446 Canine Sports Medicine and Rehabilitation
was a highly significant association between
homozygosity for the SOD1:c.118A allele and
the DM phenotype in Pembroke Welsh Corgis
and also in four other dog breeds: Boxer,
Chesapeake Bay Retriever, German Shepherd
Dog, and Rhodesian Ridgeback. Mutations in
the SOD1 gene are known to cause some forms
of familial amyotrophic lateral sclerosis (ALS or
Lou Gehrig’s disease) in humans. ALS, the most
common adult motor neuron disease, is charac
terized by loss of motor neurons causing stiff
ness and slowing of muscle movements,
difficulty speaking and swallowing, muscle
atrophy, and severe weakness.
Not all SOD1:c.118A homozygote dogs
develop clinical signs. Initially DM appeared to
be an autosomal recessive disease with incom
plete penetrance, whereas most human SOD1
mutations in human ALS are autosomal domi
nant. Thus, homozygosity for the E40K mutation
in SOD1 is a major risk factor for canine DM. The
DM‐associated SOD1:c.118A allele has been
detected in over 100 different dog breeds and
mixed breeds; thus is widespread in the canine
population (Zeng et al., 2014). The mutant allele
appears to be very common in some breeds
(Zeng et al., 2014) and DM is considered a rec
ognized health issue by the breed club health
committees (see the AKC Canine Health
Foundation website: http://akcchf.org/)..) More
recently, DM has also been histopathologically
confirmed in a few heterozygous dogs (Zeng et
al., 2014). The occurrence of DM in a heterozy
gote seems plausible since most human SOD1
mutations cause dominant ALS. Nonetheless,
the age at onset for many dogs has exceeded the
mean life expectancy of dogs, indicating that
DM has an age‐related, incomplete penetrant
mode of inheritance. Recently, Ivansson and col
leagues (2016) reported a modifier locus within
the SP110 nuclear body protein (SP110) on
canine chromosome 25 that affects risk and age
of onset of DM in Pembroke Welsh Corgis
SOD1:c.118A homozygotes and is associated
with altered changes and expression in the gene
isoform of SP110 that may be relevant to disease
progression.
A second SOD1 mutation (c.52A > T), predict
ing a T18S missense mutation that was homozy
gous, has been identified in an affected Bernese
Mountain Dog (Wininger et al., 2011). This
mutant allele appears to be restricted to the
Bernese Mountain Dog breed but is less com
mon than the c.118A allele (Zeng et al., 2014). In
addition, a few c.52 T + c.118A compound hete
rozygous Bernese Mountain Dogs with DM
have been identified (Pfahler et al., 2014; Zeng et
al., 2014). This finding serves as a reminder that
direct DNA tests indicate the presence or absence
of disease‐causing alleles but cannot be used to
rule out a diagnosis because other sequence vari
ants in the same gene or in a different gene might
produce a similar disease phenotype.Clinical spectrumDogs with DM follow a stereotypical pattern of
clinical signs that initially begins with an asym
metrical UMN pelvic limb paresis and general
proprioceptive ataxia, which progresses to LMN
paraparesis and then spreads to involve the tho
racic limbs and brainstem. The homogeneous
progression represents degeneration of the sen
sory and upper and lower motor neurons.
Clinical presentation has been categorized into
four clinical disease stages (Coates & Wininger,
2010). Clinical signs emerge as an asymmetrical
spastic paraparesis and general proprioceptive
ataxia (stage 1), progressing to nonambulatory
paraparesis/paraplegia with pelvic limb LMN
signs within 1 year from disease onset (stage 2).
Neurological deficits progress to include tho
racic limb weakness (stage 3) followed by flaccid
tetraplegia, generalized muscle atrophy, and
brainstem dysfunction (stage 4) (Coates et al.,
2007; Awano et al., 2009; Coates & Wininger,
2010; Shelton et al., 2012; Ogawa et al., 2014). As
LMN signs become more profound in terminal
disease, dogs often have difficulty swallowing
and barking and lose respiratory function
(Awano et al., 2009; Ogawa et al., 2014).Early disease (upper motor neuron signs)
The earliest clinical signs of DM are general
proprioceptive ataxia and mild spastic paresis
in the pelvic limbs. Worn nails and the appear
ance of asymmetrical pelvic limb lameness are
common. At disease onset, asymmetry of signs
and spinal reflex abnormalities consistent with
UMN paresis (T3–L3 spinal cord segments)
are commonly reported. Patellar reflexes may
be normal or exaggerated to clonus; however,
hyporeflexia early in the course of the disease has
also been reported (Griffiths & Duncan, 1975).