SPINAL MUSCULAR ATROPHY

Dr. C. Kannan, Post Graduate, MGMCRI, Pudhucherry, India

1. Spinal muscular atrophy Dr. C. Kannan 1 st year postgraduate Pediatrics department MGMCRI

2. Today’s discussion is on Introduction Aetiology Mode of inheritance Classification Signs and symptoms Diagnosis of spinal muscular atrophy Treatment Rehabilitation Prognosis and Researches

3. Introduction Spinal muscular atrophies (SMAs) are Degenerative diseases of motor neurons Begins in fetal life and Continue to be progressive in infancy and childhood Motor neurons spared are Cranial nerves III, IV, and VI to extra ocular muscles Sacral spinal cord innervating urethra and anal sphincter muscles Upper motor neurons.

4. After cystic fibrosis (1:6,000), SMA is the next most fatal disease with this genetic profile, with an incidence of 1:6,000 to 1:10,000 births. Second most common neuromuscular disease, following Duchenne muscular dystrophy. The frequency of carriers ( heterozygotes ) is one in 40 to 60 people.

5. Aetiology Pathologic continuation of Programmed cell death (apoptosis) of neuroblasts Normal in embryonic life The survivor motor neuron gene (SMN) Arrests apoptosis of motor neuroblasts SMN mutation leads to persistence of apoptosis, even in later life.

6. SMN is caused by Homozygous mutation Deletion of the SMN1 gene Telomeric region of chromosome 5q13. Severity increases with Involvement of number of copies of SMN2 gene Similar to SMN1 gene Centromeric region of chromosome 5q13.

7. Genetic alteration to the SMN1 gene leads to Reduction in survival motor neuron (SMN) protein. SMN2 gene produces only 25% of SMN protein, So it can’t compensate for SMN 1 gene. The lack of the SMN protein leads to Degeneration of alpha (α) motor neurons In the ventral horn of spinal cord.

8. Mode of Inheritance SMA disorders are inherited in an autosomal recessive manner.  Autosomal recessive inheritance Child must inherit a copy of the defective gene from both parents. These parents are likely to be asymptomatic. Often affects more than one person in the same generation.  Kennedy’s disease, an adult form of SMA is X-linked inherited, Sons will be affected and Daughters will become carriers.

9. Classification SMA in children is classified into four types based on A ges of onset, S everity and Progression of symptoms.  

10. All four types are caused by defects in the SMN1 gene. SMA type 1 ( Werdnig -Hoffmann disease or severe infantile form ) SMA type 2 ( late infantile or slow progressive form) SMA type 3 ( Kugelberg-Welander disease or chronic form) SMA type 4 (Adult onset SMA) Other forms of SMA include: Type 0 form of SMA Congenital SMA with arthrogryposis Kennedy’s disease

11. Clinical features P rogressive degeneration of lower motor neurons i.e., N erve cells in the brain stem and spinal cord W hich controls essential voluntary muscle activities like S peaking, Walking, B reathing, and S wallowing will be gradually lost  

12. When there are disruptions in the signals between LMNs and muscles The muscles gradually weaken and may begin wasting away and Develop uncontrollable twitching called fasciculation.   When there are disruptions in the signals between UMNs and LMNs The limb muscles develop stiffness called spasticity. Movements become slow and effortful. Knee and ankle jerks become overactive. 

13. SMA type 1 ( Werdnig-Hoffmann disease or infantile-onset SMA) E vident by the time a child is 6 months old presents with H ypotonia (severely reduced muscle tone) Diminished limb movements, L ack of tendon reflexes, F asciculations , tremors, swallowing F eeding difficulties and impaired breathing. 

14. Some children also develop scoliosis or other skeletal abnormalities.  Affected children never sit or stand and the vast majority usually die of respiratory failure before the age of 2 .  However, the survival rate in individuals with SMA type I has increased in recent years, in relation to the growing trend toward more proactive clinical care.

15. SMA type II (The I ntermediate form) U sually begin between 6 and 18 months of age.  Children may be A ble to sit without support U nable to stand or walk unaided, Bulbar weakness combined with swallowing difficulties, can lead to reduced weight gain in some children.

16. Difficulties with coughing and with cleaning secretions from the trachea Fine trembling (known as fasciculation) Can suffer from Scoliosis and contractures as they age. The progression of disease is variable.  Life expectancy is around 10 to 40 years.

17. SMA type III ( Kugelberg-Welander disease) A ppears between 2 and 17 years of age presents with A bnormal gait, D ifficulty running, Cl imbing steps or rising from a chair and F ine tremor of the fingers.  The lower extremities are most often affected. 

18. Complications include Scoliosis and Joint contractures Chronic shortening of muscles or tendons around joints Caused by abnormal muscle tone and weakness, Which prevents the joints from moving freely.  Individuals with SMA type III may be prone to respiratory infections, but with care may have a normal lifespan.

19. Type IV (Adult-onset SMA) Onset: 18-50 years. Symptoms and characteristics: Generalised muscle weakness and wasting, muscle twitches are common. Prognosis: Symptoms remain relatively mild and has little impact.

20. Inheritance Autosomal recessive and dominant forms. In Type IV SMA, individuals should Life expectancy can be improved with rehabilitation measures

21. Type 0 form Present during perinatal period Highly fatal Motor neuron degeneration in the spinal cord Starts as early as midgestation

22. Other forms Congenital SMA with A rthrogryposis A rare disorder. P ersistent contracture of joints with fixed abnormal posture of the limb. Manifestations include S evere contractures, S coliosis, C hest deformity, R espiratory problems, U nusually small jaws, and D rooping of the upper eyelids.

23. Kennedy’s disease P rogressive spinobulbar muscular atrophy Onset: 15 and 60 years of age.  Affected individuals may have Enlargement of the male breasts or Develop noninsulin-dependent diabetes mellitus.

24. The onset of symptoms varies and includes Weakness and atrophy of the facial, jaw, and tongue muscles leading to problems with chewing, swallowing and speech.  Early symptoms may include muscle pain and fatigue.  Weakness in arm and leg muscles closest to the trunk with Muscle atrophy and fasciculations .  Sensory loss in the feet and hands. 

25. Diagnosis Molecular genetic tests To identify deletions or mutations of the SMN1 gene. This test identifies at least 95% of SMA Types I, II, and III. E lectromyography to record t he electrical activity F rom the brain and spinal cord to a peripheral nerve root in A rms and legs that controls muscles During contraction and at rest.

26. Nerve conduction velocity studies Which measure electrical energy by Assessing the nerve’s ability to send a signal. Muscle biopsy used to diagnose Neuromuscular disorders and may also reveal if A person is a carrier of a defective gene that could be passed on to children. Laboratory tests of blood, urine, and other substances.

27. Treatment Pharmacological There is no cure and treatment consists of managing the symptoms and preventing complications. Muscle relaxants such as baclofen, tizanidine , and the benzodiazepines may reduce spasticity.  Botulinum toxin may be used to treat jaw spasms or drooling.  Excessive saliva can be treated with amitriptyline, glycopyolate , and atropine or by botulinum injections into the salivary glands.  Antidepressants may be helpful in treating depression. 

28. Rehabilitation O ccupational and physiotherapy improves P osture, P revent joint immobility Slow muscle weakness and atrophy.  Stretching and strengthening exercises reduces S pasticity, I ncrease range of motion and K eeps circulation flowing.  Some individuals requires additional therapy for S peech, C hewing and swallowing difficulties. 

29. Applying heat may relieve muscle pain.  Assistive devices such as Supports or braces, Orthotics, Speech synthesizers and Wheelchairs may improve the quality of life with SMA.

30. Rehabilitation Proper nutrition and a balanced diet are essential to maintaining weight and strength.  People who cannot chew or swallow may require insertion of a feeding tube.  Non-invasive ventilation at night can prevent apnoea in sleep some individuals may also require assisted ventilation due to muscle weakness in the neck, throat and chest during daytime.

31. Prognosis Prognosis varies depending on the type of SMA.  SMA type 1 & 2 and SMA type 0 are fatal. Kennedy’s disease Course varies and slowly progressive.  Ambulatory until late in the disease.  L ife expectancy for usually normal. People with SMA S table for long periods I mprovement should not be expected.   

32. R esearches Scientists are devoloping gene therapy T o halt motor neuron destruction and S low disease progression in mouse models of SMA.  Scientists have found that A nti-sense oligonucleotides C an block or correct the processing of RNA molecules, W hich are the intermediates between genes and proteins.  These compounds have shown therapeutic promise in animal models

33. THANK YOU !!