Download DCM in Dobermann is a disease with variable Prevalence and

DCM in Dobermann is a disease with variable Prevalence and variable Incidence over time: risk period
for developing the disease can be between juvenile ages to most aged dogs (8 old). Disease is mortal
in all cases and average time of survival is short. With these characteristics of the Dobermann DCM,
most adequate method to evaluate the frequency of the disease in the population is the study of
Accumulated Prevalence over a long trial period (5 years in this study).
Most accurate evaluation of risk of the DCM disease in the Dobermann population is given when we
calculate the Accumulated Prevalence dividing the” total number of all affected dogs” of all age classes
during the trial period, not by the total number of dogs but by the “total number of healthy dogs”, not
including those with the disease, since they are not at risk of developing it.
Is in this case Accumulated Prevalence representative of the average risk of DCM for the
subpopulation of European Dobermann? Yes! If the sample is representative (and it is),
accumulated prevalence (58.2%) is the average risk. A prevalence of 58.2% for DCM means that now
in a random group of 1000 healthy European Dobermanns, they are a most probable distribution of
582 of dogs that will be affected by DCM at some point in their lives, and 418 dogs not affected. It's
that simple!
Is it enough and representative sample to obtain an accuracy scientific conclusion?I guess
so. A level of statistical significance P<0.05 does not seem a lax level of significance. It is the most
used significance level in veterinary epidemiological studies. Otherwise 5 years is a long enough time
to obtain an accurate measure of DCM risk. Geographical distribution of the sample including dogs
from Germany, the Netherlands, Austria, Switzerland, Italy, and some eastern European countries
seems representative also.
But you are right, 412 Dobermanns can be a small number; a sample of 4000 is better and a sample
of 40 is worse. Obviously, the main way to reduce the random error is increase the size of the sample.
The appropriate size of a sample in an epidemiological study is not chosen at random but are
calculated based on statistical formulas which relate the size of the sample with trial variables as level
of statistical significance requested, probability of not detecting a real error, relative size of groups
compared, etc.
Your argument is very clever but biased and confuses. If I deny the representativeness of the
sample size shredding the validity… I remember you that scientific protocols are strict, and expert
scientific referees evaluate the validity of the results, all methods (included the statistical methods and
representativeness of the sample size), consulted bibliography and adequate relation of the discussion
and conclusions topics with experimental data and cited bibliography before it publication in a
scientific journal. The Journal of Veterinary Internal Medicine is not a “gossip magazine” it is the
official publication of the American College of Veterinary Internal Medicine, the European College of
Veterinary Internal Medicine, the European College of Veterinary Neurology, and the European College
of Equine Internal Medicine, with a vey prestigious Editorial Board and an impact factor of 2.168, one
most higher between Veterinary Sciences Journals.
Is the data of Accumulate Prevalence for DCM of European Dobermanns 58.2% all the
truth? All statistical data ere subject to a degree of uncertainty but surely it is more near the exact
value that our erratic speculations. In any case there appears a Dobermann forum the most
appropriate place to discuss the validity of a scientific paper between neophytes. We would have to be
grateful to the authors for their contribution, although their findings are an “inconvenient truth” for
many people. When numbers appear fade fables.
Data of prevalence reported in the Discussion by the same authors for dogs from the United States or
Canada vary between 45 and 63% (average between extreme values =54%). Is it a coincidence?
Surely not: same founders + same bottleneck + same selection method on popular sires (although
different popular sires) = same result. A catastrophe! Probably causative gene(s) are ancestral genes
concentrated during selection (not recent mutations) but this matter little now. I think that the
appropriate response to these data is to question our methods and strategies, not the
validity and meaning of a scientific data.
What about interbreed risk of DCM? Interbreed quantitative relative risk of DCM is not
documented in the bibliography. There are some quantitative data not corrected for the risk
population of each breed (the number of live individuals of every breed, variable according to the
popularity of each). In the paper of Petric et al. (Dilated Cardiomyopathy in Doberman Pinschers:
Survival, causes of death and a pedigree review in a related line. J. Vet. Cardiol. 2002; 4:17–24) there
are some data restrained to a territory (Slovenia). These data can give us some perspective of how
things. Selecting data in this paper only for breeds ordinarily considered as “breed at risk” for DCM in
the literature (Dobermann, Boxer, Great Dane, Newfoundland and English Cocker Spaniel).
