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Collagen VI deficiency in Ullrich's disease.

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Collagen VI Deficiency in Ullrich’s Disease
Itsuro Higuchi, MD,1 Masahito Suehara, MD,2
Hiroyuki Iwaki, MD,1 Masanori Nakagawa, MD,1
Kimiyoshi Arimura, MD,1 and Mitsuhiro Osame, MD1
Ullrich’s disease is a unique congenital disorder described by
Ullrich in 1930.1 The major clinical findings include muscle
weakness and wasting, striking contractures of the proximal
joints, and hyperflexibility of the distal joints from an early
infantile stage. This disease is considered to be a distinct entity of multisystemic involvement inherited as an autosomal
recessive trait. Two patients, a 20- and a 21-year-old male,
with sporadic cases of Ullrich’s disease are presented. The
patients showed generalized muscle weakness, hypotonia, hyperextensibility of the distal joints, and contractures of the
proximal joints. The clinical course was progressive, and they
underwent tracheotomy because of respiratory failure between the ages of 17 and 18 years. On histochemical examination of biceps brachii muscle, proliferating connective tissue and marked variation in muscle fiber diameter were
recognized. We performed an immunohistochemical study
on components of the extracellular matrix in biopsied skeletal muscle and skin specimens. The monoclonal antibodies
used were collagen IV (Boehringer Mannheim, Indianapolis,
IN), collagen VI (Fuji Chemical, Takaoka, Japan, and ICN
Biomedicals, Aurora, OH), collagen VII (Chemicon, Temecula, CA), and other components of the extracellular matrix. We found a characteristic hallmark of Ullrich’s disease
in the two patients. Collagen VI expression was completely
deficient in the skeletal muscle and skin specimens from the
two patients with Ullrich’s disease (Fig).
Collagen VI is a widely expressed protein with cell adhesive properties. Mutations in the genes that code for collagen
VI subunits (i.e., COL6A1, COL6A2, and COL6A3) have
been reported in Bethlem’s myopathy.2,3 It has been reported
that the immunohistochemical expression of collagen VI in
Bethlem’s myopathy is not deficient but reduced and suggested that the disease results from functional protein haploinsufficiency of collagen VI. Because patients with Ullrich’s
disease have no dominant family history and exhibit marked
distal joint laxity and hyperflexibility, it has been considered
that both diseases are different clinical entities until now. Although molecular genetic analysis of collagen VI in these patients with Ullrich’s disease is underway, it is important to
determine whether the genetic defect in Ullrich’s disease constitutes structural mutations of collagen VI or enzymatic defects of collagen VI biosynthesis.
In conclusion, our findings suggest that immunohistochemical collagen VI analysis may greatly improve the quality of diagnosis of Ullrich’s disease, which can be classified as
one of the heritable collagen disorders. This is the first report
on a pathogenetic defect in Ullrich’s disease.
Third Department of Internal Medicine, Faculty of
Medicine, Kagoshima University, Kagoshima, and 2National
Okinawa Hospital, Okinawa, Japan
1. Ullrich O. Kongenitale atonisch-sklerotische Muskeldystrophie
ein weiterer Typus der heredodegenerativen Erkrankungen des
neuromuskularen Systems. Z Ges Neurol Psychiatr 1930;126:
© 2001 Wiley-Liss, Inc.
Fig. Immunohistochemical analysis of collagen VI (A–C) and
collagen IV (D–F) in biopsied muscle specimens from two patients with Ullrich’s disease (Case 1: A, D; Case 2: B, E) and
a control patient (C, F). Collagen VI is deficient in the two
patients with Ullrich’s disease. Normal collagen IV expression
can be seen in all patients.
2. Jöbsis GJ, Keizers H, Vreijling JP, et al. Type VI collagen mutations in Bethlem myopathy, an autosomal dominant myopathy
with contractures. Nat Genet 1996;14:113–135.
3. Pan TC, Zhang RZ, Pericak-Vance MA, et al. Missense mutation in a von Willebrand factor type A domain of the a3(VI)
collagen gene (COL6A3) in a family with Bethlem myopathy.
Hum Mol Genet 1998;7:807– 812.
