Clinical diagnosis and genetic testing guide for Charcot-Marie-Tooth hereditary neuropathy type 4 (CMT4

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Pagon A, Ada! MP, Bird "#, et al., editors. $eneevie%s& 'Internet(. )eattle *+A,-
.niversity of +ashington, )eattle/ 011234502.
Charcot3Marie3"ooth Neuro6athy "y6e 4
Synonyms: CMT2; Charcot-Marie-Tooth Disease, Axonal Type; HMSN2; Hereditary
Motor and Sensory Neuropathy 2 !ncludes: CMT2A", CM2A2, CMT2#, CMT2#",
CMT2#2, CMT2C, CMT2D, CMT2$%"&, CMT2&, CMT2', CMT2!%(, CMT2H%), CMT2*,
CMT2N, CMT2+, CMT2,
"ho!as # Bird, M#
)eattle 7A Medical Center
#e6art!ents of Neurology and Medicine
.niversity of +ashington
)eattle, +ashington
to!nro89u.%ashington.edu
Initial Posting- )e6te!ber 4:, 011;/ Last evision- Nove!ber 0:, 4502.
Summary
Disease characteristics Charcot3Marie3"ooth hereditary neuro6athy ty6e 4 *CM"4, is an
a<onal *non3de!yelinating, 6eri6heral neuro6athy characteri8ed by distal !uscle
%eakness and atro6hy, !ild sensory loss, and nor!al or near3nor!al nerve conduction
velocities. CM"4 is clinically si!ilar to CM"0, although ty6ically less severe. Peri6heral
nerves are not enlarged or hy6ertro6hic. "he subty6es of CM"4 are si!ilar clinically and
distinguished only by !olecular genetic findings.
Dia-nosis%testin- "he diagnosis is based on clinical findings and =M$>NC7
characteristics. "he 0? genes in %hich !utations are kno%n to cause CM"4 subty6es
are KIF1B *CM"4A0,, MFN2 *CM"4A4,, RAB7A *for!erlyRAB7,
*CM"4B,, LMNA *CM"4B0,, MED25 *CM"4B4,, TRPV4 *CM"4C,, GARS *CM"4#,, NEF
L *CM"4=>0@,, HSPB1 *CM"4@,, MPZ *CM"4I>A,, GDAP1 *CM"4H>B,, HSPB8 *CM"4L,,
AARS *CM"4N,, DYNC1H1 *CM"4C,, and LRSAM1 *CM"4P,.
Mana-ement Treatmet "# ma$#e%tat$"%- "reat!ent by a tea! including a neurologist,
6hysiatrists, ortho6edic surgeons, 6hysical, and occu6ational thera6ist/ s6ecial shoes
and>or ankle>foot orthoses *A@C, to correct foot dro6 and aid %alking/ surgery as needed
for severe 6es cavus/ forear! crutches, canes, %heelchairs as needed for !obility/
e<ercise as tolerated/ sy!6to!atic treat!ent of 6ain, de6ression, slee6 a6nea, restless
legs syndro!e.
Pre&et$" "# %e'"(ar) '"m*+$'at$"%- #aily heel cord stretching to 6revent AchillesD
tendon shortening.
S,r&e$++a'e- Monitoring gait and condition of feet to deter!ine need for bracing, s6ecial
shoes, surgery.
A-et%.'$r',m%ta'e% t" a&"$(- Cbesity, %hich !akes a!bulation !ore difficult/
!edications kno%n to cause nerve da!age *e.g., vincristine, isonia8id, nitrofurantoin,.
/t0er- Career and e!6loy!ent counseling.
'enetic counselin- CM"4B0, CM"4B4, and CM"4H>B are inherited in an autoso!al
recessive !anner/ all other subty6es of CM"4 are inherited in an autoso!al do!inant
!anner. Most 6robands %ith autoso!al do!inant subty6es of CM"4 have inherited the
disease3causing !utation fro! an affected 6arent. "he offs6ring of an affected individual
%ith autoso!al do!inant CM"4 are at a ?5E risk of inheriting the altered gene.
#iagnosis
Clinical Diagnosis
Charcot3Marie3"ooth hereditary neuro6athy ty6e 4 *CM"4, is diagnosed clinically in
individuals %ith the follo%ing-
A 6rogressive 6eri6heral !otor and sensory neuro6athy
Nerve conduction velocities *NC7s, that are usually %ithin the nor!al range *F:53
:? !>s,, although occasionally in a !ildly abnor!al range *253:5 !>s,
=M$ testing that sho%s evidence of an a<onal neuro6athy %ith such findings as
6ositive %aves, 6oly6hasic 6otentials, or fibrillations and reduced a!6litudes of
evoked !otor and sensory res6onses
$reatly reduced co!6ound !otor action 6otentials *CMAP,
A fa!ily history consistent %ith autoso!al do!inant inheritance
"esting
Ner.e /iopsy does not sho% the hy6ertro6hy or onion bulb for!ation seen in Charcot3
Marie3"ooth hereditary neuro6athy ty6e 0 *CM"0, but instead sho%s loss of !yelinated
fibers %ith signs of regeneration, a<onal s6routing, and atro6hic a<ons %ith
neurofila!ents.
Molecular Genetic Testing
'enes @ifteen genes in %hich !utations are kno%n to cause subty6es of CM"4 have
been identified 'GHchner I 7ance 455Jb( *"able 0,.
Table 1. Genes Associated with CMT2 Subtypes
CMT2 Subtype Gene Reference
CMT2A1 KIF1B 1 Zhao et al [2001]
CMT2A2 MFN2 2 Verhoeven et al [2006]
CMT2B RAB7A Verhoeven et al [2003]
CMT2B1 LMNA De Sandre-Giovannoli et al [2002]
CMT2B2 MED25 Leal et al [2009]
CMT2C TRPV4
Auer-Grumbach et al [2010], Deng et al [2010], Landour et al
[2010]
CMT2D GARS
CMT2E/1F NEFL
CMT2F
HSPB1 (HSP27
)
Evgrafov et al [2004]
CMT2I/J MPZ Sowden et al [2005]
CMT2H/K GDAP1 Barhoumi et al [2001], Claramunt et al [2005]
CMT2L
HSPB8 (HSP22
)
Tang et al [2005]
CMT2N AARS McLaughlin et al [2012]
CMT2O DYNC1H1 Weedon et al [2011]
CMT2P LRSAM1 Guernsey et al [2010], Weterman et al [2012]
0. @ound in one fa!ily
4. e6resents a66ro<i!ately 45E325E of CM"4
$.idence 0or locus hetero-eneity Another locus for CM"4 has been !a66ed/ no gene
has yet been identified *see "able 4,.
Table 2. CMT2: Other Locus
CMT2 Subtype Chromosomal Locus Reference
CMT2G 12q12-q13.3 Nelis et al [2004]
Clinical testin- 1CMT2A", CMT2A2, CMT2#, CMT2#", CMT2#2, CMT2C, CMT2D,
CMT2$%"&, CMT2&, CMT2!%(, CMT2H%), CMT2*, CMT2N2
Table 3. Summary of Molecular Genetic Testing Used in CMT2
Gene 1 / Locus
Name
Test Method
Mutations
Detected 2
Proportion of
CMT2
Attributed to
Mutations in
This Gene
Mutation
Detection
Frequency 3
Test
Availability
KIF1B / CMT2A1
Sequence
analysis
Sequence
variants 4
Rare Unknown Clinical
MFN2 / CMT2A2
Sequence
analysis and
mutation
scanning 5,6
Sequence
variants 4
20% Unknown Clinical
Deletion /
duplication
analysis 6
Exonic or
whole-gene
deletions
RAB7A / CMT2B
Sequence
analysis
Sequence
variants 4
LMNA / CMT2B1
Sequence
analysis
Sequence
variants 4
Rare
Unknown
Clinical
Deletion /
duplication
analysis 7
Exonic or
whole-gene
deletions
Unknown,
none reported
MED25 / CMT2B2
Sequence
analysis
Sequence
variants 4
Mutation
scanning of
select exons 5
Sequence
variants in
exon 9 4,5
Targeted
mutation
analysis
p.Ala335Val
TRPV4 / CMT2C
Sequence
analysis
Sequence
variants 4
Rare Unknown
Clinical
Sequence
analysis of
select exons
Sequence
variants in
exons 5,6 4,5
Rare Unknown
GARS / CMT2D Sequence
analysis
Sequence
variants 4
Rare Unknown,
none reported
Clinical
Deletion /
duplication
analysis 7
Exonic or
whole-gene
deletions
NEFL / CMT2E/1F
Sequence
analysis
Sequence
variants 4
HSPB1 / CMT2F
Sequence
analysis
Sequence
variants 4
Rare
Unknown,
none reported
Clinical
Deletion /
duplication
analysis 7
Exonic or
whole-gene
deletions
Unknown / CMT2G
Linkage
analysis
Not applicable Rare Not applicable Research
MPZ / CMT2I/J
Sequence
analysis,
mutation
scanning 6
Sequence
variants 4
Rare
Unknown
Clinical
Deletion /
duplication
analysis 7
Deletions or
duplications
Unknown,
none reported
GDAP1 / CMT2H/K
Sequence
analysis
Sequence
variants 4
HSPB8 / CMT2L
Sequence
analysis
Sequence
variants 4
Rare
Unknown
Clinical
Deletion /
duplication
analysis 7
Exonic or
whole-gene
deletions
Unknown,
none reported
AARS / CMT2N
Sequence
analysis
Sequence
variants 4
DYNC1H1 / CMT2O
Sequence
analysis
Sequence
variants 4
LRSAM1 / CMT2P
Sequence
analysis of
select exons
Sequence
variants in
exon 25 4
0. )ee "able A. $enes and #atabases for chro!oso!e locus and 6rotein na!e.
