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 [2] [4]. 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 [2] [4]. These changes lead to scoliosis, fractures and significant reduction of joint mobility [2]. 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 [2] [4]. In fact, respiratory complications are the most important and most common cause of death in SMA type 1 [2] [4]. 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 [5].

• Weakness

  Hospital and Murdoch Children's Research Institute, Melbourne, Australia. [email protected] Abstract Spinal muscular atrophy (SMA) is a relatively common, profoundly disabling and incurable disease that presents in early childhood with hypotonia, weakness [ncbi.nlm.nih.gov]

  They include severe weakness or 'floppiness', poor head control, weak cry and cough, and difficulty with swallowing and feeding. SMA type 2: This develops within the first three years of life. [rch.org.au]

  Muscle weakness severely impairs motor development, such as sitting, standing, and walking. [ghr.nlm.nih.gov]

  They can all cause weakness and difficulty moving, but how bad these problems are varies. Intelligence and learning ability aren't affected by any type of SMA. [nhs.uk]

  Babies with SMA type 1 face many physical challenges, including muscle weakness and trouble breathing, coughing, and swallowing. They may need breathing assistance or a feeding tube. [curesma.org]

• Feeding Difficulties

  Poor sucking ability and reduced swallowing are frequent, leading to feeding difficulties. Deep tendon reflexes are absent. Respiratory failure is common. [orpha.net]

  At birth, infants with SMARD1 are often noted to have a weak cry, inspiratory stridor, feeding difficulties, and congenital contractures, especially foot deformities. [genedx.com]

  In the past, the treatment of SMA has been based on management of the complications of weakness, feeding problems and breathing difficulties. [rch.org.au]

• Recurrent Infection

  The natural history of SMA Type 1 indicates that bulbar muscle weakness, skeletal muscle weakness in the neck and intercostal muscle weakness lead to respiratory impairment, poor clearance of airway secretions, risk of aspiration and recurrent infections [globenewswire.com]

• Poor Feeding

  Once a child is diagnosed with SMA, physical therapists and other health care professionals can reduce some of the additional complications that occur following birth, such as developmental delay, poor feeding, abnormal postures and scoliosis, loss of [choosept.com]

• Pediatric Disease

  Retrieved 18 November 2019. ^ a b c d e "FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality". U.S. [en.wikipedia.org]

• Respiratory Distress

  In order to do so, the data of 141 patients presenting themselves with respiratory distress and the phenotype of a spinal muscular weakness was analyzed by hierarchical cluster analysis. [refubium.fu-berlin.de]

  Spinal muscular atrophy with respiratory distress type 1 (SMARD1). [ghr.nlm.nih.gov]

  Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare inherited disorder characterized by distal muscle weakness and respiratory failure. [genedx.com]

  Symptomatic newborns have severe hypotonia, may have respiratory distress, may be unable to feed, and rapidly progress to death early in infancy. [ncbi.nlm.nih.gov]

  Spinal Muscular Atrophy Respiratory Distress (SMARD) SMARD is a very rare form of SMA type 1 that affects the upper spinal cord more than the lower spinal cord. [curesma.org]

• Constipation

  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 [symptoma.com]

  Constipation is a common problem for infants with SMA, and some patients may have acid reflux. Treatment for these symptoms should be discussed with the healthcare team to find the best option. [smanewstoday.com]

  At constant risk of respiratory infection and pneumonia, and issues with feeding, constipation, airway maintenance and ensuring healthy bodily function presents real emotional, physical and financial challenges for parents. [smaaustralia.org.au]

  Constipation is a common problem as is being able to control excessive drooling (secretions), and getting proper nutrition and calories for proper weight gain. [smasupport.com]

  Common side effects include a higher risk of respiratory tract infection and constipation. There may also be a risk of bleeding and kidney problems. [medicalnewstoday.com]

• Delayed Gastric Emptying

  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 [symptoma.com]

