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Spinal Muscular Atrophy (spinal + muscular_atrophy)

Distribution by Scientific Domains

Medical Sciences	64%
Life Sciences	30%

Distribution within Medical Sciences

Neurology	32%
Pediatrics	17%
Pathology	10%

Selected Abstracts

Malignant Ventricular Arrhythmia in a Case of Adult Onset of Spinal Muscular Atrophy (Kugelberg,Welander Disease)

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 3 2009
MARKUS ROOS M.D.
We present a case of a 43-year-old male patient with adult onset of spinal muscular atrophy (SMA). The patient first came to our attention with atrioventricular (AV) block. A dual-chamber pacemaker (DDD-PM) was implanted. Four years later, the PM data log showed occurrence of frequent episodes of nonsustained ventricular tachycardia (NSVT). The episodes progressed in duration and frequency. An electrophysiological study revealed prolonged His-ventricular (HV) interval duration and induction of sustained ventricular tachycardia. The patient was successfully upgraded to a prophylactic dual-chamber cardioverter defibrillator. Our case is the first description of a patient with adult-onset SMA (Kugelberg,Welander disease [KWD]) and malignant ventricular arrhythmias. [source]

The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy

JOURNAL OF NEUROCHEMISTRY, Issue 6 2009
Sebastian Lunke
Abstract As the leading genetic cause for infantile death, Spinal Muscular Atrophy (SMA) has been extensively studied since its first description in the early 1890s. Though today much is known about the cause of the disease, a cure or effective treatment is not currently available. Recently the short chain fatty acid valproic acid, a drug used for decades in the management of epilepsy and migraine therapy, has been shown to elevate the levels of the essential survival motor neuron protein in cultured cells. In SMA mice, valproic acid diminished the severity of the disease phenotype. This effect was linked to the ability of the short chain fatty acid to suppress histone deacetylase activity and activate gene transcription. Since then, the study of different histone deacetylase inhibitors and their epigenetic modifying capabilities has been of high interest in an attempt to find potential candidates for effective treatment of SMA. In this review, we summarize the current knowledge about use of histone deacetylase inhibitors in SMA as well as their proposed effects on chromatin structure and discuss further implications for possible treatments of SMA arising from research examining epigenetic change. [source]

Psychopathology and familial stress , comparison of boys with Fragile X syndrome and Spinal Muscular Atrophy

THE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 7 2002
A. Von Gontard
Background: Chronic illness and mental retardation are both associated with an increased rate of behavioural problems in children and with considerable emotional strain in families. The aim of the study was to analyse and compare the specific effects of two exemplary conditions on familial stress and coping. Methods: Forty-nine boys with Fragile X syndrome (FXS) were compared with 46 boys with Spinal Muscular Atrophy (SMA) and 32 male controls. Intelligence was measured with the RAVEN or K-ABC tests. Psychopathology was assessed with the CBCL questionnaire and a structured psychiatric interview (Kinder-DIPS), parental stress with the QRS, coping with the F-COPES and social support with the F-SOZU questionnaires. Results: The mean age of the FXS boys was 8.6, of the SMA boys 12.7 and of the controls 11.2 years. The mean IQ was 47 for the FXS, 112 for the SMA and 103 for the control groups. According to the CBCL, 89.8% of the FXS boys, 21.7% of the SMA and 15.7% of the controls had a total score in the borderline or clinical range. The rates were 63.3%, 34.8% and 21.9% for internalising and 67.3%, 10.9% and 18.8% for externalising behaviour, respectively. 81.6% of the FXS and 10.9% of the SMA patients had a DSM-IV or ICD-10 psychiatric diagnosis. The most common were ADHD (FXS: 36) and Separation Anxiety Disorder (SMA: 4). In total, parental stress was significantly higher in the FXS than in the SMA families (and in both compared to controls). There were no major inter-group differences regarding social support and familial coping. Conclusions: Children with FXS are severely mentally retarded and have a high rate of mainly externalising disorders. Despite good coping abilities and social support, this is associated with high familial stress. The SMA boys, with an intelligence in the upper normal range, are no more deviant than their healthy controls. Parental stress is lower in the SMA families with good coping abilities. In conclusion, families with mentally retarded children are in even greater need of help than those of children with severe chronic illness/physical handicap. Abbreviations: SMA: Spinal Muscular Atrophy; FXS: Fragile X syndrome. [source]