4. )ee Molecular $enetics for infor!ation on allelic variants.
2. "he ability of the test !ethod used to detect a !utation that is 6resent in the
indicated gene
:. =<a!6les of !utations detected by seKuence analysis !ay include s!all
intragenic deletions>insertions and !issense, nonsense, and s6lice site !utations/
ty6ically, e<onic or %hole3gene deletions>du6lications are not detected. @or issues to
consider in inter6retation of seKuence analysis results, click here.
?. )elected e<ons for testing !ay vary a!ong laboratories.
J. )eKuence analysis and !utation scanning of the entire gene can have si!ilar
detection freKuencies, although !utation scanning detection rates !ay vary
considerably a!ong laboratories as that !ethod is highly de6endent on details of the
!ethodology e!6loyed.
L. "esting that identifies deletions>du6lications not readily detectable by seKuence
analysis of the coding and flanking intronic regions of geno!ic #NA/ included in the
variety of !ethods that !ay be used are- Kuantitative PC, long3range PC,
!ulti6le< ligation3de6endent 6robe a!6lification *MLPA,, and chro!oso!al
!icroarray *CMA, that includes this gene>chro!oso!e seg!ent.
"esting )trategy
To esta/lish the dia-nosis o0 a CMT2 su/type the 6roband should first be tested for
!utations in MFN21 MPZ, and G2B1 *encoding conne<in 24,, as !utations in these genes
are !ost co!!only res6onsible for this syndro!e, 6robably accounting for 45E34?E of
cases 'GHchner I 7ance 455Jb, Bienfait et al 455L, )a6orta et al 4500(.
Note- If there is !ale3to3!ale trans!ission in the fa!ily it is not necessary to test for
!utations in G2B1, an M3linked gene.
If no !utation is identified in these three genes, !any neurologists do no further genetic
testing because the other kno%n genes are Kuite rare and !any genetic causes re!ain to
be discovered. Affected individuals %ho %ish to e<haust all 6ossibilities !ay %ant to
6roceed %ith the other tests relevant to CM"4 *e.g., NEFL, GDAP1, RAB7A1 MED251
TRPV41 AARS,. If the 6henoty6e includes vocal cord 6aresis, !olecular genetic testing
of GDAP1 andTRPV4 is a66ro6riate.
,renatal dia-nosis and preimplantation -enetic dia-nosis 1,'D2 for at3risk
6regnancies reKuire 6rior identification of the disease3causing !utation in the fa!ily.
$enetically elated *Allelic, #isorders
KIF1B. CM"4A is the only 6henoty6e kno%n to be associated %ith KIF1B.
MFN2. CM"4A is the only 6henoty6e kno%n to be associated %ith MFN2.
RAB7A. CM"4B is the only 6henoty6e kno%n to be associated %ith RAB7A.
LMNA. In addition to CM"4B0, the follo%ing 6henoty6es are associated %ith 6athogenic or
nor!al variations in LMNA-
Hutchinson3$ilford 6rogeria syndro!e *H$P) or 6rogeria,
Autoso!al do!inant =!ery3#reifuss !uscular dystro6hy ty6e 4 *=M#4,.
)ee =!ery3#reifuss Muscular #ystro6hy *=#M#,.
Autoso!al recessive =!ery3#reifuss !uscular dystro6hy ty6e 4 *=M#4,.
)ee =#M#.
Autoso!al do!inant fa!ilial dilated cardio!yo6athy and conduction syste! defects
*CM#0A,. )ee #ilated Cardio!yo6athy Cvervie%.
Autoso!al do!inant #unnigan3ty6e fa!ilial 6artial li6odystro6hy *@PL#,
Autoso!al do!inant li!b3girdle !uscular dystro6hy 0B *L$M#0B,. )ee Li!b3
$irdle Muscular #ystro6hy Cvervie%.
A nor!al allelic variant in LMNA *NMN0L5L5L.4-c.015;CF", associated %ith
obesity3related traits in Canadian COi3Cree
Autoso!al recessive !andibuloacral dys6lasia *MA#,. A co!6ound hetero8ygous
!utation 6.'Arg:L0Cys(P 'Arg?4LCys( in a 4;3year3old %o!an %ith !andibuloacral
dys6lasia, 6reviously diagnosed as Qaty6ical 6rogeria,Q %as re6orted 'Cao I Hegele
4552(.
Aty6ical +erner syndro!e 'Chen et al 4552(
A single case re6ort of a !ale hetero8ygous for the !utation 6.Arg022Leu %ith
li6oatro6hy, disse!inated %hite skin 6a6ules, hy6ertro6hic cardio!yo6athy, he6atic
steatosis, and insulin resistance 'Cau< et al 4552(
Co3occurrence of !yo6athy and neuro6athy 'Benedetti et al 455?, +alter et al
455?(
)ee CMIM 0?5225 for additional references regarding other la!ino6athies.
TRPV4. In addition to CM"4C, TRPV4 has been associated %ith both brachyol!ia and
!eta6hyseal dys6lasia 'ock et al 455;, Brako% et al 4551(.
GARS. In addition to CM"4#, the other 6henoty6e associated %ith !utations in GARS is
hereditary !otor neuro6athy ty6e ? *HMN 7, 'Antonellis et al 4552(.
NEFL. CM"4=>0@ is the only 6henoty6e kno%n to be associated %ith !utations in NEFL.
HSPB1. CM"4@ is the only 6henoty6e kno%n to be associated %ith !utations in HSPB1.
MPZ. In addition to CM"4I and CM"4A, !utations in MPZ are associated %ith CM"0B
*see CM"0, ')enderek et al 4555(.
GDAP1. In addition to CM"4H>B, autoso!al recessive CM":A is associated %ith
!utations in GDAP1.
HSPB8. In addition to CM"4L, !utations in HSPB8 have been re6orted in distal hereditary
!otor neuro6athy ty6e 4 *dHMNII, 'Irobi et al 455:b(.
AARS. CM"4N is the only 6henoty6e kno%n to be associated %ith !utations in AARS.
DYNC1H1. CM"4C is the only 6henoty6e kno%n to be associated %ith !utations
in DYNC1H1.
LRSAM1. CM"4P is the only 6henoty6e kno%n to be associated %ith !utations
in LRSAM1.
Clinical #escri6tion
Natural History
Charcot3Marie3"ooth hereditary neuro6athy ty6e 4 *CM"4, is a disorder of 6eri6heral
nerves in %hich the !otor syste! is !ore 6ro!inently involved than the sensory syste!,
although both are involved 'Pareyson I Marchesi 4551(. "he affected individual ty6ically
has slo%ly 6rogressive %eakness and atro6hy of distal !uscles in the feet and>or hands
usually associated %ith de6ressed tendon refle<es and !ild or no sensory loss. "he
clinical syndro!e overla6s e<tensively %ith CM"0. +ith the e<ce6tion of CM"4B, CM"4
tends to be less disabling and to cause less sensory loss than CM"0 'Bienfait et al
455J, Pareyson et al 455J(.
Affected individuals usually beco!e sy!6to!atic bet%een ages five and 4? years 'Bienfait
et al 455J(, though onset ranges fro! infancy %ith delayed %alking to after the third
decade. "he ty6ical 6resenting sy!6to! is %eakness of the feet and ankles. "he initial
6hysical findings are de6ressed or absent tendon refle<es %ith %eakness of foot
dorsifle<ion at the ankle. Baets et al '4500( revie% the clinical 6resentations in the first year
of life.
"he adult %ith CM"4 ty6ically has bilateral foot dro6, sy!!etric atro6hy of !uscles belo%
the knee *stork leg a66earance, and absent tendon refle<es in the lo%er e<tre!ities.
Ho%ever, brisk tendon refle<es and e<tensor 6lantar res6onses have been re6orted as
%ell as asy!!etric !uscle atro6hy in u6 to 0?E of affected individuals 'Bienfait et al
455L(.
Atro6hy of intrinsic hand !uscles is less freKuently 6resent and tendon refle<es !ay be
intact in the u66er li!bs.
Pro<i!al !uscles usually re!ain strong. Brisk tendon refle<es and e<tensor 6lantar
res6onses have been re6orted 'Bienfait et al 455L(.
Mild sensory deficits of 6osition, vibration, and 6ain>te!6erature !ay occur in the feet or
sensation !ay be intact. Pain, es6ecially in the feet, is re6orted by about 45E3:5E of
affected individuals '$e!ignani et al 455:(. Hearing i!6air!ent has been re6orted
'Bienfait et al 455J(.
C6tic atro6hy !ay occur in CM"4A 'GHchner et al 455J(.