Cathepsin D Polymorphism Not Associated with
Alzheimer’s Disease in Japanese
Toshifumi Matsui, MD,1 Yu-ichi Morikawa, BS,1
Masayoshi Tojo, BS,1 Nobuyuki Okamura, MD,1
Masahiro Maruyama, MD,1 Hisao Hirai, MD,1
Hiroshi Chiba, MD,1 Sachio Matsushita, MD,2
Susumu Higuchi, MD, PhD,2 Hiroyuki Arai, MD, PhD,1
and Hidetada Sasaki, MD, PhD1
We read with interest the report of Papassotiropoulos and
colleagues regarding the association between the Ala224Val
(C3 T) polymorphism encoded at cathepsin D (catD) exon
2 and the development of Alzheimer’s disease (AD).1 In this
report, they demonstrated that the catD*T allele was significantly overrepresented in AD patients (11.8%) compared
with nondemented control subjects (4.9%) and that a combination of apolipoprotein E (ApoE) ε4 and catD*T allele
further increased the risk of AD. Because several studies have
shown that catD is one of the putative enzymes that are capable of cleavage of ␤-amyloid precursor protein,2 the
Table. Genotype and Allele Frequency of Cathepsin D Gene Ala224Val Polymorphism in AD Cases and Control Subjects: A
Comparison Between Japanese and Caucasians
Japanese AD (n ⫽ 275, clinical cases)
271 (98.5%)
4 (1.5%)
0 (0%)
546 (99.3%)
4 (0.7%)
Japanese control subjects (n ⫽ 479)
Caucasian AD (n ⫽ 69, autopsy cases)
471 (98.3%)
60 (87.0%)
7 (1.5%)
8 (11.6%)
1 (0.2%)
1 (1.4%)
949 (99.1%)
128 (92.8%)
9 (0.9%)
10 (7.2%)
43 (86.0%)
6 (12.0%)
1 (2.0%)
92 (92.0%)
8 (8.0%)
Caucasian control subjects (n ⫽ 50)
Significantly different between Japanese and Caucasians at p ⬍ 0.0001 (␹2 ⫽ 52.9, df ⫽ 1).
AD ⫽ Alzheimer’s disease; NS ⫽ not significant.
Ala224Val polymorphism may be associated with amyloid ␤
protein deposition in AD brain.
In the present study, we undertook two case-control studies, one in Japanese and the other in Caucasians from the
United States. We investigated Ala224Val polymorphism at
catD in 754 Japanese: 275 patients (78 males and 197 females, 74.4 ⫾ 8.9 years old) diagnosed with probable AD
according to the National Institute of Neurlogical and Communicative Disorders and Stroke-Alzheimer’s Disease and
Related Disorders Association (NINCDS-ADRDA) criteria3
and 479 age-matched control subjects (257 males and 222
females, 74.9 ⫾ 6.1 years old), who were communitydwelling elderly people judged cognitively normal by the
Mini-Mental State Examination. Of the 119 Caucasians we
studied, 69 had autopsy-confirmed AD (77.8 ⫾ 8.0 years
old), and 50 were control subjects (61.1 ⫾ 14.6 years old).
All subjects were genotyped at the Ala224Val polymorphism
at catD and the ApoE polymorphism according to the procedure described previously.1,4
As shown in the Table, Ala224Val polymorphism and allele frequency were not significantly different in AD cases
and control subjects in either Japanese or Caucasians. Notably, there was significantly lower catD*T allele frequency in
Japanese than in Caucasians (Japanese 0.9% vs Caucasians
7.6%). Even after stratification according to the ApoE genotype, the association did not reach a significant level (data
not shown). Although we studied larger Japanese samples
than those in the previous studies and we also examined
autopsy-confirmed Caucasian cases, which might have a substantial advantage in diagnostic accuracy compared to the
previous studies conducted in living patients,1,5 we failed to
detect an association between the Ala224Val polymorphism
and the development of AD in either ethnic group. Our results did show racial diversity in the catD Ala224Val polymorphism and allele distributions, suggesting the possibility
that the association may be a function of race. Further studies will be needed in a larger series of autopsy-confirmed
cases in different ethnic groups to draw firm conclusions
about this issue.
We extend deep appreciation to Dr. J.Q. Trojanowski and Dr.
