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PubMed1998

Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I-III from the point of view of progression and severity.

Mild to moderately elevated creatine kinase (CK) activity is a frequent biochemical finding in proximal spinal muscular atrophy (SMA). In a collaborative study on all types of childhood and juvenile onset SMA, we analysed the CK activity of 504 SMA patients (138 type I, 127 type II, 144 type IIIa, and 95 type IIIb patients). Under the assumption of a lognormal distribution of CK activity as the most appropriate statistical model, CK levels were transformed into logarithms and compared by standard deviation scores = CK-SDS (log). CK activity was statistically different between early and later onset SMA: in SMA I and II, about one-third of patients showed CK-SDS (log) >2 SD, the analysis of the means did not show significant differences. In SMA III, CK-SDS (log) was significantly higher (p < 0.01) than in the two other groups, which was most pronounced in SMA IIIb. More than 90% of SMA IIIb patients showed CK-SDS (log) values >2 vs. 57% in SMA IIIa. As similar values were obtained for a subgroup of 100 patients in whom the diagnosis of autosomal recessive SMA was confirmed by a deletion of the telomeric copy of the survival motor neuron gene, our results can be considered representative for SMA I-III. There was no correlation between CK level and disease duration. The fact that patients were ambulatory or chair-bound had no influence on CK activity in type III SMA. There was no sex influence in SMA I, II and IIIa. The observed higher male values in the group SMA IIIb are most likely the result of a lack of female patients with onset after puberty.

Adolescent↗

PubMed2005

Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy.

PURPOSE: To prospectively evaluate several diffusion-tensor magnetic resonance (MR) imaging indexes (mean diffusivity [MD], fractional anisotropy [FA], and eigenvalues) of corticospinal tract impairment in patients with progressive muscular atrophy (PMA) and patients with amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: This study had institutional review board approval, and written informed consent was obtained from all subjects. Eight male patients with PMA (mean age, 63 years +/- 13 [standard deviation]), eighteen patients with ALS (14 men and four women; mean age, 64 years +/- 7), and twelve control subjects (four men and eight women; mean age, 65 years +/- 6) underwent diffusion-tensor MR imaging at which 25 spin-echo echo-planar imaging diffusion-weighted images (b = 1000 sec/mm2) were acquired along noncollinear directions. MD and FA were measured along the corticospinal tracts in each patient and subject. Changes in diffusion along and orthogonal to fiber bundles in patients were evaluated by using diffusion-tensor eigenvalues. Differences in diffusion-tensor imaging indexes between patients with PMA and those with ALS, as compared with these indexes in control subjects, were evaluated with Mann-Whitney testing. Correlations between diffusion-tensor imaging indexes and clinical variables were estimated with Pearson and Spearman rank correlation testing. RESULTS: As compared with MD (697.1 x 10(-6) mm2/sec +/- 28.1) and FA (0.585 +/- 0.032) in control subjects, MD was typically significantly increased (734.7 x 10(-6) mm2/sec +/- 41.2, P = .035) and FA significantly decreased (0.534 +/- 0.053, P = .037) along the corticospinal tracts in patients with ALS, while these parameters showed no significant change in patients with PMA (MD, 707.0 x 10(-6) mm2/sec +/- 44.2; FA, 0.559 +/- 0.028). Estimation of diffusion-tensor eigenvalues revealed normal diffusion along fiber tracts in all patients, while diffusion was increased orthogonal to fiber tracts only in patients with typical ALS. In patients with ALS, MD correlated with disease duration while FA correlated with disease severity. CONCLUSION: Diffusion-tensor MR imaging reveals corticospinal tract impairment in ALS but not in PMA.

Aged↗

PubMed1992

Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy.

Expansion of the trinucleotide repeat (CAG)n in the first exon of the androgen receptor gene is associated with a rare motor neuron disorder, X-linked spinal and bulbar muscular atrophy. We have found that expanded (CAG)n alleles undergo alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of instability in male meiosis than in female meiosis. We also found evidence for a correlation between disease severity and CAG repeat length, but other factors seem to contribute to the phenotypic variability in this disorder.

Base Sequence↗

PubMed1997

Correlation between deletion patterns of SMN and NAIP genes and the clinical features of spinal muscular atrophy in Japanese patients.

