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PubMedDate not supplied

Spinal motoneuron function in lower motor neuron disease: normal corticomotoneuronal and peripheral Ia EPSPs in patients with spinal muscular atrophy.

Responses of single tibialis anterior motor units to transcranial magnetic stimulation and to a synchronized Ia volley evoked by peripheral electrical nerve stimulation were obtained in patients with distal spinal muscular atrophy and compared to normal controls. Estimations of excitatory postsynaptic potential (EPSPs) by cross-correlations revealed no difference in rise time of EPSPs for both groups of subjects despite considerable changes in macro-EMG parameters of the motor units studied in patients with spinal muscular atrophy (SMA). The results indicate that voluntarily activated spinal motoneurons in SMA are capable of normal excitatory responses to transcranial magnetic as well as peripheral Ia stimulation.

Action Potentials↗
PubMed1984

Fasciculation of the eyelids: an additional clue to clinical diagnosis in spinal muscular atrophy.

Fasciculation of the eyelids was observed in five of eleven children with spinal muscular atrophy (SMA); two had severe SMA and three were of intermediate severity. Three other children with intermediate SMA and the two children with mild SMA did not show eyelid fasciculations. This could provide an additional clinical sign to tongue fasciculation and hand tremor in the diagnosis of SMA in childhood.

Adolescent↗
PubMed1993

[Spinal muscular atrophy in childhood. Possibilities and limits of clinical and molecular genetic diagnosis].

The proximal spinal muscular atrophies (SMA) are a clinically and genetically heterogeneous group of neuromuscular disorders which are characterized by selective degeneration of motor neurons in the spine and brainstem. The clinical features resemble other muscle diseases, the diagnostic criteria of proximal SMA have recently been defined by the International SMA Consortium. The classification of the clinical picture in different subgroups is still a focus of discussion. At present it seems likely that childhood onset SMA represents a broad spectrum of various ages of onset and different degrees of disability. Apart from different modes of inheritance, there is further evidence of heterogeneity in proximal SMA. The autosomal recessive forms represent the second frequent recessive disorder after cystic fibrosis, whereas autosomal dominant inheritance is an exception in childhood onset SMA. There are no convincing reports of X-linked SMA hitherto. With mapping of acute and chronic forms of childhood SMA to chromosome 5q11.2-13.3 diagnosis by use of DNA markers in affected families has become available. The current possibilities but also problems and limitations of genotype analysis are discussed, with special regard to the application of prenatal diagnosis. We report on the first experiences with prenatal diagnosis in 37 SMA families.

Adolescent↗
PubMed2003

MR findings of spinal muscular atrophy Type II: sibling cases.

We present magnetic resonance (MR) findings of siblings affected by spinal muscular atrophy (SMA) Type II. MRI of their thighs showed severe muscle atrophy and fatty infiltration. Selective preservation of the adductor longus muscle, the gracilis muscle, and the sartorius muscles was observed, suggesting a characteristic finding of SMA Type II. These findings were more severe in the older patient.

Child, Preschool↗
PubMed1998

Diagnosis of spinal muscular atrophy in an SMN non-deletion patient using a quantitative PCR screen and mutation analysis.

We report a child with clinical findings consistent with Werdnig-Hoffmann disease (spinal muscular atrophy type I) who was found not to have the homozygous absence of the survival motor neurone (SMN(T)) gene observed in approximately 95% of spinal muscular atrophy patients. A quantitative PCR based dosage assay for SMN(T) copy number showed that this patient possessed a single copy of the SMN(T) gene. Heteroduplex and sequence analysis of the remaining copy of SMN(T) showed a 2 base pair deletion within exon 4 which produces a frameshift and premature termination of the deduced SMN(T) protein. This protocol of initial SMN(T) gene dosage analysis followed by mutation detection allows identification of SMA compound heterozygotes (patients lacking one copy of SMN(T) and having another mutation in their other copy), thereby increasing the sensitivity of SMA molecular diagnosis.

Cyclic AMP Response Element-Binding Protein↗
PubMed1993

Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene.

The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoint linkage analysis was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene.

Base Sequence↗
PubMed1995

Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays.

The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both a YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array.

Base Sequence↗
PubMed2002

Spinal muscular atrophy in black South Africans: concordance with the universal SMN1 genotype.

