Search results for "spinal muscular atrophy"
showing 10 items of 26 documents
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
2018
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformati…
Drosophila SMN2minigene reporter model identifies moxifloxacin as a candidate therapy for SMA
2018
Spinal muscular atrophy is a rare and fatal neuromuscular disorder caused by the loss of alpha motor neurons. The affected individuals have mutated the ubiquitously expressed SMN1 gene resulting in the loss or reduction in the survival motor neuron (SMN) protein levels. However, an almost identical paralog exists in humans: SMN2. Pharmacological activation of SMN2 exon 7 inclusion by small molecules or modified antisense oligonucleotides is a valid approach to treat SMA. Here we describe an in vivo SMN2 minigene reporter system in Drosophila motor neurons that serves as a cost-effective, feasible, and stringent primary screening model for identifying chemicals capable of crossing the conser…
Apoptosis-related Proteins in Skeletal Muscle Fibers of Spinal Muscular Atrophy
1997
There is evidence that apoptosis in spinal muscular atrophies (SMA) is not restricted to motor neurons but also affects muscle fibers. Studying the expression of several apoptosis-associated proteins we found constant expression of bax in muscle fibers, which promoted cell death. The expression of bax correlated with defective innervation of muscle fibers was also indicated by upregulation of N-CAM. While in early-onset SMA atrophic as well as normo- and hypertrophic muscle fibers displayed expression of bax, muscle fibers in late-onset SMA and peripheral neuropathies showed bax-expression only in atrophic fibers. Other investigated apoptosis-associated factors comprised interleukin-1 beta …
Functional properties of motor units in motor neuron diseases and neuropathies.
1997
The relationship between the size of single motor unit (MU) action potentials and their twitch properties was estimated in patients with spinal muscular atrophy (SMA, n = 5) and amyotrophic lateral sclerosis (ALS, n = 10), as well as in patients with peripheral nerve lesions (PNL, n = 9). The data obtained from these groups were compared to normal controls (n = 8). In controls, the single MU twitch force was highly correlated to the corresponding EMG potential size in terms of macro EMG area. An enlargement of MUs, due to collateral sprouting and reflected by increased potential size and twitch force, was found in regenerating PNL and in slowly progressing SMA. Both parameters were highly c…
Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: hexosaminidase A deficiency with late clinical onset in fo…
1997
Tay-Sachs disease is a genetically determined neurodegenerative disorder, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminidase. Clinically, there is severe encephalomyelopathy leading to death within the first few years of life. Hex A activity is usually absent in tissue and body fluids of these patients. Juvenile and adult Hex A deficiencies are less severe but rare variants with some residual Hex A activity. All these variants are most prevalent among Ashkenazi Jews. We describe a non-Jewish family in which four adult brothers and sisters had markedly reduced Hex A activities and onset of symptoms in the second decade o…
Ultrasound-guided lumbar puncture for nusinersen administration in spinal muscular atrophy patients.
2020
Background and purpose The purpose was to report the results of ultrasound-guided lumbar puncture for the administration of nusinersen in spinal muscular atrophy (SMA) patients with complex spines. Methods Eighteen SMA patients (five children, five adolescents and eight adults) with either severe scoliosis or spondylodesis were evaluated for ultrasound-guided lumbar puncture. Ultrasound was performed with a 3.5 MHz transducer to guide a 22 gauge × 15 mm needle, which was placed in the posterior lumbar space following a parasagittal interlaminar approach. Results Twelve patients had undergone spinal instrumentation (nine growing rods and three spinal fusion) whilst the other six showed sever…
Homozygous SMN1 exons 1-6 deletion: pitfalls in genetic counseling and general recommendations for spinal muscular atrophy molecular diagnosis.
2012
We report on a rare homozygous intragenic deletion encompassing exons 1-6 of the SMN1 gene in a patient with spinal muscular atrophy (SMA) born into a consanguineous family. This exceptional configuration induced misinterpretation of the molecular defect involved in this patient, who was first reported as having a classic SMN1 exon 7 deletion. This case points out the possible pitfalls in molecular diagnosis of SMA in affected patients and their relatives: exploration of the SMN1 exon 7 (c.840C/T alleles) may be disturbed by several non-pathological or pathological variants around the SMN1 exon 7. In order to accurately describe the molecular defect in an SMA-affected patient, we propose to…
Carrier screening for spinal muscular atrophy in Italian population
2014
Spinal muscular atrophy (SMA) is an autosomal-recessive neuromuscular disorder characterized by motor neuron degeneration in the anterior horn of the spinal cord and brain stem, resulting in progressive muscle weakness and atrophy. The responsible survival motor neuron gene (SMN1; HGNC: 11117) is localized in 5q11.2-13.3. Screening for carriers of SMA is necessary for effective clinical/prenatal diagnosis and genetic counselling. In this study, the copy number of SMN1 gene was determined from a southern Italian population to estimate carrier frequency. This is the first report addressing the estimation of SMA carrier frequency in an Italian population. Our results show that the SMA carrier …
Post-translational modifications in the survival motor neuron protein
2004
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by a progressive loss of the spinal motoneurons. The SMA-determining gene has been termed survival motor neuron (SMN) and is deleted or mutated in over 98% of patients. The encoded gene product is a protein expressed as different isoforms. In particular, we showed that the rat SMN cDNA produces two isoforms with Mr of 32 and 35 kDa, both localized in nuclear coiled bodies, but the 32 kDa form is also cytoplasmic, whereas the 35 kDa form is also microsomal. To determine the molecular relationship between these two isoforms and potential post-translational modifications, we performed transfection experiments with a …
Survival of patients with spinal muscular atrophy type 1.
2013
BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive disease and is usually fatal in the first year of life. METHODS: A retrospective chart review was performed of SMA1 patients and their outcomes according to the following choices: letting nature take its course (NT); tracheostomy and invasive mechanical ventilation (TV); continuous noninvasive respiratory muscle aid (NRA), including noninvasive ventilation; and mechanically assisted cough. RESULTS: Of 194 consecutively referred patients enrolled in this study (103 males, 91 females), NT, TV, and NRA were chosen for 121 (62.3%), 42 (21.7%), and 31 (16%) patients, respectively. Survival at ages 24 and 48 months was higher in …