Spinal muscle atrophy SMA: make it easy

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    Spinal muscle atrophy SMA: make it easy Spinal muscle atrophy SMA: make it easy Presentation Transcript

    • 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
    • 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
    • Genetics
    • 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.