Christopher Clark, University of Pennsylvania, Philadelphia, for
providing the Caucasian cases and control samples.
Department of Geriatric Medicine, Tohoku University School
of Medicine, Sendai, and 2Department of Psychiatry,
Kurihama National Hospital, Kanagawa, Japan
1. Papassotiropoulos A, Bagli M, Kurz A, et al. A genetic variation
of cathepsin D is a major risk factor for Alzheimer’s disease.
Ann Neurol 2000;47:399 – 403.
2. Wolfe MS, Xia W, Moore CL, et al. Peptidomimetic probes
and molecular modeling suggest that Alzheimer’s gammasecretase is an intramembrane-cleaving aspartyl protease. Biochemistry 1999;38:4720 – 4727.
3. Mckhann G, Drachman D, Folstein M, et al. Clinical diagnosis
of Alzheimer’s disease: report of the NINCDS-ADRDA Work
Group under auspices of Department of Health and Human
Services Task Force of Alzheimer’s disease. Neurology 1984;34:
939 –94.
4. Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet 1991;337:1158 –1159.
5. Crawford FC, Freeman MJ, Schinka J, et al. The genetic association between cathepsin D and Alzheimer’s disease. Neurosci
Lett 2000;289:61– 65.
Tracking of Alzheimer’s Disease Progression with
Cerebrospinal Fluid Tau Protein Phosphorylated
at Threonine 231
Harald Hampel, MD,1 Katharina Buerger, MD,1
Russell Kohnken, PhD,2 Stefan J. Teipel, MD,1
Raymond Zinkowski, PhD,2 Hans-Juergen Moeller, MD,1
Stanley I. Rapoport, PhD,3 and Peter Davies, PhD4
Major efforts are underway to investigate therapeutic strategies that have the potential to slow Alzheimer’s disease (AD)
progression. To evaluate the effect of these interventions, biological markers are needed that reflect progression of AD
In AD, abnormal phosphorylation of tau protein is associated with neurofibrillary tangles. Longitudinally, no significant overall change of total tau protein (t-tau) levels in cerebrospinal fluid (CSF) is found in mildly to moderately
demented AD patients.1,2 It is suggested that phosphorylation of tau protein at threonine 231 (p-tau231) seems to be
specific for AD and occurs early in the disease course.3 To
our knowledge, p-tau231 has not been studied longitudinally
Annals of Neurology
Vol 49
No 4
April 2001
in AD CSF. We asked whether the CSF level of p-tau231
could be used as a marker of AD progression.
Up to 7 spinal taps (mean interval 17.0 ⫾ 14.8 months,
range 0.4 – 66.3) were performed on 17 patients with probable
AD (NINCDS-ADRDA criteria4; 9 men, 8 women; age at
baseline 65.8 ⫾ 9.1 years; MMSE score at baseline 17.6 ⫾
5.7 points, range 4 –26). Baseline values were compared to values in 12 age- and gender-matched healthy controls (HC). AD
patients were not treated with acetylcholinesterase inhibitors.
P-tau231 was measured by a newly developed enzymelinked immunosorbent assay (ELISA).5 For each patient, 80
␮l of CSF were analyzed per well in duplicate wells. A pool
of AD CSF was used to produce a standard curve. Levels of
p-tau231 found in patient CSF samples are expressed in terms
of the volume of AD CSF pool that gave an equivalent signal
(␮l CSF eq). To measure t-tau, we used a commercially
available ELISA (Innogenetics, Zwijndrecht, Belgium).
