Lysosomal Storage Disease Lagotto Romagnolo type (LSD)
Lysosomal storage disease Lagotto Romagnolo type (LSD) is an inherited neurodegenerative disease affecting Lagotto Romagnolo breed. It is a relatively newly discovered disorder and its genetic background has been studied and clarified as collaboration between the University of Helsinki and the University of Bern. Lysosomal storage disease Lagotto Romagnolo type (LSD) is one form of wider group of metabolic disorders known as Lysosomal Storage Diseases (LDSs) which are known to affect humans, dogs, cats and mice. There are around 50 different forms of LSD and they vary among each other in their symptoms, severity and genetic cause. There is one common biochemical characteristic of all LSDs, they are all a result of an abnormal accumulation of substances inside the lysosome.
Symptoms and characteristics
A lysosome is a cell organelle found in most animal cells. They are involved in many metabolic processes, such as degradation of polymers, cell secretion, plasma membrane repair, cell signaling and energy metabolism. They are also considered as ”recycling center” of cells, due to their role in processing unwanted or worn out material in a cell into a substance usable for the cell. This activity is enabled due to activity of lysosomal enzymes and lysosomal autophagy activity. They are known as the autophagy-lysosome pathway and the ubiquitin-proteasome system and their activities are interlinked. When the enzymes are absent or present only in small amounts, or when lysosomal autophagy is aberrant, the processing pathway cannot be proceeded, and the unprocessed material builds up and gets stored and excess in the cell. When the unprocessed material builds up to a certain excess level in the cell, lysosomal storage disease symptoms appear.
Age of onset in affected dogs is variable, between 4 months to 4 years of age. Affected dogs suffer from progressive cerebellar ataxia, and its severity varies among dogs. Cerebellar ataxia in LSD affected Lagotto Romagnolo dogs may be accompanied by abnormal eye movements, known as episodic nystagmus and clumsiness. Behavioral changes have been noticed, such as restlessness, depression and aggression towards people and other dogs. Histological examination reveals cerebellar degeneration and vacuolar changes in different tissues, such as neurons, secretory epithelia and mesenchymal cells that are able to develop into the various tissues. Widespread swelling and accumulation of clear vesicles in the cytoplasm of neuronal cells or central and peripheral nervous system is present.
Lysosomal Storage Disease Lagotto Romagnolo type (LSD) is associated to a mutation of ATG4D gene. This mutation links to an abnormal autophagy-lysosome pathway, causing this neurodegenerative disorder. During researches, it has been established that 12% of Lagotto Romagnolo dogs are carriers for the disorder.
It is inherited as an autosomal recessive disorder. Dog can be clear, carrier or affected. Healthy parents of an affected dog are obligate heterozygotes, and therefore carry one mutant allele. Heterozygotes are carriers and show no symptoms. At conception, each cub has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Kyöstilä K, Syrjä P, Jagannathan V, Chandrasekar G, Jokinen TS, Seppälä EH, et al. (2015): A Missense Change in the ATG4D Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease. PloS Genet 11(4): e1005169. doi:10.1371/journal.pgen.1005169