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Autosomal dominant inheritance of hereditary canine spinal muscular atrophy.

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Autosomal Dominant Inheritance of
Hereditary Canine Spinal Muscular Atrophy
George H. Sack, Jt, MD, PhD," Linda C. Cork, DVM, PhD,iS Jeanette M. Morris,#
John W. Griffin, MD," and Donald L. Price, MDB
~
~~~~
Hereditary canine spinal muscular atrophy (HCSMA) is a motor neuron disease in Brittany spaniels. Three phenotypes
are recognized (accelerated, intermediate, and chronic) and are distinguished on the basis of rate of progression and age
at onset. Breeding studies within a kindred of more than 125 dogs (Brittany spaniel and beagle-Brittany outcrosses)
have established an autosomal dominant inheritance for HCSMA. Pups homozygous for the trait have accelerated
disease, whereas heterotygous dogs have intermediate or chronic disease. The reason for the two phenotypes in
heterozygotes is under study. HCSMA provides a unique opportunity to study the genetic and pathophysiological
mechanisms of a motor neuron disease, and findings may have broad relevance to investigations of autosomal dominant
degenerative disorders of the central nervous system.
Sack GH Jr, Cork LC, Morris JM, Griffin JW, Price DL Autosomal dominant inheritance of hereditary canine
spinal muscular atrophy. Ann Neurol 15:369-373, 1984
Hereditary canine spinal muscular atrophy (HCSMA)
is a recently described genetic disorder of Brittany
spaniels { 5 , 7, 131. Affected animals have clinical features (weakness, muscle atrophy, fasciculations, and
fibrillations) and pathological changes (chromatolysis,
neurofilamentous swellings of proximal axons, and loss
of lower motor neurons) in common with human
motor neuron diseases, including the spinal muscular atrophies of infancy and childhood (MerdnigHoffmann disease and Kugelberg-Welander syndrome) and the adult-onset motor neuron disease
amyotrophic lateral sclerosis (ALS) 13, 4, 10, 171.
A colony of Brittany spaniels was established at The
Johns Hopkins Medical Institutions, and several generations of dogs were bred. Three phenotypes appeared:
an early-onset, rapidly progressive type (reminiscent of
Werdnig-Hoffmann disease) and two more slowly progressive types (analogous to the juvenile and adult
forms of human motor neuron disease). During this
study two other traits, apparently unlinked to motor
neuron disease, were identified: cleft palate and a
deficiency of the third component of complement (C3)
{22); these entities will be described in later reports.
Study of over 125 dogs in these matings, including
especially informative offspring of outcrosses into
beagles, has delineated at least one important autosomal dominant form of HCSMA. Elucidation of this
segregation pattern has provided a reasonable hypothesis to explain some of the phenotypic variations
and suggests approaches for future investigation.
From the Departments of 'Medicine, "Pediatrics, "Physiological
Chemistry, and $Pathology, the 'John F. Kennedy Institute, the tDivision of Comparative Medicine, the SNeuroPathology Laboratory,
Department of Pathology, the llNeuromuscular Laboratory, Department of Neurology, and the TNeuroparhology hbordtory, Departments of Pathology, Neurology, and Neuroscience, the Johns Hopkins University School of Medicine, Baltimore MD 21205.
Received Mar 30, 1982, and in revised form Aug 29. Accepted for
publication Sept 3 , 1983.
i ~ i
Address reprint requests to D~sack, M~~~~clinic, ~ i ~ Med.
ical ~
~the johns~Hopkins~Universiq
~ School iof Medicine,
~ 60 1 ~
Broadway, Baltimore, MD
205,
Materials and Methods
The pedigree of the dogs with HCSMA is shown in Figure 1.
Purebred Brittany spaniels in this colony are members of the
kindred of the first animal in whom HCSMA was identified
(111-4). That animal's sister (111-1)was mated to her sire (A),
and she and their progeny (IV) provided the foundation
breeding stock. Subsequently a related female in litter I (1-1)
was included in test matings. Test matings also were made to
an unrelated Brittany spaniel bitch (B) and to purebred
beagle bitches (C, D).
All dogs within the colony have had muscle biopsies for
diagnosis beginning at 6 months of age or earlier. Biopsies
have been repeated periodically until euthanasia or natural
death. The age of each dog at death or at its most recent
muscle biopsy is shown on the pedigree (see Fig 1). All dogs
that were killed or died of disease have been studied postmortem. Stillborn pups, or those dying within the neonatal
period, also were examined. Although autolysis prevented
definitive diagnosis in some neonates, in at least one pup
(XV) the disease was present at birth.