A fe% individuals have vocal cord or 6hrenic nerve involve!ent resulting in difficulty %ith
6honation or breathing '#e!atteis et al 4550, )ulica et al 4550(.
estless legs and slee6 a6nea have been associated %ith CM"4 'Aboussouan et al 455L(.
CM"4 is 6rogressive over !any years, but affected individuals e<6erience long 6lateau
6eriods %ithout obvious deterioration. In so!e, the disease can be so !ild as to go
unrecogni8ed by the affected individual and 6hysician. "he disease does not decrease life
s6an.
CMT2 su/types
CMT2A *co!6rising CM"4A0 and CM"4A4, has a ty6ical CM" 6henoty6e %ith
onset in the second or third decade of distal !uscle %eakness and atro6hy, less
severe sensory loss, and de6ressed tendon refle<es. NC7s fall %ithin the nor!al or
near3nor!al range, co!6atible %ith an a<onal neuro6athy. Clinical features of
fa!ilies %ith MFN2 !utations are described by GHchner et al '455:a( and BiOi!a et
al '455?(. C6tic atro6hy !ay occur in CM"4A 'GHchner et al 455J(. CM"4A can
!i!ic multiple sclerosis including %hite !atter lesions on brain MI '$enari et al
4500, Blein et al 4500a(. =arly3onset, severe 6ure !otor neuro6athy is co!!on in
CM"4A %ith !utation in MFN2 '@eely et al 4500(.
CMT2# has 6ro!inent sensory loss %ith distal ulceration/ controversy e<ists
regarding its e<act classification. Additional 6henoty6e infor!ation is 6resented
in Auer3$ru!bach et al '4555(, 7erhoeven et al '4552(, andHoulden et al '455:(.
Late onset *age F?5 years, has been noted ')hi!i8u et al 4505(.
CMT2#" is found 6ri!arily in Algeria. Mean age of onset is 0: years *range J34L
years,/ functional disability ranges fro! !ild to severe '"a8ir et al 455:(.
CMT2#2 occurred in a Costa ican fa!ily %ith adult onset 'Leal et al
4550, Berghoff et al 455:(.
CMT2C is associated %ith freKuent vocal cord and 6hrenic nerve 6aralysis
so!eti!es reKuiring tracheoto!y ')antoro et al 4554, Mc=ntagart et al 455?, Chen
et al 4505, #eng et al 4505, Landoure et al 4505(. Mild sensory loss %as noted in
the individuals re6orted by #yck et al '011:(.
CMT2D is characteri8ed by 6redo!inantly distal !otor %eakness %ith %asting of
the hand !uscles 'Antonellis et al 4552(.
CMT2$%"& has been re6orted in several fa!ilies %ith a 6rogressive sensory and
!otor neuro6athy. "he full range of 6henoty6e !ay overla6 %ith the CM"0
syndro!e characteri8ed by slo% NC7 '$eorgiou et al 4554,Aordanova et al
4552, GHchner et al 455:a(. A Belgian fa!ily had NC7s ranging fro! 4? to :4 !>s,
overla66ing both a<onal and de!yelinating 6henoty6es '#e Aonghe et al 4550(. A
ussian fa!ily had relatively nor!al NC7 and hy6erkeratosis 'Mersiyanova et al
4555(. It is unkno%n if the 6resence of hy6erkeratosis is coincidental or re6resents
variable e<6ressivity of the CM"4=>0@ 6henoty6e.
CMT2& has been re6orted in a single ussian fa!ily %ith distal %eakness, atro6hy,
and sensory loss beginning bet%een ages 0? and 4? years. "his disorder is si!ilar
to distal hereditary !otor neuro6athy *HMN,, e<ce6t that there is no sensory loss in
HMN 'Is!ailov et al 4550, =vgrafov et al 455:, Irobi et al 455:a(. Mutations
in HSPB1 occurred in :E of a series of CM"4 cases in Italy 'Ca66oni et al 4500(.
Pri!ary !otor neuro6athy has been described ')olla et al 4505( but sensory loss
can occur 'ossor et al 4504(.
CMT2' has been re6orted in a single )6anish fa!ily 'Nelis et al 455:(.
CMT2H has associated 6yra!idal features 'Barhou!i et al 4550( and CMT2) is
associated %ith the 6.Arg045"r6 and 6."hr0?LPro !utations in GDAP1 'Clara!unt
et al 455?(.
CMT2! has only !ild slo%ing of NC7 'Li et al 455J(.
CMT2( "he MPZ !utation 6."hr02:Met is associated %ith an a<onal neuro6athy
%ith deafness and Argyll obertson 6u6ils 'Cha6on et al 0111(. In addition, the
6athogenic allelic variants 6."hr02:Met and 6.As6;?7alhave been associated %ith
a<onal neuro6athy and !arked sensory i!6air!ent, AdieDs 6u6il, and deafness
'Misu et al 4555(.
CMT2* has been re6orted in a single Chinese fa!ily, %ith onset bet%een ages 0?
and 22 years and nor!al NC7 '"ang et al 455:, "ang et al 455?(.
CMT2N has been re6orted in t%o @rench fa!ilies and in one Australian fa!ily. "he
recurrent loss3of3function AARS !utation 6.Arg241His segregates %ith and results
in the CM" 6henoty6e in each of these fa!ilies 'Latour et al 4505, McLaughlin et al
4504(.
CMT2+ has been re6orted in a large fa!ily %ith childhood onset of delayed !otor
!ilestones associated %ith 6rogressive distal lo%er li!b %eakness, 6es cavus,
variable sensory loss, and nor!al nerve conductions. Cccasional 6ro<i!al
%eakness and %addling gait %ere noted '+eedon et al 4500(.
CMT2, has been re6orted in a large rural Canadian fa!ily %ith onset of
6rogressive distal !uscle %eakness and atro6hy usually starting in young adulthood
'$uernsey et al 4505(. Nerve electro6hysiology %as consistent %ith an a<onal
neuro6athy. "he inheritance %as autoso!al recessive and associated %ith a
ho!o8ygous single nucleotide change in an intronic consensus acce6tor s6licing
site of LRSAM1. +eter!an et al '4504( re6orted a three3generation #utch fa!ily
%ith onset in the second or third decade of slo%ly 6rogressive distal %eakness and
atro6hy %ith !ild sensory loss and an a<onal neuro6athy. "he disease %as
autoso!al do!inant and caused by a fra!eshift !utation *6.LeuL5;Arg fs"er4;,
in LRSAM1. Nicolaou et al '4504( have described a !ulti3generational )ardinian
fa!ily %ith a s6lice site !utation in LRSAM1 resulting in a fra!eshift and sto6
codon *6.AlaJ;2Profs"er2,.
CMT2%DHTKD1. Mu et al '4504( have re6orted a large Chinese fa!ily %ith
autoso!al do!inant CM"4 and a nonsense !utation *c.0:??"F$/ 6."yr:;?"er, in
e<on ; of DHTKD1, the gene encoding dehydrogenase =0 and transketolase
do!ain3containing 6rotein 0.
Neuropatholo-y "he disease 6rocess is 6resu!ed to occur in the a<on or cyto6las! of
the anterior horn cell neuron. Anterior horn cell loss has been found in t%o auto6sies
')chroder 455J(.
In CM"4=, electron !icrosco6y has sho%n giant a<ons %ith accu!ulation of disorgani8ed
neurofila!ents '@abri8i et al 455:(.
$enoty6e3Phenoty6e Correlations
@e% s6ecific genoty6e36henoty6e correlations are kno%n. Considerable variability of
6henoty6e has been observed %ithin fa!ilies %ith CM"4A 'GHchner et al 455:a, Blein et al
4500a(.
C6tic atro6hy is associated %ith !utations in MFN2 '7erhoeven et al 455J, GHchner et al
455J(.
)o!e !utations in TRPV4 are associated %ith diseases of bone '7er!a et al 4505(.
Penetrance
Penetrance is usually nearly co!6lete. Ho%ever, because so!e subty6es of CM"4 are
associated %ith adult onset of sy!6to!s, 6enetrance is age de6endent.
No!enclature
CMT2A. "his disorder is also kno%n as hereditary !otor and sensory neuro6athy 7I
*HM)N 7I,.
CM"4 %ith 6yra!idal signs, also kno%n as hereditary !otor and sensory neuro6athy 7
*HM)N 7,, has been associated %ith MFN2 !utations 'Ghu et al 455?( and %ith !utations
in BSCL2 'Bienfait et al 455L( *see BSCL2 3elated Neurologic #isorders ,.
CMT2C Previously this has so!eti!es been called sca6ulo6eroneal s6inal !uscular
atro6hy.
CMT2$%"&. )o!e individuals %ith !utations in NEFL, %hich ty6ically cause CM"4=, !ay
have slo% NC7s, resulting in a diagnosis of CM"0@. "o acco!!odate these t%o
6henoty6es associated %ith !utations in NEFL, the designation CM"4=>0@ has been
used.
Prevalence
"he overall 6revalence of hereditary neuro6athies is esti!ated at a66ro<i!ately 2-05,555
6o6ulation. About 25E of these individuals *0-05,555, !ay have CM"4. "he 6revalence of
the various subty6es of CM"4 is unkno%n. CM"4A re6resented 2.:E30JE of all CM"
fa!ilies in Nor%ay and )6ain res6ectively 'Braathen et al 4505, Casasnovas et al 4505(.
