Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human genome has two homologous survival motor neuron genes, SMN1 and SMN2. Although deletions of SMN1 are frequently reported in childhood-onset spinal muscular atrophy (SMA), SMN2 have been found to be intact in patients with the disorder. We report on a 5-year-old boy with childhood-onset SMA who has a homozygous deletion of SMN2. He had wasting, weakness, and hyporeflexia, predominantly in the distal muscles. The muscles involved showed chronic neurogenic changes on electromyogram. There was no sensory involvement. A nerve conduction study showed near normal conduction velocity with reduction in the amplitude of the compound muscle action potential. Analysis of polymerase chain reaction-restriction fragment length polymorphism as well as single-strand conformation polymorphism on exons 7 and 8 of the SMN genes revealed the SMN2-deletion. Base sequencing and densitometric analysis of the critical region (exon 7) did not show any microdeletion or duplication of SMN1, but confirmed the deletion of SMN2. We conclude that a deletion of SMN2 may also result in the SMA phenotype.
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PMID:SMN2-deletion in childhood-onset spinal muscular atrophy. 1197 91

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disorder characterised commonly by proximal muscle weakness and wasting in the absence of sensory signs. Deletion or disruption of the SMN1 gene causes the disease. The SMN1 gene is located within an inverted duplication on chromosome 5q13 with the genes SMN2, NAIP and GTF2H2. MLPA analysis of 13 Cypriot SMA patients revealed that, 12 patients carried a homozygous SMN1 gene deletion and one patient carried two copies of the SMN1 gene. Two of 13 cases were a consequence of a paternally originating de novo mutation. Five genotypes were identified within the population, with the most frequent being a homozygous SMN1 and NAIP genes deletion. In conclusion, genotype-phenotype correlation revealed that SMN2 is inversely related to disease severity and that NAIP and GTF2H2 act as negative modifiers. This study provided, for the first time, a comprehensive overview of gene copy numbers and inheritance patterns within Cypriot SMA families.
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PMID:Genetic findings of Cypriot spinal muscular atrophy patients. 2601 50

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.
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PMID:Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy. 2879 78