Introduction

Spinal muscular atrophy (SMA) is a genetic disorder which affect nervous system and is characterized with progressive distal motor neuron weakness. SMA is a hereditary (autosomal recessive) neuromuscular disease which leads to paralysis and death in childhood (1).  4 form of SMA were identified; type zero is the fetus form of disease which causes death in early infancy. 

1)      Type I: Infantile (Werdnig-Hoffmann disease)

2)      Type II: Intermediate (Dubowitz disease).

3)      Type III: Juvenile (Kugelberg–Welander disease)

4)      Type IV: adult onset (2).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a type of distal spinal muscular atrophy with diaphragm involvement; its clinical manifestation varies in different patients. Infants had severe symptoms from birth with frog like position or bell shaped deformity in chest. Foot deformities and contractures are common in SMARD1 patients (3). Disease pathology base is anterior horn motor neuron degeneration like SMA. And it is also an autosomal recessive disorder. SMARD1 is a rare condition and there are about 100 case report of this condition from all around the world (4).

The survival motor neuron (SMN) protein level reduces in patients with SMA. Two different genes code survival motor neuron protein in human genome. In SMA patients have homozygous changes of SMN1 with at least unique copy of SMN2.  Genetic changes in chromosome 5 q 13 (mutation, deletion, or rearrangement) are responsible for SMA (5-7). More than 95% of children with SMA have homozygous deletion of SMN I gene axons 7 and 8. Other patients might have changes in SMN II gene (5). Spinal muscular atrophy is the second common neuromuscular disease after Duchenne muscular dystrophy and its incidence is one in every 10000-25000 birth. SMA mortality and morbidity depends on the age at disease onset. Early onset form of SMA such as type zero and I are mortal in 95% of cases (6). Pulmonary complications like respiratory failure and infections are the most common cause of death (5). Male were affected in type I and II in comparison with female individuals (7). Consanguineous marriages are frequent in Iranian population, so it is estimated that SMA prevalence might be higher in our country (8).

Skeletal and intercostal muscles denervation lead to weakness, hypotony, hyporeflexia, respiratory failure, symmetric muscle atrophy and paralysis in patients with SMA. Manifestations are prominent in proximal muscle of lower extremities (9).

Children who suffer from spinal muscular atrophy show no sign of central nervous system involvement; loss of muscle tone (hypotony) poor sucking reflex, and floppy baby are the most common presentation in acute infantile form of SMA. Mean survival life is estimated about 6 months in this children and death happens due to Respiratory failure (10). Chronic infantile form manifestations are developmental motor lag, difficulties in standing or walking. Patients might survive for 30 years (2). Respiratory infections cause death in this type of SMA. Chronic juvenile type (Kugelberg–Welander disease) occurs after 18 months old and most of them have normal life span. Motor skills might disrupt in some cases. Type IV is similar to type III, and disease is benign (1). The aim of this study is to review Spinal muscular atrophy (SMA) clinical and molecular manifestations.   

Method and material

For reviewing SMA, we searched Pubmed. Our key word was spinal muscle atrophy in children. We filtered our results to abstract available, English articles in the past 5 years. We found 262 articles. Finally 8 articles we selected for review. Almost all articles were case reports or case series.   

Findings

The creatine kinase (CK) serum is in normal range in patients with SMA type I, CK level is slightly raised in other type of SMA (1). It was confirmed that CK level is normal in young patients and rises in older ones (11). Cerebrospinal fluid (CSF) indexes are normal in all patients (7). Electrodiagnostic (EDX) test demonstrate fasciculation, fibrillation, sharp waves with high amplitude. Electromyography (EMG) might show neroguenic damage in some patients with SMA (11). Muscle biopsy shows atrophy. Genetic analyses are necessary to confirm SMA diagnosis (8).  In table_1 result of molecular analysis in SMA patients showed.

Table_1: result of genetic assessment in SMA

It seems that deletion in SMN gene is responsible for SMA pathology and other deletion associate with severe presentation of SMA. SMN2 copy number is related to spinal muscular atrophy. Prenatal diagnosis can be confirmed by placental biopsy at 10 weeks of gestation.

Some studies suggested that ELIZA could detect small changes in SMN protein concentration and might be useful in SMA diagnosis (17). 

Discussion

Children who suffer from spinal muscular atrophy show no sign of central nervous system involvement; loss of muscle tone (hypotony) poor sucking reflex, and floppy baby are the most common presentation in acute infantile form of SMA. Mean survival life is estimated about 6 months in this children and death happens due to Respiratory failure (10). Chronic infantile form manifestations are developmental motor lag, difficulties in standing or walking. Patients might survive for 30 years (2). Respiratory infections cause death in this type of SMA. Chronic juvenile type (Kugelberg–Welander disease) occurs after 18 months old and most of them have normal life span. Motor skills might disrupt in some cases. Type IV is similar to type III, and disease is benign (1).

There is no curative treatment for spinal muscular atrophy, and supportive treatment should be considered to improve patients’ quality of life and independency. Splint, braces and orthoses could be used if needed (9).  Chest physiotherapy, oxygen and antibiotics could be customized to each case (10).

Fibroblast culture confirmed higher SMN2 gene expression after 4-phenylbutyrate (PBA) treatment in SMA type I, II, III (11). Hydroxyurea (HU) might promote SMN mRNA production and increases SMN2 gene expression (12).  Sodium valproate could improve muscle function in SMA type III and IV, valproate probable mechanism is promoting SMN2 gene transcription (13).

New treatment strategies focus on gene therapy or invent method to increase survival motor neuron protein level. In one study it was shown that salbutamol could be used in spinal muscular atrophy as a therapeutic option, but response to treat depends on SMN2 copy numbers (18).

Conclusion: spinal muscle atrophy is a relatively common neuromuscular disease, and genetic findings are important for its diagnosis and predict patients prognosis.