Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancesyndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord and motor nuclei in the lower brainstem. There are 5 clinical types of SMA, each with a distinctive clinical presentation unified by motor weakness. The earlier presentations are associated with more severe motor weakness affecting a child’s ability to reach the developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth of sitting or walking. In the more severe types, breathing and swallowing may also become difficult as the disease progresses. The prognosis of SMA is poor. In the less severe types, adults have a normal lifespan. The initial diagnosis is made clinically and confirmed using genetic testing. Management is mostly supportive although novel therapies are being developed. The prognosis depends on the clinical type.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Spinal muscular atrophy (SMA) is a spectrum of autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancesyndromes characterized by progressive proximal muscle weakness and atrophy, possibly due to degeneration of the anterior horn cells in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord and motor nuclei in the lower brainstem.

Classification

  • Type 0: prenatal-onset SMA
    • Presence of only 1 copy of the survival motor neuron 2 gene (SMN2
    • Decreased fetal movement in late pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
    • Manifests with severe, flaccid paralysis
  • Type 1: infantile SMA, also called Werdnig-Hoffman disease
    • Onset before 6 months of age
    • Never able to sit up independently
  • Type 2: intermediate form, also called Dubowitz disease
    • 20% of cases
    • Onset between 3 and 15 months of age
    • Unable to stand or walk independently
  • Type 3: juvenile form, also called Kugelberg-Welander disease
    • 30% of cases
    • Onset between 18 months and 18 years of age
    • Normal lifespan
  • Type 4: adult SMA (mildest form)
    • < 5% of cases
    • Presence of 4–8 copies of SMN2
    • Able to maintain ambulation throughout life
    • Normal lifespan

Epidemiology

  • 2nd-most common autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder (after cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis), causing significant morbidity and mortality
  • Incidence: calculated to be 1 in 11,000 in the US among all ethnicities
  • Carrier frequency: 1 in 47 Caucasians and 1 in 72 African American individuals

Pathophysiology

  • Homozygous deletion of the survival motor neuron 1 gene (SMN1) loss of synthesis of survival motor neuron protein
  • Extra copies of SMN2 determine the phenotypic expression/clinical severity.
  • Dysfunctional SMN protein → anterior horn cells in the spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord and motor nuclei in the lower brainstem undergo degeneration → progressive muscle weakness
  • Mechanisms by which the lack of normal SMN protein causes SMA pathology are unclear.
  • Pathophysiology in a mouse model (2014) shows skeletal muscle damage preceding motor neuron damage.

Clinical Presentation

Spinal muscular atrophy presents as a lower motor neuron lesion syndrome with muscle weakness, which is more severe in types 0, 1, and 2.

Type 0: decreased fetal movement in late pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care

  • Documented polyhydramnios Polyhydramnios Polyhydramnios is a pathological excess of amniotic fluid. Common causes of polyhydramnios include fetal anomalies, gestational diabetes, multiple gestations, and congenital infections. Patients are often asymptomatic but may present with dyspnea, extremity swelling, or abdominal distention. Polyhydramnios, fetal growth restriction Fetal growth restriction Fetal growth restriction (FGR), also known as intrauterine fetal growth restriction (IUGR), is an estimated fetal weight (EFW) or abdominal circumference < 10th percentile for gestational age. The term small for gestational age (SGA) is sometimes erroneously used interchangeably with FGR. Fetal Growth Restriction, and pulmonary hypoplasia Pulmonary hypoplasia Pulmonary hypoplasia is the lack of normal fetal development of the pulmonary parenchyma. The condition is characterized by a decreased number of alveoli and bronchial generations. Oligohydramnios is a notable cause, but conditions that restrict lung development or lead to fetal lung compression can also result in pulmonary hypoplasia. Pulmonary Hypoplasia
  • After birth:
    • Severe hypotonia and weakness
    • Areflexia
    • Facial diplegia (paralysis on both sides)
    • Arthrogryposis (multiple joint contractures)
    • Congenital heart defects
    • No motor milestones are achieved.

