Molecular basis of hereditary neuropathies cmt hnpp
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Molecular Basis of Hereditary Neuropathies: CMT, HNPP. Haythum O Tayeb R3, Neurology. Talk Objective. Brief review of the genetics and molecular biology of CMT & HNPP with clinical correlation. Outline.

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Molecular basis of hereditary neuropathies cmt hnpp

Molecular Basis of Hereditary Neuropathies:CMT, HNPP

Haythum O Tayeb

R3, Neurology

Talk objective
Talk Objective

  • Brief review of the genetics and molecular biology of CMT & HNPP with clinical correlation


  • 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

Hereditary neuropathies
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)

Evaluate the polyneuropathy the hereditary domain
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)

Discerning the phenotype
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

Discerning the phenotype1
Discerning the phenotype

  • Associated abnormalities: hints to particular (uncommon) forms

    • Deafness

    • Tremor

    • CNS involvement

    • Diaphragmatic paralysis

    • Vocal cord paralysis

    • Pupillary abnormalities

    • Mental retartdation

Discerning the phenotype2
Discerning the phenotype

  • CMT1: demyelinating (NCV < 38)

  • CMT2: axonal (NCV>38)

  • “intermediate CMT”

  • HNPP

Peripheral myelin protein pmp 22
Peripheral myelin protein (PMP-22)

  • a small membrane glycoprotein in compact peripheral myelin

  • Chromosome 17p11.2

  • Autosomal Dominant inheritance

  • Function: unknown. “Dosage sensitive”.

Mutated pmp22 in cmt1a
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.

Mutated pmp22 in hnpp
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

Myelin protein zero mpz
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 *

Mutated mpz cmt1b and even cmt2
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

Connexin 32 cx32
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*

Cx32 mutations cmtx
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)

Litaf cmt1c
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

Early growth response egr2 cmt1d
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

Other myelin proteins cmt4
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

Cmt 2 the axon
Cmt 2 – the axon

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

Cmt2 genotypes
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


  • 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.


  • 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


  • Questions or comments…?