  Specialty Collaborations & Other Services Gastro-Intestinal & Bowel Function Gastrointestinal problems such as reflux, delayed gastric emptying, and constipation are common. [medicalhomeportal.org]

• Dysphagia

  Feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. [smartspeechtherapy.com]

  Children with type I SMA have early dysphagia and early placement of G-tube with Nissen fundoplication is often necessary to prevent aspiration and pneumonia. [medicalhomeportal.org]

• Dysphagia

  Feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined. [smartspeechtherapy.com]

  Children with type I SMA have early dysphagia and early placement of G-tube with Nissen fundoplication is often necessary to prevent aspiration and pneumonia. [medicalhomeportal.org]

• Fasciculation of the Tongue

  They will see if the muscles are floppy or flaccid, to check for deep tendon reflexes and muscle fasciculation of the tongue muscle. [medicalnewstoday.com]

  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 [symptoma.com]

• Tongue Atrophy

  Other features include poor head control, a bell-shaped chest, weak cry and cough, tongue atrophy and fasciculation, and paradoxical breathing. Type II SMA presents later in the first year of life or up to about 2 years of age. [medicalhomeportal.org]

• Muscular Atrophy

  atrophy type 1 with paradoxical breathing were placed on high-span PIP+PEEP when sleeping from the point of diagnosis of spinal muscular atrophy. [ncbi.nlm.nih.gov]

  atrophy SMN2 gene copy numbers are variable in individuals with spinal muscular atrophy. [togetherinsma-hcp.com]

• Muscle Weakness

  The weakness soon spreads to all muscles; however, within 2 years, the muscle weakness typically stops getting worse. Some individuals may retain a low level of muscle function, while others lose all ability to move their muscles. [ghr.nlm.nih.gov]

  It is caused by a loss of specialized nerve cells, called lower motor neurons, leading to muscle weakness and muscle cell death. [smanewstoday.com]

  Infants may present with a ‘frog leg’ posture due to muscle weakness and hypotonia. Facial weakness is minimal or absent. Life expectancy is normally less than 2 years. [genomicseducation.hee.nhs.uk]

  Children with SMA may have muscle weakness and poor muscle tone, and may not reach milestones such as sitting or crawling. [rch.org.au]

  […] have weak muscles, minimal muscle tone, and feeding and breathing problems. [medicalnewstoday.com]

• Myopathy

  Differential diagnosis Differential diagnoses include SMA2, congenital muscular dystrophies, congenital myopathies, some early-onset mitochondrial disorders, and carbohydrate metabolism disorders (see these terms). [orpha.net]

  Part two then addresses the complete range of specific neuromuscular diseases: neuronopathies, peripheral neuropathies, neuromuscular junction disorders, muscle ion channel disorders, myopathies, and miscellaneous neuromuscular disorders and syndromes [books.google.ro]

  […] with bone health J Child Neurol published online 17th January 2013 A.Nadeau, G.D’Anjou, G.Debray, Y.Robitaille, L.Simard and M.Vanasse, A newborn with Spinal Muscular Atrophy Type 0 presenting with a clinicopathological picture suggestive of myotubular myopathy [sma-europe.eu]

• Fracture

  Maximize Calcium and Vitamin D intake, and consider bisphosphonates with a history of fractures. (See Osteoporosis and Pathologic Fractures.) [medicalhomeportal.org]

  Orthotics may be used to support standing and ambulation in toddlers -Usually lightweight KAFO's -Assisted walking programs may begin -Safety is crucial 2* increased fracture risk and falls due to weakness -Supported walking can decrease -Contractures [quizlet.com]

  These changes lead to scoliosis, fractures and significant reduction of joint mobility. [symptoma.com]

  Infantile spinal muscular atrophy variant with congenital fractures in a female neonate: evidence for autosomal recessive inheritance. J Med Genet. 2002;39(1):74-7. Bach JR, Baird JS, Plosky D, Navado J, Weaver B. [rarediseases.org]