Type 1: presents before age 6 months of age

  • Severe and symmetric flaccid paralysis
  • Infants do not achieve the ability to sit without support.
  • “Frog-like” posture with hips abducted
  • Bulbar weakness: 
    • Weak cry
    • Poor sucking and swallowing reflexes
    • Pooling of secretions
    • Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue fasciculations
    • Increased risk of aspiration and FTT
  • Progressive respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
  • Bell-shaped chest
  • Cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. Overview of the Cranial Nerves are spared:
    • Preserved eye movement
    • Normal expression/facial muscles

Type 2: presents at 3–15 months of age

  • Progressive proximal weakness in legs > arms:
    • The ability to sit independently is delayed and then lost in teenage years.
    • Inability to stand or walk
  • Sparing of the face and eye muscles
  • Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue fasciculations
  • Areflexia
  • Muscular weakness → progressive scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis
  • Small amplitude myoclonic tremor-like movements of the hands (polyminimyoclonus) 
  • Ankylosis of the mandible
  • Joint contractures
  • Respiratory muscle weakness and scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis from progressive muscular weakness → restrictive lung disease

Type 3: presents from 18 months of age to the end of adolescence

  • Achieve independent ambulation → later presents with progressive proximal muscle weakness in legs > arms
    • Falls
    • Difficulty climbing stairs
  • May develop foot deformities Foot deformities Foot deformities in children include congenital or acquired malformations of the feet. Two common examples are talipes equinovarus, commonly known as clubfoot, and metatarsus adductus, also called metatarsus varus. Foot Deformities
  • Most individuals do not develop scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis or respiratory muscle weakness.
  • Many individuals become wheelchair-bound as the disease progresses.

Type 4 (mildest phenotype): presents in adulthood

  • Mild proximal muscle weakness (lower extremities)
  • Ambulation is usually maintained.

Diagnosis

Spinal muscular atrophy should be suspected in any infant with unexplained weakness or hypotonia. Definitive diagnosis requires genetic testing.

Genetic testing

  • Gold standard
  • Targeted mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations analysis to confirm SMN1 deletion
  • For parents of an affected child: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancemode of inheritance → 
    • 25% chance of an affected child
    • 50% chance of a carrier
    • 25% chance of an unaffected child
  • Slight deviation with SMA:
    • 2% of affected individuals have a de novo SMN1 variant with only 1 parent being a carrier of that variant →
    • Siblings are not at increased risk for SMA.
  • Carrier testing is indicated for at-risk relatives.
  • Prenatal testing is indicated for women having a family member with a confirmed diagnosis of SMA (by genetic testing).
  • Newborn Newborn A neonate, or newborn, is defined as a child less than 28 days old. A thorough physical examination should be performed within the first 24 hours of life to identify abnormalities and improve outcomes by offering timely treatment. Physical Examination of the Newborn screening was added to the Recommended Uniform Screening Panel (RUSP) in 2018, and SMA screening is being conducted in many states.
    • The RUSP consists of a list of disorders recommended by the US Department of Health and Human Services for newborn screening in the state.
    • Only tests for SMA due to homozygous deletion of exon 7 in SMN1

Electromyography (EMG) and muscle biopsy

  • Formerly, a standard component of diagnostic evaluation
  • Rarely used now because of the availability of molecular genetic testing
Muscle biopsy in sma

Muscle biopsy at 10 months of age (H&E, ×200) with marked perimysial and endomysial fibrosis and fatty infiltration with groups of small fibers and scattered hypertrophic fibers

Image: “Muscle biopsy in SMA” by . License: CC BY 2.5

Management

Current management is mostly supportive and multidisciplinary (including palliative care).

Supportive care

  • Respiratory support:
    • Noninvasive: BiPAP
    • Invasive:
      • Tracheostomy/ventilation
      • Considered when noninvasive ventilation is insufficient
    • Chest physiotherapy for secretion mobilization and clearance
    • Tracking of forced vital capacity
  • Nutritional support:
    • Early gastrostomy for growth failure in types 1 and 2
    • Supplemented nutrition reduces the likelihood of aspiration.
  • Orthopedic support:
    • Physical therapy
    • Spinal bracing for scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis

Disease-modifying therapy

Gene therapy: 3 agents are now available in the US.