Spinal muscular atrophy: Recent advances and future prospects

MUSCLE AND NERVE, Issue 1 2002
Sophie Nicole PhD
Abstract Spinal muscular atrophies (SMA) are characterized by degeneration of lower motor neurons associated with muscle paralysis and atrophy. Childhood SMA is a frequent recessive autosomal disorder and represents one of the most common genetic causes of death in childhood. Mutations of the SMN1 gene are responsible for SMA. The knowledge of the genetic basis of SMA, a better understanding of SMN function, and the recent generation of SMA mouse models represent major advances in the field of SMA. These are starting points towards understanding the pathophysiology of SMA and developing therapeutic strategies for this devastating neurodegenerative disease, for which no curative treatment is known so far. © 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 4,13, 2002 [source]

Quantification of SMN1 and SMN2 genes by capillary electrophoresis for diagnosis of spinal muscular atrophy

ELECTROPHORESIS, Issue 13 2008
Chun-Chi Wang
Abstract We present the first CE method for the separation and quantification of SMN1 and SMN2 genes. Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder deleted or mutated in SMN1 gene and retained at least one copy of SMN2 gene. However, these two genes are highly homologous, differentiation and quantification of SMN1 and SMN2 are therefore required in diagnosis to identify SMA patients and carriers. We developed a fluorescence-labeled conformation-sensitive CE method to quantitatively analyze PCR products covering the variable position in the SMN1/SMN2 genes using a copolymer solution composed of hydroxyethylcellulose and hydroxypropylcellulose. The DNA samples included 24 SMA patients, 52 parents of SMA patients (obligatory carriers), and 255 controls. Those 331 samples were blind analyzed to evaluate the method, and the results compared with those obtained using denaturing HPLC (DHPLC). Validation of accuracy was performed by comparing the results with those of DHPLC. Nine of total samples showed different results. Diagnosis of one fetus DNA among them was related to abortion or not, which was further confirmed by gel electrophoresis and DNA sequencing. Our method showed good coincidence with them, and proved the misdiagnosis of DHPLC. This simple and reliable CE method is a powerful tool for clinical genotyping of large populations to detect carriers and SMA patients. [source]

Carrier frequency of SMA by quantitative analysis of the SMN1 deletion in the Iranian population

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2010
M. Hasanzad
Background and purpose:, Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder. Carrier frequency studies of SMA have been reported for various populations. Although no large-scale population-based studies of SMA have been performed in Iran, previous estimates have indicated that the incidence of autosomal recessive disorder partly because of the high prevalence of consanguineous marriage is much higher in the Iranian population than in other populations. Methods:, In this study, we used a reliable and highly sensitive quantitative real-time PCR assay with SYBR green I dye to detect the copy number of the SMN1 gene to determine the carrier frequency of SMA in 200 healthy unrelated, non-consanguineous couples from different part of Iran. Results:, To validate the method in our samples, we determined the relative quantification (RQ) of patients with homozygous deletion (0.00) and hemyzygous carriers (0.29,0.55). The RQ in 10 of 200 normal individuals were within the carrier range of 0.31,0.57, estimating a carrier frequency of 5% in the Iranian population. Conclusions:, Our data show that the SMA carrier frequency in Iran is higher than in the European population and that further programs of population carrier detection and prenatal testing should be implemented. [source]

Spinal muscular atrophy: Recent advances and future prospects

Spinal muscular atrophy: the challenges of ,doing the right thing'

PEDIATRIC ANESTHESIA, Issue 11 2009
NIALL C. T. WILTON MRCP FRCA
First page of article [source]

Molecular analysis of the SMN and NAIP genes in Iranian spinal muscular atrophy patients

PEDIATRICS INTERNATIONAL, Issue 2 2009
Omid Omrani
Abstract Background:, Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. SMA is clinically classified into three subgroups based on the age of onset and severity. The majority of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neuron (SMN) gene. The purpose of the present study was to determine the frequency of SMN and neuronal apoptosis inhibitory protein (NAIP) gene deletions in Iranian SMA patients. Experience in prenatal diagnosis of SMA in this population is also reported. Methods:, To study the frequency of deletions of SMN and NAIP genes in an Iranian sample group, 75 unrelated SMA patients (54 type I, eight type II and 13 type III) were analyzed according to the methods described by van der Steege et al and Roy et al. Results:, Homozygous deletion of SMN1 exons 7 and/or 8 were identified in 68 out of 75 patients (90%). Deletion of exon 5 of the NAIP gene was found in 40/54 of type I, 2/8 of type II and 1/13 of type III patients. Conclusions:, Deletion of the SMN1 gene is a major cause of SMA in Iran, and NAIP gene deletions were common in the present patients with type I SMA. Also, the incidence of NAIP deletion is higher in more severe SMA. [source]

