Beruflich Dokumente
Kultur Dokumente
CMT
Subtype
Patients with
GeneticallyDefined CMT
(n 5 527) (%)
All Patients
with CMT
(n 5 787)
(%)
CMT1A
290
55.0
36.9
CMT1B
45
8.5
5.7
CMT1X
80
15.2
10.2
Males
44
8.4
5.6
Females
36
6.8
4.6
CMT2A
21
4.0
2.7
HNPP
48
9.1
6.1
Total
484
91.8
61.5
January 2011
Results
Distribution of CMT Subtypes
A total of 1,024 patients were evaluated at our CMT
clinic between 1997 and 2009, of which 787 were diagnosed with CMT. Of the 237 patients who did not have
CMT, 118 were diagnosed with a different condition
while 119 were determined to be an unaffected family
member of a patient with CMT.
Of the 787 patients with CMT (67%), 527
patients had or received a specific genetic diagnosis, while
in 260 patients with CMT no specific mutation was
identified. The most prominent CMT subtypes identified
in our clinic were CMT1A, CMT1X, hereditary neuropathy with liability to pressure palsies (HNPP), CMT1B,
and CMT2A (Table 1). All other CMT subtypes
accounted for less than 1% of all patients with genetically defined CMT each. Only 1.8% of patients with
CMT1 were without a genetic diagnosis. These patients
were defined as having a demyelinating phenotype and a
dominant family history. Of patients with CMT2,
65.6% were without a genetic diagnosis. These patients
were defined as having an axonal phenotype and a dominant family history (Table 2). The distribution of genetic
subtypes identified in our clinic was similar to the distribution of patients identified by multiple laboratories that
perform diagnostic testing for CMT (reviewed in England and colleagues7,8). Comparing our results to those
from these laboratories (their results follow in parentheses), we identified CMT1A in 82% (80%) of patients
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CMT Types
Patients by
CMT Type (%)
All Patients
with CMT
(n 5 787) (%)
CMT1A
290
66.8
55.0
36.9
CMT1B
45
10.4
8.5
5.7
CMT1C
1.2
1.0
0.6
CMT1D
0.2
0.2
0.1
CMT1E
1.2
1.0
0.6
CMT1X
80
18.4
15.2
10.2
Males
44
10.1
8.4
5.6
Females
36
8.3
6.8
4.6
Total
426
98.2
80.8
54.1
CMT1 Unknown
1.8
1.0
Total
434
55.2
CMT2A
21
21.9
4.0
2.7
CMT2D
3.1
0.6
0.4
CMT2E
4.2
0.8
0.5
CMT2K
5.2
1.0
0.6
Total
33
34.4
6.3
4.2
CMT2 Unknown
63
65.6
8.0
Total
96
12.2
CMT4A
14.3
0.2
0.1
CMT4C
42.9
0.6
0.4
CMT4F
14.3
0.2
0.1
CMT4J
28.6
0.4
0.3
Total
1.4
0.9
were able to diagnose 7 patients with AR CMT, accounting for 0.90% of all patients with CMT (see Table 2).
Additionally, we have 25 affected siblings without parents
or other family members affected with CMT who are
therefore likely to have AR inheritance for which we have
no genetic diagnosis. If these patients were included in our
analysis, up to 4% of our patients with CMT would have
AR CMT. In addition, we have 77 patients without a family history who are therefore classified as having sporadic
CMT, some of whom also may have an AR disorder.
We detected 11 patients with more than 1 subtype
of CMT, as identified by genetic testing. These patients
Volume 69, No. 1
CMT
Subtypes
Affected
Families (n)
All Patients
with CMT
(n 5 787) (%)
CMT1A/1E
1.0
0.6
CMT1E/1B
0.6
0.4
CMT1X/1B
0.4
0.3
CMT1A/1C
0.2
0.1
Total
11
2.1
1.4
Categorization
All Patients
with CMT
(n 5 787) (%)
3.1
1.0
19
7.3
2.4
63
24.2
8.0
61
23.5
7.8
31
11.9
4.0
22
8.5
2.8
2.7
0.9
17
6.5
2.2
Other
14
5.4
1.8
January 2011
25
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Genetic Test
Number
of Times
Ordered
Number
of Hits
Hit
Rate
(%)
PMP22
duplication/deletion
40
32
80
PMP22 sequencing
18
11
MPZ sequencing
31
29
GJB1 sequencing
25
24
MFN2 sequencing
51
14
with CMT1X15 fell into this category, whereas this phenotype was less common for patients with CMT1B
(14.6%).
The second phenotype we defined as infantile onset
in which patients do not begin walking until they are at
least 15 months of age. These patients are often severely
affected and are likely to require above the knee bracing,
walkers, or wheelchairs for ambulation by 20 years of
age. Over 35% of our patients with CMT1B fell into
this category.16
The third phenotype was defined as adult onset, in
which patients did not develop symptoms of CMT until
adulthood, often not until approximately 40 years of age.