We conducted molecular analysis of two candidate genes for spinal muscular atrophy (SMA), the survival motor neuron gene (SMN) and the neuronal apoptosis inhibitory protein gene (NAIP), in 16 Japanese patients with SMA and compared the phenotypic features of SMA in these patients with the corresponding genotypes. Exons 7 and/or 8 of SMN were homozygously deleted in 11 SMA type I (Werdnig-Hoffmann disease) patients, two SMA type II patients and one SMA type III patient. Exons 5 and 6 of NAIP were homozygously deleted in six SMA type I patients. No patient had a deletion in NAIP without a deletion in SMN. Mechanical ventilation was required during the first 7 months of life in the SMA type I patients who had a deletion in both SMN and NAIP. Ventilatory support was initiated within 2 years after birth in patients who had a deletion in SMN but not in NAIP. We detected homozygous deletion of exon 5 of NAIP in the unaffected mothers of two SMA type I patients. In these families, the patients exhibited a deletion in both SMN and NAIP. The parents and unaffected siblings of these patients did not have a deletion in SMN. The present findings support the hypothesis that SMN deletion plays an important role in the development of SMA and suggest that combined deletion of both SMN and NAIP may be relevant for determining the disease severity.

Asian People↗

PubMed1999

A role for polyproline motifs in the spinal muscular atrophy protein SMN. Profilins bind to and colocalize with smn in nuclear gems.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the loss of alpha-motoneurons in the spinal cord followed by atrophy of skeletal muscles. SMA-determining candidate genes, SMN1 and SMN2, have been identified on human chromosome 5q. The corresponding SMN protein is expressed ubiquitously. It is coded by seven exons and contains conspicuous proline-rich motifs in its COOH-terminal third (exons 4, 5, and 6). Such motifs are known to bind to profilins (PFNs), small proteins engaged in the control of actin dynamics. We tested whether profilins interact with SMN via its polyproline stretches. Using the yeast two-hybrid system we show that profilins bind to SMN and that this binding depends on its proline-rich motifs. These results were confirmed by coimmunoprecipitation and by in vitro binding studies. Two PFN isoforms, I and II, are known, of which II is characteristic for central nervous system tissue. We show by in situ hybridization that both PFNs are highly expressed in mouse spinal cord and that PFN II is expressed predominantly in neurons. In motoneurons, the primary target of neurodegeneration in SMA, profilins are highly concentrated and colocalize with SMN in the cytoplasm of the cell body and in nuclear gems. Likewise, SMN and PFN I colocalize in gems of HeLa cells. Although SMN interacts with both profilin isoforms, binding of PFN II was stronger than of PFN I in all assays employed. Because the SMN genes are expressed ubiquitously, our findings suggest that the interaction of PFN II with SMN may be involved in neuron-specific effects of SMN mutations.

Amino Acid Motifs↗

PubMed1994

[An adult case of tethered cord syndrome with lipoma and thoraco-lumbar syringomyelia presenting slow progressive muscular atrophy in the lower limbs].

A 23-year-old man developed slowly progressive muscle weakness from the age of 10, followed by paresthesia and urinary disturbance. The physical examination showed bilateral muscular atrophy in the lower limbs and dissociated sensory disturbance below Th8. Although there was normal appearance of spinal X-P, MRI revealed conus medullaris at S2 involved thoraco-lumbar syringomyelia with extramedullary lipoma. After the operation for laminectomy of L5-S2 and untethering without direct surgery for syringomyelia, post-operated MRI exhibited definite shrinkage of the syrinx. It suggested that thoraco-lumbar syringomyelia in the present case was not congenital anomaly, but secondary outcome to tethered cord syndrome.

Adult↗

PubMed1997

Degeneration of cocultures of spinal muscular atrophy muscle cells and rat spinal cord explants is not due to secreted factors and cannot be prevented by neurotrophins.

We have shown recently that cocultures of muscle cells from infantile spinal muscular atrophy (SMA) patients innervated by motoneurons of normal rat spinal cord explants undergo a degeneration process, suggesting that muscle may play a role in this atrophy, which previously has been considered to be a pure motoneuron disease. Conditional media of SMA cocultures did not affect control healthy nerve muscle cocultures. Conversely, conditioned media of control cocultures were unable to prevent degeneration of SMA cocultures. Moreover, neurotrophic factors, thought to be of help in motoneuron disease treatment, did not protect SMA cocultures from premature death. Our results suggest that the abnormal phenotype observed in nerve-muscle coculture (1) is not due to the release of a toxic factor nor to the lack of a secreted survival factor, and (2) does not respond to neurotrophin treatment.

Animals↗

PubMed1989

Long-term ventilatory support in spinal muscular atrophy.

Before ethical issues regarding prolonging life in patients with degenerative disease can be considered, the quality of life with medical intervention must be delineated. We have followed 15 patients with spinal muscular atrophy who have been treated with mechanical ventilation. They have received assisted ventilation for an average of 8 years 10 months (range 5 months to 23 years 10 months). Three of the patients required full-time ventilator assistance at the time of initiation of ventilation; the remaining 12 used nighttime ventilation for an average of 8 years 7 months. Nine patients continue to receive nighttime ventilation only. Two patients died after 5 years and 14 years of assisted ventilation, respectively. Of the 10 patients more than 18 years of age, three graduated from college, two are in college, three graduated from high school, and two completed eleventh grade. One patient is a mother of a healthy child. Two patients are employed, and two others have found fulfilling volunteer work. Ventilator support has not significantly interfered with these patients' plans and expectations.

Adolescent↗

PubMedDate not supplied

Pulmonary function assessment in patients with spinal muscular atrophy type II and type III.

In this study, we used a spirometer to measure pulmonary function of 48 patients (4.3 to 34 years old), with type II and type III spinal muscular atrophy (SMA) and compared our findings according to the two SMA types, sex, functional grade, and degree of scoliosis. SMA patients were stratified into three groups based on severity and the age at which the symptoms began: type I, type II, and type III SMA patients were also classified into four functional grades depending upon whether they were able to 1) sit with support, 2) sit independently, 3) walk with assistance, or 4) walk independently. A restrictive pattern was found in all SMA patients who were found to have impaired lung function. The highest functional group had normal or nearly normal pulmonary functions. The lowest functional group, however, were found to have the worst pulmonary functions. Patients with type III SMA had better lung function than type II. We found a significant inverse relationship between pulmonary function and scoliosis, but no significant difference in pulmonary functioning with respect to gender. As the functional grade decreases, chest care needs to be intensified to prevent respiratory tract infections.

Adolescent↗

PubMed1997

Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number.

The survival motor neuron (SMN) transcript is encoded by two genes, SMNT and SMNC. The autosomal recessive proximal spinal muscular atrophy that maps to 5q12 is caused by mutations in the SMNT gene. The SMNT gene can be distinguished from the SMNC gene by base-pair changes in exons 7 and 8. SMNT exon 7 is not detected in approximately 95% of SMA cases due to either deletion or sequence-conversion events. Small mutations in SMNT now have been identified in some of the remaining nondeletion patients. However, there is no reliable quantitative assay for SMNT, to distinguish SMA compound heterozygotes from non-5q SMA-like cases (phenocopies) and to accurately determine carrier status. We have developed a quantitative PCR assay for the determination of SMNT and SMNC gene-copy number. This report demonstrates how risk estimates for the diagnosis and detection of SMA carriers can be modified by the accurate determination of SMNT copy number.

Amino Acid Sequence↗

PubMed2001

Juvenile asymmetric segmental spinal muscular atrophy (Hirayama's disease): three cases without evidence of "flexion myelopathy".

Compression of the cervical spinal cord during neck movements ("flexion myelopathy") was proposed to be the main pathomechanism of juvenile asymmetric spinal muscular atrophy (JASSMA). We present 3 patients with the clinical appearance of JASSMA and typical high-intensity signals in the anterior horn cell region of the lower cervical spinal cord (T2-weighted magnetic resonance images) but without evidence of dynamic spinal cord compression. In all these patients pathomechanism distinct from mechanical damage must be assumed.

Adolescent↗

PubMed1997

Spinal muscular atrophy gene wobbler of the mouse: evidence from chimeric spinal cord and testis for cell-autonomous function.

