Molecular Basis of Hereditary Neuropathies: CMT, HNPP

1. Molecular Basis of Hereditary Neuropathies:CMT, HNPP Haythum O Tayeb R3, Neurology

2. Talk Objective • Brief review of the genetics and molecular biology of CMT & HNPP with clinical correlation

3. Outline • Introduction with a general view of clinical evaluation for a possible hereditary neuropathy • Discerning the clinical and electrophysiologic phenotype • Genes and proteins involved demyelinating hereditary neuropathies • Genes and proteins involved in axonal CMT (CMT2) • Conclusion

5. Hereditary neuropathies • heterogeneous group of diseases • insidious onset and indolent course over years to decades. • They are common eg CMT 1:2500 • Classification (clinical vs molecular)

7. Evaluate the polyneuropathy: the hereditary domain • Onset and progression • Pattern • Distribution (distal vs proximal, symmetry) • Motor, Sensory, autonomic • Medical, drug, dietary history • Family history • long-standing • No systemic involvement • inheritance(AD, AR, X-lined, sporadic)

8. Discerning the phenotype • Onset • in the first two decades of life (classic) • Early onset, severe (dejerine sottas) • Late onset, mild • Severity, distribution, quality of motor/sensory involvement • Inheritance: AD, AR, X-linked, sporadic

9. Discerning the phenotype • Associated abnormalities: hints to particular (uncommon) forms • Deafness • Tremor • CNS involvement • Diaphragmatic paralysis • Vocal cord paralysis • Pupillary abnormalities • Mental retartdation

10. What can you discern in the clinic?

11. Discerning the phenotype • CMT1: demyelinating (NCV < 38) • CMT2: axonal (NCV>38) • “intermediate CMT” • HNPP

12. CMT - genotypes

13. molecular Genetics of CMT and HNPP: myelin vs axon

14. Peripheral myelin protein (PMP-22) • a small membrane glycoprotein in compact peripheral myelin • Chromosome 17p11.2 • Autosomal Dominant inheritance • Function: unknown. “Dosage sensitive”.

15. Mutated pmp22 in cmt1a • 1.5 megabase tandem duplication of the region containing the PMP-22 gene accounts for 70% CMT1A • Takes place during meiosis • Abnormal gain of function • Heterozygous 1.5 fold overexpression • Homozyogous  2 fold overexpression • In transgenic mice: PMP22 forms protein aggregates in endosomes. • Mis-sense mutations  A minority of CMT1A with a severe hypomyelinatingneuropathy phenotype.

16. Mutated PMP22 in HNPP • deletion of the same 1.5 megabase is found in 85% of HNPP • The remaining: frame-shift or nonsense mutations causing functional changes in the protein

17. Myelin protein zero (MPZ) • the major peripheral myelin glycoprotein • MPZ gene: chromosome 1q22-23 • Function: adhesion molecule in the formation and compaction of peripheral myelin *

18. Mutated MPZ: CMT1b and even CMT2 • Mutations  gain (toxicity of the misfolded protein) or loss (reduced amounts) of-function • divergent manifestations • CMT1B • DSS, and hypomyelination neuropathy • CMT2 (axonal rather than demyelinating!) • Mild CMT phenotype (axonal NCS) • CMT2J (Thr 124 Met mutations): late onset, marked sensory loss, deafness, and pupillary abnormalities

19. Connexin-32 (Cx32) • A gap junction protein • found in noncompactedparanodal loops and Schmidt-Lantermann incisures. • also in oligodendroglia (CNS). • Gene: GJB1 on chromosome Xq • X-linked dominant*

20. Cx32 Mutations: cmtX • CMTX • mis-sense mutations (mild clinical phenotype) • nonsense &frame-shift (more severe phenotypes) • Loss of function • Men affected more severely • Phenotype maybe difficult to distinguish from CMT1 and CMT2 • “Intermediate NCS” • CNS involvement reported (ABER, MRI)

21. Litaf: CMT1c • lipopolysaccharide-induced tumor necrosis factor-α [TNF-α]): a lysosomal protein • chromosome 16p13. • Mutations • Mis-sense mutations in CMT1C families • Phenotype: classic CMT1 • Autosomal dominant CMT1 families not linked to either CMT1A or CMT1B

22. Early growth response (egr2): cmt1d • encodes a transcription factor expressed that regulates the expression of myelin proteins including PMP-22, P0, Cx32, and periaxin in Schwann cells • Chromosome 10q21-q22 • Mutations • CMT1D • DSS, congenital hypomyelination neuropathy • Respiratory compromise, cranial nerve dysfunction

23. Other myelin proteins: Cmt4 • Severe childhood-onset, autosomal-recessive demyelinating neuropathies or CMT4 • myotubularin-related protein-2 (MTMR2), • N-myc downstream regulated gene-1 (NDRG1) • Ganglioside-induced differentiation-associated protein-1 (GDAP1) • Early growth response (EGR2) • Periaxin • Others CMT4F Periaxin Severe CMT/DSS

25. Cmt 2 – the axon • Associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, mitochondrial function and protein translation

26. Cmt2 genotypes • CMT2A1 (1p35) • kinesin protein - axonal transport of synaptic vesicles • CMT2A2 (1p36) • Most common CMT2 • Mitofusin2 (mitochondrial) • Early, more severe • +/- optic atrophy • CMT2B (3q13-22) • prominent sensory ,foot ulcerations • similar to HSN1 (no lancinating pain) • CMT2C (12q24) • Vocal cord respiratory failure, shortened life expectancy • CMT2D (7p14) • weakness and atrophy more severe in hands than feet

27. Cmt2…

28. Conclusions • HNs are heterogeneous clinically, electrophysiologically and genetically. • The evaluation starts with discerning the phenotype. • CMT can generally be classified to demyelinating (CMT1 and 4) and axonal (CMT2) . • HNPP is hereditary liability to multiple compression neuropathies with a demyeinating neuropathy. • Demyelinating HN result from a variety of mutations in gene encoding proteins related to myelin structure and function (e.g. PMP-22 in CMT1A and HNPP, MPZ in CMT1B, CX32 in CMTX). • CMT2, axonal, results from mutations in genes encoding proteins involved in axonal transport, mitochondrial function and translation (e.g. kinesin, mitofusin) • Inheritance is mostly AD except for CMTX and uncommon AR forms eg CMT4 and others.

29. references • Neurology in clinical practice, 5th edition, Walter G. Bradly and others • Sorting out the inherited neuropathies. Practical Neurology 2007; 7;93-105 • The dominantly inherited motor and sensory neuropathies: clinical and molecular advances. Muscle and Neurve 2006; 33:589-597

30. Thanks… • Questions or comments…?