5-(N -ethyl-N-isopropyl)-amiloride enhances SMN2 exon 7 inclusion and protein expression in spinal muscular atrophy cells

ANNALS OF NEUROLOGY, Issue 1 2008
Chung-Yee Yuo PhD
Objective Spinal muscular atrophy (SMA) is a common inherited neuromuscular disorder caused by homozygous loss of function of the survival motor neuron 1 (SMN1) gene. All SMA patients carry at least one copy of a nearly identical SMN2 gene. However, a critical nucleotide change in SMN2 results in alternative splicing and exclusion of exon 7 in the majority of SMN2 messenger RNA (mRNA), thus producing a low level of functional SMN protein. Increasing SMN protein production by promoting SMN2 exon 7 inclusion could be a therapeutic approach for SMA. It has been shown that cellular pH microenvironment can modulate pre-mRNA alternative splicing in vivo. In this study, we tested whether inhibitors of the Na+/H+ exchanger can modulate the exon 7 splicing of SMN2 mRNA Methods We treated SMA lymphoid cell lines with Na+/H+ exchanger inhibitors and then measured SMN2 exon 7 splicing by reverse transcriptase polymerase chain reaction and SMN protein production by Western blotting and immunofluorescence Results We found that treatment with an Na+/H+ exchanger inhibitor, 5-(N -ethyl-N-isopropyl)-amiloride (EIPA), significantly enhances SMN2 exon 7 inclusion and SMN protein production in SMA cells. In addition, EIPA increases the number of nuclear gems in SMA cells. We further explored the underlying mechanism, and our results suggest that EIPA may promote SMN2 exon 7 inclusion through upregulation of the splicing factor SRp20 in the nucleus Interpretation Our finding that EIPA, an inhibitor of the Na+/H+ exchanger, can increase SMN protein expression in SMA cells provides a new direction for the development of drugs for SMA treatment. However, further translational studies are needed to determine whether this finding is applicable for SMA treatment or just a proof of cellular pH effect on SMN splicing. Ann Neurol 2007 [source]

Valproic acid increases SMN levels in spinal muscular atrophy patient cells,

ANNALS OF NEUROLOGY, Issue 5 2003
Charlotte J. Sumner MD
Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7,containing SMN transcript and SMN protein in type I SMA patient,derived fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA. Ann Neurol 2003;54:647,654 [source]

Valproic Acid Promotes Neurite Outgrowth in PC12 Cells independent from Regulation of the Survival of Motoneuron Protein

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 3 2006
Jeroen van Bergeijk
Spinal muscular atrophy (SMA) is a neurodegenerative disorder of motoneurons. The disease is caused by deletions or mutations of the survival of motoneuron gene 1 (SMN1). The amount of protein expressed from the second gene, SMN2, correlated with the severity of the clinical phenotype. The histone deacetylase inhibitor valproic acid (VPA) has been shown to increase the total cellular amount of functional SMN protein and is therefore considered as a drug candidate for treatment of SMA. In this study, we analyzed the effects of VPA in PC12 cells, a model system for neuronal differentiation, with regard to neurite outgrowth and SMN expression. VPA promoted neurite outgrowth in PC12 cells. However, this effect did not correlate with upregulation of SMN protein levels, suggesting a SMN-independent mechanism for VPA regulation of neurite outgrowth. [source]

Cerebellar ataxia, anterior horn cell disease, learning difficulties, and dystonia: a new syndrome.

