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PubMedDate not supplied

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2.

PURPOSE: This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing. METHODS: From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients. RESULTS: Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients. CONCLUSIONS: SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing. Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information.

Alleles↗
PubMed1982

Juvenile spinal muscular atrophy: a new hexosaminidase deficiency phenotype.

A 24-year-old Ashkenazi Jewish man was evaluated for a nine-year history of progressive leg weakness with fasciculations. Electromyography, nerve conduction velocities, muscle biopsy, and serum creatine kinase were consistent with anterior horn cell disease. On rectal biopsy, ganglion cells were filled with membranous cytoplasmic bodies and an unusual submucosal layer of periodic acid-Schiff positive histiocytes filled with granules was seen. Hexosaminidase A in serum and leukocytes was severely decreased in the patient and partially decreased in parents and a brother. A paternal relative had classic infantile Tay-Sachs disease. Juvenile spinal muscular atrophy in this patient, closely resembling the Kugelberg-Welander phenotype, resulted from an alpha-locus hexosaminidase deficiency disorder, possibly a genetic compound of HEX alpha 2 and a milder hexosaminidase alpha-locus allele. Other cases of hexosaminidase deficiency have included anterior horn cell disease as part of a more complex disorder, but this is the first case, to our knowledge, of a hexosaminidase deficiency disorder presenting as spinal muscular atrophy.

Adult↗
PubMed2005

Moving ahead in language: observations on a report of precocious language development in 3-4 year old children with spinal muscular atrophy type II.

Benony and Benony in a recent issue of this Journal have presented new data on the precocity of language acquisition in children with type II spinal muscular atrophy (SMA), at age 36-47 months. They refer to our interim report of advanced early language development in these motor-impaired children, which covers the age period 18-35 months. Here, we provide more details of our findings and discuss them in relation to their report and our theory of the role of the procedural system in language learning.

Child, Preschool↗
PubMed1996

YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p.

Despite rapid progress in the physical characterization of murine and human genomes, little molecular information is available on certain regions, e.g., proximal mouse chromosome 11 (Chr 11) and human chromosome 2p (Chr 2p). We have localized the wobbler spinal atrophy gene wr to proximal mouse Chr 11, tightly linked to Rab1, a gene coding for a small GTP-binding protein, and Glnsps1, an intronless pseudogene of the glutamine synthetase gene. We have now used these markers to construct a 1.3-Mb yeast artificial chromosome (YAC) contig of the Rab1 region on mouse Chr 11. Four YAC clones isolated from two independent YAC libraries were characterized by rare-cutting analysis, fluorescence in situ hybridization (FISH), and sequence-tagged site (STS) isolation and mapping. Rab1 and Glns-ps1 were found to be only 200 kb apart. A potential CpG island near a methylated NarI site and a trapped exon, ETG1.1, were found between these loci, and a new STS, AHY1.1, was found over 250 kb from Rab1. Two overlapping YACs were identified that contained a 150-kb region of human Chr 2p, comprising the RAB1 locus, AHY1.1, and the human homologue of ETG1.1, indicating a high degree of conservation of this region in the two species. We mapped AHY1.1 and thus human RAB1 on Chr 2p13.4-p14 using somatic cell hybrids and a radiation hybrid panel, thus extending a known region of conserved synteny between mouse Chr 11 and human Chr 2p. Recently, the gene LMGMD2B for a human recessive neuromuscular disease, limb girdle muscular dystrophy type 2B, has been mapped to 2p13-p16. The conservation between the mouse Rab1 and human RAB1 regions will be helpful in identifying candidate genes for the wobbler spinal muscular atrophy and in clarifying a possible relationship between wr and LMGMD2B.

Animals↗
PubMed1993

Juvenile lower cervical spinal muscular atrophy in Taiwan: report of 27 Chinese cases.

Clinical observations as well as electromyographic studies were carried out on 27 Taiwanese Chinese patients deemed to be suffering from a rare, unique and self-limiting variant of lower motor neuron disease affecting the upper limbs with juvenile onset and a marked male preponderance. The results agree with previous descriptions of the disease except for the higher incidence of triceps affection. The term 'juvenile lower cervical spinal muscular atrophy', which describes the disease more accurately, is being proposed. The geographic relevance is discussed.

Adolescent↗
PubMed1998

Congenital unilateral speckled lentiginous blue nevi with asymmetric spinal muscular atrophy.