Only one study has reported on the genetic basis of spinal muscular atrophy (SMA) in South African subjects. This was conducted in the Johannesburg region and has suggested that black South Africans only (indigenous Africans) differ from the norm. We have explored this further by DNA studies in 30 unrelated and racially diverse patients who reside in the Western Cape, and who were assessed as SMA subjects according to the internationally accepted inclusion criteria for SMA. These subjects were seen at the neurology clinic at Red Cross Children's Hospital in Cape Town during the period 1980-2001. Four had the type 1 form of SMA, 16 had type 2 and 10 had type 3. All patients were found to be homozygous for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene. Six additional patients had anterior horn cell disease but were negative for the SMN1 gene deletion. All six had exclusion features listed in the international guidelines. This study shows that all patients from the Western Cape, which included 12 black South Africans, are no different genetically or phenotypically from the internationally recognized form of typical SMA.

Black People↗
PubMed1999

Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems.

The survival of motor neurons (SMN) gene is the disease gene of spinal muscular atrophy (SMA), a common motor neuron degenerative disease. The SMN protein is part of a complex containing several proteins, of which one, SIP1 (SMN interacting protein 1), has been characterized so far. The SMN complex is found in both the cytoplasm and in the nucleus, where it is concentrated in bodies called gems. In the cytoplasm, SMN and SIP1 interact with the Sm core proteins of spliceosomal small nuclear ribonucleoproteins (snRNPs), and they play a critical role in snRNP assembly. In the nucleus, SMN is required for pre-mRNA splicing, likely by serving in the regeneration of snRNPs. Here, we report the identification of another component of the SMN complex, a novel DEAD box putative RNA helicase, named Gemin3. Gemin3 interacts directly with SMN, as well as with SmB, SmD2, and SmD3. Immunolocalization studies using mAbs to Gemin3 show that it colocalizes with SMN in gems. Gemin3 binds SMN via its unique COOH-terminal domain, and SMN mutations found in some SMA patients strongly reduce this interaction. The presence of a DEAD box motif in Gemin3 suggests that it may provide the catalytic activity that plays a critical role in the function of the SMN complex on RNPs.

Amino Acid Motifs↗
PubMed2003

Allele-specific amplification of exon 7 in the survival motor neuron (SMN) genes for molecular diagnosis of spinal muscular atrophy.

There are two highly homologous survival motor neuron (SMN) genes in humans but molecular defects in the SMN1 gene cause spinal muscular atrophy (SMA). More than 90% of SMA patients are shown to have a homozygous deletion of exon 7 in the SMN1 gene. Therefore, a simple test for exon 7 deletion would be very useful in the molecular diagnosis of SMA. However, limited methods are available, and most of these methods utilize expensive instruments and consumables. Here, we describe a simple allele-specific PCR test, which can be performed using standard equipment in DNA laboratories. The principle of the test is based on a single nucleotide difference (C versus T) between the exon 7 of SMN1 and SMN2 genes. Using allele-specific primers, two PCR amplifications are performed for each sample to amplify a 404-bp diagnostic fragment, and consequent electrophoresis of PCR products on agarose gel provides definitive information concerning the exon 7 deletion To rule out false negatives, a 500-bp fragment from the N-acetyltransferase gene was coamplified as an internal control in each test. We have, so far, analyzed 41 SMA samples with our method, and tested the validity of results using an independent restriction fragment length polymorphism (RFLP) method. Genotyping results obtained by both methods were in complete agreement for all of the samples analyzed. Our method can also be used to detect heterozygous deletion of exon 7 in SMN genes, if the relative intensities of the diagnostic and internal control bands are determined.

Alleles↗
PubMedDate not supplied

Assessment of nonallelic genetic heterogeneity of chronic (type II and III) spinal muscular atrophy.

We have previously reported the mapping of the chronic (type II/intermediate and type III/mild/Kugelberg-Welander) form of the childhood-onset spinal muscular atrophies (SMA) to chromosome 5q11.2-13.3, with evidence for nonallelic genetic heterogeneity within a small sample of seven families [Brzustowicz et al., Nature 1990;344:540-541]. We now report the results of linkage analysis and heterogeneity testing on a set of 38 families with chronic SMA. Significant evidence for nonallelic heterogeneity was detected among these families, with the predominant locus for chronic SMA mapping to a 0.51-cM region on 5q, between the loci D5S6 and MAP1B. The estimated proportion of linked families, alpha, was 0.91, with a 2.3-unit support interval of 0.75 to 0.98. The indication that some families diagnosed with chronic SMA are not linked to chromosome 5q must be considered in strategies to map the SMA locus. The relevance of these findings to acute SMA (SMA type I, severe, Werdnig-Hoffmann disease) is still unknown.

Adolescent↗
PubMed2006

[The expression of SMN2 gene mRNA in neuron-like cells derived from patients with spinal muscular atrophy].