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 11 2000
Jo M Wilmshurst MRCP SpR Paediatric Neurology
The following case reports describe a new condition of cerebellar ataxia, anterior horn cell disease, dystonia, and learning difficulties. Four cases are described. The condition appears to be of autosomal recessive inheritance as the group is made up of two pairs of sisters. All cases were evident by 3 years of age. Anterior horn cell disease was of a type not previously described at this age in association with cerebellar ataxia. Further genetic studies suggest the condition is not allelic with spinal muscular atrophy having no evidence of deletion of the survival motor neurone gene. [source]

Universal multiplex PCR and CE for quantification of SMN1/SMN2 genes in spinal muscular atrophy

ELECTROPHORESIS, Issue 7 2009
Chun-Chi Wang
Abstract We established a universal multiplex PCR and CE to calculate the copy number of survival motor neuron (SMN1 and SMN2) genes for clinical screening of spinal muscular atrophy (SMA). In this study, one universal fluorescent primer was designed and applied for multiplex PCR of SMN1, SMN2 and two internal standards (CYBB and KRIT1). These amplicons were separated by conformation sensitive CE. Mixture of hydroxyethyl cellulose and hydroxypropyl cellulose were used in this CE system. Our method provided the potential to separate two 390-bp PCR products that differ in a single nucleotide. Differentiation and quantification of SMN1 and SMN2 are essential for clinical screening of SMA patients and carriers. The DNA samples included 22 SMA patients, 45 parents of SMA patients (obligatory carriers) and 217 controls. For evaluating accuracy, those 284 samples were blind-analyzed by this method and denaturing high pressure liquid chromatography (DHPLC). Eight of the total samples showed different results. Among them, two samples were diagnosed as having only SMN2 gene by DHPLC, however, they contained both SMN1 and SMN2 by our method. They were further confirmed by DNA sequencing. Our method showed good agreement with the DNA sequencing. The multiplex ligation-dependent probe amplification (MLPA) was used for confirming the other five samples, and showed the same results with our CE method. For only one sample, our CE showed different results with MLPA and DNA sequencing. One out of 284 samples (0.35%) belonged to mismatching. Our method provided a better accurate method and convenient method for clinical genotyping of SMA disease. [source]

Quantification of SMN1 and SMN2 genes by capillary electrophoresis for diagnosis of spinal muscular atrophy

Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology

JOURNAL OF ANATOMY, Issue 6 2008
Lyndsay M. Murray
Abstract Wallerian degeneration and dying-back pathology are two well-known cellular pathways capable of regulating the breakdown and loss of axonal and synaptic compartments of neurons in vivo. However, the underlying mechanisms and molecular triggers of these pathways remain elusive. Here, we show that loss of translation elongation factor eEF1A2 expression in lower motor neurons and skeletal muscle fibres in homozygous Wasted mice triggered a dying-back neuropathy. Synaptic loss at the neuromuscular junction occurred in advance of axonal pathology and by a mechanism morphologically distinct from Wallerian degeneration. Dying-back pathology in Wasted mice was accompanied by reduced expression levels of the zinc finger protein ZPR1, as found in other dying-back neuropathies such as spinal muscular atrophy. Surprisingly, experimental nerve lesion revealed that Wallerian degeneration was significantly delayed in homozygous Wasted mice; morphological assessment revealed that ~80% of neuromuscular junctions in deep lumbrical muscles at 24 h and ~50% at 48 h had retained motor nerve terminals following tibial nerve lesion. This was in contrast to wild-type and heterozygous Wasted mice where < 5% of neuromuscular junctions had retained motor nerve terminals at 24 h post-lesion. These data show that eEF1A2 expression is required to prevent the initiation of dying-back pathology at the neuromuscular junction in vivo. In contrast, loss of eEF1A2 expression significantly inhibited the initiation and progression of Wallerian degeneration in vivo. We conclude that loss of eEF1A2 expression distinguishes mechanisms underlying dying-back pathology from those responsible for Wallerian degeneration in vivo and suggest that eEF1A2 -dependent cascades may provide novel molecular targets to manipulate neurodegenerative pathways in lower motor neurons. [source]

Malignant Ventricular Arrhythmia in a Case of Adult Onset of Spinal Muscular Atrophy (Kugelberg,Welander Disease)

The emerging role of epigenetic modifications and chromatin remodeling in spinal muscular atrophy

Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2009
Gyula Acsadi
Abstract Mutations of the survival motor neuron (SMN) gene in spinal muscular atrophy (SMA) lead to anterior horn cell death. The cause is unknown, but motor neurons depend substantially on mitochondrial oxidative phosphorylation (OxPhos) for normal function. Therefore, mitochondrial parameters were analyzed in an SMA cell culture model using small interfering RNA (siRNA) transfection that decreased Smn expression in NSC-34 cells to disease levels. Smn siRNA knock-down resulted in 35% and 66% reduced Smn protein levels 48 and 72 hr posttransfection, respectively. ATP levels were reduced by 14% and 26% at 48 and 72 hr posttransfection, respectively, suggesting decreased ATP production or increased energy demand in neural cells. Smn knock-down resulted in increased mitochondrial membrane potential and increased free radical production. Changes in activity of cytochrome c oxidase (CcO), a key OxPhos component, were observed at 72 hr with a 26% increase in oxygen consumption. This suggests a compensatory activation of the aerobic pathway, resulting in increased mitochondrial membrane potentials, a condition known to lead to the observed increase in free radical production. Further testing suggested that changes in ATP at 24 hr precede observable indices of cell injury at 48 hr. We propose that energy paucity and increased mitochondrial free radical production lead to accumulated cell damage and eventual cell death in Smn-depleted neural cells. Mitochondrial dysfunction may therefore be important in SMA pathology and may represent a new therapeutic target. © 2009 Wiley-Liss, Inc. [source]

Cognitive impairment in neuromuscular disorders

MUSCLE AND NERVE, Issue 1 2006
Maria Grazia D'Angelo MD
Abstract Several studies have suggested the presence of central nervous system involvement manifesting as cognitive impairment in diseases traditionally confined to the peripheral nervous system. The aim of this review is to highlight the character of clinical, genetic, neurofunctional, cognitive, and psychiatric deficits in neuromuscular disorders. A high correlation between cognitive features and cerebral protein expression or function is evident in Duchenne muscular dystrophy, myotonic dystrophy (Steinert disease), and mitochondrial encephalomyopathies; direct correlation between tissue-specific protein expression and cognitive deficits is still elusive in certain neuromuscular disorders presenting with or without a cerebral abnormality, such as congenital muscular dystrophies, congenital myopathies, amyotrophic lateral sclerosis, adult polyglucosan body disease, and limb-girdle muscular dystrophies. No clear cognitive deficits have been found in spinal muscular atrophy and facioscapulohumeral dystrophy. Muscle Nerve, 2006 [source]

Gene-based treatment of motor neuron diseases,

MUSCLE AND NERVE, Issue 3 2006
Thais Federici PhD
Abstract Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation. Muscle Nerve, 2005 [source]

Oxidative stress in developmental brain disorders

NEUROPATHOLOGY, Issue 1 2009
Masaharu Hayashi
Oxidative stress is one of the predisposing factors in adult neurological disorders. We have examined the involvement of oxidative stress in child-onset neurodegenerative disorders, and here we review the findings from our analysis. In cases of Cockayne syndrome, the oxidative products of lipids and proteins were increased in the globus pallidus; however, oxidative nucleotide damage that coincided with reduced copper/zinc superoxide dismutase (Cu/ZnSOD) expression was observed in cases of xeroderma pigmentosum, and these patients also presented increased oxidative stress markers in urine samples. In spinal muscular atrophy, lipid peroxidation in conjunction with oxidative DNA damage was observed in motor neurons. Cases of subacute sclerosing panencephalitis presented oxidative nucleoside damage in cerebral cortical neurons at early disease stages, which were subsequently replaced by lipid peroxidation in glial cells of cerebral white matter. In relation to progressive myoclonic epilepsy, oxidative damage to DNA, proteins, and lipids appeared to coincide with cerebral and cerebellar cortical lesions of neuronal ceroid-lipofuscinosis. Patients with Lafora disease also presented an increase in oxidative stress markers for DNA and/or lipids in the brain and urine. These findings imply involvement of oxidative stress in developmental brain disorders; antioxidant agents could prove to be useful for treating patients with those disorders. [source]

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

PATHOLOGY INTERNATIONAL, Issue 10 2003
Chisato Nakada
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. [source]

