Discussion on MOTOR NEURON DISEASES.pptx

Discussion on Motor neuron ds by final year

1. MOTOR NEURON DISEASES S L. LATHIKA FINAL YEAR MBBS

2. UMN AND LMN LESIONS:

3. Difference between UMN & LMN Lesions:- Features UMN lesion LMN lesion Site of lesion From motor cortex to cranial nerve nuclei in brain and Anterior horn cells in spinal cord .(Cerebral hemisphere, cerebellum, brain stem). From Anterior horn cells to motor end plate ( Nerve roots, peripheral nerves,neuromuscular Junction, muscle). 2. Bulk of muscl es No wasting Wasting present 3. Tone of muscles Hypertonia Hypotonia 4. Type of paralysis Spastic paralysis Flaccid paralysis 5. Deep tendon reflexes Exaggerated Diminished or absent 6. Superficial reflexes Absent Present 7. Babinski sign Present Absent 8. Fasciculations Absent Present

4. AMYOTROPHIC LATERAL SCLEROSIS Most common progressive motor neuron disease An example of a devastating neurodegenerative disorder.

5. PATHOLOGY ┌──────────────────────┴───────────────────────┐ │ Lower Motor Neuron loss Upper Motor Neuron loss (Anterior horn cells, bulbar) (Motor cortex, corticospinal tracts) │ │ Muscle atrophy ( Amyotrophy ) Spasticity, weakness Lateral sclerosis

6. PATHOLOGY Hallmark : Degeneration and death of both lower motor neurons (anterior horn cells & bulbar motor neurons) and upper motor neurons (motor cortex pyramidal neurons). Leads to progressive muscle weakness and atroph y (amyotrophy) and hardening of corticospinal tracts (lateral sclerosis). In some cases, associated with frontotemporal dementia due to cortical neuron degeneration.

7. Other motor neuron diseases Bulbar palsy & SMA – mainly lower motor neurons. Pseudobulbar palsy, PLS, HSP – mainly upper motor neurons.

8. Cellular Pathology: Motor neurons shrink, accumulate lipofuscin . Cytoskeleton disruption is early and severe. Proximal axonal swelling called “spheroid”. Ubiquitin-positive aggregates (incl. TDP-43 protein) found in neurons. Astroglial proliferation & microglial activation accompany degeneration.

9. LIPOFUSCIN SPHEROID

10. Progr ession: Death of motor neurons denervation & atrophy of muscle fibers. Reinnervation is limited compared to other motor neuron diseases. Results in progressive muscle atrophy , fibrillary gliosis, and firmness of lateral columns.

11. Selective neuronal death : sensory system and cerebellar functions usually spared. Cognition preserved except in cases with associated dementia. Characteristic finding: ubiquitin-positive neuronal inclusions.

12. PATHOGENESIS OF ALS: Cause of sporadic ALS : Not well defined and multiple mechanisms contribute. Genetic causes (3 groups):- Protein instability & degradation defects Mutations in SOD1, ubiquilin-1/2, p62 → abnormal protein degradation → motor neuron death.

13. 2. RNA processing/transport abnormalities Mutations in C9orf72, TDP-43, FUS → defective RNA metabolism. C9orf72 : abnormal hexanucleotide repeat expansion (GGGGCC) → toxic RNA foci + sequestration of transcription factors. Leads to widespread RNA dysregulation. 3. Cytoskeletal/axonal transport defects Mutations in profilin-1, dynactin → impaired axonal transport.

14. MECHANICAL MECHANISMS : ALS pathology involves multiple cellular processes : Excitotoxicity Defective autophagy Impaired axonal transport Oxidative stress ER stress & unfolded protein response Mitochondrial dysfunction

15. Hexanucleotide expansions (C9orf72) → disrupt nucleocytoplasmic transport. Genes like GLE1 (mRNA export protein) → mutations cause severe infantile motor neuron disease. Astrocytes & microglia strongly influence disease progression. Neuroinflammation accelerates motor neuron death.

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