Spinal Muscle Atrophy SMA Prof Dr Hussein Abdeldayem,MD Chief and Professor of Pediatric Neurology
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.
DEFINITION• SMA is caused by Progressive death of AHC• AR• ABN OF SMN GENE (CHROMOSOME 5) so defect in SMN protein
CLASSIFICATION• SMA 0 = congenital SMA• SMA 1= Werdnig- Hoffman disease• SMA 2 = LATE INFANTILE• SMA 3= JUVENILE (K W Syndrome)• SMA 4= ADULT
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.
Genetics• 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.
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
Treatment• Specific: ???? Gene therapy• Non Specific• Prevention: Family counseling, I U fetal detection
HISTORY• Was first described in the 1890s by Guido Werdnig of the university of Viena and Johann Hoffmann of Heidelberg University.
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
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
Clinical features – TYPE 1Muscle 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 •
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
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)
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
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.
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 reinnervatedby the sprouting of surviving nerves and are 3-4 times larger than normal.
Genetics SMA type I: Mutations • Mostly SMN1 deletions –Few missense point mutations in – SMN1SMN2 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
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.
Why are only motor neuronsand muscle are affected in SMA ?
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.
The Role of SMN in SMA - 2SMA 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.