0021-7557/10/86-04/261 Jornal de Pediatria Copyright © 2010 by Sociedade Brasileira de Pediatria REVIEW ARTICLE Spinal muscular atrophy: diagnosis, treatment and future prospects Mariana T. C. Baioni,1 Celia R. Ambiel2 Abstract Objective: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. Sources: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. Summary of the findings:SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients’ lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. Conclusions: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients’ residual muscle function, as well as offering better quality of life and life expectancy. J Pediatr (Rio J). 2010;86(4):261-270: Spinal muscular atrophy, motor neuron, therapy, SMN1 gene, SMN protein, valproic acid. Introduction Spinal muscular atrophy (SMA) is a neurodegenerative This genetic alteration to the SMN1 gene is responsible disease with autosomal recessive heredity. After cystic for a reduction in survival motor neuron (SMN) protein. The fibrosis (1:6,000), SMA is the next most fatal disease with SMN2 gene does not completely compensate for the absence this genetic profile, with an incidence of 1:6,000 to 1:10,000 of SMN1 expression because it only produces 25% of SMN births.1 The frequency of carriers (heterozygotes) is one protein.4 The lack of the SMN protein leads to degeneration in 40 to 60 people.2 of alpha (α) motor neurons located in the ventral horn of This disease is caused by a homozygous mutation or the spinal cord, which leads to progressive and symmetrical muscle weakness and paralysis.2 deletion of the survival motor neuron gene 1 (SMN1), which should be located in the telomeric region of chromosome Clinical classification of SMA is based on age at onset 5q13. The principal determinant of severity is the number and maximum motor function acquired, with the following of copies of SMN2, a gene that is similar to SMN1 and is categories: 1) severe (type I, severe SMA or Werdnig- located in the centromeric region.3 Hoffmann disease); 2) intermediate (type II or chronic 1. Especialista, Fisiologia Humana, Universidade Estadual de Maringá (UEM), Maringá, PR, Brazil. 2. Doutora, Biologia Celular. Professora, Fisiologia Humana, UEM, Maringá, PR, Brazil. No conflicts of interest declared concerning the publication of this article. Suggested citation: Baioni MT, Ambiel CR. Spinal muscular atrophy: diagnosis, treatment and future prospects. J Pediatr (Rio J). 2010;86(4):261-270. Manuscript submitted Aug 26 2009, accepted for publication Oct 14 2009. doi:10.2223/JPED.1988 261 262 Jornal de Pediatria - Vol. 86, No. 4, 2010 Spinal muscular atrophy - Baioni MT & Ambiel CR SMA); 3) mild (type III, juvenile SMA or Kugelberg-Welander Type III SMA: (also known as juvenile SMA or Kugelberg- disease); and 4) type IV (adult SMA).3 Other authors5-7 Welander syndrome) onset is after 18 months, but the actual classify SMA into just three categories: severe, intermediate age varies greatly. According to Wirth et al.,10 when the and mild. disease emerges before 3 years of age it is classified as Type SMA is a difficult disorder to diagnose and treatment IIIa SMA, whereas when onset is later, it is called Type IIIb is uncertain. Diagnosis is based on evidence, both SMA. The difference between the two is preservation of the electrophysiological and histological, of denervation of the ability to walk. Patients with Type IIIa are able to walk until muscle.3 Nowadays, diagnosis is confirmed by molecular they are 20, while Type IIIb patients will be able to walk for 11 analysis to demonstrate an absent SMN1 gene exon 7.2 their whole lives. Problems with swallowing, coughing or nocturnal hypoventilation are less common than in patients Since this is a progressive neurodegenerative disease, with Type II, but may still be observed. As they age, these patients with SMA require special care, which can halt patients may develop scoliosis. The principal characteristic disease progression and prolong their lives. The objective of these patients is that they are able to walk independently, of this bibliographic review article is to describe the clinical and life expectancy is indeterminate.3 and laboratory profile of SMA patients and report on recent genetic and molecular discoveries and the future prospects Type IV SMA: there is no consensus on the age of onset 3 for treatment, thereby