Atrophy
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The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.
SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.
In 1995, the spinal muscular atrophy disease-causing gene, termed the survival motor neuron (SMN), was discovered. [9] Each individual has 2 SMN genes, SMN1 and SMN2. More than 95% of patients with spinal muscular atrophy have a homozygous disruption in the SMN1 gene on chromosome 5q, caused by mutation, deletion, or rearrangement. However, all patients with spinal muscular atrophy retain at least 1 copy of SMN2, which generates only 10% of the amount of full-length SMN protein versus SMN1. This genomic organization provides a therapeutic pathway to promote SMN2, existing in all patients, to function like the missing SMN1 gene. [10]
The mortality and/or morbidity rates of spinal muscular atrophy are inversely correlated with the age at onset. High death rates are associated with early onset disease. In patients with SMA type I, the median survival is 7 months, with a mortality rate of 95% by age 18 months.
Call your doctor to schedule a complete medical examination if you believe you may have muscle atrophy or if you are unable to move normally. You may have an undiagnosed condition that requires treatment.
Optic disc atrophy typically shows focal, wedged-shaped temporal optic atrophy, however diffuse atrophy may be present. As the primary pathology is the papillomacular bundle, central, centrocecal and paracentral scotomas are the most common visual field defects. Color vision deficits are common. Visual-evoked responses in affected individuals show diminished amplitudes and prolonged latencies. Pattern electroretinograms show a reduced N95 component [5].
Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder.
Spinal muscular atrophy is a group of inherited disorders that cause progressive muscle degeneration and weakness. Spinal muscular atrophy (SMA) is the second leading cause of neuromuscular disease. It is usually inherited as an autosomal recessive trait (a person must get the defective gene from both parents to be affected).
There are several types of SMA called subtypes. Each of the subtypes is based on the severity of the disorder and the age at which symptoms begin. There are three types of SMA that affect children before the age of 1 year. There are two types of SMA, type IV and Finkel type, that occur in adulthood, usually after age 30. Symptoms of adult-onset spinal muscular atrophy are usually mild to moderate and include muscle weakness, tremor and twitching.
Three types of SMA affect children before age one year. Type 0 is the most severe form of spinal muscular atrophy and begins before birth. Usually, the first symptom of type 0 is reduced movement of the fetus that is first seen between 30 and 36 weeks of the pregnancy. After birth, these newborns have little movement and have difficulties with swallowing and breathing.
Type I spinal muscular atrophy (called Werdnig-Hoffman disease) is another severe form of SMA. Symptoms of type 1 may be present at birth or within the first few months of life. These infants usually have difficulty breathing and swallowing, and they are unable to sit without support.
Type III SMA (called Kugelberg-Welander disease or juvenile type) is a milder form of SMA than types 0, I or II. Symptoms appear between early childhood (older than age 1 year) and early adulthood. Individuals with type III SMA are able to stand and walk without help. They usually lose their ability to stand and walk later in life. There are two other types of spinal muscular atrophy, type IV and Finkel type that occur in adulthood, usually after age 30. Symptoms of adult-onset SMA are usually mild to moderate and include muscle weakness, tremor and twitching.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life.
Spinal muscular atrophy (SMA) is a severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. The disease was first described in the 1890s by Werdnig [1] and by Hoffmann [2]. The genetic defect was localized to 5q11.2-q13.3 a century later [3] with the identification of the survival motor neuron gene (SMN) gene as the disease-causing gene in 1995 [4].
Two almost identical SMN genes are present on chromosome 5q13: the telomeric or SMN1 gene, which is the spinal muscular atrophy- determining gene, and the centromeric or SMN2 gene.
SMN genes encode for SMN protein which is ubiquitously expressed and localized in the cytoplasm and in the nucleus, and is particularly abundant in motor neurons of the spinal cord [25]. Within the nucleus, SMN protein is concentrated in dot-like structures associated with coiled (Cajal) bodies, named \"gems\" (gemini of coiled bodies) [26]. Although the exact cellular function of SMN protein responsible for the pathogenesis of SMA remains unknown, cells from patients with spinal muscular atrophy contain fewer gems compared controls and carriers [26].
Animal models by disruption of SMN has been obtained in yeast, nematode, fly, zebrafish, and mouse. These models of spinal muscular atrophy have not only been fundamental for increasing knowledge about the molecular and cellular pathways of SMN, but also to better understand the mechanism(s) of disease, and to provide a platform from which high-throughput genetic and drug screens can be performed [27]. However Spinal muscular atrophy mutant mice that die soon after birth (low copy SMN2+/+;Smn -/-) preclude detailed analysis of pathogenic mechanisms and preclinical drug testing [28] However, this disease severity can be tempered to intermediate and mild phenotypes by adding additional transgenes that express various wild-type isoforms or weak mutant forms of SMN [29]. 59ce067264