Cathepsin-A Related Arteriopathy with Strokes And Leukoencephalopathy (CARASAL) is a rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

that is caused by mutation in a gene ''CTSA'' which is located on a

chromosome 20 Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 66 million base pairs (the building material of DNA) and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was fully sequenced i ...

. This disease is allelic to Galactosialidosis. This disease usually begins with a

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, decreased concentration, abnormalities in gait, lack of inhibition, also it usually presents with

migraine Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

, depression,

vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...

and high blood preasure.

Symptoms

The signs of this disease are:

, mini-stroke,

facial palsy Facial nerve paralysis is a common problem that involves the paralysis of any structures innervated by the facial nerve. The pathway of the facial nerve is long and relatively convoluted, so there are a number of causes that may result in facial ...

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

, depression, problems with concentration and movements,

, difficulty in swallowing, slurring of speech, sicca symptoms, problems with

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...

and drug-resistant hypertension. This condition usually manifest in the third to fifth decades of life.

Cause

CARASAL is caused by mutation of the CTSA which codes enzyme Cathespin A. CTSA gene is located on 20q13.12. This disease is inherited in

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

fashion, which means that mutation of one gene copy is enough to cause the disorder. According to some studies, the c.973C→T (p.R325C)

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

is associated with that disorder.

Pathophysiology

Cathespin A is a lysosomal enzyme which main function is to form complex between

β-galactosidase β-Galactosidase (EC 3.2.1.23, beta-gal or β-gal; systematic name β-D-galactoside galactohydrolase) is a glycoside hydrolase enzyme that catalyzes hydrolysis of terminal non-reducing β-D-galactose residues in β-D-galactosides. (This enzym ...

and Neurominidase 1 in

lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

to protect them from degradation. Also it is known that Cathespin A degrades

Endothelin-1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells, as well as by cells in the heart (affecting contractility) and kidney (affecting sodium handling). The prote ...

and consequently it is known that Endothelin-1 might cause inhibition of oligodendrocyte progenitor cell maturation and remyelination through reactive astrocytes mechanism. As mentioned at the beginning of the article, CARASAL is allelic to Galactosialidosis, although Galactosialidosis is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

disorder.

Diagnosis

CARASAL can be diagnosed by MRI investigation and by confirmation of the mutation in CTSA gene, also CARASAL should be considered in case of: * Middle-age patients with Cerebral Small Vessel Disease (cSVD). * Positive family history of stroke. * Broad, unexplained, infra/supratentorial white and grey matter hyperintensities (a.k.a. bright signals on MRI image). * Neurotological problems.

Treatment

This disease doesn't have a cure, although symptomatic management is available.

Prognosis

It is believed that life expectancy is similar to unaffected person.

History

CARASAL was described in 5 French patients by Herve et al.

References

{{reflist Brain disorders Leukodystrophies Genetic diseases and disorders Cerebrovascular diseases