In other species: domestic cat , taurine cattle , indicine cattle (zebu) , sheep , Japanese quail

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 232300 (trait) , 606800 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Cross-species summary: Also called Pompe disease, Pompe's disease, acid maltase deficiency, and generalised glycogenesis type II. A lysosomal storage disease in which there is a buildup (storage) of glycogen, due to the lack of the enzyme alpha-glucosidase, whose task is to break down glycogen into its constituent glucose molecules. Characterised by poor growth, incoordination, muscle weakness and eventual recumbency.

Species-specific symbol: GSDII

History: This canine disorder was first reported by Mostafa (1970), in a Swedish Lapland dog.

Molecular basis: Adopting the comparative candidate-gene approach (based on similarity of diagnostic signs with humans), Seppälä et al. (2013) sequenced the canine GAA gene (encoding acid α-glucosidase) in "two affected Finnish Lapphunds, their dam and an unrelated healthy 8-year-old Finnish Lapphund as control", revealing a causal nonsense mutation: a "c.2237G>A mutation leading to a premature stop codon at amino acid position 746", i.e. p.W746*. Using a cell line established decades ago from tongue tissue, the authors "were able to establish that one of the originally described Swedish Lapphunds with Pompe disease (born in 1979) was also homozygous for the same c.2237G>A mutation". Exactly the same mutation in the human GAA gene causes the same disease (see the MIM entry above).

Clinical features: Affected dogs exhibit regurgitation and recurrent vomiting of mucus. Constant panting, dyspnoea, dysphonia, and dysphagia are evident at 13 months (Seppälä et al., 2013). Loss of condition, progressive muscular weakness, and exercise intolerance may become apparent (Almodóvar-Payá et al., 2020). Glycogen storage disease II (GSD II) in dogs may lead to decreases in ALP, and increases in ALAT, BUN, and glucose levels (Walvoort et al., 1984). Biochemical studies demonstrated a severe deficiency of acid α-glucosidase activity in heart, skeletal muscle, and liver fibroblasts. Glycogen content was substantially elevated in the heart and skeletal muscle (Walvoort et al., 1982). Haematology shows increases in monocyte count and increases in mean platelet volume at 18 months (Seppälä et al., 2013). Radiographs of affected dogs show dilatation of the oesophagus and cardiac enlargement; ultrasound indicates liver changes (Seppälä et al., 2013). GSD II is often associated with clinical heart disease and myocardial hypertrophy (Walvoort et al., 1984). [IT thanks DVM student Jed Stevens, who provided the basis of this contribution in April 2022]

Pathology: Acid α-glucosidase is responsible for the degradation of glycogen to glucose in lysosomes. Dogs with GSD II are significantly deficient in active acid α-glucosidase, leading to the accumulation of glycogen inside lysosomes of the heart, skeletal muscle, and smooth muscle (Almodóvar-Payá et al., 2020). This excessive glycogen storage may lead to progressive muscular weakness, cardiac hypertrophy, cardio-respiratory failure, and death (Walvoort et al.,1985; Seppälä et al., 2013). A finding unique to GSD II in dogs is the megaoesophagus and its associated symptoms of regurgitation and vomiting (Seppälä et al., 2013). [IT thanks DVM student Jed Stevens, who provided the basis of this contribution in April 2022]

Prevalence: Seppälä et al. (2013) "screened 95 Finnish Lapphunds, 99 Lapponian Herders and 34 Swedish Lapphunds" for the c.2237G>A; p.W746* causal mutation, observing 5%, 2% and zero carriers, respectively. This mutation was not present in 304 dogs from 21 other breeds. The same authors state that they "identified carriers from Lapponian Herders although no affected cases have been reported in this breed".

Breeds: Finnish Lapphund (Dog) (VBO_0200523), Lapponian Herder (Dog) (VBO_0200814), Swedish Lapphund (Dog) (VBO_0201315).
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: