1. Spinal muscular atrophy (SMA) is caused by degeneration of motor neurons in the spinal cord and brainstem due to a defect in the SMN1 gene resulting in low levels of the SMN protein. 2. SMA is classified into five types based on age of onset and severity of symptoms - from very severe Type 1 to milder adult-onset Type 4. 3. Diagnosis involves family history, physical exam, genetic testing, and other tests like EMG; there is currently no cure but supportive care can help manage symptoms.

1. Spinal Muscle Atrophy SMA
Prof Dr Hussein Abdeldayem,MD
Chief and Professor of Pediatric
Neurology

2. SMA –spinal muscular atrophy
• The spinal muscular
atrophies (SMAs) are
characterized by
degeneration of the
anterior horn cells in
the spinal cord and
motor nuclei in the
lower brainstem.

3. DEFINITION
• SMA is caused by Progressive death of AHC
• AR
• ABN OF SMN GENE (CHROMOSOME 5) so
defect in SMN protein

4. CLASSIFICATION
• SMA 0 = congenital SMA
• SMA 1= Werdnig- Hoffman disease
• SMA 2 = LATE INFANTILE
• SMA 3= JUVENILE (K W Syndrome)
• SMA 4= ADULT

7. Genetics
• Autosomal recessive
disorder caused by
homozygous deletions
or mutations of the
SMN1 gene at the 5 q11
locus.
• There are two copies of
the smn gene on
chrom. 5q that code for
SMN protein – SMN1
and SMN2.

8. • All SMA patients have reduced fl-smn protein :
– Type 1 – 9%
– Type 2 – 14%
– Type 3 – 18%
– Carriers – 45 -55%
• When levels approach 23% - motor neuron
function is normal.
Genetics

9. O/E
DENERAL HYPOTONIA
FULL FACE , NORMAL EYES
TONGUE FASCICULATIONS
PARADOXICAL BREATHING

12. SMA II

13. Investigations
• EMG: fibrillation potentials, denervation, and
increased amplitude.
Nerve Conduction velocity : normal.
• Molecular gene testing for SMA gene : for the
baby, carrier detection and Prenatal DNA
testing: Prenatal DNA analysis of chorionic
villous biopsy (the deletion of arm 5q)
• CPK, lactic acid, LDH= N

14. Treatment
• Specific: ???? Gene therapy
• Non Specific
• Prevention: Family counseling, I U fetal
detection

16. HISTORY
• Was first described in the 1890s by Guido
Werdnig of the university of Viena and Johann
Hoffmann of Heidelberg University.

17. Frequency:
• The acute infantile-onset SMA (type I)
affects approximately 1 per 10,000 live
births.
• The chronic forms (types II and III), 1 per
24,000 births

18. Clinical features – TYPE 1
• Werding Hoffman / infantile onset SMA
• Weakness and profound hypotonia – first few
months of life
• Normal social awareness and interaction
• Limited spontaneous movement
• Deep tendon reflexes are absent
• Sphincter tone and sensation are intact

19. Clinical features – TYPE 1
•
Muscle trembling can be seen in fingers
and fasciculitations are often present in
the tongue
•
Pectus excavatum and flaring of the
lower ribs (weak intercostal muscles)
•
Feeding difficulties – FTT
•
Aspiration
•
Rarely survive beyond 2 yrs

20. Clinical features – TYPE 2
• Milestones are usually normal until onset – 6-
18 months.
• Legs are weaker then arms – failure to walk
• Deep tendon reflexes – variable pattern
• Usually sit without support, some walk with
bracing
• Survive into adolescence and beyond
• Good pulmonary function

21. Clinical features – TYPE 3
• Kugelberg-Welander disease
• Independent ambulation achieved
• Normal survival
• Onset of weakness after 18 mo – often late
childhood or adolescence
• Waddling gait with lumbar lordosis
• Decrease in motor units over time has been
documented (despite clinical picture)

22. Diagnosis
• Clinical, physical exam, family Hx
• Lab:
– CK level is usually normal in SMA type I and
normal or slightly elevated in the other types
– Cerebrospinal fluid findings are normal
– Genetic testing, both prenatally and postnatally

23. Diagnosis
• Nerve conduction studies – normal or slightly
decreased velocities, the sensory nerve action
potentials are normal.
•
Electromyography – abnormal spontaneous
activity with fibrillations and positive sharp
waves. The mean duration and amplitude of
motor unit action potentials are increased.

24. Histology
•
Muscle biopsy: large groups of circular
atrophic type 1 and 2 muscle fibers
intersperseded among fascicles of
hypertrophied type 1 fibers. The
enlarged fibers have been reinnervated
by the sprouting of surviving nerves and
are 3-4 times larger than normal.

25. Genetics

26. Genetics
•
SMA type I: Mutations
–
Mostly SMN1 deletions
–
Few missense point mutations in
SMN1
–
SMN2 gene copy number: Often
2
•
SMA type II
–
Mutations convert SMN1 gene to
SMN2
–
SMN2 gene copy number: > 3
–
Missense point mutations more
common
•
SMA type III
–
SMN2 gene copy number: > 3
–
Missense point mutations more
common

27. Genetics

28. SMN protein
•
Expressed in most tissues
•
High levels are found in spinal motor neuron
•
SMN exist in the cell as a part of a large
complex that regulates the assembly of a
specific class of RNA protein complexes -
which is essential for pre-mRNA splicing.
•
The function of SMN protein is linked to the
control of protein synthesis.

29. Why are only motor neurons
and muscle are affected in
SMA ?

30. The Role of SMN in SMA -1
•
SMA is a direct consequence of a defect in
pre-RNA splicing:
•
The affected motor neurons, being large, high
energy requiring cells, have a lower tolerance for
depleted SMN levels and are uniquely sensitive.

31. The Role of SMN in SMA - 2
•
SMA is a consequence of a motor neuron
specific function of the SMN protein:
–
From observations demonstrating the
accumulation of the SMN protein in the axons
and growth cones of neuron like cells in vitro
and anterior horn cells in vivo.