• Joint Deformity

  People with this condition may experience the following symptoms: Joint deformities that impede mobility Infants may be born with broken bones Kennedy’s disease is one type of X-linked spinal muscular atrophy. [cedars-sinai.edu]

  Affected infants move less in the womb, and as a result they are often born with joint deformities (contractures). They have extremely weak muscle tone (hypotonia) at birth. [ghr.nlm.nih.gov]

  If a child requires surgery for scoliosis or other joint deformities, intensive preoperative and postoperative physical therapy can help prevent respiratory complications and loss of strength or function. Assistive Devices. [choosept.com]

• Reduced Fetal Movement

  There may be a history of reduced fetal movements in utero. Mortality/morbidity: median survival is 7 months - 95% die before 18 months. SMA type II Age of onset: 6-18 months. Features: developmental motor delay (delay in sitting, standing). [patient.info]

• Limb Weakness

  As the disease progresses patients may notice limb weakness starting in the pelvis or shoulders, or weakness of the facial and tongue muscles. Symptoms of SMA-LED often develop in infancy or early childhood. [cedars-sinai.edu]

  Symptoms include tremors of the hands, muscle cramps, limb weakness, and twitching. While it can also cause difficulty walking later in life, this type of SMA doesn't usually alter life expectancy. [healthline.com]

• Average Intelligence

  The brain is not affected, and they have been tested to have at least average to above average intelligence. Please do not make the mistake of treating them as mentally impaired!! [smasupport.com]

  Some even have above-average intelligence. Encourage your child to take part in as many age-appropriate activities as possible. A classroom is a place where your child can excel, but they still might need help with managing their workload. [healthline.com]

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 [4] [5]. Pulse oxymetry, spirometry and arterial blood gas analysis (ABG) is also important in assessing the degree of respiratory failure [4]. 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 [4]. The results are provided after 2-4 weeks [4].

• Excessive Drooling

  Constipation is a common problem as is being able to control excessive drooling (secretions), and getting proper nutrition and calories for proper weight gain. [smasupport.com]

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 [2] [4], 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 [2] [8]. 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 [2]. 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 [7]. 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 [9]. 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 [11]. 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 [4]. 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 [10].

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 [1] [2]. 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 [7]. 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 [10].

Various reports have indicated that the incidence rate of spinal muscular atrophies (SMAs) is estimated at 1 per 6,000-10,000 live births [3] [6] [9]. Approximately 60% of cases are attributed to type 1 [3]. An overall carrier frequency is established at 1 in 54 individuals, but significant variations exist across ethnic groups [3]. 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 [3].

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 [3]. Through still unexplained events, nucleotide sequence change occur in exon 7, thus impairing its role in the production of the SMN2 gene [10]. Consequently, SMN1 gene is not fully produced, and its absence is the reason for the onset of symptoms seen across all SMA types [7]. Interestingly, the severity of symptoms depends on the number of viable SMN2 copies and their ability to compensate for lack of SMN1 expression [10]. 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 [7], 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 [10]. 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 [1]. 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 [2] [3]. Spinal muscular atrophy type 1 (also known as Werdnig-Hoffmann disease), comprises approximately 60% of all cases [2] [3], and is considered as the most severe form of all SMAs, as virtually all patients die within the first two years of life [4]. Symptoms start in early infancy (from 0-6 months of age) [4], most prominent being hypotonia, absent tendon reflexes, and inability of infants to sit or control their head [5]. 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 [5]. In fact, respiratory failure is the most common cause of death in this patient population [5] [6]. Although infants experience profound failure to thrive, their cognitive skills are usually intact [5]. 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 [4] [7]. 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 [8], assisted ventilation, as well as use of assistive devices and orthoses to enable basic daily functions [4] [7]. 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 [9]. Unfortunately, current prognosis of patients is poor, although some authors have documented patients reaching early childhood [8].

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.

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