aiding health professionals to of Type IV SMA. Russman reports that it emerges after 10 8 make rapid diagnoses and provide early and appropriate years of age, whereas Wang et al. state that weakness therapeutic support. normally emerges during the second or third decade of life, or at about 30 years of age. Motor function involvement is mild and there are no problems with deglutition or Development respiration. These patients are able to walk normally and Classification of SMA have normal life expectancy.3,8 There are four SMA classifications, based on age at disease onset and maximum motor function acquired. Clinical features of SMA Type I SMA: (also known as severe SMA, Werdnig- Since only α motor neurons are lost progressively, only Hoffmann disease or acute SMA) is characterized by early motor function is compromised and sensory neurons are onset (between 0 and 6 months of age), by a failure to unaffected. This loss of function leads to weakness and to acquire the ability to sit up and by very short life expectancy progressive symmetrical atrophy of the proximal voluntary (less than 2 years).3 Children diagnosed with this form have muscles of the legs, arms and, sometimes, the trunk, as very little control of their heads and cough and cry weakly. the disease progresses.8 They lose the ability to swallow and feed before they reach A number of unusual clinical features are observed in 1 year of age. Trunk and limb weakness normally spreads SMA. One of these is the distribution of muscle weakness, to the intercostal muscles, making it unlikely that a normal which is more compatible with a myopathic disorder than respiratory cycle will develop. Although the intercostal with a neurogenic disorder.12 Proximal muscles are more muscles are affected, the diaphragm is initially spared. involved than distal muscles, legs are more affected The risk of early mortality is usually associated with bulbar than arms and arms are more affected than the face and 8 dysfunction and respiratory complications. Historically, diaphragm.8,12 In other words, muscle weakness and atrophy these children have a short life expectancy (less than 2 does not have a homogeneous distribution. The severity years), but, thanks to improved clinical care, over recent of muscle weakness is related to age at onset and children 9 years survival has improved. with the most severe form of the disease (Type I SMA) Type II SMA: (or chronic SMA) generally becomes can appear normal at birth, but present muscle weakness symptomatic at around 6 to 18 months, but it may emerge a few months later.8 earlier. Some patients classified as having type II SMA Furthermore, the clinical course followed by SMA patients are able to sit up unaided while others can remain sitting who survive beyond childhood demonstrates that loss of if they are positioned, but cannot sit up unaided.3 Better muscle strength is normally most evident at diseases onset developed patients are able to remain standing if provided and that, after this, residual muscle power can remain stable with support, but will nevertheless be unable to learn to walk. for months or years.12,13 Bulbar weakness, combined with swallowing difficulties, can lead to reduced weight gain in some children. Furthermore, these patients may have problems with coughing and Molecular genetic basis of SMA with cleaning secretions from the trachea, may have fine Genetic studies have shown that SMA is caused by trembling (known as fasciculation) and can suffer from absence of the SMN1 gene, which should be located in scoliosis and contractures as they age.8 Life expectancy is the telomeric region of chromosome 5.12,14,15 This gene around 10 to 40 years.3,8 was identified in 1995 by Lefebvre et al.16 and has nine Spinal muscular atrophy - Baioni MT & Ambiel CR Jornal de Pediatria - Vol. 86, No. 4, 2010 263 exons that code for the SMN protein. All patients still The SMN protein is widely distributed in all cells of 18,22 retain at least one copy of a very similar gene - SMN2 the body. It is found in the nuclei of cells and within – which is located in the centromeric part of the same the nucleus it binds to certain structures involved with chromosome. The absence of SMN1 is caused either by removing non-coding sequences (introns) from the pre- a deletion or by a conversion that transforms SMN1 into MRNA (messenger ribonucleic acid).