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Cardiac and respiratory failure in limb-girdle muscular dystrophy 2I.

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Cardiac and Respiratory
Failure in Limb-Girdle
Muscular Dystrophy 2I
Maja Poppe, MD,1 John Bourke, MD,2
Michelle Eagle, PhD,1 Patrick Frosk, BSc,3
Klaus Wrogemann, PhD,3 Cheryl Greenberg, MD,3
Francesco Muntoni, MD,4 Thomas Voit, MD,5
Volker Straub, MD,5 David Hilton-Jones, MD,6
Cheerag Shirodaria, MD,7 and Kate Bushby MD1
Mutations in the gene encoding fukutin-related protein
cause limb-girdle muscular dystrophy 2I. In this multicenter retrospective analysis of 38 patients, 55.3% had
cardiac abnormalities, of which 24% had developed cardiac failure. Heterozygotes for the common C826A mutation developed cardiac involvement earlier than homozygotes. All patients initially improved while receiving
standard therapy. Independent of cardiac status, forced
vital capacity was below 75% in 44.4% of the patients.
There was no absolute correlation between skeletal muscle weakness and cardiomyopathy or respiratory insufficiency. These complications are a primary part of this
specific type of limb-girdle muscular dystrophy, with important implications for management.
Ann Neurol 2004;56:738 –741
The relationship between skeletal myopathy and cardiomyopathy is complex. Muscle disorders may result from
mutations in genes that independently cause cardiomyopathy,1 and cardiomyopathy forms part of the phenotype
of some muscle diseases.2 Proteins involved in muscular
dystrophies may be altered in acquired cardiac disease.1
Although the causative biochemical defects often may be
present in both skeletal and cardiac muscle, in individual
types of muscular dystrophy the relative risk of involvement of skeletal and cardiac muscle may be different, with
important implications for management.
From the 1Institute of Human Genetics and 2Department of Cardiology, University of Newcastle upon Tyne, Newcastle upon Tyne,
United Kingdom; 3Departments of Biochemistry and Medical Genetics and Pediatrics, University of Manitoba, Winnipeg, Canada;
Department of Paediatrics, Imperial College, Hammersmith Hospital Campus, London, United Kingdom; 5Department of Pediatrics and Paediatric Neurology, University Hospital Essen, Germany;
Departments of Clinical Neurology and 7Cardiology, Radcliffe Infirmary and John Radcliffe Hospital, Oxford, United Kingdom.
Received May 3, 2004, and in revised form Jul 1. Accepted for
publication Aug 5, 2004.
Published online Oct 28, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20283
Address correspondence to Dr Bushby, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon
Tyne NE1 3BZ, United Kingdom. E-mail:
Annals of Neurology
Vol 56
No 5
November 2004
Mutations in the gene encoding fukutin-related protein (FKRP) cause a subset of congenital muscular dystrophy (MDC1C) and a subset of limb-girdle muscular
dystrophy (LGMD2I), which is a relatively frequent
form of LGMD in white patients.3–5 In most white
LGMD2I patients, a common C826A mutation is
found either homozygously or heterozygously.4 – 6 Early
reports suggested that LGMD2I might cause cardiac
and respiratory failure.5– 8 We performed this multicenter retrospective study to assess the prevalence and
nature of these complications in a large group of
LGMD2I patients.
Subjects and Methods
Patients and Investigations
All 38 LGMD2I patients attending the muscle centers of
Newcastle upon Tyne; Hammersmith Hospital, London; and
Oxford (UK) and Essen (Germany) were identified (26
women: age range, 10 – 61 years, followed for 1–11 years).
Twenty-three of the patients were homozygous for C826A,
and 15 were heterozygous with different second mutations.
Patients were assigned to a severity group according to standard assessments performed during routine follow-up. These
functional stages followed the scheme of Walton (modified
by us).9 From the assessment of progress through the various
functional stages with time, the course of the skeletal muscle
disease in individual patients was assigned as either slow,
gradual, or rapid.
To assess the prevalence of cardiorespiratory involvement
in LGMD2I, J.B. reviewed results of investigations (electrocardiogram and echocardiogram). Cardiac involvement (CI)
was defined by the presence of left ventricular regional wall
motion abnormality (defined as a left ventricular segment in
which the systolic motion score is below normal); for the
purpose of scoring regional wall motion, the left ventricle
was divided into nine segments from two planes, and each
segment was scored from 0 to 2, where normal motion
scores were 2, hypokinesis 1, and akinesis 0)10, or reduced
left ventricular fractional shortening (male ⬍28%; female
⬍25%) on echocardiography. Possible CI was defined as
presence of electrocardiogram (EKG) abnormalities alone
with or without borderline left ventricular dysfunction.