A phenotype was assigned on the basis of rate of progression of disease and the clinical and histopathological criteria
shown in the Table. O n the basis of clinical and pathological
criteria, three phenotypes have been defined: accelerated,
intermediate, and chronic.
369
~
~
,
Q SLOW
0 INTERMEDIATE
ACCELERATED
3 5 - A G E ( I N M O N T H S ) AT DIAGNOSIS
A N D / O R DEATH
@ FEMALE
BEAGLE
S T I L L B I R T H S OR NEONATAL D t A T r l S
27 I 7
12
8
Pups with accelerated disease (Fig 2) were identified easily
because of their rapidly progressive weakness and striking
postmortem findings [6]. Distinction between intermediate
and chronic phenotypes was more difficult. Dogs with intermediate disease (Fig 3) usually developed weakness in the
first 6 months of life, and paresis progressed at an appreciable
rate. Despite abnormal electromyographic findings, the two
dogs classified as showing chronic disease had little obvious
weakness, and their clinical signs did not change appreciably
over many months. Dog IV- 1 shows denervation atrophy o n
muscle biopsy, but dog A was killed elsewhere at 14 years of
age because of a gastric adenocarcinoma and severe renal
disease. No significant loss of motor neurons in the spinal
cord was evident postmortem. Muscle was not made available
8
12
12
12
3
25
14
2 5 31
14
8
F i g 1 . Pedigree of Brittany spaniels. shouing hrredituty runiwe
spinal muscular atroph.11 and outbreeding t o bugles. Age at deuth
(inchding neonutcd deatb.r, and at diagnosis is indirated. Postmortem examination.c uiere done on all dog.) d y i n g during the
study.
for examination, and thus the diagnosis was not confirmed
histologically.
Histological features of the abnormalities identified in
these dogs have been described {6, 71. Muscle atrophy was
much more severe proximally than distally; therefore, paraspinous muscles wete routinely biopsied. Pups with accelerated disease have chromatolysis and massive numbers of
Clinrral aiid Pathological Changes in Hereditay Canine Spinal Mu rrular Atrophy Phenotypes”
Phenotype
Age at Onset
Clinical Signs
Pathological Changes
Accelerated
6 wk-3 mo
Intermediate
6 mo-3 yr
Axonal swellings and chromatolysis in
pups less than 4 mo old
Denervation atrophy of muscles and
axonal swellings in dogs more than 4
mo old
Chronic
3 1 yr
Unclassified
Normal
...
Severe weakness and atrophy by 6-8 wk;
tetraparesis by 3 mo
Weakness, atrophy, and evidence of
denervation on EMG or muscle biopsy
between 6 mo and 1 yr; tetraparesis by
2-3 yr
Weakness, atrophy, and denervation at
1-2 yr
Mild weakness at less than 1 yr
N o evidence of HCSMA
...
Denervation atrophy of muscles; n o data
on central nervous system
No unequivocal evidence of HCSMA
N o evidence of HCSMA
‘Only a small group of dogs has been placed in the category “unclassified.”These young dogs died or were killed as part of the experimental
studies. Some had “equivocal” neurological signs but laclced axonal swellings in the nervous system o r clear evidence of denervation atrophy in a
variety of muscle groups. Some of these dogs may belong in the category “intermediate” or “chronic” bur did not fulfill all the criteria for those
categories. Dogs classified as “normal” have shown no evidence of motor neuron disease at postmortem study (a minimum o f nine levels of spinal
cord were examined) and have shown no abnormalities on muscle biopsies.
EMG = electromyogram; HCSMA
370 Annals of Neurology
=
hereditary canine spinal muscular atrophy.
Vol 15 No 4
April 1384
I
XXIII
I
I
XXIV
XXVl
13
0
12
12
12
3
25
14 25
31
14
E
Q SLOW
0D E A D
@
@
INTERMEDIATE
ACCELERATED
0
10
17
17
3
0
I3
I3
0
FEMALE BEAGLE
S T I L L B I R T H S OR N E O N A T A L DEATHS
Fig 4. Pedigree details of Brittanylbeagle crossej (derifredfrom
data in Figure 1).