In a large study of $er!an individuals %ith a CM"4 6henoty6e *LLJ,, $ess et al
'4502( found the follo%ing 6ercentages- 00E had CM"M0, ;E had CM"4Aand JE had the
rare giant a<onal neuro6athy. A!ong those %ith CM"4, 2?E had a genetic diagnosis.
ossor et al '4502( sho% the 6revalence of various subty6es of CM"4 and note that L?E
of cases have no kno%n associated gene. )ee @igure 0.
#ifferential #iagnosis
)ee CM" Cvervie%, 6articularly to e<clude 6otentially treatable causes of acKuired
neuro6athy.
Charcot3Marie3"ooth hereditary neuro6athy ty6e 4 *CM"4, can so!eti!es be difficult to
distinguish fro! chronic idio6athic a<onal neuro6athy.
Bienfait et al '455J( found e<tensive clinical overla6 bet%een individuals %ith CM"0A and
CM"4, %hile noting that 6eo6le %ith CM"0A are !ore likely to have earlier3onset disease,
foot defor!ity, and total arefle<ia.
A !edian !otor NC7 of 2; !>s is often used as a threshold for differentiating CM"0 fro!
CM"4/ ho%ever, the CM"4 6henoty6e can result fro! !utations in genes 6ri!arily
associated %ith CM"0 and CM"M0 '$utierre8 et al 4555, Roung et al 4550, )hy et al
455:(.
CM"4C rese!bles t%o other disorders-
A si!ilar, but 6ure !otor syndro!e %ithout sensory loss, ter!ed distal hereditary
!otor neuro6athy 7II *dHM737II, and linked to chro!oso!e 4K0: 'Mc=ntagart et al
4550(
Autoso!al do!inant !otor neuro6athy %ith vocal 6aralysis associated %ith a
!issense !utation in the DCTN11 encoding the 6rotein dynactin 0 'Puls et al 4552(
)everal different ty6es of autoso!al do!inant hereditary a<onal neuro6athy !ay cause
6redo!inantly sensory sy!6to!s, including the Qburning feet syndro!eQ ')togbauer et al
0111, Auer3$ru!bach et al 4552(. @a!ilies %ith hereditary sensory neuro6athy
*including hereditary sensory neuro6athy ty6e 0 caused by !utations in SPTLC1 'BeOaoui
et al 4550(, usually do not have !otor sy!6to!s such as !uscle %eakness, but findings
can so!eti!es overla6 %ith CM"4B.
Bellone et al '4554( re6orted a fa!ily %ith autoso!al do!inant !utilating neuro6athy that
%as not linked to the CM"4B locus or the H)N0 locus.
"he CM"4 6henoty6e !ay so!eti!es be associated %ith signs of s6asticity *e.g.,
hy6eractive tendon refle<es and>or Babinski signs,. "his 6henoty6e has so!eti!es been
referred to as HM)N 7. "%o affected fa!ilies have been re6orted by 7ucic et al '4552(.
Cne gene associated %ith this 6henoty6e has been identified *see BSCL2 3elated
Neurologic #isorders,.
Another for! of autoso!al do!inant !otor and sensory neuro6athy fro! Ckina%a has
been !a66ed to 2K02 '"akashi!a et al 0111(. "he relationshi6 of this entity to CM"4B,
%hich is linked to a si!ilar region, is undeter!ined.Ishiura et al '4504( have found
!utations in TFG causing hereditary !otor and sensory neuro6athy %ith 6ro<i!al
do!inant involve!ent. Lee et al '4502( have found the sa!e !utation in TFG in a Borean
fa!ily %ith 6ro<i!al do!inant HM)N.
@e!ales %ith CM"M0 *G2B1, encoding conne<in 24, !ay have a CM"4 6henoty6e.
Boyer et al '4500( have re6orted hetero8ygous !utation in INF2 associated %ith childhood3
onset CM" syndro!e later co!6licated by renal glo!erulosclerosis. Nerve conductions
have varied fro! !oderately slo% to nor!al.
An intermediate 0orm of CM" inherited in an autoso!al do!inant !anner has been
described/ affected individuals have a relatively ty6ical CM" 6henoty6e %ith nerve
conduction velocities that overla6 those observed in CM"0 *de!yelinating for!, and
CM"4 *a<onal for!,. Motor NC7s in these fa!ilies usually range bet%een 4? and ?5
!>sec.
At least three chro!oso!al loci *06, 05K, and 016, for this inter!ediate for! have
been identified by linkage analysis 'Bennerson et al 4550, 7erhoeven et al 4550(.
Mutations in YARS and DNM2 !ay cause this syndro!e.
Lo6e83Bigas et al '4550( have described an autoso!al do!inant neuro6athy
associated %ith hearing i!6air!ent caused by a !utation in G2B3, encoding the
6rotein conne<in 20. Although the sural nerve 6athology sho%ed de!yelination
co!6atible %ith CM"0, the nerve condition velocities %ere not !arkedly slo% and
!ay suggest a clinical diagnosis of CM"4.
+eedon et al '4500( have described a large four3generation fa!ily %ith childhood3
onset a<onal CM" and a !issense !utation *6.His25JArg, in DYNC1H1, the gene
encoding cyto6las!ic dynein 0 heavy chain 0.
Mutations in DNM2 *dyna!in 4, usually cause centronuclear !yo6athy, but there
!ay be an overla6 %ith a 6redo!inantly CM"4 6resentation 'Boh! et al 4504(.
Blein et al '4500b( have re6orted several fa!ilies %ith an autoso!al do!inant
sensory neuro6athy associated %ith hearing loss and later de!entia caused by
!utations in DNMT1. )ee DNMT1 3elated #e!entia, #eafness, and )ensory
Neuro6athy.
Mitochondrial causes Mitochondrial abnor!alities are kno%n to so!eti!es be
associated %ith 6eri6heral neuro6athy. Mutations in the nuclear gene MFN2 6roduce
abnor!al !itochondrial fusion>fission and resultant neuro6athy *CM"4A,. Mutations in the
!itochondrial geno!e !ay also be associated %ith neuro6athy, for e<a!6le
in NAP. Pitceathly et al '4504( have re6orted an a<onal 6redo!inantly !otor neuro6athy
associated %ith the !.10;?"FC !utation in MT3ATP4.
Note to clinicians: @or a 6atient3s6ecific Ssi!ultaneous consultT related to the !ost
co!!on ty6e of CM"4 *CM"4A4,, go to , an interactive diagnostic decision su66ort
soft%are tool that 6rovides differential diagnoses based on 6atient findings *registration or
institutional access reKuired,.
Manage!ent
Evaluations Following Initial Diagnosis
"o establish the e<tent of disease in an individual diagnosed %ith Charcot3Marie3"ooth
hereditary neuro6athy ty6e 4 *CM"4,, the follo%ing evaluations are reco!!ended-
Physical e<a!ination to deter!ine e<tent of %eakness and atro6hy, 6es cavus, gait
stability, and sensory loss
Nerve conduction velocity *NC7,
Co!6lete fa!ily history
Medical genetics consultation
"reat!ent of Manifestations
"reat!ent is sy!6to!atic. Affected individuals are often evaluated and !anaged by a
!ultidisci6linary tea! that includes neurologists, 6hysiatrists, ortho6edic surgeons, and
6hysical and occu6ational thera6ists '$randis I )hy 455?(.
"he follo%ing !ay be indicated-
)6ecial shoes, including those %ith good ankle su66ort
Ankle>foot orthoses *A@C, to correct foot dro6 and aid %alking
Crtho6edic surgery to correct severe 6es cavus defor!ity '$uyton I Mann 4555(
@orear! crutches or canes for gait stability/ fe%er than ?E need %heelchairs.
"reat!ent of slee6 a6nea or restless legs 'Aboussouan et al 455L(
=<ercise is encouraged %ithin the individualDs ca6ability and !any individuals re!ain
6hysically active.
Pain and de6ression should be treated sy!6to!atically '$e!ignani et al 455:, Padua et
al 455J(.
Prevention of )econdary Co!6lications
#aily heel cord3stretching e<ercises are hel6ful in 6reventing AchillesD tendon shortening.
)urveillance
$ait and condition of feet should be !onitored to deter!ine need for bracing, s6ecial
shoes, or surgery.
Agents>Circu!stances to Avoid
Cbesity is to be avoided because it !akes %alking !ore difficult.
Medications %hich are to<ic or 6otentially to<ic to 6ersons %ith CM" co!6rise a range of
risks including-
De0inite hi-h ris3 7inca alkaloids *7incristine,
"his category should be avoided by all 6ersons %ith CM", including those
%ho are asy!6to!atic.
+ther potential ris3 le.els )ee "able :. @or !ore infor!ation, click here *6df,.
Table 4. Medications Potentially Toxic to Persons with CMT
Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or vitamin B12 deficiency)
- Perhexiline (not used in US)
- Pyridoxine (mega dose of vitamin B6)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)
Click here *6df, for additional !edications in lesser3risk categories.
"he !edications listed here 6resent differing degrees of 6otential risk for %orsening
CM" neuro6athy. Al%ays consult your treating 6hysician before taking or changing
any !edication.
0. Based on- +ei!er I Pod%all '455J(. )ee also $raf et al '011J(, Nishika%a et al
'455;(, and Porter et al '4551(.
