In other species: emu , cattle , pig

Categories: Lysosomal storage disease

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 252920 (trait) , 609701 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Also known as Sanfilippo syndrome type B

Molecular basis: Raj et al. (2020) sequenced "All six exons and adjacent regions of the [comparative candidate] NAGLU gene . . . from six healthy appearing and three affected Schipperkes" and discovered a likely causal variant, namely "an insertion consisting of a 40–70 bp poly-A and an 11 bp duplication of the exonic region preceding the poly-A (XM_548088.6:c.2110_2111ins[A(40_70);2100_2110]) is predicted to insert a stretch of 13 or more lysines followed by either an in-frame insertion of a repeat of the four amino acids preceding the lysines, or a frameshift. The clinically affected Schipperkes were homozygous for this insertion, and the sequenced healthy dogs were either heterozygous or homozygous for the wild-type allele".

Clinical features: Affected dogs show clinical signs of cerebellar disease including ataxia and tremor with adult onset at approximately three years of age (Ellinwood et al., 2003).

Pathology: Egeland et al. (2020) "evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred."

Prevalence: Raj et al. (2020) reported that "Screening of Schipperkes from North America, Europe, Australasia, and Russia revealed carrier dogs in all these regions, indicating the worldwide distribution of the mutant allele".

Control: Raj et al. (2020): "From 2003–2019, 3219 Schipperkes were genotyped. Of these, 1.5% were homozygous for this insertion and found to be clinically affected, and 23.6% were heterozygous for the insertion and were clinically healthy, the remaining 74.9% were homozygous for the wild-type and were also clinically healthy. The number of dogs homozygous and heterozygous for the insertion declined rapidly after the initial years of genotyping, documenting the benefit of a DNA screening program in a breed with a small gene pool."

Genetic testing: The results of 17 years of testing for this variant are reported under the "Control" heading above and presented in detail in Table 2 and Figure 3 of Raj et al. (2020).

Breed: Schipperke.

Associated gene: