haythum o tayeb r3, neurology. brief review of the genetics and molecular biology of cmt & hnpp...
TRANSCRIPT
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…?