=valuation of elatives at isk
)ee $enetic Counseling for issues related to testing of at3risk relatives for genetic
counseling 6ur6oses.
Pregnancy Manage!ent
Argov I de 7isser '4551( revie%ed 6regnancy issues in hereditary neuro!uscular
disorders including CM". About ?5E of %o!en %ith CM" describe increased %eakness
during 6regnancy that usually resolves 6ost 6artu! 'udnik3)choneborn et al 0112(.
C6erative deliveries %ere re6orted !ore co!!only in %o!en %ith CM" in Nor%ay 'Hoff et
al 455?(. $reen%ood I )cott '455L( have described the obstetric a66roach to %o!en %ith
!ild and severe for!s of CM".
A recent $er!an study revie%ed J2 6regnancies in 22 individuals %ith CM" 'A%ater et al
4504( and found no increase in the freKuency of Cesarean sections, force6s deliveries,
6re!ature births, or neonatal 6roble!s. About one third of !others felt a %orsening of
CM" sy!6to!s during 6regnancy/ in one fifth of !others the changes %ere felt to be
6ersistent.
"hera6ies .nder Investigation
)earch Clinical"rials.gov for access to infor!ation on clinical studies for a %ide range of
diseases and conditions. Note- "here !ay not be clinical trials for this disorder.
Cther
Career and e!6loy!ent choices !ay be influenced by 6ersistent %eakness of hands
and>or feet.
$enetic Counseling
Geet$' '",%e+$- $% t0e *r"'e%% "# *r"&$($- $($&$(,a+% a( #am$+$e% 5$t0 $#"rmat$" "
t0e at,re1 $0er$ta'e1 a( $m*+$'at$"% "# -eet$' ($%"r(er% t" 0e+* t0em ma6e $#"rme(
me($'a+ a( *er%"a+ (e'$%$"%7 T0e #"++"5$- %e't$" (ea+% 5$t0 -eet$' r$%6 a%%e%%met
a( t0e ,%e "# #am$+) 0$%t"r) a( -eet$' te%t$- t" '+ar$#) -eet$' %tat,% #"r #am$+)
mem8er%7 T0$% %e't$" $% "t meat t" a((re%% a++ *er%"a+1 ',+t,ra+1 "r et0$'a+ $%%,e% t0at
$($&$(,a+% ma) #a'e "r t" %,8%t$t,te #"r '"%,+tat$" 5$t0 a -eet$'% *r"#e%%$"a+. U=#.
Mode of Inheritance
CM"4B0, CM"4B4, and CM"4H>4B are inherited in an autoso!al recessive !anner/ all
other subty6es of Charcot3Marie3"ooth hereditary neuro6athy ty6e 4 *CM"4, are inherited
in an autoso!al do!inant !anner.
CM"4P has been re6orted to be inherited in an autoso!al recessive !anner in one fa!ily
and in an autoso!al do!inant !anner in one fa!ily.
isk to @a!ily Me!bers U Autoso!al #o!inant CM"4
,arents o0 a pro/and
Most individuals %ith autoso!al do!inant CM"4 have an affected 6arent.
A 6roband %ith autoso!al do!inant CM"4 !ay have the disorder as the result of a
ne% gene !utation. "he 6ro6ortion of cases caused by (e "&" !utations is
unkno%n but likely very s!all.
eco!!endations for the evaluation of 6arents of a 6roband %ith an a66arent (e
"&" !utation include neurologic e<a!ination and !olecular genetic testing if the
!utation in the 6roband has been identified.
Note- Although !ost individuals diagnosed %ith autoso!al do!inant CM"4 have an
affected 6arent, the fa!ily history !ay a66ear to be negative because of failure to
recogni8e the disorder in fa!ily !e!bers, early death of the 6arent before the onset of
sy!6to!s, or late onset of the disease in the affected 6arent.
Si/s o0 a pro/and "he risk to sibs de6ends on the genetic status of the 6robandDs
6arents.
If a 6arent has a disease3causing !utation, the risk to the sibs is ?5E.
+hen the 6arents are clinically unaffected, the risk to the sibs of a 6roband a66ears
to be lo%. No instances of ger!line !osaicis! have been re6orted, although it
re!ains a 6ossibility.
+00sprin- o0 a pro/and =very child of an individual %ith autoso!al do!inant CM"4 has
a ?5E chance of inheriting the !utation.
+ther 0amily mem/ers o0 a pro/and "he risk to other fa!ily !e!bers de6ends on the
status of the 6robandDs 6arents. If a 6arent is affected and>or has a disease3causing
!utation, his or her fa!ily !e!bers are at risk.
isk to @a!ily Me!bers U Autoso!al ecessive CM"4
,arents o0 a pro/and
"he 6arents of an affected child are obligate hetero8ygotes and therefore carry one
!utant allele.
Hetero8ygotes *carriers, are asy!6to!atic.
Si/s o0 a pro/and
At conce6tion, each sib of an affected individual has a 4?E chance of being
affected, a ?5E chance of being an asy!6to!atic carrier, and a 4?E chance of
being unaffected and not a carrier.
Cnce an at3risk sib is kno%n to be unaffected, the risk of his>her being a carrier is
4>2.
Hetero8ygotes *carriers, are asy!6to!atic.
+00sprin- o0 a pro/and "he offs6ring of an individual %ith autoso!al recessive CM"4
are obligate hetero8ygotes *carriers, for a disease3causing !utation.
+ther 0amily mem/ers o0 a pro/and =ach sib of the 6robandDs 6arents is at a ?5E risk
of being a carrier.
Carrier #etection
Carrier testing for at3risk fa!ily !e!bers for autoso!al recessive for!s of CM"4 is
6ossible if the disease3causing !utations have been identified in the fa!ily.
elated $enetic Counseling Issues
Considerations in 0amilies 4ith an apparent de noo mutation +hen neither 6arent of
a 6roband %ith an autoso!al do!inant condition has the disease3causing !utation or
clinical evidence of the disorder, it is likely that the 6roband has a (e "&" !utation.
Ho%ever, 6ossible non3!edical e<6lanations including alternate 6aternity or !aternity
*e.g., %ith assisted re6roduction, or undisclosed ado6tion could also be e<6lored.
&amily plannin-
"he o6ti!al ti!e for deter!ination of genetic risk and discussion of the availability
of 6renatal testing is before 6regnancy. )i!ilarly, decisions regarding testing to
deter!ine the genetic status of at3risk asy!6to!atic fa!ily !e!bers are best !ade
before 6regnancy.
It is a66ro6riate to offer genetic counseling *including discussion of 6otential risks to
offs6ring and re6roductive o6tions, to young adults %ho are affected or at risk.
Testin- o0 at-ris3 asymptomatic adults Asy!6to!atic adults at risk of having inherited
a !utation associated %ith autoso!al do!inant CM"4 !ay %ish to 6ursue further clinical
evaluation and NC7 testing. No treat!ent is available to individuals early in the course of
the disease. "hus, such testing is for 6ersonal decision !aking only.
Testin- o0 at-ris3 asymptomatic indi.iduals durin- childhood "esting of at3risk
asy!6to!atic individuals %ho are younger than age 0; years is not a66ro6riate. )ee also
the National )ociety of $enetic Counselors 6osition state!ent on genetic testing of !inors
for adult3onset conditions and the A!erican )ociety of Hu!an $enetics and A!erican
College of Medical $enetics 6oints to consider- ethical, legal, and 6sychosocial
i!6lications of genetic testing in children and adolescents.
DNA /an3in- is the storage of #NA *ty6ically e<tracted fro! %hite blood cells, for 6ossible
future use. Because it is likely that testing !ethodology and our understanding of genes,
!utations, and diseases %ill i!6rove in the future, consideration should be given to
banking #NA of affected individuals.
Prenatal "esting
If the disease3causing !utation*s, have been identified in the fa!ily, 6renatal diagnosis for
6regnancies at increased risk is 6ossible by analysis of #NA e<tracted fro! fetal cells
obtained by a!niocentesis *usually 6erfor!ed at V0?30; %eeksT gestation, or chorionic
villus sa!6ling *usually 6erfor!ed at V05304 %eeksT gestation,. )uch testing !ay be
available through laboratories that offer either testing for the gene of interest or custo!
testing.
Note- $estational age is e<6ressed as !enstrual %eeks calculated either fro! the first day
of the last nor!al !enstrual 6eriod or by ultrasound !easure!ents.
eKuests for 6renatal testing for conditions %hich *like CM"4, do not affect intellect or life
s6an are not co!!on. #ifferences in 6ers6ectives !ay e<ist a!ong !edical 6rofessionals
and %ithin fa!ilies regarding the use of 6renatal testing, 6articularly if the testing is being
considered for the 6ur6ose of 6regnancy ter!ination rather than early diagnosis. Although
!ost centers %ould consider decisions regarding 6renatal testing to be the choice of the
6arents, discussion of these issues is a66ro6riate.
