Spinal muscular atrophies are a group of neurodegenerative disorders in which genetic mutations lead to progressive damage of motor neurons in the spinal cord. Type 1 is most severe, with a very early onset of numerous symptoms that lead to death within the first few years of life in the vast majority of cases. The diagnosis rests on clinical and laboratory criteria. Supportive measures are currently the mainstay of therapy.
The clinical presentation of SMA type 1 starts during the first six months of life, when failure to sit up is noted, as well as a weak cry, swallowing and feeding difficulties, and inability of infants to control their heads  . Hypotonia and weakness of the limbs is frequently seen, and is usually accompanied by intercorstal muscle weakness, resulting in a bell-shaped trunk, chest wall collapse and abdominal prolapse due to excessive activation of abdominal muscles in respiration  . These changes lead to scoliosis, fractures and significant reduction of joint mobility . Additional findings include atrophy and fasciculations of the tongue, gastrointestinal problems (gastroesophageal reflux, constipation, and delayed gastric emptying) bulbar dysfunction and respiratory complications such as impaired coughing, hypoventilation during sleep and recurrent infections  . In fact, respiratory complications are the most important and most common cause of death in SMA type 1  . One of the main distinguishing features of SMAs is complete preservation of cognition, as children are alert and responsive to commands, which can be a significant observation when discussing the differential diagnosis .
A presumptive diagnosis of SMA type 1 can be made based on the clinical presentation and its onset in very early life, while additional information from patient history that can reveal the presence of the disease in other family members may support clinical suspicion. In that case, diagnostic workup should comprise serum levels of creatine kinase (CK), electrophysiological testing (EMG), and nerve conduction studies, which will show typical signs of motor neuron disease and provide solid grounds to request genetic testing, since it is not widely available  . Pulse oxymetry, spirometry and arterial blood gas analysis (ABG) is also important in assessing the degree of respiratory failure . To confirm SMA type 1 (and all other types), tests that detect deletion of the SMN gene should be carried out, as a 95% sensitivity and nearly 100% specificity rate is observed . The results are provided after 2-4 weeks .
The principles of therapy is still focused on supportive measures that attempt to improve the quality of life of patients suffering from deleterious symptoms seen in SMA type 1. Most importantly, respiratory measures should be instated as soon as possible, examples being airway clearance with cough assistance, nocturnal or continuous noninvasive assisted ventilation, tracheotomy and mechanical ventilation  , depending on the severity of pulmonary complications. Swallowing difficulties necessitate placement of a feeding tube through which specially designed diets, probiotics, prokinetic agents, proton pump inhibitors and histamine-receptor blockers are given  . Use of orthoses, as well as orthopedic and surgical procedures, but also encouragement to perform as much physical activity as possible are implemented with a goal of preventing further deterioration of musculoskeletal system . A number of pharmacological agents have been used in SMA patients - neuroprotective drugs (riluzole), creatine, albuterol, antisense oligonucleotides (ASOs), quinazoline derivatives and histone deacetylase (HDAC) inhibitors, all requiring further studies to determine their potential efficacy . Gene, stem cell and small molecular therapies, however, seem to be more promising strategies for the future, as their efficacy is being increasingly recognized in animal models . At this moment, unfortunately, SMA patients rely only on symptomatic care and directed therapy does not exist yet.
SMAs are considered to be the most common genetic cause of infant mortality, and the second most common cause (after cystic fibrosis) of death due to an autosomal recessive genetic disorder . Type 1 carries the poorest prognosis of all SMAs, as a very early onset of symptoms, but also the lack of directed therapy, invariably leads to death in the first few years of life . Nevertheless, early recognition of the disorder can be quite important for these patients and their parents, primarily to allow the possibility of entering clinical trials .
All types of SMAs are autosomal recessive in nature, and homozygous mutations of the survival motor neuron 1 (SMN1) gene located on chromosome 5q13 is the underlying cause  . Under physiologic conditions, SMN1 and SMN2, a pseudogene homolog from which most of SMN1 is generated, differ by only five nucleotides, one of them being the exon 7 coding region that is present on SMN2 . Due to still undisclosed mechanisms, mutations lead to alternative splicing of exon 7 that is, generating an unstable SMN2 that cannot produce a complete SMN1 gene and its respective protein .
Various reports have indicated that the incidence rate of spinal muscular atrophies (SMAs) is estimated at 1 per 6,000-10,000 live births   . Approximately 60% of cases are attributed to type 1 . An overall carrier frequency is established at 1 in 54 individuals, but significant variations exist across ethnic groups . In the United States, carrier frequency for Caucasians was determined to be 1 in 47 individuals, whereas 1 in 72 African Americans are heterozygotes for SMA .