Fig 2. Fz generation Brittanylbeaglepup (XXV-1) (shownjust
prior t o euthanasia) with the accelerated form of hereditdvy
canine spinal muscular atrophy, quadriparetic at 1.3 weeks of
age. Both F , parents had intermediate disease. Note severe muscle
atrophy andflaring of costal rib margins. Pup was unable to lift
its head but had full extraocular movements.
Fig 3. Thirty-one-month-old Brittany spaniel (lV-4) with intermediateform of hereditaty canine spinal muscular atrophy
(shownjust prior to euthanasia). Note complete paresis of bind
limbs and drooping head from severely weak cervical muscles. The
dog was able t o maintain sitting posture briejy when placed upright but was unable to achieoe thii unaided.
axonal swellings. Dogs with intermediate disease have loss of
motor neurons and smaller numbers of axonal swellings.
Results
The most common phenotype is the intermediate
form, seen in the original propositus (Fig 1, 111-4).
Thirty-two dogs have intermediate disease: 11-1; 111-3,
4 ; 1V-4, 5; V-3; VI-1, 3, 4, 6 ; VII-1, 4; VIII-2; XI-3;
XII-4, 5; XV-1; XVII-3; XVIII-3, 4; XIX-1, 3; XXI1; XXII-1, 4; XXIII-2; XXIV-I, 5; XXV-2, 4, 7 ; and
XXVI-1. The appearance of 38g1of dogs (22 of 58)
with the intermediate form of HCSMA in crosses with
one normal parent (11-1; 111-3, 4; IV-4, 5; V-3; VI-1, 3,
4, 6 ; VII-1, 4; VIII-2; XII-4, 5; XIII-0; XVII-3; XIX1, 3; XX-0; XXIII-2; XXIV-1, 5; and XXVl-I) suggests that a single dominant gene can explan at least
some of the data. The observation that all four pups
with the accelerated form (IX-1, 2; XXI-4; XXV-1)
resulted from matings in which both parents had the
intermediate form of HCSMA is compatible with the
homozygous state of the mutant gene.
Because the nature of the chronic phenotype was
unclear (A, IV-I), we decided to place the gene on
another background. A male Brittany spaniel with the
intermediate form of HCSMA (IV-5) was mated to
two apparently healthy female beagles (Fig 4). The F,
litters of these crosses (XXIII, XXIV) contained one
male and two females with the phenotype of their sire.
These Brittany spaniellbeagle crossbreeds were called
“Briggles.” When the affected male XXIII-3 was
mated to his two affected half-sisters (XXIV-1, 4), the
F2 generation included fourteen classifiable pups (two
died at birth, apparently without HCSMA; another had
equivocal results o n muscle biopsy). Of these fourteen,
two had accelerated disease (XXJ-4, XXV-l), six had
intermediate disease (XXI-1; XXII-1, 4; XXV-2, 4,
7), and six were clinically normal. There was no
difficulty in distinguishing affected from unaffected
dogs, and the progression in all heterozygotes (XXI-1;
XXII-I, 4; XXV-2, 4, 7 ) was similar. Results from
these crosses clearly suggest transmission of HCSMA
as a single autosomal gene, detectable in the heterozygote and causing severe involvement in the homozygote (accelerated form).
Mating of a chronically affected male (IV-1) to a
healthy female beagle (D) produced a litter of five pups
(XXVI). One of these pups was affected with intermediate motor neuron disease. The other chronically
affected male (A) was not available for mating with
beagles. However, he sired six affected dogs of twelve
classifiable progeny in matings with three unaffected
Brittany spaniels.
Sack et al: Inheritance of HCSMA
371
Discussion
Inspection of the initial pedigree in 1979 suggested a
recessive inheritance of HCSMA, but, as was noted at
that time, this hypothesis was based on only 20 animals
13, 7, 131, some of which were less than 6 months old.
These dogs are kindreds 11, 111, IV, and IX (see Fig 1).
An important feature underlying this interpretation
was the apparent normality of the original sire (A) and
the dams in rnatings 11 and 111. We now have modified
this interpretation based on (1) recognition of the
chronic type of HCSMA and its documentation in IV1; (2) study of the progeny of breedings to a normal
Brittany bitch (VII and VIII); and (3) Briggle crossbreeding data showing clear autosomal dominant transmission (XXI to XXV). Sex ratios do not indicate any
sex influence on segregation. The data do not suggest
an effect of age of sire or dam on progeny phenotype.
There is no apparent effect of birth order on severity.
Litter size does not appear to limit expression.