We describe a 30-year-old man presenting with congenital widespread unilateral hyperpigmented areas on the right side of the face and limbs that were studded with multiple blue nevi. There was nevus of Ota-like scleral involvement of the right eye. Histologic examination showed common blue nevi, one in association with lentigo. For this unusual type of dermal melanocytosis we propose the term, congenital unilateral speckled lentiginious blue nevi. In addition, the patient had monomelic spinal muscular atrophy of his right shoulder girdle and arm.

Adult↗
PubMed2000

[Survival motor neuron gene and neuronal apoptosis inhibitory protein gene deletion in patients with spinal muscular atrophy].

OBJECTIVE: To investigate the frequencies of gene deletion survival motor neuron telomere (SMNTel) exon 7 and neuronal apoptosis inhibitory protein gene (NAIP) exon 5 in 55 Chinese spinal muscular atrophy (SMA) patients, and compare the relationship between these two candidate genes and the disease. METHODS: PCR-SSCP method was used to detect the deletion of SMNTel exon 7, direct visualization of PCR products by agarose electrophoresis was used to detect the deletion of NAIP exon 5 in 55 SMA patients with type I and type II. 40 normal individuals were involved in the study as controls. RESULTS: Homozygous deletion of the SMNTel exon 7 was identified in 92% (23/25) of SMA type I patients and 90% (27/30) of SMA type II patients. The same deletion was found in two mothers and one father of SMA patients. There was no homozygous deletion found in normal controls. None of the homozygous deletion of NAIP exon 5 was found in 55 SMA patients and normal controls. Only two patients were found to have the heterozygous deletion. CONCLUSIONS: The frequency of homozygous deletion of SMNTel exon 7 was 90.1%. Our data support that SMN gene is strongly associated with SMA.

Adult↗
PubMed2003

Extended phenotype of pontocerebellar hypoplasia with infantile spinal muscular atrophy.

Pontocerebellar hypoplasia (PCH) is rarely associated with anterior horn cell disease and designated as PCH-1. This phenotype is characterized by severe muscle weakness and hypotonia starting prenatally or at birth with a life span not exceeding a few months in most cases. Milder disease courses with later onset and longer survival are normally not diagnosed as PCH-1. We describe the clinical and neuroradiological findings in nine patients out of six siblingships with evidence of cerebellar defects and early onset spinal muscular atrophy (SMA), representing a broad spectrum of clinical variability. In all patients, the diagnosis of SMA (Werdnig-Hoffmann disease) was made on the basis of electrophysiological data and muscle biopsy; however, genetic testing failed to confirm the diagnosis of infantile SMA with a gene defect on chromosome 5q and resulted in clinical reevaluation. Age at onset was after a normal period in the first months of life in three siblingships and pre- and postnatally in the other three families. Life span was 2-4 years in patients with later onset, and age at death occurred after birth or within months in the more severe group. Two siblingships showed discordant ages at death despite similar treatment. In contrast to the previous definition of PCH-1, our observations suggest the existence of milder phenotypes with pontocerebellar hypoplasia or olivopontocerebellar atrophy in combination with anterior horn cell loss. A pontine involvement is not necessarily seen by neuroimaging methods. The genetic basis of PCH-1 remains to be determined. The gene locus for infantile SMA on chromosome 5q could be excluded by linkage studies. Parental consanguinity and affected siblings make autosomal recessive inheritance most likely.

Abnormalities, Multiple↗
PubMed2003

Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy.

Cardiac ankyrin repeat protein (CARP), which is structurally characterized by the presence of four ankyrin repeat motifs in its central region, is believed to be localized in the nucleus and to participate in the regulation of cardiac-specific gene expression in cardiomyocytes. However, we recently found that CARP was induced in skeletal muscle by denervation, leading us to speculate that CARP may be induced under some pathological conditions. In the present study, we immunohistochemically analyzed the expression of CARP in 11 cases of spinal muscular atrophy (SMA) and 14 cases of congenital myopathy. In SMA, CARP was expressed selectively in severely atrophic myofibers, suggesting that CARP expression may reflect the status of muscle atrophy. Furthermore, in the congenital myopathies, the expression patterns of CARP were distinct among the subtypes, which included nemaline myopathy, myotubular myopathy, central core disease, and congenital fiber type disproportion. Although CARP was preferentially expressed in severely damaged myofibers in nemaline myopathy, it was not detected in central core disease. These findings suggest that immunohistochemical evaluation of CARP may be helpful in the diagnosis of SMA and the congenital myopathies.