Human hereditary neurodegenerative diseases are genetically and mechanistically very heterogeneous and so are spinal muscular atrophies and cerebellar ataxias in the mouse, despite the common phenomenon of neuronal death. In this species, a number of mutations impair spermiogenesis in addition to neuron survival. Among these, the wobbler mutation on proximal chromosome 11 of the mouse leads to motoneuron degeneration in brain stem and spinal cord and to a defect of spermiogenesis. Chimeric mice of the type wr?/wr? <--> +/+ were produced, and their allelic status at the wr locus was determined by PCR diagnosis of a closely linked marker. Two overt chimeras, one female (XX <--> XX) and one male (XY <--> XY) were identified as wr/wr <--> +/+ and analyzed with respect to their pathological phenotype. Although there was patchy astrogliosis in the spinal cords of both chimeras, their motor performances were overtly normal and muscles were without signs of denervation. The male's testes revealed a mosaic pattern of normal and pathological spermatids. As no progeny was derived from wr spermatids, the spermatocytes appear as a primary target of the wr mutation in testis. Our results argue against a humoral mechanism of the wobbler disease and indicate a cell-autonomous action of the wr gene both in testis and in spinal cord.

Animals↗

PubMed1994

[Pathomechanism of juvenile muscular atrophy of unilateral upper extremity (Hirayama's disease)--extensibility and asymmetry of the cervical posterior dural wall].

We performed myelography in chin-up position during neck flexion in 20 patients with juvenile muscular atrophy of unilateral upper extremity, and we also performed CT-myelography in rotational position during neck flexion in 15 of them. In this disease, in which posterior lower cervical dural wall shifts anteriorly and compresses the spinal cord during neck flexion, we found that the anterior dural shift and cord compression became lessened by making chin-up without changing the position of neck flexion. By measuring the posterior dural length from foramen magnum to C6 vertebra on the profile of myelogram in neutral and neck flexion posture, we found that the posterior lower cervical dural wall of this disease was less extensible during neck flexion than that of control cases. On CT-myelogram the spinal cord compression of muscularly atrophic side increased by the neck rotation to the non-atrophic side during neck flexion, which is the position of maximum extension of posterior dural wall. The spinal cord compression decreased by the rotation to the atrophic side. We think that the low extensibility and asymmetry of posterior lower cervical dural wall may be the cause of this disease and its laterality may be relevant to unilaterality of this disease. These findings could also explain the efficacy of cervical immobilization by using cervical coller.

Adolescent↗

PubMedDate not supplied

Preservation of central motor conduction in patients with spinal muscular atrophy type II.

We evaluated the central (motor cortex to C8 motoneuron) and peripheral (C8 motoneuron to the muscle) motor conduction in 14 limbs of 7 patients with the intermediate form of spinal muscular atrophy (SMA II). The central motor conduction time (CMCT) was calculated using motor evoked potentials (MEPs) by transcranial magnetic stimulation and the results of a conventional F wave study. Peripheral conduction abnormality was found in 6 median nerves (43%) and 10 ulnar nerves (71%). Even in these patients with peripheral conduction abnormalities, the CMCT was consistently normal whenever the MEP was recorded. These results indicate that the motor conduction of the corticospinal fibers remains normal in SMA II.

Adolescent↗

PubMed1999

Prenatal prediction of spinal muscular atrophy in Chinese.

We used linkage analysis, non-isotope SSCP (single-strand conformation polymorphism) and PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) for prenatal diagnosis of spinal muscular atrophy (SMA). A total of 26 cases from 20 SMA families (16, type 1 and 4) were evaluated. 5 out of 26 fetuses were affected and, following genetic counselling, the parents decided to terminate the pregnancies. Aborted fetal tissues were examined and the diagnosis was confirmed in each case. The 21 unaffected cases were either normals (12 cases) or carriers (9 cases). These children have been followed for six months to two and a half years. No false-negative or false-positive results on prenatal testing were found. We conclude that prenatal diagnosis of SMA is reliable and accurate.

Deoxyribonucleases, Type II Site-Specific↗

PubMed1981

Sensory ganglioneuropathy in infantile spinal muscular atrophy. Light and electronmicroscopic findings in two cases.

