simulated those of cervical spondylotic amyotrophy. Myelography demonstrated root avulsion of the right C5 and C6 roots. CT myelography revealed traumatic meningocele. Therefore a clinical diagnosis of cervical root avulsion resulting from unrecognized birth injury was made. The reason of motor dominant pictures of this case may be vulnerability of the anterior nerve roots to traction injury.

Arm↗
PubMed2004

Post-translational modifications in the survival motor neuron protein.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with M(r) of 32 and 35kDa, both localized in nuclear coiled bodies, but the 32kDa form is also cytoplasmic, whereas the 35kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a double-tagged rat SMN. Immunoblot and immunostaining studies demonstrated that the 32kDa SMN isoform derives from the full length 35kDa, through a proteolytic cleavage at the C-terminal. Furthermore, the 35kDa SMN isoform is physiologically phosphorylated in vivo. This may modulate its interaction with molecular partners, either proteins or nucleic acids.

3T3 Cells↗
PubMed2004

Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells.

Spinal muscular atrophy (SMA) is a recessive disorder involving the loss of motor neurons from the spinal cord. Homozygous absence of the survival of motor neuron 1 gene (SMN1) is the main cause of SMA, but disease severity depends primarily on the number of SMN2 gene copies. SMN protein levels are high in normal spinal cord and much lower in the spinal cord of SMA patients, suggesting neuron-specific regulation for this ubiquitously expressed gene. We isolated genomic DNA from individuals with SMN1 or SMN2 deletions and sequenced 4.6 kb of the 5' upstream regions of the these. We found that these upstream regions, one of which is telomeric and the other centromeric, were identical. We investigated the early regulation of SMN expression by transiently transfecting mouse embryonic spinal cord and fibroblast primary cultures with three transgenes containing 1.8, 3.2 and 4.6, respectively, of the SMN promoter driving beta-galactosidase gene expression. The 4.6 kb construct gave reporter gene expression levels five times higher in neurons than in fibroblasts, due to the combined effects of a general enhancer and a non-neuronal cell silencer. The differential expression observed in neurons and fibroblasts suggests that the SMN genes play a neuron-specific role during development. An understanding of the mechanisms regulating SMN promoter activity may provide new avenues for the treatment of SMA.

Analysis of Variance↗
PubMed2000

Survival motor neuron protein modulates neuron-specific apoptosis.

Spinal muscular atrophy (SMA) is attributed to mutations in the SMN1 gene, leading to loss of spinal cord motor neurons. The neurotropic Sindbis virus vector system was used to investigate a role for the survival motor neuron (SMN) protein in regulating neuronal apoptosis. Here we show that SMN protects primary neurons and differentiated neuron-like stem cells, but not cultured cell lines from virus-induced apoptotic death. SMN also protects neurons in vivo and increases survival of virus-infected mice. SMN mutants (SMNDelta7 and SMN-Y272C) found in patients with SMA not only lack antiapoptotic activity but also are potently proapoptotic, causing increased neuronal apoptosis and animal mortality. Full-length SMN is proteolytically processed in brains undergoing apoptosis or after ischemic injury. Mutation of an Asp-252 of SMN abolished cleavage of SMN and increased the antiapoptotic function of full-length SMN in neurons. Taken together, deletions or mutations of the C terminus of SMN that result from proteolysis, splicing (SMNDelta7), or germ-line mutations (e.g., Y272C), produce a proapoptotic form of SMN that may contribute to neuronal death in SMA and perhaps other neurodegenerative disorders.

Alphavirus Infections↗
PubMed1994

Use of BiPAP by nasal mask in the treatment of respiratory insufficiency in pediatric patients: preliminary investigation.

A device for nasally applied bilevel positive airway pressure, BiPAP (Respironics Inc., Murrysville, PA), is currently being evaluated for the treatment of respiratory failure in pediatric and adult patients. This retrospective case review examines our experience with using BiPAP in the treatment of acute ventilatory deterioration in pediatric patients with chronic respiratory insufficiency. All patients who presented to the intensive care unit with chronic respiratory insufficiency and ventilatory failure but without hypoxia were given a trial on BiPAP. Fifteen patients, ages 4-21 years, received such ventilatory support. Four of them had cystic fibrosis (CF) and 11 had neuromuscular disease (2, spinal muscular atrophy; 7, Duchenne muscular dystrophy; 1, spinal cord injury; and 1, myopathy of undetermined origin). Hospital days, respiratory rates, resting heart rates, arterial blood gases, serum bicarbonates, and subjective assessment by parents and or patients of dyspnea, sleep pattern, and activity tolerance were compared prior to and after initiation of BiPAP. Patients were followed from 1 day to 21 months. In 14 of 15 patients placement of an artificial airway could be avoided. Significant decreases in hospital days, respiratory rate, heart rate, serum bicarbonate, and arterial PCO2 were observed after initiation of BiPAP. Decline in dyspnea (87% with severe distress at rest prior vs. 80% comfortable at rest after BiPAP), increased activity tolerance (57% attending school after BiPAP vs. none prior to BiPAP), and improved quality of sleep (93% with comfortable sleep, no daytime somnolence vs. none with comfortable sleep and 36% with daytime somnolence prior to BiPAP).(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1997

SMN gene analysis of the spinal form of Charcot-Marie-Tooth disease.

The spinal form of Charcot-Marie-Tooth disease (spinal CMT) is a rare genetic disorder of the peripheral nervous system, the genetic basis of which remains unknown. To test the hypothesis that a defect of survival motor neuron (SMN), the determining gene for spinal muscular atrophy (SMA), would result in spinal CMT, 18 unrelated spinal CMT patients were studied. Nine of them were sporadic cases and the other nine belonged to unrelated autosomal dominant pedigrees. None of the 18 patients showed deletions involving SMN exons 7 or 8, the most frequent gene alteration found in SMA. In addition, haplotype analysis in two large autosomal dominant pedigrees showed that the 5q13 locus was not segregating with the spinal CMT locus. Therefore, neither the sporadic nor the familial cases of spinal CMT are associated with a SMN gene deletion, nor are the familial cases linked to the 5q13 region, indicating that this neuropathy is genetically different from SMA.

Charcot-Marie-Tooth Disease↗