Dobermann accumulate more risk (almost double) than all others breeds at risk. Newfounland is not a
popular breed but all others can be considered with a similar popularity. Approximate conclusion but it
indicates a disturbing tendency.
What about selection of the progenitors? The DCM is an ugly disease: autosomal dominant
inheritance with reduced penetrance (Meurs et al. A prospective genetic evaluation of familial dilated
cardiomyopathy in the Doberman pinscher. J Vet Intern Med. 2007; 21(5): 1016-20). Incomplete
penetrance means that not all genotypes content the causative gene(s) exhibit DCM phenotype. More
is reduced the level of penetrance more important is the percent of “silent carriers” in the not affected
population.
Incomplete penetrance diseases is most likely a result of the way of a gene interacts with other genes
as well as environmental factors of endogenous origin (for example sex hormones, immune system,
etc) or exogenous origin (for example stress, food, etc). For simplicity and to understand the
prospective risk for DCM in the selection of the progenitors, we can think in an inheritance model of a
“major dominant gene D” responsible of DCM in Doberman and analyze it as a monogenic Mendelian
trait. Just some examples:
First scenario: Penetrance 1 for DD homozygote and 0.5 for Dd heterozygote genotypes. In this
scenario only rest an approximate 17.6 % of free dd genotype in the population; p(D)=0.58;
q(d)=0.42.
Second scenario: Penetrance 0.75 for DD homozygote and 0.5 for Dd heterozygote genotypes. In this
scenario only rest an approximate 8.8 % of free dd genotype in the population; p(D)=0.70;
q(d)=0.30.
Another time approximate but disturbing. Even when a test is available we will certainly have to use
heterozygous silent carriers Dd*, otherwise breeding population (dd) would be very small.
Paper of Petric et al. (Dilated cardiomyopathy in Doberman Pinschers: Survival, causes of death and a
pedigree review in a related line. J Vet Cardiol 2002; 4:17–24) show that occult DCM cases (sudden
death) are half that previously diagnosed DCM cases (congestive heart failure). Also diagnosed DCM
cases (congestive heart failure) are more frequent in the more aged dogs (average =7.1 years old)
and sudden death DCM cases are more frequent in dogs that have died younger. In this case, sample
is restricted to a group of 21 affected Slovenian Dobermanns, but data may be indicative: half of all
cases are occult to the ECHO-EKG Holter scanning diagnostic.
A most detailed analysis of data of accumulate prevalence from West et al. show two age peaks for
the Incidence (new cases in age groups) at 2-4 years (minor) and 6-8 years (major). This distribution
is worrying for the progenitor’s selection because age class 6-8 shows an incidence of 31.1%, almost
1/3 of new cases of DCM in this age group, too late.
Risk perception is subjective and everyone can see the glass half full or half empty as it seems. It
is discussed in this section about Fedor. Can be him an affected DD or Dd? Probably no, because he
has almost surpassed the age at risk (8 years). Can be him a silent carrier DD* or Dd*? Maybe yes,
maybe not (his mother is probably affected DD or Dd). The time and the incidence of DCM in their
progeny (the sample is very large) will reveal its likely condition. Otherwise if he is a silent carrier,
most probably Dd*, no problem. In fact I have proposed before the use of heterozygous silent carriers
Dd* when a genetic test can be available.
However, is a safe practice that a male as Fedor breed 150 or 200 bitches? No. If he is a free
genotype dd for DCM this practice is bad (popular sire effect), if he is a silent carrier Dd* worse
because he would contribute to spread the risk allele D in the population and increasing the DCM
prevalence.