An additional four male homozygous C826A patients
with cardiomyopathy were identified among the Hutterite
LGMD2I population of Canada. These patients could not
be included in the prevalence calculations, but data on them
and the European patients with CI were studied together to
define the course and nature of CI and the relationship between skeletal and cardiac muscle disease.
Respiratory function was assessed by forced vital capacity
(FVC), with normal defined as greater than 75% of age- and
height-adjusted norm. Results of pulse oximetry and requirement for home nocturnal ventilation were noted.
Statistical Analysis
Kaplan–Meier analysis was used to compare cardiac involvement in heterozygotes and homozygotes where the
end point was detection of cardiac impairment. No patients were censored because of loss of follow-up data or
drop out. Curves were compared using the log-rank test
to generate a p value, and confidence intervals were
computed as 1.96 times the standard error in each direction.
Cardiac Involvement
Fifteen LGMD2I patients had CI, and six had possible
CI, giving an overall prevalence of 55.3% (21 of 38).
CI was more frequent in men, with 83% (10 of 12) of
men but only 42.3% (11 of 26) of women affected.
However, a higher proportion of the male patients (7
of 12) compared with the female patients (8 of 26)
were heterozygous for the common mutation, and
Kaplan–Meier analysis (Fig) with subdivision by
C826A homozygosity or heterozygosity showed an earlier tendency to develop cardiomyopathy in heterozygotes. Sixty-six percent of heterozygotes are predicted
to develop CI by age 20 years, and 100% by age 39
years. Among homozygotes, 4.4% are predicted to have
CI by age 20 years, and 100% would be expected to
have CI by age 58 years.
At the time of reporting, 83% (n ⫽ 35) of the patients retained independent ambulation. The mean age
of presentation with skeletal muscle weakness was 15.2
years (range, infancy to 43 years). Forty-five percent
(n ⫽ 19) of the patients showed slow, 33% (n ⫽ 14)
gradual, and 21% (n ⫽ 9) rapid progression of weakness, and 66% of these (n ⫽ 6/9) were compound heterozygote for C826A.
The tendency for cardiomyopathy to develop earlier
Fig. Kaplan–Meier plot of cardiac involvement in patients with
limb-girdle muscular dystrophy type 2I who are heterozygous or
homozygous for the mutation C826A. Kaplan–Meier analysis
shows a significant difference between heterozygotes and homozygotes (median age of cardiac involvement for heterozygotes, 20
years of age; homozygotes, 51 years of age; 95% confidence interval of ratio, ⫺0.03989 to 0.8242; log-rank test, p ⬍ 0.0001).
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
in patients with C826A heterozygosity therefore mirrors a tendency for themes patients to have more severe
skeletal myopathy. However, there was no strict correlation between cardiomyopathy and muscle weakness
in individuals; 88% (22 of 25) of the patients with CI
could still walk at least 200 meters.
The course of CI could be defined in the 15 European patients and four Canadians with definite cardiac
involvement: 8 of 19 (42%) developed symptomatic cardiac failure at a mean age of 37.8 years (range, 18 –58
years), and three died at ages 18, 40, and 67 years. Of
19 patients, 11 (57.9%) had left ventricular dysfunction
in the absence of cardiac symptoms, of whom three had
segmental dilated cardiomyopathy and the rest global dilated cardiomyopathy. Serial measurements of left ventricular parameters in 10 cases showed deterioration over
time. The eight symptomatic patients were treated with
diuretics and angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors were started in 11 others because of evidence of progressive abnormalities. There
was initial improvement on therapy in all treated patients, but it was not maintained in two, who currently
await cardiac transplantation.
All patients were in sinus rhythm with normal conduction intervals. EKGs from 14 of the 19 patients with
definite CI were reviewed, and 11 (57.9%) were abnormal, with a common finding of dysmorphic notched
p-waves unlike the EKG changes seen in other forms of
muscular dystrophy. Among the six patients with possible cardiac involvement, the same p-wave abnormalities
were seen in five. Mean fractional shortening in this
group was 35.5% (range, 27– 47%). An additional seven
patients (not included in the definition of either possible
or definite CI) had p-wave changes only with normal
left atrial dimensions. Given the trend we have observed
for progressive EKG and echocardiographic abnormalities in patients with definite CI, it is likely that a proportion of those with minor changes will meet the criteria for definite CI during longer follow-up.