Biomarkers↗
PubMed1996

[Population genetics of spinal muscular atrophy].

A population genetic study of spinal amyotrophy (SMA) in six Russian and three Central Asian regions was carried out. In total, 29 patients with autosomal recessive (AR) infantile proximal SMA (SMA I-III) and four patients with rare SMA forms with an unspecified type of inheritance were revealed. In Russian populations, the prevalence of SMA I-III is similar (1.5-2.5/100000), it is one of the most common hereditary neurological diseases. A tendency toward nonuniform territorial SMA prevalence is observed in genetically subdivided populations. The lesser SMA I-III prevalence in Central Asian populations might be due in part to inbreeding depression. A segregation frequency of 0.21 is in accordance with AR inheritance; the proportion of sporadic cases is 3%. Clinical genealogical data support the genetic unity of forms I-III. The origin of pedigrees with SMA in distant relatives is discussed.

Asia, Central↗
PubMed2004

Bone mineral density in a paediatric spinal muscular atrophy population.

BACKGROUND/OBJECTIVE: Reduced bone mineral density is a feature of patients with reduced mobility. The aim of this study was to assess bone mineral density in children with spinal muscular atrophy (SMA) and to evaluate bone mineral density in relation to age and motor disability. PATIENTS AND METHODS: We analysed bone mineral density measurements on twelve patients (4 with SMA type II, mean age 8.2 years [range 6.2 - 11.8]; 8 with SMA type III, mean age 11.8 years [range 5.5 - 20]). Dual-energy X-ray absorptiometry (DXA) was used to determine total body bone mineral density. The results were matched with published normative data for age and sex for a white Caucasian population. RESULTS: The total body bone mineral density values were in the normal range in 10 out of the 12 SMA patients studied, all below the age of 17 (mean age 8.8 years [range 5.5 - 16.33]). Four of them had SMA II and six had had SMA III and were still ambulant. Total body bone mineral density was, however, below 2 SD in the remaining 2 patients aged 19.7 and 20 years, respectively. Both had SMA III but had lost independent ambulation for a period of 3.5 years. CONCLUSION: Our results suggest that bone mineral density was surprisingly normal in most of the young SMA children studied. This is in contrast to what is reported in other conditions characterised by reduced mobility such as Duchenne muscular dystrophy. However, there was a tendency to decreasing bone mineral density with increasing age, not always related to the ability to walk, with the two eldest patients having the lowest values in spite of a relatively good mobility. These findings suggest that factors other than mobility are likely to have an effect on SMA bone mineral density.

Absorptiometry, Photon↗
PubMed1999

Prenatal diagnosis of spinal muscular atrophy type I (Werdnig- hoffmann) by DNA deletion analysis of cultivated amniocytes.

AIM: Presentation of a prenatally diagnosed case of Werdnig-Hoffmann disease, the most severe type of spinal muscular atrophy. METHODS: DNA obtained from cultivated amniocytes was analyzed for deletions in the survival motor neuron gene and neuronal apoptosis inhibitory protein gene. RESULTS: The fetus was diagnosed as an affected homozygote for deletions in exon 7 and exon 8 of the survival motor neuron gene. No deletions of exon 5 in the neuronal apoptosis inhibitory protein gene were found. CONCLUSION: Direct DNA deletion analysis of the survival motor neuron gene and neuronal apoptosis inhibitory protein gene in affected families represents a highly reliable and fast method for prenatal diagnosis of Werdnig-Hoffmann disease.

Adult↗
PubMed2002

Evaluation of therapeutic electrical stimulation to improve muscle strength and function in children with types II/III spinal muscular atrophy.

The study aimed to evaluate the effect of low-intensity night-time therapeutic electrical stimulation (TES) on arm strength and function in children with intermediate type spinal muscular atrophy (SMA). The design was a randomized controlled trial with a 6-month baseline control period. Children were evaluated at baseline, 6, and 12 months. TES was applied from 6 to 12 months to the deltoid and biceps muscle, of a randomly selected arm with the opposite arm receiving a placebo stimulator. Thirteen individuals with SMA between 5 to 19 years of age were recruited into the study and eight completed the 12-month assessment. No statistically significant differences between the treatment and control arm were found at baseline, 6, and 12 months for elbow flexors, or shoulder abductors on quantitative myometry or manual muscle testing. There was no significant change in excitable muscle mass assessed by M-wave amplitudes, nor function on the Pediatric Evaluation of Disability Inventory (self-care domain). Therefore, in this study there was no evidence that TES improved strength in children with SMA.