Mean ⫾ SD CSF levels at baseline in AD patients and HC,
respectively, were 53.3 ⫾ 25.5 and 2.2 ⫾ 11.7 ␮l CSF eq
(p-tau231) and 496.2 ⫾ 204.6 and 312.2 ⫾ 98.2 pg/ml (ttau). Thus, mean concentrations of both p-tau231 and t-tau
levels were elevated significantly (p-tau231: p ⬍ 0.001; t-tau:
p ⬍ 0.005) in AD patients vs HC. Longitudinally, p-tau231
concentrations decreased linearly with time in AD patients
( p ⬍ 0.03, one-sample t-test, two-tailed). Mean rate of decline
was ⫺4.2 ␮l CSF eq ⫻ year⫺1 (SD ⫾6.8). The concentration
of t-tau did not change significantly with time ( p ⫽ 0.47;
⫺11.9 pg/ml ⫻ year⫺1, SD ⫾66.3). Furthermore, rate of
change of p-tau231 was correlated with the MMSE score at
baseline (Spearman’s rho ⫽ 0.70, p ⬍ 0.01), with a more
pronounced rate of decline with advanced cognitive impair-
Fig. Correlation between MMSE score at baseline and rate of
change in cerebrospinal fluid p-tau231 in 16 of the 17 Alzheimer’s disease patients investigated longitudinally. Mean rate of
cognitive decline (MMSE score) was ⫺3.63 points per year
(SD ⫾3.9).
ment (Fig). This was not found for t-tau (rho ⫽ 0.38, p ⫽
0.15). Neither parameter was correlated with age at baseline or
with rate of cognitive decline (change in MMSE score over
time). Furthermore, longitudinal changes of p-tau231 and t-tau
levels in AD patients were not correlated with each other
(rho ⫽ 0.30, p ⫽ 0.24). One outlier did not change statistical
The decrease of CSF p-tau231 with AD progression might
reflect the increasing sequestration of p-tau231 into the tangle, suggesting that p-tau231 becomes more insoluble rather
than entering into the CSF, whereas solubility of t-tau remains unaffected. We suggest that p-tau231 be further investigated as a specific biomarker candidate for AD progression.
Such a marker would be particularly useful to evaluate therapeutic interventions in disease-modifying drug trials.
Department of Psychiatry, Dementia Research Section and
Memory Clinic, Ludwig-Maximilian University, Munich,
Germany; 2Molecular Geriatrics Corporation, Vernon Hills,
IL; 3Brain Physiology and Metabolism Section, National
Institute on Aging, National Institutes of Health, Bethesda,
MD; 4Department of Pathology, Albert Einstein College of
Medicine, Bronx, NY
1. Andreasen N, Minthon L, Clarberg A, et al. Sensitivity, specificity, and stability of CSF-tau in AD in a community-based
patient sample. Neurology 1999;53:1488 –1494.
2. Sunderland T, Wolozin B, Galasko D, et al. Longitudinal stability of CSF tau levels in Alzheimer patients. Biol Psychiatry
1999;46:750 –755.
3. Vincent I, Zheng JH, Dickson DW, et al. Mitotic phosphoepitopes precede paired helical filaments in Alzheimer’s disease.
Neurobiol Aging 1998;19:287–296.
4. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA
Work Group under the auspices of Department of Health and
Human Services Task Force on Alzheimer’s disease. Neurology
1984;34:939 –944.
5. Kohnken R, Buerger K, Zinkowski R, et al. Detection of tau
phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer’s disease patients. Neurosci Lett 2000;287:187–190.
Plasma Levels of Amyloid ␤ Proteins Did Not
Differ Between Subjects Taking Statins and Those
Not Taking Statins
Takahiko Tokuda, MD, PhD,1 Akira Tamaoka, MD,
PhD,2 Sayoko Matsuno, MD,2 Shunpei Sakurai, MD,1
Hirohide Shimada, MD, PhD,1 Hiroshi Morita, MD,
PhD,1 and Shu-ichi Ikeda, MD, PhD
There is emerging evidence linking Alzheimer’s disease (AD)
and cholesterol dynamics. Apolipoprotein E, widely recognized as the most common risk factor for AD,1 is originally
a lipid transport protein that plays an important role in cholesterol homeostasis. Alzheimer-like amyloid ␤ protein (A␤)
immunoreactivity was induced in the brains of rabbits fed
with high dietary cholesterol.2 It has also been shown that
␤-hydroxy-␤-methylglutaryl-CoA reductase inhibitors (statins), which can reduce intracellular cholesterol level, have
an inhibiting effect on A␤ production in cultured cells.3
Annals of Neurology
Vol 49
No 4
April 2001
Table. Summary of This Study: Plasma Concentrations of A␤ Species, Total Cholesterol, and HDL Cholesterol
No. of Sex
Age (yr)
Subjects (M/F) (mean ⫾ SD)
Subjects with statins
Subjects without statins 23
64.3 ⫾ 7.6
60.0 ⫾ 13.3
A␤x-40 (pM)
(mean ⫾ SE)
A␤x-42 (pM)
(mean ⫾ SE)
Total chol
(mean ⫾ SE)
HDL chol
(mean ⫾ SE)
238.0 ⫾ 10.9
226.5 ⫾ 22.3
21.9 ⫾ 2.9
19.3 ⫾ 2.3
190.5 ⫾ 6.6
200.1 ⫾ 8.8
52.8 ⫾ 2.7
55.8 ⫾ 3.2
HDL chol ⫽ plasma concentration of high-density lipoprotein (HDL) cholesterol (mg/dl); total chol ⫽ plasma concentration of cholesterol
However, it remains uncertain whether statins also decrease
A␤ production in vivo.
To explore the effect of statins on A␤ production in human bodies, we measured plasma levels of both A␤x-40 and
A␤x-42 in subjects who were taking statins and age-matched
control subjects not taking statins. Informed consent was obtained from each subject as appropriate. Those subjects were
clinically free of neurological symptoms and cognitively normal. Subjects taking statins were 22 Japanese patients with
hypercholesterolemia (15 males and 7 females; age, 64.3 ⫾
7.6 years). Either 10 mg of Pravastatin or 5 mg of Simvastatin in a daily dosage was given to each patient. The control group consisted of 23 age- and gender-matched Japanese
(15 males and 8 females; age, 60.0 ⫾ 13.3 years). Blood
samples were collected from these subjects when they were
fasting. After separation of plasma from blood cells, concentrations of A␤ species were measured with enzyme-linked
immunosorbent assays that can specifically recognize either
A␤x-40 or A␤x-42.4,5 Statistical analysis was performed by
the Mann-Whitney U test.
We previously reported that plasma levels of A␤ species in
patients with Down’s syndrome reflect the ability of their
bodies to produce these A␤s.5 As shown in the Table, there
were no significant differences in the concentration of
A␤x-40 or A␤x-42 in plasma between the statin-taking subjects and the control subjects, suggesting that clinically available statins do not decrease A␤ production in human bodies.
An alternative interpretation of our results is that A␤ production and/or secretion into human plasma may not depend on statin itself but on the level of plasma cholesterol,
which was not different between the two groups examined,
given that the patient group was taking statins. To clarify
these issues, further studies are necessary, especially examining changes in the levels of plasma A␤ proteins before and
after the administration of statin in the same individual.
Institute of Clinical Medicine, University of Tsukuba, Ibaraki,
1. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to ␤-amyloid and increased
frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 1993;90:1977–1981.
2. Sparks DL, Scheff SW, Hunsaker JC 3rd, et al. Induction of
Alzheimer-like ␤-amyloid immunoreactivity in the brains of
rabbits with dietary cholesterol. Exp Neurol 1994;126:88 –94.
3. Simons M, Keller P, De Strooper B, et al. Cholesterol depletion
inhibits the generation of ␤-amyloid in hippocampal neurons.
Proc Natl Acad Sci USA 1998;95:6460 – 6464.
4. Suzuki N, Cheung TT, Cai XD, et al. An increased percentage
of long amyloid ␤ protein secreted by familial amyloid ␤ protein precursor (␤APP717) mutants. Science 1994;264:1336 –
5. Tokuda T, Fukushima T, Ikeda S, et al. Plasma levels of amyloid ␤ proteins A␤1-40 and A␤1-42 (43) are elevated in
Down’s syndrome. Ann Neurol 1997;41:271–273.
In the December 2000 issue, Factors Predicting Prognosis of Epilepsy after Presentation with Seizures by
Dr. B. K. MacDonald et al. contained the following
two errors:
1. In the first paragraph of the Discussion section,
the percentages in the text do not agree with
those in Table 5. The figures given in the table
are correct.
2. On page 837, the multiplicative factor should
read 1/ n, not 1/n.
Department of Medicine, Shinshu University School of
Medicine, Matsumoto, and 2Department of Neurology,
The authors regret the errors.
Annals of Neurology
Vol 49
No 4
April 2001
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deficiency, disease, ullrich, collagen
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