Haythum O Tayeb

R3, Neurology

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

heterogeneous group of diseases

insidious onset and indolent course over years to decades.

They are common eg CMT 1:2500

Classification (clinical vs molecular)

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)

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

Associated abnormalities: hints to particular (uncommon) forms

DeafnessTremorCNS involvementDiaphragmatic paralysisVocal cord paralysisPupillary abnormalitiesMental retartdation

CMT1: demyelinating (NCV < 38)

CMT2: axonal (NCV>38)

“intermediate CMT”

HNPP

a small membrane glycoprotein in compact peripheral myelin

Chromosome 17p11.2 Autosomal Dominant inheritance Function: unknown. “Dosage sensitive”.

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.

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

the major peripheral myelin glycoprotein MPZ gene: chromosome 1q22-23 Function: adhesion molecule in the formation

and compaction of peripheral myelin *

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

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*

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)

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

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

CMT1DDSS, congenital hypomyelination

neuropathyRespiratory compromise, cranial nerve

dysfunction

• 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

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

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…?