We could continue discussing on many other suspect dogs and the discussion would be endless with
the same results among the sceptics and the cautious. I do not think starting a “witch hunt” as
convenient and would not lead anywhere. Only objective and scientific data is that prevalence of
the disease in Europe is 58.2%. A shame! This number has a reasonable explication only when a
strong popular sire effect has disseminated the disease in the population. Retrospective origin of DCM
in the North American Dobermanns is documented by the DCM status of famous Seven Sires (for
example see Rod Humphries in Doberman Pinchers Magazine: The Cardiomyopathy Chronicles 1), in
Europe data are scattered on different dogs but not in a synthetic article.
In absence of a genetic diagnostic, only reasonable way to prevent the increasing of the DCM
prevalence in the population it is risk diversification. Risk diversification only works when you
reduce the genetic quote of each individual in the Dobermann population. Limitation of litters by
sire is necessary. Is limitation possible? It seems that no with the actual state of opinion of
influential people and hierarchies. DCM is not Von Willebrand disease (rarely mortal and recessive),
DCM is dominant although with incomplete penetrance but mortal in all affected dogs. What do you
ameliorate without selection on health if a 58% of born dogs will die of DCM before 8 old?
Is it coherent that the average longevity of the breed (7-8 years) is closely approximates with the
limit risk age (8 old) for DCM and with data of pravalence (58%) in this study? Another coincidence?
Unless we act now the percentage of affected dogs will continue to grow. What priority in this
catastrophic situation, multi Ch & ZTP criteria of selection? If you add a criterion of clean DCM
bloodline, how many dogs rest in this group? Sufficient number to make an amelioration job without
going into a population bottleneck?
Your proposal that everything will remain as always, it is a proposal for risk. It's like if you
recommended to a lung cancer patient continue smoking. Well, there is a subtle difference: the lung
cancer patient can choose but the dog does not, the choice is dictated by the breeder. No, unless we
act now, things that go wrong likely will get worse. I repeat, only reasonable way it is risk
diversification and to limit sire utilisation.
I am aware that the reality, although inconvenient, it is stronger than any scientific or ethical
argument. Perhaps the happiness of the innocent is least annoying, except for the affected dogs and
for the breed survival. Even the Devil has advocates, usually much because he is very powerful, but
not dogs.
Amicably:
Ronindobe wrote:
I just want the data to do my job at the highest level possible. I believe the expressed mission of
all these owner/breeders is always the same. Not interested in blame or the past decisions in
programs, just in facts about dogs and lines. Help me or get out of the way.
It may be suprising how quickly the situation can be improved with concerted effort and
information. The hope I found in the remarks of Sonia was that 42% of stock may be unaffected
and useable for establishing clean lines and dilute others. Of course which are they?
Hi Ronindobe:
Thank you very much for your kind words. I take this very seriously because I am very concerned
about the situation of the breed about genetic diseases. One of my dogs died from a genetic disease
(hepatic) very young (2.5 years old) and their suffering left me a deep mark. I will try to respond you
as clearly (my English is not my best) as possible and I added a final review of Dobermann DCM state
of the art in my knowledge. To some it may be excessive but I think it's always good to have a
synthesis of most relevant aspects for the breeders.
About your breeding plan.
I agree with you that most probably scenario is the first (penetrance 1 for DD genotype and 0.5 for Dd
genotype). Segregation analysis of some groups in the pedigree of DCM affected dogs (paper of Meurs
et all, [1] fig.1, p.1017) makes me think that this is the most likely scenario.
In this scenario Fedor can be a silent carrier Dd*, but in my opinion Gino (linebreed in your dogs), can
be a most probably silent carrier Dd* for his pedigree antecedents and collaterals. In this scenario:
But if you change the Dd affected by a Dd* silent carrier you will obtain the same result.
This illustrates the possible case which a test mating of full siblings for eliminates in a bloodline one
autosomal dominant disease with reduced penetrance, as DCM, not accomplish its goal. We can apply
the same corollary than for Fedor. In you concerns, obviously the risk of a dog in your program
decrease as his position goes back in the pedigree, but only if this risk has been diluted in the
matings. It’s a crossword puzzle or rather a minesweeper (DD mines double explosives than Dd or
Dd* mines).