,reimplantation -enetic dia-nosis 1,'D2 of CM"4= has been re6orted ')hara6ova et al
455:(. Prei!6lantation genetic diagnosis of other CM"4 subty6es !ay be an o6tion for
so!e fa!ilies in %hich the disease3causing !utation*s, have been identified.
esources
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"r-a$:at$"% a(."r re-$%tr$e% #"r t0e 8ee#$t "# $($&$(,a+% 5$t0 t0$% ($%"r(er a( t0e$r
#am$+$e%7 GeeRe&$e5% $% "t re%*"%$8+e #"r t0e $#"rmat$" *r"&$(e( 8) "t0er
"r-a$:at$"%7 F"r $#"rmat$" " %e+e't$" 'r$ter$a1 '+$'6 0ere7
Association CMT &rance
02 allWe de $rXce
2?0:5 )aint Aubin du Cor!ier
@rance
,hone: ;45 5LL ?:5/ 4 :L 4L 1J :0
%%%.c!t3france.org
Charcot-Marie-Tooth Association 1CMTA2
4L55 Chestnut )treet
Chester PA 015023:;JL
,hone: ;553J5J34J;4 *toll3free,/ J053:11314J:
&ax: J053:11314JL
$mail: info9charcot3!arie3tooth.org
%%%.charcot3!arie3tooth.org
$uropean Charcot-Marie-Tooth Consortium
#e6art!ent of Molecular $enetics
.niversity of Ant%er6
Ant%er6 Ant%er6en B34J05
Belgiu!
&ax: 52 4J?0554
$mail: gisele.s!eyers9ua.ac.be
Hereditary Neuropathy &oundation, !nc
0L?0 4nd Avenue
)uite 052
Ne% Rork NR 0504;
,hone: ;LL3:J2304;L *toll3free,/ 4043L443;21J
$mail: info9hnf3cure.org
%%%.hnf3cure.org
National *i/rary o0 Medicine 'enetics Home 5e0erence
Charcot3Marie3"ooth disease
NC#! 'enes and Disease
Charcot3Marie3"ooth syndro!e
T5$AT-NMD
Institute of $enetic Medicine
.niversity of Ne%castle u6on "yne
International Centre for Life
Ne%castle u6on "yne N=0 2BG
.nited Bingdo!
,hone: :: 5 010 4:0 ;J5?
&ax: :: 5 010 4:0 ;LL5
$mail: info9treat3n!d.eu
Charcot3Marie3"ooth #isease
Association &rancaise contre les Myopathies 1A&M2
0 ue de lDInternational
BP?1
=vry 10554
@rance
,hone: P22 50 J1 :L 4; 4;
&ax: 50 J1 :L LL 04 0J
$mail: d!c9af!.genethon.fr
%%%.af!3telethon.fr
$uropean Neuromuscular Centre 1$NMC2
Lt $en van Heuts8laan J
AN Baarn 2L:2
Netherlands
,hone: 52? ?: ;5 :;0
&ax: 52? ?: ;5 :11
$mail: en!c9en!c.org
%%%.en!c.org
Muscular Dystrophy Association - 6SA 1MDA2
2255 =ast )unrise #rive
"ucson AG ;?L0;
,hone: ;553?L430L0L
$mail: !da9!dausa.org
%%%.!da.org
Muscular Dystrophy Campai-n
J0 )outh%ark )treet
London )=0 5HL
.nited Bingdo!
,hone: 5;55 J?4 J2?4 *toll3free,/ P:: 5 545 L;52 :;55
$mail: info9!uscular3dystro6hy.org
%%%.!uscular3dystro6hy.org
5DC5N ,atient Contact 5e-istry: !nherited Neuropathies Consortium
Patient Contact egistry
Molecular $enetics
I#"rmat$" $ t0e M"+e',+ar Geet$'% a( /MIM ta8+e% ma) ($##er #r"m t0at e+%e50ere $
t0e GeeRe&$e5; ta8+e% ma) '"ta$ m"re re'et $#"rmat$"7 <=#.
Table A. Charcot-Marie-Tooth Neuropathy Type 2: Genes and Databases
Locus
Name
Gene
Symbol
Chromosomal
Locus
Protein Name Locus Specific HGMD
CMT2N AARS 16q22.1
Alanyl-tRNA synthetase,
cytoplasmic
AARS @ LOVD AARS
CMT2A2 MFN2 1p36.22 Mitofusin-2
IPN Mutations,
MFN2
MFN2
homepage -
Leiden Muscular
Dystrophy pages
MFN2
CMT2B RAB7A 3q21.3 Ras-related protein Rab-7a
IPN Mutations,
RAB7A
RAB7A
homepage -
Leiden Muscular
Dystrophy pages
RAB7A
CMT2B1 LMNA 1q22 Prelamin-A/C
Human
Intermediate
Filament
Database
LMNA (lamin
C1)
Human
Intermediate
Filament
Database
LMNA (lamin
A)
Human
Intermediate
Filament
Database
LMNA (lamin
C2)
IPN Mutations,
LMNA
LMNA
homepage -
Leiden Muscular
Dystrophy pages
LMNA
CMT2B2 MED25 19q13.33
Mediator of RNA
polymerase II transcription
subunit 25
MED25
homepage -
Mendelian genes
MED25
CMT2C TRPV4 12q24.11
Transient receptor potential
cation channel subfamily V
member 4
TRPV4
homepage -
Mendelian genes
TRPV4
CMT2D GARS 7p14.3 Glycine--tRNA ligase
IPN Mutations,
GARS
alsod/GARS
genetic
mutations
GARS
homepage -
Leiden Muscular
Dystrophy pages
GARS
CMT2E NEFL 8p21.2
Neurofilament light
polypeptide
Human
Intermediate
Filament
Database NEFL
IPN Mutations,
NEFL
NEFL
homepage -
Leiden Muscular
Dystrophy pages
NEFL
CMT2F HSPB1 7q11.23 Heat shock protein beta-1
IPN Mutations,
HSPB1
HSPB1
homepage -
Leiden Muscular
Dystrophy pages
HSPB1
CMT2G Unknown 12q12-q13.3 Unknown
CMT2H/2
K
GDAP1 8q21.11
Ganglioside-induced
differentiation-associated
protein 1
IPN Mutations,
GAPD1
GDAP1
homepage -
Leiden Muscular
Dystrophy pages
GDAP1
CMT2I MPZ 1q23.3 Myelin P0 protein
IPN Mutations,
MPZ
MPZ homepage
- Leiden
Muscular
Dystrophy pages
MPZ
CMT2J MPZ 1q23.3 Myelin P0 protein
IPN Mutations,
MPZ
MPZ homepage
- Leiden
Muscular
Dystrophy pages
MPZ
CMT2L HSPB8 12q24.23 Heat shock protein beta-8 IPN Mutations, HSPB8
HSPB8
HSPB8
homepage -
Leiden Muscular
Dystrophy pages
CMT2O DYNC1H1 14q32.31
Cytoplasmic dynein 1 heavy
chain 1
alsod/DYNC1H
1 genetic
mutations
DYNC1H1
CMT2P LRSAM1 9q33.3
E3 ubiquitin-protein ligase
LRSAM1
LRSAM1
#ata are co!6iled fro! the follo%ing standard references- gene sy!bol fro! H$NC/
chro!oso!al locus, locus na!e, critical region, co!6le!entation grou6 fro! CMIM/
6rotein na!e fro! .niProt. @or a descri6tion of databases *Locus )6ecific, H$M#,
to %hich links are 6rovided, click here.
"able B. CMIM =ntries for Charcot3Marie3"ooth Neuro6athy "y6e 4 *7ie% All in CMIM,
150330 LAMIN A/C; LMNA
159440 MYELIN PROTEIN ZERO; MPZ
162280 NEUROFILAMENT PROTEIN, LIGHT POLYPEPTIDE; NEFL
600112 DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1
600287 GLYCYL-tRNA SYNTHETASE; GARS
600882 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B
601065 ALANYL-tRNA SYNTHETASE; AARS
601472 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D; CMT2D
602195 HEAT-SHOCK 27-KD PROTEIN 1; HSPB1
602298 RAS-ASSOCIATED PROTEIN RAB7; RAB7
605427
TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V,
MEMBER 4; TRPV4
605588 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1; CMT2B1
605589 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2; CMT2B2
606071 HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
606595 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F; CMT2F
606598 GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1
607677 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2I; CMT2I
607684 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E; CMT2E
607731 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2H; CMT2H
607736 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2J; CMT2J
607831 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2K; CMT2K
608014 HEAT-SHOCK 22-KD PROTEIN 8; HSPB8
608507 MITOFUSIN 2; MFN2
608591 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2G; CMT2G
608673 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L; CMT2L
609260 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2
610197 MEDIATOR COMPLEX SUBUNIT 25; MED25
610933
LEUCINE-RICH REPEAT- AND STERILE ALPHA MOTIF-CONTAINING 1;
LRSAM1
613287 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N
614228 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2O; CMT2O
614436 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P; CMT2P
Molecular $enetic Pathogenesis
"he relationshi6 of !yelin and a<on 6athology to the 6athogenesis of CM" is discussed in
detail in several revie%s 'BraOe%ski et al 4555, Berger et al 4554, Maier et al
4554, GHchner I 7ance 455Ja, GHchner I 7ance 455Jb(.ossor et al '4502( sho% the
!olecular and anato!ic relationshi6s of the various genes and 6roteins associated %ith
CM"/ see @igure 0.
KIF1B
Normal allelic .ariants KIF1B co!6rises :L e<ons and 0JL.02 kb of #NA.
,atho-enic allelic .ariants A 6.$ln1;Leu !utation %as re6orted in a single fa!ily 'Ghao
et al 4550(. )ee also "able A.
Table 5. Selected KIF1B Pathogenic Allelic Variants
DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.293A>T p.Gln98Leu
NM_015074.3
NP_055889.2
)ee Yuick eference for an e<6lanation of no!enclature. GeeRe&$e5% follo%s the
standard na!ing conventions of the Hu!an $eno!e 7ariation )ociety
*%%% .hgvs.org ,.
Normal -ene product Binesin3like 6rotein BI@0B is involved in a<onal trans6ort of
syna6tic vesicle 6recursors 'Ghao et al 4550(. "he kinesin su6erfa!ily of 6roteins is
essential for intracellular trans6ort along !icrotubules.
A/normal -ene product "here !ay be a defect in the trans6ort of syna6tic vesicles.
MFN2
Normal allelic .ariants MFN2 has 01 e<ons %ith a 44L:3b6 o6en reading fra!e.
,atho-enic allelic .ariants GHchner et al '455:b( and 7erhoeven et al '455J( have
re6orted !ore than 4? !issense !utations in MFN2. )ee also "able A.
Normal -ene product Mitofusin34, encoded by MFN21 is involved in !itochondrial
net%ork architecture and !ediates !itochondrial fusion.
A/normal -ene product Mutations in MFN2 !ay disru6t the !itochondrial fusion3fission
balance in 6eri6heral nerve. #i!inished a<onal !itochondrial trans6ort has been
described 'Baloh et al 455L(.
RAB7A
Normal allelic .ariants RAB7A has si< e<ons and ;L.1 kb of #NA.
,atho-enic allelic .ariants )ee "able A.
Normal -ene product as3related 6rotein ab3La belongs to the AB fa!ily of as3
related $"Pases essential for the regulation of intracellular !e!brane trafficking. ab3La
is involved in trans6ort bet%een late endoso!es and lysoso!es. AB3interacting
lysoso!al 6rotein *ILP, induces the recruit!ent of dynein3dynactin !otors and regulates
trans6ort to%ard the !inus3end of !icrotubules '7erhoeven et al 4552(.
A/normal -ene product Abnor!al ab3La !ay cause !alfunction of lysoso!es.
LMNA
Normal allelic .ariants LMNA has 04 e<ons s6read over 4: kb of geno!ic #NA.
,atho-enic allelic .ariants "he !ost co!!on !utation found in individuals %ith
CM"4B0 is 6.Arg41;Cys. )ee also "able A.
Table 6. Selected LMNA Allelic Variants
Class of Variant
Allele
DNA Nucleotide
Change
Protein Amino Acid
Change
Reference
Sequences
Normal c.1908C>T p.= 1
NM_170707.2
NP_733821.1
Pathogenic
c.398G>T p.Arg133Leu
c.892C>T p.Arg298Cys
*%%% .hgvs.org ,.
0. 6.Z designates that 6rotein has not been analy8ed, but no change is e<6ected.
Normal -ene product La!ins are the 6rinci6al co!6onent of the nuclear la!ina, a !aOor
6ortion of the nuclear envelo6e. "%o A3ty6e la!ins e<ist- A and C. La!ins 6lay a role in
#NA re6lication, chro!atin organi8ation, s6atial arrange!ent of nuclear 6ore co!6le<es,
nuclear gro%th, !echanical stabili8ation of the nucleus, and anchorage of the nuclear
envelo6e 6rotein.
A/normal -ene product Position 41 is located in the la!in3A>C rod do!ain. "he !anner
in %hich disru6tion of this do!ain adversely affects 6eri6heral nerve function is unkno%n.
Cther LMNA !utations are associated %ith a %ide variety of disorders *see $enetically
elated #isorders,.
MED25
Normal allelic .ariants MED25 has 0; e<ons.
,atho-enic allelic .ariants Cne 6athogenic allelic variant has been described in an
e<tended Costa ican fa!ily %ith autoso!al recessively inherited CM" neuro6athy linked
to the CMT2B2 locus in chro!oso!e 01K02.2. Affected individuals %ere ho!o8ygous for
6.Ala22?7al 'Leal et al 4551(.
Table 7. Selected MED25 Pathogenic Allelic Variants
c.1004C>T p.Ala335Val
NM_030973.2
NP_112235.2
*%%% .hgvs.org ,.
Normal -ene product MED25 encodes a L:L3a!ino acid 6rotein designated the
!ediator co!6le< subunit 4? 6rotein *reference seKuence NMN5251L2.4,. "his 6rotein is a
subunit of the hu!an activator3recruited cofactor *AC,, a fa!ily of large transcri6tional
coactivator co!6le<es. Its 6recise function in transcri6tional regulation is unkno%n.
A/normal -ene product "he 6.Ala22?7al substitution is located in a 6roline3rich region
%ith high affinity for )H2 do!ains of the Abelson ty6e. "he !utation causes a decrease in
binding s6ecificity leading to the recognition of a broader range of )H2 do!ain 6roteins.
TRPV4
Normal allelic .ariants TRPV4 has 0J e<ons/ e<on 0 of NMN540J4?.2 is non3coding.
,atho-enic allelic .ariants "he !utations in "able ; have been associated %ith CM"4C.
Table 8. Selected TRPV4 Pathogenic Allelic Variants
NM_021625.3
NP_067638.3
c.806G>A p.Arg269His
c.943C>T p.Arg315Trp
*%%% .hgvs.org ,.
Normal -ene product "P7 is a vanilloid rece6tor3related transient rece6tor 6otential
channel %hich 6lays an i!6ortant role in neural signal. "he 6rotein is co!6osed of a
cytosolic N3ter!inal region and si< trans!e!brane do!ains, including the 6ore region and
an intracellular C3ter!inal tail. "he N3ter!inal region contains the ankyrin re6eat do!ain
*A#,.
A/normal -ene product LandourW et al '4505( de!onstrated cellular to<icity and
increased constitutive and activated channel currents in "P7:3transected cells. #eng et
al '4505( sho%ed increased calciu! channel activity resulting fro! the t%o !utations
found in t%o fa!ilies %ith CM"4C. "he effect of !utations on !olecular functions like
oligo!eri8ation, surface e<6ression and ubiKuitination are revie%ed by 7er!a et al '4505(.
GARS
Normal allelic .ariants GARS is a :53kb gene %ith 0L e<ons.
Normal -ene product $lycyl3tNA synthetase ligates a!ino acids to their cognate tNA.
A/normal -ene product "he !issense !utations in this gene !ay 6roduce a loss of
function that allo%s the incor6oration of the %rong a!ino acid in the 6lace of glycine
'Motley et al 4505(.
NEFL
Normal allelic .ariants NEFL contains four coding e<ons/ the ?D ."s are highly
conserved.
,atho-enic allelic .ariants Cne fa!ily %ith CM"4=>0@ has a !utation in e<on 0
of NEFL 'Mersiyanova et al 4555( and another fa!ily has a deletion>insertion !utation in
e<on 0 *c.44N42delCCinsA$, '#e Aonghe et al 4550(. )ee also "able A.
Table 9. Selected NEFL Pathogenic Allelic Variants
c.22_23delCCinsAG p.Pro8Arg
NM_006158 .1
NP_006149 .2
*%%% .hgvs.org ,.
Normal -ene product Neurofila!ent light 6oly6e6tide, the 6rotein encoded by NEFL,
contains ?:2 a!ino acids %ith a head, rod, and tail do!ain. Neurofila!ents for! the
cytoskeletal co!6onent of !yelinated a<ons.
A/normal -ene product Bnockout !ice lacking neurofila!ents have di!inished a<on
caliber and delayed regeneration of !yelinated a<ons follo%ing crush inOury. A !ouse
!utation in Ne#+ has !assive degeneration of s6inal !otor neurons and abnor!al
neurofila!ent accu!ulation %ith severe neurogenic skeletal !uscle atro6hy. #efects in
trans6ort and asse!bly of neurofila!ents have been re6orted 'Pere83Clle et al 455:(.
HSPB1 *HSP27,
Normal allelic .ariants HSPB1 contains three e<ons %ith a central H)P453[3crystallin
do!ain.
Normal -ene product "he heat shock 6rotein beta30 *also referred to as heat3shock
6rotein 4L, has !any 6ossible functions including antia6o6totic and cyto6rotective
6ro6erties, inhibition of cas6ase activation, 6revention of aggreso!e for!ation, and
involve!ent in the neurofila!ent net%ork.
A/normal -ene product Mutations in HSPB1 result in altered neurofila!ent asse!bly
'=vgrafov et al 455:(.
MPZ
Normal allelic .ariants MPZ s6ans a66ro<i!ately seven kilobases and contains si<
e<ons.
,atho-enic allelic .ariants More than ?J 6oint !utations in MPZ have been re6orted
'Nelis et al 0111(. More than L5E of the !utations are locali8ed in e<ons 4 and 2
of MPZ coding for the e<tracellular do!ain, indicating the functional i!6ortance of this
do!ain *see also "able A,.
