1. Haythum O Tayeb R3, Neurology

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

3.  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.  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.  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.  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.  Associated abnormalities: hints to particular (uncommon) forms  Deafness  Tremor  CNS involvement  Diaphragmatic paralysis  Vocal cord paralysis  Pupillary abnormalities  Mental retartdation

10. Hereditary Neuropathy CMTHNPPHSANdHMN

11.  CMT1: demyelinating (NCV < 38)  CMT2: axonal (NCV>38)  “intermediate CMT”  HNPP

14.  a small membrane glycoprotein in compact peripheral myelin  Chromosome 17p11.2  Autosomal Dominant inheritance  Function: unknown. “Dosage sensitive”.

15.  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 hypomyelinating neuropathy phenotype.

16.  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.  the major peripheral myelin glycoprotein  MPZ gene: chromosome 1q22-23  Function: adhesion molecule in the formation and compaction of peripheral myelin *

18.  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.  A gap junction protein  found in noncompacted paranodal loops and Schmidt-Lantermann incisures.  also in oligodendroglia (CNS).  Gene: GJB1 on chromosome Xq  X-linked dominant*

20.  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.  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.  encodes a transcription factor expressed that regulates the expression of myelin proteins including PMP-22, P 0, Cx32, and periaxin in Schwann cells  Chromosome 10q21-q22  Mutations  CMT1D  DSS, congenital hypomyelination neuropathy  Respiratory compromise, cranial nerve dysfunction

23. 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.  Associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, mitochondrial function and protein translation

26.  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

28.  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.  Neurology in clinical practice, 5 th 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.  Questions or comments…?