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)
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
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
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 *
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
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
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
CMT2B
(3q13-22)
prominent sensory
,foot ulcerations
similar to HSN1 (no
lancinating pain)
CMT2C
Vocal cord respiratory
failure, shortened life
expectancy
CMT2D
(12q24)
(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; 33:589597
Questions
or comments…?