Respiratory Involvement
Independent of cardiac status, LGMD2I patients are
also at risk of respiratory failure. Only 55.5% (20 of 36)
had normal respiratory function at a mean of 32 years
(range, 11–58). The group with abnormal FVC had a
mean age of 33 years (range, 15–58). Moderate respiratory impairment (FVC, 41–75%) was found in 36%
(n ⫽ 13), and severe impairment (FVC, 19 – 40%) was
found in 8% (n ⫽ 3). Where serial measurements were
available (for between 6 months and 6 years in 66% [24
of 36] of patients), a gradual deterioration of FVC was
seen in 70.8% (17 of 24). In 23 patients, FVC was measured in sitting and supine positions, and 39% (9 of 23)
of the patients had a decrease of FVC of 15% or more
of that predicted, indicating diaphragmatic involvement.
Typical symptoms of nocturnal hypoventilation
Annals of Neurology
Vol 56
No 5
November 2004
started in eight individuals (two women, six men) at a
mean age of 34 years (range, 18 –58 years). The numbers are too low to draw any genotype–phenotype correlations, but four C826A heterozygotes required home
nocturnal ventilation at a mean age of 24 year and four
homozygotes at a mean age of 44.5 years. The relationship between respiratory muscle weakness and disease
severity is complex. Five of eight patients requiring
home nocturnal ventilation still were independently
ambulant. Patients younger than 20 years of age (n ⫽
11) had relatively good respiratory function (72% have
FVC ⬎ 75%, n ⫽ 8 of 11) despite early onset of their
skeletal muscle weakness, and there was no diaphragmatic weakness in these young patients. As patients got
older, FVC deteriorated with increasing likelihood of
diaphragmatic involvement, although the most mildly
affected patients may remain asymptomatic for years.
Survival and quality of life in muscular dystrophy depends on the recognition and treatment of associated
complications.2 This multicenter study confirms that
patients with LGMD2I are at risk of cardiac and respiratory failure that will progress with time and will
require surveillance for these potentially treatable problems. Our data also indicate that treatment with standard cardiac therapy is effective in delaying progression
from initial wall motion abnormalities/segmental cardiomyopathy or EKG-“only” changes to dilated cardiomyopathy, which needs to be confirmed on longitudinal studies. Nonetheless, some patients are likely to
show progression of their cardiac disease despite optimum drug treatment necessitating cardiac transplantation. Although patients who were heterozygous for the
common C826A mutation and a second different mutation were likely to develop cardiac abnormalities earlier, homozygous patients were also at risk.
FVC was below 75% in 44.4% of the patients, and
39% had diaphragmatic weakness. There was no absolute correlation between skeletal muscle weakness and
cardiomyopathy or respiratory insufficiency. Respiratory
failure in patients with mutations within the FKRP gene
supervened in cases in which the patients were still ambulant, and this failure frequently showed specific
involvement of the diaphragm. This is in contrast with
the situation usually observed in dystrophinopathy, or
other forms of LGMD such as sarcoglycanopathy
(LGMD2C-F) and calpainopathy (LGMD2A), in which
respiratory failure is usually seen as a very late feature
accompanying very profound skeletal muscle weakness,
and in which early diaphragmatic weakness is not a feature.11–14 Mutations in the FKRP gene are thought to
be pathogenic via alteration of glycosylation. Glycosylation defects therefore potentially define another group of
muscular dystrophies sharing a relationship between
skeletal muscle and cardiac disease.3
This work was supported by grants from the Deutsche Forschungsgemeinschaft (Po 699/2-1, M.P.; Str 498/3-2, T.V., V.S.) and by
the Canadian Institutes of Health Research (K.W., P.F.). The Muscular Dystrophy Campaign provides financial support to the Newcastle Muscle Centre, The Dubowitz Muscle Centre, Hammersmith
Hospital London, and the Oxford Muscle and Nerve Centre. V.S.,
T.V., and M.P. are members of the German network on muscular
dystrophies (MD-NET), funded by the German ministry of education and research (Bundesministerium für Bildung und Forschung,
Bonn, Germany). This work was conceived at a workshop funded
by the European Neuromuscular Centre. The funding sources stated
had no direct or indirect involvement in study design or data collection.
1. Muntoni F. Cardiomyopathy in muscular dystrophy. Curr
Opin Neurol 2003;16:577–583.
2. Bushby K, Muntoni F, Bourke J. 107th ENMC international
workshop: the management of cardiac involvement in muscular
dystrophy and myotonic dystrophy. Neuromuscular Disord
2003;13:166 –172.
3. Brockington M, Blake DJ, Prandini P, et al. Mutations in the
fukutin-related protein gene (FKRP) cause a form of congenital
muscular dystrophy with secondary laminin alpha-2 deficiency
and abnormal glycosilation of alpha-dystroglycan. Am J Hum
Genet 2001;69:1189 –1209.
4. Walter MC, Petersen JA, Stucka R, et al. FKRP (826C⬎A)
frequently causes limb-girdle muscular dystrophy in German
patients. J Med Genet 2004;41:e50.
5. Brockington M, Yuva Y, Prandini P, et al. Mutations in the
fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular
dystrophy MDC1C. Hum Mol Genet 2001;10:2851–2859.
6. Poppe M, Cree L, Bourke J, et al. The phenotype of limb-girdle
muscular dystrophy type 2I. Neurology 2003;60:1246–1251.
7. Mercuri E, Brockington M, Straub V, et al. Phenotypic spectrum associated with mutations in the fukutin-related protein
gene. Ann Neurol 2003;53:537–542.
8. Dohna-Schwake C, Ragette R, Mellies U, et al. Respiratory
function in congenital muscular dystrophy and limb girdle
muscular dystrophy 2I. Neurology 2004;60:513–514.
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Livingstone; 1981:451– 455.
10. Kober L, Torp-Pederson C, Calsen J, et al. An echocardiographic method for selecting high risk patients shortly after
acute myocardial infarction, for inclusion in multi-centre studies. Eur Heart J 1988, 9:205–213.
11. Philipps MF, Quinlivan RCM, Edwards RHT, Calverley PMA.
Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Am J Respir Crit
Care Med 2001;164:2191–2194.
12. Politano L, Nigro V, Passamano L, et al. Evaluation of cardiac
and respiratory involvement in sarcoglycanopathies. Neuromuscul Disord 2001;11:178 –185.
13. Pollitt C, Anderson LV, Pogue R, et al. The phenotype of
calpainopathy: diagnosis based on a multidisciplinary approach.
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Diphenylarsinic Acid
Poisoning from Chemical
Weapons in Kamisu, Japan
Kazuhiro Ishii, MD, PhD,1 Akira Tamaoka, MD, PhD,1
Fujio Otsuka,MD, PhD,2 Nobuaki Iwasaki, MD, PhD,3
Kenji Shin, MD,4 Akira Matsui, MD, PhD,3
Ginji Endo, MD, PhD,5 Yoshito Kumagai, PhD,6
Tetsuro Ishii, PhD,6 Shin’ichi Shoji, MD, PhD,1
Tsuyoshi Ogata, MD,7 Mutsuo Ishizaki, PhD,8
Mikio Doi, MD, PhD,8 and Nobuhiro Shimojo, PhD6
We noted a new clinical syndrome with prominent cerebellar symptoms in apartment building residents in Kamisu, Japan. The well that provided drinking water contained diphenylarsinic acid, a degradation product of
diphenylcyanoarsine or diphenylchloroarsine, which were
developed for use as chemical weapons, inducing severe
vomiting and sneezing. Characteristics of diphenylarsinic
acid poisoning include brainstem–cerebellar and cerebral
symptoms. Mental retardation associated with brain atrophy in magnetic resonance images was evident in some
infants. We must be vigilant to prevent or minimize the
effects of further diphenylarsinic acid poisoning in Japan
or elsewhere.
Ann Neurol 2004;56:741–745
Diphenylarsinic acid (DPAA) is a degradation product
of diphenylchloroarsine (Clark I) or diphenylcyanoarsine (Clark II), both of which were synthesized for the
Japanese Imperial Army as chemical weapons of emetic
type under the code name Agent Red No. 1 (Fig).
During World War II, large amounts of diphenylcyanoarsine and diphenylchloroarsine were manufactured
both in the United States and European countries as
well as in Japan.1–3 Soil and groundwater in an area
near the German–Polish border has been found to be
From the 1Departments of Neurology, 2Dermatology, and 3Pediatrics, Institute of Clinical Medicine, University of Tsukuba ,
Tsukuba; 4Department of Pediatrics, Ibaraki Prefectural University,
Ami, Ibaraki; 5Department of Preventive Medicine and Environmental Health, Osaka City University Medical School, Osaka; 6Department of Environmental Medicine, Institute of Community
Medicine, University of Tsukuba, Tsukuba, Ibaraki; 7Itako Public
Health Center, Ibaraki Prefectural Government of Japan, Itako; and
Ibaraki Prefectural Institute of Public Health, Mito, Ibaraki, Japan.
Received Mar 8, 2004, and in revised form Jul 30 and Aug 8. Accepted for publication Aug 9, 2004.
Published online Oct 28, 2004, in Wiley InterScience
( DOI: 10.1002/ana.20290
Address correspondence to Dr Ishii, Department of Neurology, Institute of Clinical Medicine, University of Tsukuba, Tennoudai
1-1-1, Tsukuba, Ibaraki 305-8575, Japan.
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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limba, girdle, respiratory, muscular, cardiaca, dystrophy, failure
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