Childhood Onset
Adult Onset
Subtotala
Subclinicalb
Unknown
Total
247
11
32
290
Age Onset
of Walking
15 mo
Age Onset
of Walking
<15 mo
Third
Decade
of Life
Fourth
Decade
of Life
Older than
Fourth
Decade
of Life
CMT1A
40 (16.2%)c
149 (60.3%)
18 (7.3%)
15 (6.1%)
25 (10.0%)
CMT1B
15 (35.7%)
6 (14.3%)
2 (4.8%)
3 (7.1%)
16 (38.1%)
42
45
CMT1X
7 (10.8%)
36 (55.4%)
9 (13.8%)
4 (6.2%)
9 (13.8%)
65
80
Males
5 (12.5%)
27 (67.5%)
4 (10.0%)
3 (7.5%)
1 (2.5%)
40
44
Females
2 (8.0%)
9 (36.0%)
5 (20.0%)
1 (4.0%)
8 (32.0%)
25
36
CMT2A
3 (15.0%)
16 (80.0%)
1 (5.0%)
20
21
HNPP
2 (4.2%)
25 (52.1%)
8 (16.7%)
11 (22.9%)
2 (4.2%)
48
48
26
Slow
Intermediate
Normal
Subtotal
NR
Not
Testedb
Total
15
>15 and
25
>25 and
35
>35 and
45
>45
CMT1A
61 (23.4%)e
162 (62.1%)
38 (14.6%)
261
12
17
290
CMT1B
8 (20.5%)
4 (10.3%)
2 (5.1%)
11 (28.2%)
14 (35.9%)
39
45
CMT1X
4 (5.3%)
17 (22.7%)
19 (25.3%)
35 (46.7%)
75
80
Males
4 (9.8%)
17 (41.5%)
13 (31.71%)
7 (17.1%)
41
44
Females
6 (17.7%)
28 (82.4%)
34
36
CMT2A
8 (100%)
21
HNPP
7 (14.9%)
40 (85.1%)
47
48
All percentages in the table were calculated using the subtotal value for each CMT subtype.
a
All tested cases with obtainable responses.
b
Exam refused.
CMT Charcot-Marie-Tooth disease; HNPP hereditary neuropathy with liability to pressure palsies; NR not recordable.
Discussion
This analysis of over 1,000 patients demonstrated that
clinical and neurophysiologic information could be useful
in focusing genetic testing for CMT. By characterizing
common phenotypes for particular forms of CMT, these
data can also be useful in determining whether a given
patient is typical or unusual for a particular genotype.
Recently, a practice parameter guideline was published
simultaneously in Neurology, Muscle and Nerve, and
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CMT
subtypesa
Childhood onset
Adult onsetb
Walk-age onset
15 months
Walk-age onset
<15 months
Subtotal
25
30
61
CMT1A
17
30
53
CMT1B
Subtotal
16
95
32
143
CMT1A
14
93
30
137
CMT1B
CMT1X
Males
Females
Subtotal
29
17
52
CMT1A
16
15
35
CMT1B
CMT1X
12
15
Males
12
15
Females
Subtotal
24
11
36
CMT1B
10
CMT1X
14
19
Males
10
13
Females
HNPP
Subtotal
33
46
85
CMT1B
13
14
CMT1X
15
25
Males
Females
12
19
17
38
Very slow
15
Slow
>15 and 25
Intermediate
>35 and 45
Normal
>45
CMT2A
HNPP
19
All patients with CMT2A have more severe phenotypes compared to the other patients with childhood onset who began walking
before 15 months of age. Patients with unobtainable CMAP amplitudes in the upper extremities are not included in this table.
b
Adult onset: If onset of symptoms was in the third decade of life or later.
CMAP compound muscle action potential; CMT Charcot-Marie-Tooth disease; HNPP hereditary neuropathy with liability to pressure palsies.
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whether to next test for AR disorders or whether research
testing for novel genes is more appropriate.
or BSCL2 (Silver syndrome) mutations often have relatively pure motor syndromes. Moreover, patients with
CMT2D often note hand impairment prior to leg
impairment that is unusual for patients with CMT.
Thus, in CMT2 we propose to use these specific phenotypes to direct additional genetic testing after initial negative testing. We also stress the need to perform nerve
conductions on proximal nerves to exclude severe demyelinating neuropathies, when CMAPs and sensory nerve
action potentials (SNAPs) are unobtainable distally.
While a detailed review of the pros and cons for
testing is beyond the scope of this manuscript, we think
it reasonable to provide some information about how we
pursue genetic testing.24 Clearly, not every patient with a
genetic neuropathy wants or needs testing to identify the
genetic cause of their disease. We believe that the ultimate decision to undergo genetic testing rests with the
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Acknowledgments
This research was supported by grants from the Muscular
Dystrophy Association (M.E.S.), the NIH (National
Institutes of Neurological Disorders and Stroke and
Office of Rare Diseases, U54NS065712 to M.E.S.), and
the Charcot Marie Tooth Association (M.E.S.).
We thank the patients and families that participated
in this study.
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Skre H. Genetic and clinical aspects of Charcot-Marie-Tooths disease. Clin Genet 1974;6:98118.
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Shy M, Lupski JR, Chance PF, et al. The hereditary motor and sensory neuropathies: an overview of the clinical, genetic, electrophysiologic and pathologic features. In: Dyck PJ, Thomas PK, eds.
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January 2011
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