Spinal Muscular Atrophy (SMA) Past Paper PDF, Summer 2024

DISORDERS OF ANTERIOR HORN CELLS, Part II Spinal Muscular Atrophy PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of Spinal Muscular Atrophy (SMA)  Describe the various...

DISORDERS OF ANTERIOR HORN CELLS, Part II Spinal Muscular Atrophy PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of Spinal Muscular Atrophy (SMA)  Describe the various forms of SMA and compare & contrast signs & symptoms  Identify diagnostic parameters and tests used to determine a medical diagnosis of SMA  Describe the general course of, and prognosis for, the various forms of SMA  Discuss the medical and/or surgical management of SMA  Identify key rehabilitation considerations for individuals with SMA SMA – Definition A group of inherited disorders characterized by degeneration and loss of anterior horn cells (AHC) in spinal cord and brainstem  AHC degeneration leads to progressive muscle weakness & atrophy – Proximal muscles usually more involved than distal muscles SMA – Incidence and Etiology  Autosomal recessive disorder – Second most common fatal autosomal recessive disorder after cystic fibrosis  Gene deletion on chromosome 5 – Most common general form of SMA-referred to as:  Classic SMA or SMN-related SMA or chromosome 5 SMA – Various subtypes exist:  SMA 0, SMA I, SMA II, SMA III, Adult SMA (IV)  Incidence: 1 in 10,000 live births – 1 in 50 carry the genetic defect SMA - Etiology  Lesscommon forms of SMA exist which are caused by mutations in other genes besides chromosome 5: VAPB gene on chromosome 20 DYNC1H1 gene on chromosome 14 BICD2 gene on chromosome 9 UBA1 gene on the X chromosome – These variants also affect LMNs but can preferentially affect certain parts of the body differently than the chromosome 5 SMA form SMA - Pathogenesis  SMN 1 gene is defective in 99% of all cases of Spinal muscular atrophy – Cause of SMA  AHC degeneration appears to result from persistence of programmed cell death – SMN1 gene mutation decreases intracellular levels of SMN (survival motor neuron) protein which is involved in prevention of neuronal cell death SMA - Pathogenesis  SMN 2 gene also present – Can compensate for absence of SMN1 gene by producing SMN protein but less effective than SMN1 gene – Severity of signs and symptoms in SMA related to how many copies of SMN2 are present  More copies of SMN2 = more SMN protein produced = less severe forms of SMA SMA – General Clinical Picture  Onset – Varies from early in utero to late in life – Majority occur during infancy or early childhood – Adult forms are very rare  Weakness – Bilateral – Symmetrical – More proximal – Facial muscles may be involved – Relative sparing of eye muscles & anal sphincter SMA – General Picture  Progressive atrophy – Flaccidity – Floppy infants  Diminished DTR’s  Normal sensory function  Normal intellectual function  Restrictive lung disease SMA – General Clinical Picture  Skeletal deformities – Very common – Onset varies  According to type of SMA  According to onset of initial symptoms – Common deformities include:  Scoliosis  Kyphosis  Lordosis  Contractures  Joint dislocation Types of Spinal Muscular Atrophy  Based on: – Age at onset – Rate of progression  Childhood SMA – SMA Type 0 – SMA Type I – SMA Type II – SMA Type III  Adulthood form – SMA Type IV SMA Type 0 (Severe Infantile SMA or Prenatal SMA)  Rarest and most severe form of the condition – Sometimes considered a severe form of SMA I  Can be evident before birth – Less movement of fetus in womb – Often born with joint deformities/contractures and congenital heart defects  Extremehypotonia at birth  Very weak respiratory muscles – Often do not survive past infancy due to respiratory failure SMA Type I (Infantile SMA) Werdnig-Hoffmann Disease  Acute severe form  Onset – Usually 0 – 6 months – May appear normal at birth  Most common form of SMA – Affects 45% - 60% of all patients with SMA SMA Type I – Clinical Features  Poor posture and positioning – Lower extremities  Flexed, abducted, externally rotated (frog position) – Upper extremities  Abducted, externally rotated, unable to move to midline against gravity  Poor head control  Hypotonic  Significant muscle weakness SMA Type I – Clinical Features  Decreased newborn movements  Decreased diaphragmatic movements  Scoliosis  Proximal muscle weakness > distal  May not achieve independent sitting  Weak cry & cough  Normal sensation & intellect SMA Type I - Course  Rapidly progressive  Severe hypotonia  Death within first 2 years for majority of cases, if not treated – Respiratory failure  With current treatments, children with SMA Type I can live longer and reach higher motor milestones such as sitting and walking SMA Type I SMA Type I https://www.youtube.com/watch?v=uOlp sKuan_c https://www.youtube.com/watch?v=yRrqbvUv6gQ SMA Type II (Intermediate SMA)  Intermediate severity  Onset – Usually between 6 and 18 months of age  Represents about 20% to 30% of cases SMA Type II – Clinical Features  Lower extremities – Flexed, abducted & externally rotated  Limitedtrunk control  Weakness  Increased risk of scoliosis  Normal sensation & intellect SMA Type II - Course  Progressive but stabilizes  Moderate to severe hypotonia (flaccid)  Usually able to achieve sitting ability  Standing or walking usually not possible – Requires power wheelchair/mobility device  Shortened lifespan – Can survive for at least 10 years after onset  Majority survive to age 25  Improved motor outcomes with current treatments SMA Type II https://www.youtube.com/watch?v=rmCQ _1oQSE4 SMA Type III (Juvenile SMA) Kugelberg-Welander Disease  Mild form  Age at onset – After 18 months – adolescence  Represents about 10% of all SMA cases SMA Type III – Clinical Features  Proximal LE weakness – Greatest with trunk, hip & knee extension  Good UE strength  Slow, continued developmental progression – All early developmental milestones are acquired  Able to sit independently  Gait & postural deviations with ambulation – Lx lordosis, waddling gait, genu recurvatum, protuberant abdomen SMA Type III - Course  Slowly progressive  Mild impairment overall  Can ambulate at some point  Usually wheelchair dependent in adulthood  Usually have normal lifespan SMA Type III https://www.youtube.com/watch?v=AIjKbTd- xOY https://www.youtube.com/watch?v=iIvLMSgtOtY SMA Type IV (Adult-Onset or Late- Onset SMA)  Usually occurs after age 30 - 35 – Less than 1% of cases  Appearsclinically similar to SMA III BUT slower, more mild progression – Mild muscle weakness – Gradual development of proximal (greater than distal) limb weakness  May also see: – Tremor and twitching (fasciculations) SMA Type IV - Course  Slowly progressive, mild motor impairments  Allmotor developmental milestones achieved  Without respiratory problems  Most individuals remain ambulatory throughout their life – May need wheelchair eventually  Normal lifespan Spinal Muscular Atrophy - Diagnosis  Clinical picture  Muscle biopsy  EMG – Decreased motor action potentials  NCV  Motor CV Slowed  Genetic testing – Blood test can identify specific mutation resulting in SMA in 95% of cases – Newborn screening becoming more standard SMA – Medical Treatment Pharmacologic treatment: Disease- modifying therapy (but not a cure) 1. Nusinersen (Spinraza) – FDA approved first drug to treat SMA in December 2016 – Administered via intrathecal injection – Clinical trials: slowed disease progression and improved motor function  Increases amount of SMN protein in CNS by affecting SMN2 gene SMA – Medical Treatment 2. Onasemnogene abeparvovec-xioi (Zolgensma) – Approved by FDA in May 2019 to treat SMA I in children less than 2 years of age – Gene therapy treatment that uses an adeno- associated virus type 9 as a vector to deliver a copy SMN1 transgene to cell nuclei; this transgene then begins encoding SMN protein SMA Type 1: How Gene Therapy Works – YouTube – Administered intravenously  Current thought is that a single dose will have a lifetime effect SMA – Medical Treatment 3. Risdiplam (Brand name, Evrysdi) – FDA Approved in August 2020 – Oral medicine which increases SMN protein production from SMN2 gene – For adults with SMA and children 2 months of age and older SMA – Medical Treatment  Symptomatic & preventative treatment – Respiratory care – Treat/Prevent musculoskeletal complications  May need surgery for hip dislocation  Scoliosis treatment – Spinal fusion – Bracing – Maintenance of head control & sitting posture – Feeding assistance/nutritional support  Feeding tube SMA - Prognosis  Variesaccording to type & age of onset  Poorer prognosis – Earlier onset – Faster progression of weakness – Respiratory distress  Best prognosis: Types III & IV – Type III  Onset > 2 yrs old; remain ambulatory during adulthood  Onset before 2 yrs: lose ambulatory ability at age 12 on average Rehabilitation Considerations  Goals for P.T. – Achieve highest level of independent living and mobility possible  Improve/maintain muscle strength and aerobic capacity – Prevent or delay development of complications  Contractures/skeletal deformities  Respiratory failure Rehabilitation Considerations  P.T. Intervention may include: – Strengthening exercises – Aerobic exercise – Developmental skill training – Aquatic therapy – Standing program – Management of respiratory complications – Management of contractures – Management of scoliosis/skeletal deformities – Prescription of/training with assistive devices