In absence of a genetic diagnostic it is also clear that as important as the clinical ECHO-EKG Holter
diagnostic (late diagnosis in many cases, half occult cases and short average time of survival) is the
knowledge of the circumstances of death (age and possible cause) of dogs and relatives to get an
estimated view of the likely condition: DD, Dd, Dd* or dd. It should be clear also that no genetic test
is uncertain in our speculations, but every one can move in a space of probability based on available
data on each dog in the pedigree and the use of common sense and a major gene model. Although we
are blind never hurts to have a cane…
Otherwise, if we combined analysis of average longevity, mortality distribution by diseases in Dutch
Dobermanns [2](table2), and accumulate prevalence of DCM in European Dobermanns [3], reasonably
we can conclude that many dogs that die by natural causes and not cancer before 8 old are most likely
to die of DCM. I say this only as a guide. You must not forget either that usually only children or
drunks tell the whole truth on the issues drawbacks and this is another variable that must be
contemplated in your crossword puzzle.
Assume that the penetrance of the heterozygote is 0.5 is a working reasonable hypothesis, but it
remains only as hypothesis. If the penetrance is more reduced for heterozygote genotype Dd:
I do not think that is very far from 0.5. We sometimes forget that genes are inherited, not
genotypes and the silent carriers Dd* disseminate the disease well as those Dd affected but
without prior notice.
About DCM mode of inheritance
Usually in Sciences a complex issue like this one is solved by successive approximations over time and
the contradictions are resolved on the basis of new researchs. Normally most recent papers include
most reliable conclusions. In my opinion Dr. Meurs’s group (Washington State University) is the most
prestigious on canine and Dobermann DCM. His work [1] about mode of inheritance includes the
monitoring of 41 dogs in four generations but specially with few dogs without diagnosis or knows
phenotypic status compared with other studies [4]. Their conclusion (autosomal dominant with
reduced penetrance) I think is more reliable. Most recent paper of Wess et al. [3] reported this mode
of inheritance from this bibliographic source, but there is notice of this mode of inheritance since 1996
(fourteen years ago) in a paper of Hammer et al. [17].
As I related in my last note for reduced penetrance diseases is most likely a result of the way of a
gene interacts with other genes as well as environmental factors of endogenous origin (for example
sex hormones, immune system, etc) or exogenous origin (for example stress, food, etc).
For example, in the paper of Petric et all.[4] is reported a major incidence between males than
females in a sample of 21 dogs of a determinate Dobermann Slovenian line with high incidence of
DCM and with a high level of inbreeding. Why this difference? For example a line may exhibit a higher
incidence in males because a particular combination of environmental factors of endogenous (most
probably) origin or exogenous origin represent a plus to attain the threshold value more readily in
males, but not necessary by interaction with genes of the X chromosome. Neither this work is oriented
to population genetics, but it is the Chapter 2 of a work oriented to Molecular genetics on searching
gene polymorphisms linked to DCM phenotypes [5]. Although the results (males biased), in this work
(preceding the paper of Meurs et al.[1]), the authors indicate in their introduction the same mode of
inheritance (autosomal dominant with reduced penetrance) from Hammer et al. [17], so authors
understand perfectly the limitations of their study.
Anyway, paper of Wess et al.[3] there is little difference between the sexes, although not significant.
If in this paper we present the results of Table 1 (p.3) in a most synthetic form than Figure 2,
grouping the data of all age classes:
We can observe that there is a little difference in the clinical signs for diagnosed females and males.
Females show more probably EKG Holter signs, whereas males show a most probably signs of EKG+
ECHO and signs of congestive heart failure. Also the sum of all cases shows a little difference (11.4%)
between females and males (44.6 and 55.4% respectively). These differences are not significant, as
they say the authors, in relation with an X linked mode of inheritance. Do they mean anything? I think
so, 412 dogs are not 21 dogs, they are many dogs. In any case nothing in relation with genes of the X
chromosome. Something in relation with sexual hormones (environmental endogenous factor) that
reduced a little the penetrance level in females? Perhaps but I don’t know. This is not a “discovery”
and surely now these authors and others are studying the different possibilities to explain this
difference.
We can not forget also that genetic structure of the autosomes (no sexual chromosomes) varies
between males and females, particularly the so-called chromosomes hotspots. Genes linkage is higher
in males near telomeres and in females near centromeres of chromosomes. In fact average
recombination rates during meiosis are higher in canine females than males (1.2 times higher). See
bellow for canine chromosome 2 these differences.
Is the DD or Dd affected status related with the variable expressivity of DCM in relationship with age
of death (0-8 years), mode of presentation (sudden death or congestive heart failure) and clinical
signs (ECHO-EKG Holter)? Another time is possible but I don’t know (but I sniff...). There must be a
reasonable explanation for variable expressivity of DCM.
What about genes involved in DCM?
Although there is increasing data on the genetic origin of DCM in Dobermann, by moment there are no
conclusive results about causative gene(s). The causative gene(s) responsible for this disease remain
unresolved. In Dobermann the searching of mutations on many genes coding cytoskeletal proteins
that have important structural functions in the cardiomyocytes (heart muscle cells), and in the
proteins associated with the connective tissues of intracellular and extracellular matrix, they have
been negatives: actin [6], desmin [7], delta sarcoglycan [8], phospholamban [9], alfa tropomyosin [5,
Ch.4], troponin C, lamin A/C, cysteine and glycine-rich protein 3, troponin T, β-myosin [10] and
calstabin2 [11].
Another possibility is that Dobermann DCM can be an autoimmune disease. Neither any success in
finding genes or markers in DLA-Class II (DQA1, DQB1 and DRB1) related with an autoimmune
response [5, Ch.7]. However metallothioneins (proteolytic enzymes) have been implicated in the
degradation and remodelling of collagen (component of connective tissue) in the diseased ventricle; it
has been shown an increase in the expression of matrix metalloproteinase-9 (MMP-9) and neutrophil
elastase in the left ventricles of Dobermanns with DCM correlated with an inflammatory cell response
[12]. But changes in the collagenous matrix are also present in normal Dobermans [13]. MMP-9 has a
protective antioxidant role and it overexpressed (high level) in unaffected Dobermanns. This can be
related with the low diversity in DLA-II genes observed in the breed [14, 15] and the Dobermann
predisposition for some autoimmune diseases. These background changes in the collagenous matrix
could be involved in the rapid progression -not causal gene(s)- of the disease in Dobermann and the
short time survival [13].
Dr. Meurs (Washington State University) in cooperation with others US universities research groups
has discovered that a gene which encodes the sarcoplasmic reticulum protein calstabin2 (control
release of calcium) it is involved in the development of Boxer's Arrhythmogenic Right Ventricular
Cardiomyopathy (ARVC) [11] and an indicative genetic test for Boxer is currently available in
Washington State University. Also Great Dane dogs with DCM demonstrate abnormal calstabin2
expression but in a contrary sense [16]. Mode of inheritance of ARVC in Boxer is similar to DCM in
Dobermann but unfortunately, the DCM phenotype in the Dobermann is not related by the same
protein calstabin2 [11].
Groups of Ljubljana & Utrech Universities found statistically significant correlations between DCM
phenotypes and a polymorphic microsatellite marker REN252E18 in the gene encoding the giant
myofilament protein Titin [5, Chp.7]. Briefly Titin's role in sarcomere structure provides a structural
framework through association with other proteins as Actin, Myosin and others, and they keeps the
thick filament centered during muscular activation.
The difference in haplotype frequencies between the DCM and the DCM-free group and the frequency
of dogs homozygous for a protector haplotype 1 and allele 260 were statistically significant. “Protector
allele” 260 is majority in DCM free phenotypes and a most frequent “risk allele” 256 in the DCM
phenotypes. Other haplotypes different that 256 exhibit the same tendency:
I don’t know why, but after this Thesis there isn’t other publication of this research group about the
Titin gene in relation with DCM in Dobermann.
Bellow table shows a resume of DCM mode of inheritance and possible genes involved for different
breeds at risk:
Obviously DCM is a complex disease with many variables among breeds, especially different founders
so different background gene alleles involved. Complex problems rarely have simple solutions, and
then we should not believe in miracles too.