Segregation of HCSMA as a single autosomal dominant gene suggests that the four pups with the accelerated form of HCSMA (IX-1, 2; XXI-4; XXV-1)
are homozygotes. Unusually severe involvement of individuals presumably homozygous for dominant traits
has been suggested for hairlessness in dogs (hypotrichosis) [I21 and, in humans, brachydactyly [16}, hereditary hemorrhagic telangiectasia [191, and achondroplasia 1141.
Although the basis for the chronic phenotype (A,
IV-1) remains unknown, its clinical and pathological
changes are distinct from those of intermediate disease
(see the Table). Breeding of A or IV-1 to either
mother (VI, XIII) or unrelated healthy Brittany
spaniels (11, 111, V, VIII) produced only intermediate
or unaffected offspring. The chronic phenotype did not
reappear in the entire pedigree.
A modifying or epistatic gene might reduce the severity of HCSMA in dogs with the chronic phenotype.
Because only male dogs expressed this phenotype,
the “modifying factor” might even be sex limited (but
not X-linked). If a single locus provided such a
modification, it segregated with the primary gene for
HCSMA only once in the six dogs in which the coupling phase could be unequivocally identified (only
from A to IV-1). Thus, there is no evidence for linkage
between a hypothetical modifying gene and HCSMA.
The more consistent behavior of HCSMA in Briggles
suggests that the effect of the “modifying factor” was
eliminated (or, alternately, did not express itself). Modifying genes might be very important for survival in the
presence of HCSMA.
The other hypothesis for the HCSMA phenotype in
Brittany spaniels involves a multilocus-threshold model
[21). The studies of Wright [23,24} on digit number in
guinea pigs serve as prototypes for this sort of analysis.
He observed the development of a fourth toe on the
372 Annals of Neurology
Vol 15 No 4
April 1984
hind foot and concluded that at least three factors (possibly four) were required and that the phenotype
reflected physiological thresholds. More data will be
needed to analyze our pedigrees in this fashion, but the
analysis should be simplified because we can begin with
a single autosomal dominant locus.
Analysis of similarities between HCSMA and human neurodegenerative disorders is complicated in
many cases by diagnostic imprecision. Some of the
pathological changes in HCSMA are similar to those
seen in ALS in adults [4,10, 17). Approximately 10 to
15% of ALS occurs as an autosomal dominant trait [1,
81, but most of the other cases are either sporadic or
otherwise genetically unclear [1 11. Homology of
HCSMA with the infantile and childhood forms of
spinal muscular atrophy is even more complicated, because of difficulties with classification that cannot be
resolved here. There are likely at least several (perhaps
many) genetic loci related to spinal muscular atrophy in
humans. The most useful observations in humans will
probably be made in large kindreds in which the
phenotype is well defined. Unfortunately, such observation is not always possible, especially with recessive
disorders and smaller families. The identification of
molecular markers that segregate with clinical phenotypes should provide an important adjunct to solving
this problem of delineation.
Although several clinical and pathological descriptions of human autosomal dominant neurological diseases are available [l5, 18, 201, they provide little insight into pathogenesis. Several mechanisms have been
proposed for diseases of this type [2}, but no primary
biochemical defect has yet been established. Recent
studies of dogs with HCSMA have demonstrated distinctly reduced slow z o n a l transport [9] that presumably is related to the clinical neuropathy. These physiological observations and the basic genetic data suggest
that the dominant phenotype in HCSMA offers an
important model for the study of the pathophysiological mechanisms of degenerative neurological disorders
that has broad relevance for animals and humans.
Supported in parr by grants from the Amyotrophic Lateral Sclerosis
Sociery of America, the H. Burnett Robinson Memorial Grant Fund,
and US Public Health Service Grants NS 10580, NS 14784, NS
15721, NS 18687, and NS RR77-llA. Drs Cork and Griffin are
recipients of Research Career Development Awards NS 00488 and
NS 00450, respectively. Dr Sack has been helped by gifts from Mr
Daniel M. Kelly and Mr and Mrs William M. Griffin, and is a Joseph
P. Kennedy, Jr, Memorial Foundation Scholar.
The authors greatly appreciate the assistance of Lula Winkler, Harold
Scott, Marilyn Pepper, Carla Jordan, Nancy Cook, and Drs Deborah
A. Meyers, Edmund A. Murphy, and Robert J . Adams.
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Sack et al: Inheritance of HCSMA
373
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