Categories: Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 232800 (trait) , 610681 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009295: glycogen storage disease VII

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 1996

Cross-species summary: Also known as Phosphofructokinase Deficiency

Species-specific description: Phosphofructokinase (PFK) deficiency is an inherited enzyme deficiency causing hemolytic crises and exertional myopathy. Genetic tests are available to detect causative mutations, which have beend identical in the English springer spaniel, American cocker spaniel, Whippet and Wachtelhund. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT and updated by IT [April 2022]

Mapping: CFA27

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Smith et al. (1996) identified the causal mutation as "a nonsense mutation in the penultimate exon of the [muscle type phosphofructokinase] M-PFK gene [now called PFKM], leading to rapid degradation of a truncated (40 amino acids) and therefore unstable M-PFK protein". The single base pair mutation (G2228A) is identical in the English springer spaniel, American cocker spaniel and Whippet (Gerber et al., 2009). Inal Gultekin et al. (2012) reported a different mutation (a point mutation (c.550C>T; p.Arg184Trp) in the same gene as being causative in Wachtelhund dogs.

Clinical features: Presenting signs include muscle cramps, exercise intolerance, and a mild increase in creatine kinase. Affected dogs can also present in hemolytic crisis with hemoglobinuria and bilirubinuria after excessive excitement, exercise, or hyperthermia. During a crisis, the dog can develop severe anemia, icterus, fever, lethargy, and anorexia. This anemia is regenerative, usually resolving within several days. Affected animals have a normal life span, usually maintaining a normal PCV but persistent bilirubinuria and reticulocytosis. Variable muscle wasting, hepatosplenomegaly, and increased total body iron stores have also been reported (Gerber et al., 2009).

Pathology: PFK, a cytosolic enzyme in the anaerobic pathway, is composed of three subunits: muscle (M-PFK), liver (L-PFK), and platelet (P-PFK) types. These subunits are present in different proportions in different tissues. Affected dogs lack PFK in skeletal muscle, and have only 20% of normal PFK activity in erythrocytes, which is from L-PFK and P-PFK expression (Gerber et al., 2009). Their PFK-deficient erythrocytes have hemoglobin with high oxygen affinity that helps to compensate for transient but severe anemic episodes (Skibild et al., 2001). Hemolytic crises in affected dogs are precipitated by hyperventilation, hyperthermia, and associated alkalemia, which induce intravascular hemolysis (Skibild et al., 2001).

Prevalence: Canine PFK deficiency has been reported in the USA, the UK, and Europe. Of 600 English Springer Spaniels screened in the USA, 14% were carriers and 6% were affected (Skibild, 2001).

Control: Dogs of breeds or families in which the disease has been reported should be tested prior to pursuing athletic work such as field trials.

Genetic testing: There is a PCR-based test available to detect the mutation in the English springer spaniel, American cocker spaniel and Whippet. A second mutation has been identified in Wachtelhund breed.

Breeds: American Cocker Spaniel (Dog) (VBO_0200038), Deutscher Wachtelhund (Dog) (VBO_0200440), English Cocker Spaniel (Dog) (VBO_0200486), Whippet (Dog) (VBO_0201421).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: