Transcript Document

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

long-standing
 Pattern
Distribution (distal vs
proximal, symmetry)
 Motor, Sensory,
autonomic

 Medical,
drug,
dietary history
 Family history
No systemic
involvement
 inheritance(AD, AR, Xlined, sporadic)
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 Onset
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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
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Deafness
Tremor
CNS involvement
Diaphragmatic paralysis
Vocal cord paralysis
Pupillary abnormalities
Mental retartdation
Hereditary
Neuropathy
CMT
HNPP
HSAN
dHMN
 CMT1:
demyelinating (NCV
< 38)
 CMT2:
axonal
(NCV>38)
 “intermediate
 HNPP
CMT”
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
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Heterozygous 1.5 fold overexpression
Homozyogous  2 fold overexpression
In transgenic mice: PMP22 forms protein
aggregates in endosomes.
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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 *

 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
 Mutations
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
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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
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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
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CMT1D
DSS, congenital hypomyelination neuropathy
Respiratory 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
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 CMT2B
(3q13-22)
prominent sensory
,foot ulcerations
 similar to HSN1 (no
lancinating pain)
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 CMT2C
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Vocal cord respiratory
failure, shortened life
expectancy
 CMT2D
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(12q24)
(7p14)
weakness and atrophy
more severe in hands
than feet
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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; 33:589597
 Questions
or comments…?