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Spinal Muscular Atrophy Type 1

SMA

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.


Presentation

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].

Limited Mobility
  • Individuals affected by SMA type III are initially able to walk, but have increasingly limited mobility as they grow and eventually, many need to use a wheelchair. Type III is also called Kugelberg-Welander disease or juvenile SMA.[michaelaevanow.com]
  • These devices allow people with even very limited mobility to use a computer to read, write, communicate, play video games, and access environmental controls.[smartspeechtherapy.com]
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[moveforwardpt.com]
Death in Infancy
  • CONTEXT: Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood.[ncbi.nlm.nih.gov]
Respiratory Distress
  • 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]
  • […] patients have been reported with juvenile onset of respiratory distress (Guenther et al., 2004; Guenther et al., 2009).[genedx.com]
  • Spinal Muscular Atrophy with Respiratory Distress (SMARD) is a rare form of SMA caused by defects in the IGHMBP2 gene. Infants with SMARD present with severe respiratory distress as well as muscle weakness.[mda.org]
  • In SMARD1, the predominating symptom is a severe respiratory distress due to a paralysis of the diaphragm.[smasupport.com]
  • Spinal muscular atrophy with respiratory distress (SMARD) is a very rare form of SMA caused by a mutation of the gene IGHMBP2. SMARD is diagnosed in infants and causes severe breathing problems.[healthline.com]
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 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]
  • Constipation should be treated aggressively as it may lead to discomfort, more problems with gastric emptying, decreased appetite, and reflux. The Portal's Constipation has management information.[medicalhomeportal.org]
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]
  • Gastro-Intestinal & Bowel Function Gastrointestinal problems such as reflux, delayed gastric emptying, and constipation are common. See Gastroesophageal Reflux Disease for medications that may be useful in treatment.[medicalhomeportal.org]
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]
  • Gastro-Intestinal & Bowel Function Gastrointestinal problems such as reflux, delayed gastric emptying, and constipation are common. See Gastroesophageal Reflux Disease for medications that may be useful in treatment.[medicalhomeportal.org]
Dysphagia
  • Feeding problems and dysphagia are common, but the underlying mechanisms of these problems are not well defined.[smartspeechtherapy.com]
Fasciculation of the Tongue
  • 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]
  • 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]
Fasciculation of the Tongue
  • 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]
  • 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]
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]
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]
  • Three children with spinal muscular atrophy type 1 underwent multiple intrathecal and intravenous infusions of mesenchymal stem cells.[ncbi.nlm.nih.gov]
  • CONTEXT: Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood.[ncbi.nlm.nih.gov]
  • CONCLUSION: Survival in spinal muscular atrophy type 1 patients has increased in recent years, in relation to the growing trend toward more proactive clinical care.[ncbi.nlm.nih.gov]
  • atrophy type 1 under 3 yrs of age.[ncbi.nlm.nih.gov]
Muscle Weakness
  • AIM: This study described end-of-life care for children affected by spinal muscular atrophy type 1 (SMA1), which is characterised by progressive muscle weakness and develops in the first six months of life.[ncbi.nlm.nih.gov]
  • BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder mainly characterized by proximal muscle weakness.[ncbi.nlm.nih.gov]
  • Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy.[ncbi.nlm.nih.gov]
  • The muscle weakness caused by SMARD1 eventually leads to complete paralysis. Intelligence is not affected.[genedx.com]
  • Many of the symptoms of SMA relate to secondary complications of muscle weakness. These can be relieved partly by therapy.[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]
  • Differential diagnosis Motor neurone disease Primary lateral sclerosis Muscular dystrophy Congenital myopathies Disorders of carbohydrate metabolism ( glycogen storage diseases ) Myasthenia gravis Poliomyelitis Investigations Blood tests Creatine kinase[patient.info]
Fracture
  • These changes lead to scoliosis, fractures and significant reduction of joint mobility.[symptoma.com]
  • -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]
  • Pediatric Endocrinology (see Services below for local providers) Consider referral for children who have low bone mineral density on Dexascan and have a history with fractures.[medicalhomeportal.org]
  • 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.[moveforwardpt.com]
Suggestibility
  • We suggest that the molecular pathogenesis of these two subtypes of lower motor neuron degeneration may be linked.[ncbi.nlm.nih.gov]
  • Migrating or rotating atelectasis may suggest the diagnosis of SMA.[ncbi.nlm.nih.gov]
  • These findings suggest that autonomic dysfunction should be examined in SMA type 1 patients with long survival, although the pathogenesis remains to be clarified.[ncbi.nlm.nih.gov]
  • No effective medical treatment has been documented for spinal muscular atrophy; however, cellular, molecular, and preclinical studies suggest that allogenic mesenchymal stem cells may play a role.[ncbi.nlm.nih.gov]
  • SUGGESTED PROGRAMMATIC ASSESSMENT* Suggested MER for Evaluation: The diagnosis is confirmed by molecular genetic testing of the SMA1 gene.[secure.ssa.gov]
Distractibility
  • We observed a beneficial distraction through the possibility to watch a movie or listen to music during the procedure. In some cases, an additional sedation was necessary.[ncbi.nlm.nih.gov]
Limb Weakness
  • 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]
  • 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]
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]
Irritability
  • 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[symptoma.com]

Workup

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].

Treatment

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.

Prognosis

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].

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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].

Patient Information

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.

References

Article

  1. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133.
  2. Baioni MT, Ambiel CR. Spinal muscular atrophy: diagnosis, treatment and future prospects [Article in English, Portuguese]. J Pediatr (Rio J). 2010;86(4):261-270.
  3. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens. Eur J Hum Genet. 2012;20(1):27-32.
  4. Wang CH, Finkel RS, Bertini ES, et al. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027-1049.
  5. Kolb SJ, Kissel JT. Spinal Muscular Atrophy. Neurol Clin. 2015;33(4):831-846.
  6. Porter RS, Kaplan JL. Merck Manual of Diagnosis and Therapy. 19th Edition. Merck Sharp & Dohme Corp. Whitehouse Station, N.J; 2011.
  7. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71.
  8. Davis RH, Godshall BJ, Seffrood E, et al. Nutritional Practices at a Glance: Spinal Muscular Atrophy Type I Nutrition Survey Findings. Journal of child neurology. 2014;29(11):1467-1472.
  9. Arnold WD, Burghes AHM. Spinal Muscular Atrophy: The Development and Implementation of Potential Treatments Running Head: Spinal Muscular Atrophy. Annals of neurology. 2013;74(3):10.1002/ana.23995.
  10. Prior TW. Spinal muscular atrophy diagnostics. J Child Neurol. 2007;22(8):952-956.
  11. Markowitz JA, Singh P, Darras BT. Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2012;46(1):1-12.

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Last updated: 2019-07-11 20:12