The pathogenesis model of SMAs remains unclear, but it is known that genetic alterations of SMN1 and SMN2 genes located on chromosome 5q13 are key events in this neurodegenerative condition. Namely, SMN2 is a homologous pseudogene of SMN1 that differs by only a few nucleotides, most important being the presence of exon 7 located in its coding region, which is involved in the production of SMN1 from SMN2 . Through still unexplained events, nucleotide sequence change occur in exon 7, thus impairing its role in the production of the SMN2 gene . Consequently, SMN1 gene is not fully produced, and its absence is the reason for the onset of symptoms seen across all SMA types . Interestingly, the severity of symptoms depends on the number of viable SMN2 copies and their ability to compensate for lack of SMN1 expression . Patients who retain only two copies of SMN2 develop SMA type 1, while preservation of three or four copies are characteristic for types 2, 3, or 4 , making the number of SMN2 genes directly responsible for determination of the SMA type.
The cause of mutations seen in SMAs are unknown and its prevention is not possible at the moment. Some authors propose that newborn screening should be carried out, so that patients can enroll into clinical trials as early as possible . Another possible strategy would be screening of relatives of individuals with any of the SMA types in order to confirm carrier state.
Spinal muscular atrophies (SMAs) are autosomal recessive disorders of progressive neuronal degeneration in the anterior horns of the spinal cord, with homozygous disruption of the survival motor neuron 1 (SMN1) gene being the underlying cause . The incidence rate of SMAs are estimated at 1 in 6,000-10,000 live births, while carrier frequency was established to be around 1 in 54  . Spinal muscular atrophy type 1 (also known as Werdnig-Hoffmann disease), comprises approximately 60% of all cases  , and is considered as the most severe form of all SMAs, as virtually all patients die within the first two years of life . Symptoms start in early infancy (from 0-6 months of age) , most prominent being hypotonia, absent tendon reflexes, and inability of infants to sit or control their head . Additional signs include swallowing and sucking difficulties as a result of weakness of the tongue, gastrointestinal irritation (constipation, reflux) and a bell-shaped chest due to improperly developed intercostal muscles that cause breathing impairment . In fact, respiratory failure is the most common cause of death in this patient population  . Although infants experience profound failure to thrive, their cognitive skills are usually intact . The initial diagnosis can be made based on clinical criteria and a positive family history, but due to a very high carrier frequency, positive family history can often be absent, in which case genetic testing is required to confirm SMA. Detection of genetic mutations, specifically exon 7 deletion on SMN1 gene on chromosome 5, carries a 95% sensitivity and nearly 100% specificity, making it the gold standard of diagnosis  . Treatment principles are currently focused on supportive care, primarily through insertion of a feeding tube and administration of elemental formulas, probiotics, and bowel-regulating agents , assisted ventilation, as well as use of assistive devices and orthoses to enable basic daily functions  . Numerous pharmacological agents have been tested without success, but recent studies illustrate the potential of gene therapy, stem cell therapy and small molecule therapies as future strategies . Unfortunately, current prognosis of patients is poor, although some authors have documented patients reaching early childhood .
Spinal muscular atrophies (SMAs) are a group of genetic diseases that cause progressive degeneration of a specific subset of motor neurons in the spinal cord. These disorders are transferred from parents to their children by an autosomal recessive pattern of inheritance. This means that either one parent must suffer from the disease or that both parents carry a copy of a mutated survival motor neuron 1 (SMN1) gene located on chromosome 5 that are subsequently transferred to their child. Individuals who harbor only one copy of the gene are known as "carriers" and large-scale studies have determined a frequency of 1 in 54 individuals, with significantly higher rates among Caucasians compared to African Americans. SMAs occur in approximately 1 in 6,000-10,000 individuals, and type 1 (also known as Werdnig-Hoffmann disease), comprises about 60% of all cases. Type 1 is the most severe form of all SMAs, with a very early onset of symptoms in the first six months of life, most important being inability of infants to sit on their own and control their heads, reduced muscle tone of the limbs, absence of tendon reflexes, a range of skeletal deformities and consequent breathing difficulties, as well as impaired swallowing and sucking that predisposes to growth failure and gastrointestinal irritation. The initial diagnosis can be made by observing signs and symptoms and confirming disease of motor neurons by conducting electromyographic (EMG) studies and several other tests, while genetic testing can be indicated to confirm clinical suspicion. The prognosis of patients suffering from SMA type 1 is very poor, as universally fatal outcomes are expected in the first few years of life, most commonly due to respiratory failure. Another reason for such poor outcomes is the absence of directed therapy, and all patients are treated by supportive measures - placement of feeding tubes to ensure adequate nutrition, various methods that assist in ventilation and correction of skeletal deformities through the use of orthoses and surgical or orthopedic procedures. Several studies have shown promising results for gene therapy, stem cell therapy and molecular therapy, however, but their introduction into clinical practice mandates further research.