Home care for chronic respiratory failure in children: 15 years experience

PEDIATRIC ANESTHESIA, Issue 4 2002
L. APPIERTO MD
Background:,Advances in paediatric intensive care have reduced mortality but, unfortunately, one of the consequences is an increase in the number of patients with chronic diseases. It is generally agreed that home care of children requiring ventilatory support improves their outcomes and results in cost saving for the National Health Service. Methods:,Since 1985, the Children's Hospital Bambino Gesù of Rome has developed a program of paediatric home care. The program is performed by a committed Home Health Care Team (HHCT) which selects the eligible patients for home care and trains the families to treat their child. During the period January 1985 to January 2001, 53 children with chronic respiratory failure were included in the home care program. Of these, seven patients were successively excluded and six died in our intensive care unit (ICU), while one still lives in our ICU since 1997. The results obtained in the remaining 46 children are reported. Results:,The pathologies consisted of disorders of respiratory control related to brain damage (26%), upper airways obstructive disease (26%), spinal muscular atrophy (22%), myopathies and muscular dystrophies (6.5%), bronchopulmonary dysplasia (6.5%), tracheomalacia (6.5%), central hypoventilation syndrome (4.3%) and progressive congenital scoliosis (2.2%). Of these 46 patients, 34 children are mechanically ventilated and the median of their ICU stay was 109.5 days (range 54,214 days), while the remaining 12 children were breathing spontaneously and the median of their ICU stay was 90.5 days (range 61,134 days). We temporarily readmitted six patients to our ICU to perform scheduled otolaryngological surgery, eight patients for acute respiratory infections and two patients for deterioration of their neurological status due to high pressure hydrocephalus for placement of a ventriculoperitoneal shunt; these 16 patients were discharged back home again. Two other patients were readmitted for deterioration of their chronic disease and died in our ICU, while seven patients died at home. Conclusions:,Thirty-seven children are still alive at home and four of them improved their respiratory condition so that it was possible to remove the tracheostomy tube. Our oldest patient has now achieved 15 years of mechanical ventilation at home. [source]

C117T variant in the SMN1 gene found in the Japanese population

PEDIATRICS INTERNATIONAL, Issue 1 2007
AHMAD HAMIM SADEWA
Abstract Background: The SMN genes are closely related to the development of spinal muscular atrophy (SMA); mutated SMN1 causes SMA and functional SMN2 modifies the severity of SMA. SMN1 and SMN2 are almost identical, being distinguished by only five base pair substitutions located at the 3'-end of the genes. Recently, a synonymous DNA variant, C117T, has been identified at the first codon of SMN2 exon 2a in the Caucasian population. It is still a question whether the variant is specific to the Caucasian population, and whether it is found only in SMN2. In order to address these questions, Japanese populations were screened for the presence of C117T in the SMN genes. Methods: To detect the C117T variant in a Japanese population, polymerase chain reaction,restriction fragment length polymorphism was performed in 33 SMA patients homozygous for SMN1 deletion and 106 control individuals. Reverse transcription,polymerase chain reaction (RT-PCR) was performed to clarify whether the variant affects the splicing process of the SMN1 gene. Results: The C117T variant was found in one out of 33 Japanese SMA patients (3.0%) and in seven out of 106 Japanese control individuals (6.6%). There was no significant difference between frequencies in the present data and those reported from the Caucasian population. Notably, the C117T variant was also detected in the SMN1 gene; a control individual with homozygous SMN2 deletion was found to have the variant on one of the SMN1 genes. RT-PCR indicated that this variant of the SMN1 gene was normally transcribed and did not affect the splicing process in this individual. Conclusions: The C117T variant was found not only in the Caucasian population, but also in the Japanese population. In addition, the variant was not specific to SMN2: it was also found in SMN1. RT-PCR indicated that the variant did not affect the splicing process. [source]

Validity of the EK scale: a functional assessment of non-ambulatory individuals with Duchenne muscular dystrophy or spinal muscular atrophy

PHYSIOTHERAPY RESEARCH INTERNATIONAL, Issue 3 2001
Birgit Steffensen
Abstract Background and Purpose The EK scale comprises ten categories (EK 1,10), each contributing to an overall picture of function in the non-ambulatory stage of Duchenne muscular dystrophy (DMD). The purpose of the present study was to investigate content and construct validity of the EK scale as a tool to discriminate between levels of functional ability in individuals with DMD or spinal muscular atrophy (SMA) who were non-ambulatory. Method Data from a sample of 56 subjects with DMD and 38 with SMA, who were non-ambulatory, were obtained from four separate studies. The relationship of functional ability by use of the EK scale and (1) muscle strength, (2) contractures, (3) forced vital capacity and (4) years of wheelchair dependency were assessed. All items of the EK scale were used except the one representing severe hypoventilation. Results Regression analyses showed that the EK sum was the most significant explanatory variable (p<0.05) of all variables measured to explain muscle strength in both DMD and SMA subjects. The individual categories of EK (1,10) all contributed as significant explanatory variables (p<0.05) to the other variables measured. Conclusions The categories and items of the EK scale were relevant and valid as means of discriminating between levels of functional performance in the population studied which was evidence of content and construct validity. Copyright © 2001 Whurr Publishers Ltd. [source]