OBJECTIVE: To detect the difference of SMN2 mRNA expression between the neuron-like cells (NLCs) derived from patients with spinal muscular atrophy (SMA). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to diagnose the patients with SMA and the controls. Mesenchymal stem cells (MSCs) were induced into neuron-like cells which become the models of neurons. The transcripts of SMN2 were testified with RT-PCR combined with sequencing. RESULTS: Two bands (266 bp and 212 bp) were found in the gel picture of RT-PCR and the band of 266 bp was the full length transcript (fl-SMN mRNA). The band of 212 bp was testified by sequencing to be deletion of the exon 7, which was the production of alternative splicing (skipping exon 7, SMNDelta7 mRNA). The expression of fl-SMN mRNA accounted for 23.2% of the total SMN mRNA in the SMA patients, being much lower than the rate in the controls (82.0%). In contrast, 76.8% of SMN gene transcripts was SMNDelta7 mRNA in the SMA patients, being much higher than the rate of 18% in the controls. CONCLUSIONS: Alternative splicing exists in SMN2 gene transcription, that is, exon 7 is skipped during the processing of SMN2 mRNA in the NLCs of SMA patients, which is one of the reasons of the full-length SMN protein lacking.

Adolescent↗
PubMed2003

Successful pregnancy in a patient with spinal muscular atrophy and severe kyphoscoliosis.

Pregnancy imposes a load on the respiratory system that is usually easily assumed because of alterations in the thoracoabdominal architecture. It is presumed that the respiratory mechanical disadvantage of severe kyphoscoliosis and the muscle weakness of spinal muscular atrophy impede these adaptations sufficiently to preclude a successful gestation. We report the case of a successful pregnancy in a woman with spinal muscular atrophy, severe uncorrected scoliosis, and the lowest spirometric values reported in the literature without the use of ventilatory support. This patient demonstrates that women with severe kyphoscoliosis and a profound ventilatory limitation can carry a successful pregnancy well into the third trimester without requiring full ventilatory support.

Adult↗
PubMed2005

Spinal muscular atrophy carrier screening by multiplex polymerase chain reaction using dried blood spot on filter paper.

Spinal muscular atrophy (SMA) is a common, often fetal, autosomal recessively inherited disease leading to progressive muscle wasting and paralysis as a result of degeneration of anterior horn cells of the spinal cord. The SMA-determining gene, called the survival of motor neuron gene (SMN), is present on 5q13 in two nearly identical copies, telomeric SMN (SMN1) and centromeric SMN (SMN2). It has been established that SMA is caused by mutations in SMN1 whereas homozygous deletion of SMN2 has apparently no pathological consequences. The aim of this study is to develop an easy and inexpensive method for the isolation of high-quality template DNA from blood samples for SMA carrier screening by multiplex polymerase chain reaction. We have developed a protocol that optimizes detection of the SMN1 copy number in the human genome, producing a specific and sensitive assay using DNA extracted from a dried blood spot on IsoCode paper.

Chromosomes, Human, Pair 5↗
PubMed2001

Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein.

The survival motor neurons (smn) gene in mice is essential for embryonic viability. In humans, mutation of the telomeric copy of the SMN1 gene causes spinal muscular atrophy, an autosomal recessive disease. Here we report that the SMN protein interacts with the zinc-finger protein ZPR1 and that these proteins colocalize in small subnuclear structures, including gems and Cajal bodies. SMN and ZPR1 redistribute from the cytoplasm to the nucleus in response to serum. This process is disrupted in cells from patients with Werdnig-Hoffman syndrome (spinal muscular atrophy type I) that have SMN1 mutations. Similarly, decreased ZPR1 expression prevents SMN localization to nuclear bodies. Our data show that ZPR1 is required for the localization of SMN in nuclear bodies.

Alternative Splicing↗
PubMed2004

Long-term observations of patients with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).

We describe 6 unrelated patients affected by infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) with prolonged survival upon mechanical ventilation (4.5-11 years), which has not been reported before. Biallelic mutations in the IGHMBP2 gene proved the diagnosis of SMARD1 in all patients. Disease onset was in the first 2 months in the described patients, starting with generalised hypotonia, failure to thrive, and early breathing difficulties. Diaphragmatic palsy was diagnosed and permanent ventilation was initiated 2-8 months after onset. Within months a more distal muscular atrophy became evident associated with joint contractures (talipes), hand drops, and fatty finger pads. Motor development remained minimal, loss of function was observed within the first year after which no further progression was recorded. Voiding dysfunction with reflux nephropathy was observed in 3 patients and has not been reported before. Further evidence of autonomic nerve dysfunction resulting in cardiac arrhythmia, hypertension, and excessive sweating was given in 2 patients. Investigative results were largely compatible with those obtained in classic SMA. However, neurogenic atrophy muscle was more pronounced in distal muscles, if examined, and there was evidence of peripheral nerve involvement at least in some patients.

Age Factors↗