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CTG trinucleotide repeat variability in identical twins with myotonic dystrophy.

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CTG Trinucleotide Repeat
Variability in Identical
Twins with Myotonic
A. L6pez de Munain, MD, A. M. C o b , PhD, E. Huguet,
PhD, J. F. Marti Mass6, MD, K. Johnson, PhD, and
M. Baiget, P h D
Myotonic dystrophy (DM) is an autosomal dominantly inherited disorder with a highly variable expression and a wide
range of symptoms. The inheritance of this disorder has been
found to be associated with the unstable elongation of a
(CTG), motif in the 3' untranslated region of protein kinase
gene fiamily member on chromosome 19 [I, 21. A positive
correlation between earlier onscdgreater severity and increasing (CTG), repeat number has been reported 131. Moreover, there is also a tendency toward an intergenerational
expansion of the repeat length underlying the phenomenon
of anticipation [ 4 ] . Mitotic instability of the repeat has been
discussed, but there are relatively few reports comparing the
pattern of expansion in monozygotic twins [ 5 , 61.W e report
the results ohpained in the study of two sets of twins where
monotygosity was established with 93.78% and 99.80% certainty, respectively, using eight polymorphic D N A markers.
l w i n Set 1
This set comprises 35-year-old female twins suffering from
a typical form of DM since their early teens. Clinicd features
include myotonia and walking difficulties due to distal lower
limb weakness. Both required bilateral cataract surgery in
their mid 20s. Recent physical examination showed mostly
concordant phenotypes and an EcoRI digest, probed with
cDNA2 S detected identically sized, approximately 3 kb
expansions ( 1,000 CTG repeats) in the lymphocyte D N A in
both sisters.
Twin Set 2
This set comprises 47-year-old females suffering from typical
DM since their early 20s. Cataracts were diagnosed in both
sisters at the age of 28 and these required surgery 7 years
later. Clinical examination showed a mild degree of neuropsychological deficit in both patients, characterized by bradypsychia and reduced intellectual skills. Except for the distal
muscle strength that was slightly more preserved in Patient
1-2 (Fig), the patients were exactly identical in the clinical
manifestations of the disease. Analysis of the size of the
(CTG), repeat in the peripheral blood of these twins using
EcoRIkDNAZS showed that they displayed different patterns of expansion, i.e., 2,300 and 1,800 CTG repeats in 1-1
and 1-2, respectively (see Fig).
Both sets of twins showed convincing evidence of genetic
concordance so that the different CTG expansion pattern
seen in the second set confirms that the instability of the
repeat occurs postzygotically. Recently, a similar finding has
been reported for another pair of monozygous twins IS],
although a previous report had detected identical patterns of
Pedigree and southern blot analysij of twin set 2. D N A from
each indioidual was digected with EcoRl and probed with
cDNA25 t o deteLt the expansion. C corresponds t o a healthy control(9 and 10 kb alleles). Identical twins I-] and 1-2 show expanded alleles of 17 and 15.5 kb, respectively.
expansion in lymphocyte D N A from two sets of monozygotic twins {G}.
The large expansions observed on transmission of DM are
due to an unknown but parental sex-related process [ 7 ] that
may occur during fertilization. The differences in the expansion sizes observed in somatic mosaicism [8} and in monozygotic twin samples appear to be much less important than
those seen during transmission and occur immediately after
fertilization. That some twin pairs show identical patterns of
expansion in the same tissues and others do not suggests that
the period during which the repeats are unstable overlaps
with the developmental time window from fertilization to
the time at which twinning occurs. After this time, it is probable that the repeat lengths become fixed as the developing
embryonic tissues undergo differentiation.
Department of Neurdoa
Hospital hTtm Sra de Aranzazu
San Sebastian, Spain
Unitat de GenBtica Molecular
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain
Luboratori d'tlemogenitira Forense
Universitat de Barcelona
Barcelona. Spain
Department of Anatomy
Charing Cross and Westminster Medicd School
London, UK
1. Harley HG, Brook JD, Rundle SA, et al. Expansion of an unstable DNA region and phenotypic variation in myoronic dystrophy.
Nature 1W2;335:545-546
2. Buxton J, Shelbourne P, Davies J, et al. Detection of an unstable
374 Copyright Q 1994 by the American Neurological Association
fraanenc of DNA specific to individuals with myotonlc dystrophi. Nature 1992;355:547-548
3 . Hunter A, Tsilfidis C , Mettler G, et al. The correlation of age of
onset with CTG trinucleotide repeat amplification in myotonic
dystrophy. J Med Genet 1992;29:774-779
4. Ashizawa T, Dubel JR, Dunne PW, et al. Anticipation in myotonic dystrophy. 11. Complex relationships between clinical fmdings and structure of the GCT repeat. Neurology 1992;42:18771883
5. Tavlor HP, Schwartzbach CJ, Gilbert JR, et al. Germline versus
somatic diversity of the p(CTG)n repeat in myotonic dystrophy.