  • Nusinersen (Spinraza): antisense oligonucleotide that increases SMN protein synthesis
    • Administered by intrathecal injection
    • Direct comparisons with other agents are not yet available.
  • Onasemnogene abeparvovec (Zolgensma): 
    • 1-time IV infusion for children < 2 years of age
    • Recombinant viral vector containing complementary DNA that encodes normal human SMN protein
  • Risdiplam (Evrysdi):
    • Oral medication for all types of SMA in individuals > 2 months
    • Corrects SMN2 splicing errors and increases the concentration of SMN protein

Complications

  • Failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive (FTT) in infants:
    • Bulbar dysfunction affects swallowing.
    • → Growth failure due to inadequate caloric intake
  • Respiratory complications:
    • Aspiration
    • Mucus plugging
    • Recurrent infections
    • Restrictive lung disease
  • GI complications:
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
    • Delayed gastric emptying
    • Gastroesophageal reflux with potential aspiration
  • Musculoskeletal complications:
    • Scoliosis
    • Joint contractures
    • Hip subluxation
    • Susceptibility to fractures
  • Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep difficulties

Prognosis

  • Types 0, 1, and 2: death due to restrictive respiratory disease and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure
    • Type 0: death at birth or in the 1st month of life
    • Type 1: death at < 2 years of age
    • Type 2: Life expectancy is variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables and ⅔ of individuals live up to 25 years of age.
  • Type 3: slowly progressive worsening of motor weakness, but individuals have a normal lifespan
  • Type 4: normal lifespan

Differential Diagnosis

  • Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome: a condition associated with the loss of the paternal chromosome 15q11-13 region, which manifests as intellectual disability, short stature, underdevelopment of sexual organs, and obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity in newborns. At birth, Prader-Willi syndrome Prader-Willi syndrome Prader-Willi syndrome (PWS) is a rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS. Prader-Willi Syndrome and Angelman Syndrome presents with hypotonia and lethargy, and feeding and breathing difficulties similar to those in SMA. Diagnosis is made based on DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure methylation testing to detect parent-specific imprinting of specific regions of chromosome 15. Management is supportive.
  • Duchenne muscular dystrophy Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that is caused by a mutation in the DMD gene. The mutation leads to the production of abnormal dystrophin, resulting in muscle-fiber destruction and replacement with fatty or fibrous tissue. Duchenne Muscular Dystrophy: an X-linked recessive genetic disorder in children caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the DMD gene, leading to muscle-fiber destruction and replacement with fatty or fibrous tissue. Affected boys present with progressive proximal muscle weakness that eventually leads to loss of ambulation, and contractures, scoliosis Scoliosis Scoliosis is a structural alteration of the vertebral column characterized by a lateral spinal curvature of greater than 10 degrees in the coronal plane. Scoliosis can be classified as idiopathic (in most cases) or secondary to underlying conditions. Scoliosis, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. Diagnosis is based on laboratory and genetic testing. Management is supportive and aimed at slowing disease progression and complications.
  • ALS ALS Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease): a sporadic or inherited neurodegenerative disease in adults that affects the upper motor neurons (UMNs) and lower motor neurons (LMNs). Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis is characterized by symptoms indicating that both the UMNs and LMNs are affected concurrently. The diagnosis is made clinically. Management is supportive and symptomatic, progressing to end-of-life care.

References

  1. Burr, P., Reddivari, A.K.R. (2021). Spinal Muscle Atrophy. StatPearls. Retrieved August 9, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK560687/
  2. Bodamer, O.A. (2021). Spinal muscular atrophy. UpToDate. Retrieved August 9, 2021, from https://www.uptodate.com/contents/spinal-muscular-atrophy
  3. Kolb, S.J., Kissel, J.T. (2015). Spinal muscular atrophy. Neurologic Clinics, 33, 831–846. https://doi.org/10.1016/j.ncl.2015.07.004
  4. Prior, T.W., et al. (2020). Spinal Muscular Atrophy. GeneReviews. Accessed August 19, 2021, from PubMed, http://www.ncbi.nlm.nih.gov/books/NBK1352/
  5. Fayzullina, S., Martin, L.J. (2014). Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA). PloS One, 9(3), e93329. https://pubmed.ncbi.nlm.nih.gov/24667816/

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