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Lysosomal Storage Disease Lagotto Romagnolo type (LSD)
| Acronym: | LSD |
| Gene: | ATG4D |
| Mutation: | c.1288G>A |
| Inheritance: | Autosomal recessive |
| Sample type: | CHS (Cheek Swab), WBE (Whole Blood EDTA) |
Genetics and characteristics
Lysosomal storage disease Lagotto Romagnolo type (LSD) is an inherited neurodegenerative disease affecting the Lagotto Romagnolo breed. It is a relatively newly discovered disorder and its genetic background has been studied and clarified as a collaboration between the University of Helsinki and the University of Bern. Lysosomal storage disease Lagotto Romagnolo type (LSD) is one form of a 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 from 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.
A lysosome is a cell organelle found in most animal cells. They are involved in many metabolic processes, such as the degradation of polymers, cell secretion, plasma membrane repair, cell signaling, and energy metabolism. They are also considered the ”recycling center” of cells, due to their role in processing unwanted or worn-out material in a cell into a substance used for the cell. This activity is enabled due to the 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 proceed, 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 various tissues. Widespread swelling and accumulation of clear vesicles in the cytoplasm of neuronal cells or central and peripheral nervous systems are present.
Lysosomal Storage Disease Lagotto Romagnolo type (LSD) is associated with a mutation of the ATG4D gene. This mutation links to an abnormal autophagy-lysosome pathway, causing this neurodegenerative disorder. During the research, it has been established that 12% of Lagotto Romagnolo dogs are carriers of the disorder. It is inherited as an autosomal recessive disorder. Dogs 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.
Results Reported As
Test Result |
Interpretation of test result |
CLEAR |
Tested mutation was not detected in animal with „clear“ result. Animal tested as clear has wild-type allele in homozygous state (i.e. two pairs of healthy alleles). It will not develop disease caused by tested mutation.* It will pass only wild-type allele to its offspring. |
CARRIER |
Tested mutation was detected in animal with „carrier“ result. Animal tested as carrier has one wild-type and one mutation allele, it is in heterozygous state. It will not develop disease caused by tested mutation.* It can pass wild-type or mutation allele to its offspring. |
AFFECTED |
Tested mutation was detected in animal with „affected“ result. Animal tested as affected has two copies of mutation alleles affecting the gene. It is likely the animal will experience a genetic disorder due to this mutation.** It will pass only mutation allele to its offspring. |
*Test excludes only tested mutation but not possible unknown mutations or factors that can lead to similar condition/symptoms.
** Potential unknown mutations or multiple other factors can possibly affect the likelihood of experiencing a genetic disorder.
References:
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