Light and electronmicroscopic findings in two cases. Neuropediatrics 12: 215-31 (1981). Two cases of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) are described in unrelated children deceased at 11 months (acute clinical onset at 6 months) and 2 years (onset at birth). Severe respiratory difficulties, hypotonia, muscular weakness and depressed tendon reflexes were the main clinical features. Bulbar palsy, bilateral ptosis, pale optic discs and atactic movements of the hands were observed in the child deceased at 11 months. Besides severe loss of anterior horn cells and neurogenic muscle atrophy there was evidence of an extensive sensory involvement in both cases. Shrinkage, vacuolation as well as chromatolytic changes of dorsal root ganglion cells, together with the evidence of a primary axonal damage in sural nerve biopsies were interpreted in terms of ganglioneuropathy of the primary sensory neurons. An invasion of fibrous astrocytes into dorsal roots constituted another striking anomaly in one case as well as a pronounced degeneration of cranial nerves V and VIII in the other case, a finding not hitherto reported in Werdnig-Hoffmann disease.

Brain↗

PubMed2001

[A study of survival motor neuron and neuronal apoptosis inhibitory protein gene in spinal muscular atrophy].

OBJECTIVE: To study the absence of survival motor neuron(SMN) gene exon 7,8 and neuronal apoptosis inhibitory protein(NAIP) gene exon 5,6 in Chinese patients with type I - IV spinal muscular atrophy (SMA) and to confirm the relationship between the deletions of SMN, NAIP and SMA phenotype. METHODS: PCR and PCR-enzyme methods were used to detect the deletions of NAIP gene exon 5,6 and SMN gene exon 7,8 in 45 SMA (I - IV) patients and 30 healthy relatives of the patients and 30 normal controls. RESULTS: Deletions of exon 7 and 8 of the telomeric SMN gene were 4/4, 2/3, 1/8 and 0/30 in type I, II, III and IV SMA patients, respectively. One patient with type II lacked the exon 7 but retained exon 8. No deletions was found in the relatives and controls(0/60). No deletions of exon 5 and 6 of the NAIP gene was detected in all the patients, healthy relatives and controls. CONCLUSIONS: Deletions of SMN gene exon 7 and 8 exa mined by PCR-enzyme digestion could be recommended as an accurate gene diagnostic method for SMA with type I and II. However, the method was not as useful in type III as in I and II for making a diagnosis of SMA. Type IV SMA, a heterogeneous disease with phenotypical similarities to type I - III SMA, may be caused by deletion of other genes. The frequency of NAIP deletion was lower in Chinese SMA patients.

Child↗

PubMed2004

Altered expression of ARPP protein in skeletal muscles of patients with muscular dystrophy, congenital myopathy and spinal muscular atrophy.

OBJECTIVES: Ankyrin-repeated protein with PEST and a proline-rich region (ARPP) is a recently identified protein with 4 ankyrin-repeated motifs in its central portion. Type 1 myofibers of skeletal muscle express high levels of ARPP. Recently, we have found that ARPP expression was induced in mouse denervated skeletal muscle. This led us to hypothesize that ARPP expression might be induced in skeletal muscle under some pathological conditions. METHODS: In this study, we performed immunohistochemical analysis of ARPP expression in biopsy specimens of muscle tissue from 15 patients with muscular dystrophies (MDs), 13 with congenital myopathies and 11 with spinal muscular atrophies (SMAs). RESULTS: The ARPP expression levels of all the specimens from MD patients appeared to be lower than control muscle levels. In contrast, the specimens from the 13 patients with congenital myopathies were all ARPP positive. We also found increased numbers of ARPP-positive myofibers in patients with congenital myopathies, and these myofibers co-expressed the slow myosin heavy chain. Indeed, it has been reported that type 1 myofibers are predominant in patients with congenital myopathies, suggesting that increased numbers of ARPP-positive myofibers in such patients may be associated with increased numbers of type 1 fibers. In patients with SMAs, we found that ARPP-positive myofibers tended to be distributed in groups. As grouped myofibers have been reported to result from the process of denervation, innervation and subsequent denervation of re-innervated myofibers, the grouped ARPP-positive myofibers in SMA patients may result from denervation of the motor units. CONCLUSIONS: These findings suggest that evaluation of ARPP may be helpful for the histological diagnosis of muscle diseases.

Adult↗