Prenatal diagnosis of spinal muscular atrophy: Indian scenario

PRENATAL DIAGNOSIS, Issue 8 2005
Akanchha Kesari
Abstract Objectives To study the psychosocial issues associated with prenatal diagnosis of SMA in India and the use of SMN1 copy number analysis for carrier detection prior to offering prenatal diagnosis. Methods Homozygous deletion of SMN1 gene was done by PCR-RFLP. Copy number analysis of SMN1 gene was performed by quantitative PCR. Results We report our experience of eight cases of prenatal diagnosis for SMA and the use of carrier detection prior to offering prenatal diagnosis. Quantitative PCR results show that SMN1 copy number analysis is useful to identify couples at risk. Conclusion Case analyses depict unique psychosocial issues associated with prenatal diagnosis of SMA from India. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Sustained improvement of spinal muscular atrophy mice treated with trichostatin a plus nutrition

ANNALS OF NEUROLOGY, Issue 4 2008
Heather L. Narver VMD
Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients. Ann Neurol 2008; 64:465,470 [source]

Prenatal diagnosis for risk of spinal muscular atrophy

BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 11 2002
I. Cuscó
Objectives Prenatal diagnosis of spinal muscular atrophy is usually performed in high risk couples by detection of a homozygous deletion in the survival motor neurone gene (SMN1). However, other relatives at risk of being carriers very often request genetic counselling and the possibility of prenatal diagnosis. The aim of this study was to validate a SMN1 gene quantitative test to help the couples formed by one spinal muscular atrophy carrier and a partner of the general population (1/200 potential risk) to achieve a less ambiguous risk result for the pregnancy. Design Spinal muscular atrophy carrier studies in at-risk individuals. Setting Department of Genetics and Gynaecology and Obstetrics in a large university hospital. Population Seventy-nine obligate carriers (more than one affected child with deletion in the offspring) and 58 non-carriers (relatives of spinal muscular atrophy families defined by marker studies) were tested to set up a quantitative analysis. The method was applied in different situations in 126 members from 34 families with spinal muscular atrophy patients. Methods DNA studies of the SMN1 gene by marker analysis and quantitative assay. Main outcome measures To determine double (non-carrier) or single dose (carrier) of exon 7 of the SMN1 gene in relatives of spinal muscular atrophy patients. Bayesian calculation of risk. Results The sensitivity and specificity of the method were 96% and 100%, respectively. Studies on different couples with an a priori risk of 1/200 allowed us to reduce the final risk to 1/5000 or to increase it to 1/4. Conclusions The quantitative method can be used to achieve a less ambiguous risk in pregnancies with a 1/200 risk and in families where no sample is available to study the index case. Screening of gamete donors when the recipient is a known carrier should also be considered. [source]

Enuresis and urinary incontinence in children and adolescents with spinal muscular atrophy

BJU INTERNATIONAL, Issue 4 2001
A. Von Gontard
Objective To assess the rate and type of urinary incontinence in a large sample of children and adolescents with spinal muscular atrophy (SMA), a genetic disorder characterized by loss of motor function caused by anterior horn degeneration. Patients, subjects and methods The study included 96 severely incapacitated patients with SMA (aged 6.0,18.11 years) who were examined in detail, including a structured interview (Kinder-DIPS), the Child Behaviour Checklist (CBCL) and a specific questionnaire for urinary incontinence. They were compared with two control groups of unaffected siblings and normal children. Results In all, 29% of the patients were wet at night and/or during the day; mostly younger children with SMA types I and II only were affected. The results of the interview were more reliable than the CBCL. The specific questionnaire revealed a variety of possible functional and neurogenic forms of wetting, including nocturnal enuresis, voiding postponement, dysfunctional voiding, stress, symptomatic (urinary tract infections, UTIs) and neurogenic incontinence. Many patients were constipated, soiled or had UTIs. The rate of behavioural problems was twice as high (32%) as normal (15%; CBCL). Conclusion Children with SMA have a high rate of urinary incontinence which is often overlooked, and not diagnosed and treated adequately. These problems should be addressed routinely by paediatricians in children referred to paediatric urological specialists. [source]