Spinal muscular atrophy (SMA) is a group of disorders involving progressive loss of spine and brainstem lower motor neurons with consequent weakness and atrophy. Sensory loss is generally absent. About 95% of SMA cases result from mutation or absence of the survival motor neuron 1 (SMN1) gene on chromosome 5q (5q SMA). There is great heterogeneity of onset and disease severity, ranging from severe prenatal and infant forms to adult-onset disorders with mild symptoms.
Over the last 25 years, understanding and practice have progressed from clinical syndromic descriptions and symptomatic treatment to diagnostic genetics and disease-modifying therapy. This article, which is Part 1 of a two-part review, considers clinical groupings, genetics, and supportive care approaches in 5q SMA. Part 2 discusses approved and promising disease-modifying therapies.
What is SMA?
Descriptions of SMA recorded in the 19th century noted progressive degeneration of spinal anterior horn cells with proximal and symmetric extremity weakness that also could involve brainstem nuclei and lead to fatal difficulties with breathing and swallowing. A worse prognosis with earlier symptom onset was also appreciated. Accumulating observations led to debate throughout the 20th century about whether the syndromes affecting infants, young children, adolescents, and adults were separate disorders.
By the mid-1990s, it was understood that SMN1 protein product deficiency underlay 5q SMA and that a second SMN gene, SMN2, produced the same protein product as SMN1 but less efficiently. Individual differences in the number of SMN2 gene copies were linked to variable severity — the more copies, the more compensation for the deficient SMN protein — and a classification scheme including untreated prognosis emerged that remains widely used in clinical work and research.
SMA type 0 has prenatal onset; it is rare and the most severe form. Death usually occurs in less than 1 month. Patients often have one SMN2 copy.
SMA type I — also called infantile-onset SMA or Werdnig-Hoffmann disease — is the most common form. Onset usually occurs before age 6 months and infants are often born with contractures and breathing difficulties. Untreated, babies do not sit independently and display hypotonia, reduced limb movement, reduced reflexes, fasciculations, feeding difficulties, and scoliosis. Death usually occurs before age 2. Patients often have two or three SMN2 copies.
SMA type II affects about 20% of SMA patients, with onset usually between 6 and 18 months of age. Children sit without support but are unable to stand or walk without assistance and may lose motor abilities. Respiratory difficulties are variable and may include treatable hypoventilation. Most live into adolescence and young adulthood. Three to four SMN2 copies are typical.
SMA type III — also called Kugelberg-Welander disease — encompasses about 30% of SMA patients. Onset is after age 18 months. Patients can walk independently but present with difficulty walking, running, or stair-climbing due to proximal leg weakness and may have hand tremor. They may develop contractures and later require a wheelchair. Most have a normal lifespan with supportive care. These patients typically have three to four SMN2 copies.
SMA type IV affects fewer than 5% of SMA patients. It is the least severe form, with onset after age 21. Patients have mild or moderate weakness tremors and may have mild breathing problems. They have a normal lifespan and four to eight SMN2 copies.
SMA assessment and management requires different outcome measures geared to communication and functional abilities of each patient, often with a focus on developmental motor milestones and maximal functional ability. Two measures used in SMA infants are the Hammersmith Infant Neurological Examination (HINE) and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale.
Diagnosis is suspected on clinical grounds and confirmed with mutation and deletion testing for SMN1 and SMN2. Because some patients may have point mutations in SMN1, gene sequencing should be considered if testing is negative but SMA is still suspected.
The Genes Involved
SMA related to SMN1 mutation or deletion is inherited in an autosomal recessive pattern; carriers rarely show symptoms. The typical cellular complement of SMN1 and SMN2 is two copies of each gene.
Normally, SMN1 accounts for about 90% of full-sized, functional SMN protein product. While SMN2 does produce functional SMN, it is co-produced with nonfunctional variations. The SMN protein is part of a SMN complex, which has a role in assembling the structures needed to process pre-RNA and in forming and maintaining dendrites and axons.
The SMN1 genetic mechanism and its consequences on cell operation and morphology offer focused and compelling targets for disease-modifying treatments. Progress in this area also highlights the need to screen newborns to identify the disease early.
“Newborn screening is one of the most effective public health programs in the United States,” Alex Kemper, MD, MPH, of Nationwide Children’s Hospital in Columbus, Ohio, who chaired an evidence-based SMA newborn screening review, told BreakingMED in an email correspondence.
“Newborns with spinal muscular atrophy often do not have any symptoms at birth,” Kemper explained. “Early treatment following identification through screening can be lifesaving.”
SMA is now on the recommended newborn screening panel in the U.S., but not all states have added it. Prior to screening, the estimated birth prevalence of SMA was about 1 in 10,000.
Support Matters
Before nusinersen (Spinraza) received FDA approval in 2016 for pediatric and adult SMA, treatment was largely symptomatic and supportive. Nusinersen, along with onasemnogene abeparvovec (Zolgensma; approved in 2019 for infantile-onset SMA) and investigational drugs such as risdiplam, open an exciting chapter in SMA that builds on clinical and genetic findings in a focused and actionable way.
These treatments highlight, rather than diminish, the importance of symptomatic and supportive measures to maximize function. “Optimal nutrition delivery, based on a comprehensive nutritional assessment, may help improve long-term functional outcomes in SMA,” Nilesh Mehta, MD, of Boston Children’s Hospital, explained to BreakingMED in an email.
“Patients with SMA type 1, for example, may have baseline malnutrition and are at risk of nutritional deterioration during intercurrent illness,” Mehta continued. “Difficulties with feeding and gastrointestinal disturbances, such as constipation and reflux, can result in suboptimal nutrient intake.”
In all cases, proper nutrition with adequate calories is required. Feeding and swallowing function, weight, and fluid and fiber intake need to be monitored. Attention from nutritionists and use of a feeding tube may be necessary.
Scoliosis, rib deformity, joint instability, and contractures also may need to be assessed, monitored, and addressed. Orthopedic support or intervention may be required. Strengthening and stretching through physical and occupational therapy can improve posture, contribute to effective blood circulation, reduce spasticity, and help prevent joint immobility.
Assistive devices including braces, orthotics, and wheelchairs may become necessary if function is lost with age. Pain from contractures and joint immobility also should also be evaluated.
A critical issue is breathing, which may be compromised by weakness of the muscles of inspiration, neck, face, or chest, as well as scoliosis and contractures. Pulmonary assessment and monitoring needs vary with type of SMA but may include use of day and/or night oxygen or ventilation assistance. Regular breathing exercises and chest physiotherapy can be helpful.
All SMA patients can be managed noninvasively, said John Bach, MD, of Rutgers New Jersey Medical School in Newark in an email correspondence with BreakingMED. “It is unnecessary for anyone with any SMA to have a tracheostomy tube,” he emphasized. “Intubated ventilator-unweanable patients always can be extubated to continuous noninvasive ventilator support.”
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About 95% of SMA is caused by deletion or mutation of the SMN1 gene with loss of SMN protein, causing progressive loss of lower motor neurons in the spinal cord and brainstem. SMN protein is implicated in RNA processing as well as axon and dendrite metabolism.
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With genetic understanding has come the possibility and now reality of targeted disease-modifying treatments. Supportive measures to maximize function are important as new treatments emerge.
Paul Smyth, MD, Contributing Writer, BreakingMED™
Kemper, Mehta, and Bach reported no disclosures.
Cat ID: 130
Topic ID: 82,130,730,130,138,192,925