Neurology 1993;43(suppl):A280
6. Dubel J, Perryman B, Epstein H, Ashizawa T. Mitotic instability
of the CTG repeat region of the myotonin-protein kinase (MTPK) gene associated with myotonic dystrophy (DM). Am J Hum
Genet 1992;5 I(suppI):A213
7. Cobo AM, Baiget M, Z p e z de Munain A, et al. Sex-related
difference in intergenerationalexpansion of myotonic dysrrophy
gene. Lancet 1993;341:11~9-1160
8. Lvedan C, Hofmann-Radvanyi H, Shelbourne P, et al. Myotonic
dystrophy: size- and sex-dependent dynamics of CTG meiotic
instability, and somatic mosaicism. Am J Hum Genet 1993;52:
Andrew Eisen, MD, FRCP(C), and Heather Stewart, BSc
W e commend Blexrud and colleagues (11 for tackling the
always worrying problem of benign fasciculation. The case
against “benign fasciculation,” heralding amyotrophic lateral
sclerosis (ALS) in their retrospective study has been convincingly documented.
The reader, however, is left with the impression that fasciculation in the absence of other neurological deficit should
never be of concern. This is not so. Twenty-one of 312
(6.77{1)consecutive patients seen in our ALS clinic, who fulfilled the criteria of typical ALS, had fasciculation as the first
and, at the time, only manifestation of their disease. The
mean time interval between developing fasciculation and
other deficits was 7.2 months (range, 2.4-13.6 mo) [2]. The
majority of patients were men (n = 17). The mean age of
patients who had fasciculation as their initial manifestation
was not different from other patients with ALS (55.7
yr compared with 57.3 13.6 yr). Patients were only considered if they or their spouse sought medical help for the particular problem of fasciculation. Careful inquiry into the history of patients with ALS reveals that many notice
fasciculations (usually with muscle cramps) for weeks,
months, and rarely years before the onset of neurological
deficit. Thus, fasciculation as an early feature of ALS may be
commoner than we suspect.
Blexrud and colleagues 11) do not re11 us whether there
are electromyographic features of benign versus nonbenign
fasciculations. W e would argue that benign fasciculation is
not a good term since it is possible to distinguish it from
fasciculation of more concern on electromyographic grounds.
Most fasciculation associated with ALS is of long duration
and high amplitude. Narrowing the recording band pass (500
or even 1000 Hz to 10 or 20 kHz) reveals that such fasciculation is often complex and composed of many muscle fibers.
The potential is frequently unstable and its components may
demonstrate increased electromyographic jitter or blocking.
In contrast, fasciculation recorded from patients who do not
go on to develop serious disease [up to the last time of follow-up) is invariably simple and stable and the potentials
resemble those of normal voluntary recruited motor units.
As pointed out by Blexrud and colleagues [I], a large
number of their patients were medically educated, thus
prompting their seeking medical attenrion. In contrast, it is
rare for patients who subsequently develop ALS to seek medical aid at a time when the only manifestation of their disease
is fasciculation. However, we are presently following “unaffected“ members of two families with familial ALS, several
of whom have complex fasciculations as described above. I t
remains to be seen if any develop other evidence of the
There is no doubt that many normal people who never
develop serious neurological disease have lifelong fasciculation (and cramps). Most if not all become aware of the prohlem at a young age. O n the other hand, we firmly believe
that caution is required when fasciculation starts for the fmt
time after the age of 45 years. Some will clearly go on to
develop ALS.
Neu romuscuiav Dmases Uriit f‘ErtlGi
V~ncowerGeneral Ho@ttd
855 West 12th Aoeenue
Vancozver. B C , VSZ lh19, Canada
I. Blexrud MD, Windebank AJ, Daube JR. Long-term follow-up of
12 1 parients with benign fasciculations. Ann Neurol 1093;34:
2. Eisen A, Pant 8,MacNeil M, Stewart H. Fasciculations as an
initial feature of amyotrophic lateral sclerosis. Can J Neurol Sci
Marceil D. Blexrud, Anthony J. Windebank, MD, and
Jasper R. Daube, M D
The comments by Drs Eisen and Stewart are very appropriate
and do match our experience. There is no doubt that in
retrospect many patients observe fasciculation as their first
symptom of amyotrophic lateral sclerosis (ALS). As implied
by Dr Eisen, it is very rare for patients to present at this
stage. They tend to present when weakness or incoordination
has developed. Ic is our experience, however, that patients
who have fasciculation alone as the first symptom of ALS
always have electromyographic (EMG) abnormalities when
they present with fasciculation. ‘Chis does provide the opportunity to stress again that the subjects in this study had both
a normal complete tieuroiogical examination and normal
EMG, performed by experienced observers. When these criteria are met, we believe that one can strongly reassure the
Eisen and Stewart also raised the question about the EMG
features of benign versus nonbenign fasciculations. The study
was not designed to evaluate that question; however, the
Annals of Neurology
Vol 35 No 3 March 1934
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repeat, identical, ctg, trinucleotide, twin, variability, myotonic, dystrophy
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