Incidence and prevalence.: Incidence and prevalence. Although rare, SMA is the most common fatal neuromuscular disease of infancy and the third most common diagnosis of neuromuscular diseases seen in clinics for children 18 years. (Iannaccone ST et al),2005 One in 50 people carries this autosomal recessive GeneSMA I has the highest incidence of the three types, but because these children usually do not survive past age 2 years, SMA II and III are more prevalent than SMA I.5 Estimates based on a national voluntary registry and a few prospective studies give a frequency of 8 to 11 per 100,000 live births.True adult onset of all cases acount less than 10% with mean age at onset is 30 year,ranges from 20 to late 40.
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SMA type I is called Werdnig-Hoffmann disease or infantile onset SMA: SMA type I. SMA type I is called Werdnig-Hoffmann disease or infantile onset SMA Weakness and profound hypotonia are noticeable in the first few months of life.(less than 6 month) There is a striking discrepancy between the infant’s normal social awareness and Interaction and motor development. Spontaneous movements are very limited except in the hands and feet, and the infant lies on his or her back in a frog-leg position. Deep tendon reflexes are absent but sphincter tone and sensation are intact.Polyminimyoclonus, or muscle trembling, can be seen in the fingers, and fasciculations are often present in the tongue. Because intercostal muscles are weak, the diaphragm is used to breathe and pectus excavatum and flaring of the lower ribs result; sparing facial and extra ocular muscle. The babies tire easily when feeding and may lose weight and fail to thrive. Both weaknesses from malnutrition and respiratory insufficiency cause susceptibility to aspiration.
The most common cause of death is respiratory failure; children rarely survive beyond age 2 years. In type 2 disease, intermediate orjuvenile SMA: SMA type II. In type 2 disease, intermediate orjuvenile SMA Milestones are usually normal until onset of weakness between 6 and 18 months of age.The legs tend to be weaker than the arms, so children often come to medical attention because of failure to walk. The pattern of deep tendon reflexes may be variable.
Children can sit without support when placed, sometimes walk with bracing, and are now surviving into adolescence and beyond. Good pulmo- nary function and care seems to be a key to prolonged survival. SMA type III. In patients with the mildest form,type 3 (Kugelberg-Welander disease),: SMA type III. In patients with the mildest form,type 3 (Kugelberg-Welander disease), Onset of apparent weakness may be anytime after age 18 months, but is often in late childhood or adolescence. It may be confused with limbgirdle muscular dystrophy.
The gait is typically waddling with lumbar lordosis, genu recurvatum, and a protuberant abdomen. Deep tendon reflexes may be present or absent. Independent ambulation is achieved and survival is usually normal.Patients with SMA III with onset 3 years of age have a less severe form and are classified as SMA IIIb to distinguish them from the more severe cases starting before 3 years (SMA IIIa)If onset of weakness is later than age 2 years, it is highly likely that ambulation will be possible into the fifth decade or beyond. Although the clinical picture may not be typical of a neurodegenerative disease, a decrease in motor units over time has been documented. Spinal-bulbar muscular atrophy (SBMA or Kennedy disease): Spinal-bulbar muscular atrophy (SBMA or Kennedy disease) SBMA is a relatively benign motor neuron disorder. It has been suggested that SBMA has little effect on survival.It is is caused by expanded polyglutamines within the androgen receptor protein encoded by exon 1 of the androgen receptor gene.(x linked recessive) Age at onset or severity of disease has been weakly linked to increased size of CAG trinucleotide expansion.
Patients with SBMA typically present with progressive neuromuscular weakness that most commonly includes the bulbar muscles. Fasciculations are a prominent feature of both.Patients have varied involvement of the lower motor and sensory neurons and endocrine systems(testcular atrophy,feminization,inferrtility,diabetes and gynecomastia ). Slide 19: While SBMA may have a number of non-neurologic features, it is the neurologic deficits that are the most problematic.
Patients with SBMA have varied phenotypes From asymptomatic to progressive limb and bulbar weakness mimicking amyotrophic lateral sclerosis (ALS). Some patients may present in an asymptomatic period with elevated creatine kinase or transaminases.D /D: The neurologic deficits associated with SBMA are very similar to those of ALS.
The principal difference is the absence of upper motor neuron involvement in SBMA and the X-linked inheritance pattern. SMA is an autosomal recessive disorder caused by homozygous deletions or mutations of the SMN1 gene at the 5 q11 locus which result in reduction of full length (fl-SMN) protein necessary for lower motor neuron function.
There are two copies of the SMN gene on chromosome 5q that code for SMN protein: SMN1 and SMN2. SMN1 encodes fl-SMN protein, while SMN2 mostly encodes a protein that is lacking in exon 7 (7-SMN, a less stable protein).
The severity of the disease can be modified by extra copies of the SMN2 gene. All patients have reduced levels of fl-SMN protein, but those with the phenotype of SMA type 1 have as little as 9% of the normal amount of fl-SMN, those with SMA type 2 have 14%, and with SMA type 3, about 18%.
Once fl-protein levels approach 23% of normal levels, motor neuron function appears normal, and carriers usually have 45 to 55% fl-SMN protein. Therapeutic chalanges and research: Therapeutic chalanges and research Since the disease phenotype is proportional to the amount of fl-SMN present, one strategy for pharmacologic intervention in SMA is to enhance production of fl SMN. Mechanisms for potential specific therapies include enhanced expression of the SMN2 gene, altering SMN2 transcript splicing to increase the level of fl-SMN RNA, HDAC inhibitors used in humans for other clinical conditions are phenylbutyrate and hydroxyurea. Studies of sodium butyrate in a mouse model and lymphoid cell lines from patients with SMA showed promise, as have cell culture studies of valproic acid.
Acyclorubicin has shown ability to raise SMN levels in fibroblasts from patients with SMA I, but has a high toxicity profile. Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H.Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci USA 20–9813. Sumner CJ, Huynh TN, Markowitz JA, et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells.
Ann Neurol 2003.Brichta L, Hofmann Y, Hahnen E, et al. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet 20–2489.Jarecki J, Chen J, Whitney M, et al. Identification and profiling of compounds that increase full-length SMN2 nRNA levels.
Presented at the Sixth Annual International Spinal Muscular Atrophy Research Group Meeting; Chicago, IL; 2002.