Table 10. Selected MPZ Pathogenic Allelic Variants
DNA Nucleotide Change
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.254A>T
p.Asp85Val
(p.Asp75Val)
NM_000530.5
NP_000521.1
c.401C>T
p.Thr134Met
(p.Thr124Met)
*%%% .hgvs.org ,.
0. 7ariant designation that does not confor! to current na!ing conventions
Normal -ene product Myelin P5 6rotein is a !aOor structural co!6onent of 6eri6heral
!yelin re6resenting about ?5E of 6eri6heral !yelin 6rotein by %eight and about LE of
)ch%ann cell !essage. It is a ho!o6hilic adhesion !olecule of the i!!unoglobulin fa!ily
that 6lays an i!6ortant role in !yelin co!6action. It has a single trans!e!brane do!ain,
a large e<tracellular do!ain, and a s!aller intracellular do!ain.
A/normal -ene product #ifferent !utations affect all 6ortions of the 6rotein and !ay
alter !yelin adhesion. =ither de!yelinating or a<onal 6henoty6es can result.
GDAP1
Normal allelic .ariants GDAP1 has si< e<ons, 02.1 kb of #NA, and a 055L3nucleotide
o6en reading fra!e.
,atho-enic allelic .ariants )ee also "able A.
Table 11. Selected GDAP1 Pathogenic Allelic Variants
c.358C>T p.Arg120Trp
NM_018972.2
NP_061845.2
*%%% .hgvs.org ,.
Normal -ene product $anglioside3induced differentiation3associated 6rotein30 'Ba<ter et
al 4554(
A/normal -ene product It is s6eculated that !utations !ay 6revent the correct
cataly8ing ) conOugation of reduced $CH, resulting in 6rogressive attrition of both a<ons
and )ch%ann cells.
HSPB8 *HSP22,
Normal allelic .ariants HSPB8 has three e<ons and s6ans about 0J kb.
,atho-enic allelic .ariants "hree !utations have been re6orted. )ee "able 04 'Irobi et
al 455:b, "ang et al 455?(.
Table 12. Selected HSPB8 Pathogenic Allelic Variants
c.423G>T p.Lys141Asn
NM_014365.2
NP_055180.1
c.423G>C p.Lys141Asn
c.421A>G p.Lys141Glu
*%%% .hgvs.org ,.
Normal -ene product H)PB; *also called H)P44, is a 6hos6hor 6rotein that interacts
%ith H)PB0.
A/normal -ene product Mutant H)PB; 6roteins interact %ith H)PB0 and for!
aggregates that !ay lead to dysfunctional a<onal trans6ort and dysregulation of the
cytoskeleton 'Irobi et al 455:b(.
AARS
Normal allelic .ariants AARS has 40 e<ons and is located on chro!oso!e 0J.
,atho-enic allelic .ariants "%o !utations have been associated %ith CM"
*6.Arg241His and 6.$luLL;Ala,. )ee "able 02. "he !utation 6.AsnL0"yr *c.400AF", !ay
also be 6athogenic.
Table 13. Selected AARS Pathogenic Allelic Variants
c.986G>A p.Arg329His
NM_001605.2
NP_001596.2
c.2333A>C p.Glu778Ala
*%%% .hgvs.org ,.
Normal -ene product Alanyl3tNA synthetase attaches alanine to tNA !olecules in
cyto6las! and !itochondria co!6leting the first ste6 in 6rotein translation.
A/normal -ene product @unctional studies suggest these are loss of function !utations
'McLaughlin et al 4504(.
DYNC1H1
,atho-enic allelic .ariants Cne hu!an !utation has been described *6.His25JArg,
by +eedon et al '4500(. )ee "able 0:.
Table 14. Selected DYNC1H1 Pathogenic Allelic Variants
c.917A>G p.His306Arg NM_001376.4 (MIM600112)
*%%% .hgvs.org ,.
Normal -ene product :,J::3a!ino acid 6rotein. #RNC0H0 is a subunit of cyto6las!ic
dynein, the 6ri!ary !otor 6rotein 6roducing retrograde a<onal trans6ort in neurons.
A/normal -ene product Presu!ably the abnor!al 6rotein 6roduces defective retrograde
a<onal trans6ort in 6eri6heral nerves.
LRSAM1
,atho-enic allelic .ariants A single autoso!al do!inant and a single autoso!al
recessive !utation have been described. )ee "able 0?.
Table 15. Selected LRSAM1 Pathogenic Allelic Variants
c.2121_2122 insGC p.Leu708ArgfsTer28
--
AG>AA exon 24 Intronic splice site
*%%% .hgvs.org ,.
Normal -ene product A ubiKuitin ligase *=2, involved %ith sorting ubiKuitinylated
cyto6las!ic cargo *")$050,/ L543a!ino acid L53kd 6rotein
A/normal -ene product #isturbs sorting of ubiKuitinylated cargo in neuronal cyto6las!.
eferences
Medical $enetic )earches- A s6eciali8ed PubMed search designed for clinicians that is
located on the PubMed Clinical Yueries 6age
Published Guidelines/Consensus Statements
0. A!erican )ociety of Hu!an $enetics and A!erican College of Medical $enetics.
Points to consider- ethical, legal, and 6sychosocial i!6lications of genetic testing in
children and adolescents. Available online. 011?. Accessed 003J302. 'PMC free
article- PMC0;502??( 'PubMed- L:;?0L?(
4. National )ociety of $enetic Counselors. Position state!ent on genetic testing of
!inors for adult3onset disorders. Available online. 4504. Accessed 003J302.
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Cha6ter Notes
Revision History
0: Nove!ber 4502 *tb, evision- figure added to Prevalence and Molecular
$enetics 'ossor et al 4502(
00 Auly 4502 *tb, evision- additions to Prevalence and #ifferential #iagnosis
2 Aanuary 4502 *cd, evision- seKuence analysis of select e<ons
of LRSAM1 available clinically
02 #ece!ber 4504 *tb, evision- !utations in DHTKD1 identified as causative of a
for! of CM"4 'Mu et al 4504(
02 )e6te!ber 4504 *tb, evision- addition of Nicolaou et al '4504(, Ishiura et al
'4504(, Pitceathly et al '4504(
25 August 4504 *cd, evision- seKuence analysis
for MED25 and DYNC1H1 available clinically
? Auly 4504 *!e, Co!6rehensive u6date 6osted live
1 @ebruary 4504 *tb, evision- !utations in DYNC1H1 re6orted to be associated
%ith CM"4C/ !utation in LRSAM1 associated %ith CM"4P
44 #ece!ber 4500 *tb, evision- !utations in AARS cause CM"4N.
0? )e6te!ber 4500 *tb, evision- #ifferential #iagnosis U inter!ediate for! of
CM"
0; August 4500 *cd, evision- targeted !utation analysis for 6.Ala22?7al
in MED25 associated %ith CM"4B4
0 March 4500 *cd, evision- edits to "esting )trategy
4L Aanuary 4500 *cd, evision- testing available clinically for CM"4C
4L May 4505 *cd, evision- edits to Agents>Circu!stances to Avoid
00 March 4505 *!e, Co!6rehensive u6date 6osted live
L Aanuary 455; *cd, evision- 6renatal diagnosis for CM"4# available
0J August 455L *!e, Co!6rehensive u6date 6osted to live +eb site
25 Aanuary 455L *tb, evision- seKuence analysis clinically available on a li!ited
basis for CM"4#
25 #ece!ber 455? *cd, evision- testing and 6renatal diagnosis for CM"4B
clinically available/ 6renatal diagnosis for CM"4A clinically available
40 #ece!ber 455? *tb, evision- #ifferential #iagnosis U HM)N37
0: Aune 455? *tb, evision- CM"4B added
: May 455? *!e, Co!6rehensive u6date 6osted to live +eb site
J #ece!ber 455: *tb, evision- testing
1 )e6te!ber 455: *tb,cd, evision- M@N4 added/ seKuence analysis clinically
available
1 August 455: *tb,cd, evision- CM"4B0
40 Aune 455: *tb, evision- CM"4@
05 May 455: *tb, Author revisions
0 A6ril 455: *tb, evision- 6renatal diagnosis available for CM"4=
L A6ril 4552 *!e, Co!6rehensive u6date 6osted to live +eb site
04 )e6te!ber 4550 *tb, Author revisions
4: Auly 4550 *tb, Author revisions
4L Aune 4550 *tb, Author revisions
01 Aune 4550 *tb, evision- CM"4A gene found
42 March 4550 *tb, Author revisions
0J Aanuary 4550 *tb, Author revisions
4? August 4555 *!e, Co!6rehensive u6date 6osted to live +eb site
0? Aune 4555 *tb, Author revisions
0? May 4555 *tb, Author revisions
2 @ebruary 4555 *tb, Author revisions
04 Cctober 011; *tb, Author revisions
4: )e6te!ber 011; *6b, evie% 6osted to live +eb site
A6ril 011J *tb, Criginal sub!ission
@igures

@igure 0. $enetic diagnoses in CM" and related disorders
@ro! ossor et al '4502(/ re6rinted %ith 6er!ission
Co6yright f 011234502, .niversity of +ashington, )eattle. All rights reserved.
@or !ore infor!ation, see the $eneevie%s Co6yright Notice and .sage #isclai!er.
@or Kuestions regarding 6er!issions- ad!asst9u%.edu.
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