Activities of Daily Living↗
PubMed1993

Mitochondrial cardiomyopathy and scapuloperoneal spinal muscular atrophy in a child.

A 14-year old boy was admitted for signs of heart failure and scapuloperoneal muscle weakness. He fulfilled the clinical, functional and diagnostic criteria for dilated cardiomyopathy. There was also a moderate increase in pulmonary vascular resistance. The immunohistochemical examination of the heart muscle revealed a slightly positive phytohemagglutinin reaction and minimal IgM deposits without complement. The electron microscopy examination disclosed increased numbers of abnormal mitochondria disrupting the usual cell structure; the mitochondria were of various sizes with irregular and abnormal structure of the cristae. The scapuloperoneal spinal muscular atrophy was mild and diagnosed according to clinical and electromyographic findings. Light microscope examination of the skeletal muscle revealed hypotrophic fibers. This patient is presumed to have postinflammatory mitochondriopathy and is currently being managed on low-dose digitalis, diuretics and captopril.

Adolescent↗
PubMed1996

[A case of X-linked bulbar and spinal muscular atrophy with impaired neuromuscular transmission].

A 43-year-old man suffered from weakness of the upper limbs and easy fatigability. Low frequency (3 Hz) repetitive nerve stimulation (RNS) showed a marked waning with a maximum decrement of 20% of M wave amplitude. This remarkable waning was partially reduced by an administration of 60 mg bromopyridostigmine. High frequency RNS (30 Hz), however, did not induced waxing. Tensilon test and anti-AchR antibody were negative. The CAG repeat in androgen receptor gene was abnormally expanded ((CAG)n = 47), which confirmed a diagnosis of X-linked bulbar and spinal muscular atrophy. (BSMA). In some ALS patients, impaired neuromuscular transmission has been reported. The impaired neuromuscular transmission in ALS occurs in cases with rapidly progressive muscle wasting, suggesting that this abnormality is related to rapidly degenerating motor nerve endings. However, impaired neuromuscular transmission as seen in this patient has not been well documented in BSMA.

Adult↗
PubMed1983

Adult-onset rapidly progressive spinal muscular atrophy of shoulder girdle with gammopathy.

The paper reports on clinical and pathologic findings in a 51-year-old man who presented with rapidly progressive spinal muscular atrophy associated with relatively early respiratory paralysis. Clinical diagnosis was based on typical EMG, and bioptic and enzyme findings. In the CSF protein and cell content were normal, the IgG concentration was high, the IgG/Alb quotient increased, intrathecal synthesis of IgG was evident, and oligoclonal gammopathy was found. All of these findings generally appear in neuroallergic diseases. Total loss of anterior-horn cells, demyelination of fasciculus cuneatus and spinothalamic pathways, as well as round Lafora-body like inclusions, preponderantly in the white matter, were observed with light microscopy. Electron microscopic examination revealed reoviruses in the glia cells of the damaged motor zone.

Anterior Horn Cells↗
PubMed2001

Osteoclast-stimulating factor interacts with the spinal muscular atrophy gene product to stimulate osteoclast formation.

We have recently identified and cloned an intracellular peptide termed osteoclast-stimulating factor (OSF) that increases osteoclast (OCL) formation and bone resorption through a cellular signal transduction cascade, possibly through its interaction with c-Src or related family members. To further identify participants in the OSF signaling cascade, we used yeast two-hybrid screening with Saccharomyces cerevisiae, and we found that the 40-kDa spinal muscular atrophy disease-determining gene product, survival motor neuron (SMN), interacts with the OSF-Src homology 3 domain. Reverse transcription-polymerase chain reaction analysis of SMN mRNA expression in cells of the OCL lineage demonstrates that expression of the exon 7 splice variant of SMN is restricted to mature OCLs, whereas the unspliced transcript was expressed in OCL precursors as well as mature OCLs. Treatment of murine bone marrow cultures with conditioned media (5% (v/v)) from 293 cells transiently expressing the SMN cDNA significantly increased OCL formation, compared with treatment with conditioned media from mock-transfected cells. Furthermore, OCL-stimulatory activity by OSF or SMN was abolished by antisense constructs to SMN or OSF, respectively. These data confirm the participation of SMN in the OSF-enhanced expression of an OCL stimulator. OSF-SMN interaction may provide more insights into novel cellular signaling mechanisms that may play an important role in congenital bone fractures associated with type I spinal muscular atrophy disease.

Animals↗