Fabry's disease pathophysiology: Difference between revisions
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Genetics | Genetics | ||
*[[Fabry's disease]] follows an [[X-linked recessive]] [[inheritance]] pattern. | *[[Fabry's disease]] follows an [[X-linked recessive|X-linked]] [[inheritance]] pattern. Since it is also manifests in women who are [[heterozygous]] in different severity due to [[X chromosome inactivation]] it being called [[X linked inheritance|X linked recessive disease]] is misleading. | ||
* | *Since its an [[X linked inheritance]] males are [[homozygous]] and pass the disease to all daughters but not son. | ||
* | *Females are [[heterozygous]] with 50% chance of passing the gene to daughter and sons. | ||
* | *Females can present with a varied type of presentation from being [[asymptomatic]] to having severe symptoms like in the classic form of the disease seen in males due to [[X chromosome inactivation|skewed non random X chromosome inactivation.]] | ||
*[[Gene|Gene location]]: [[GLA|GLA gene]] encodes information for [[Alpha-Galactosidase A Deficiency|alpha-Gal-A]] | |||
*[[Locus (genetics)|Locus]]: [[Chromosome X (human)|Long arm of chromosome X]] | |||
*Position: Xq22 | |||
*[[GLA]] has 7 [[exons]] over 12,436 [[Base pairs|base pairs.]] | |||
*Extensive [[Allele|allelic heterogenity]] but no [[Locus (genetics)|genetic locus heterogenity.]] | |||
*[[Mutations]] comprise of [[Missense mutation|Missense]], [[Nonsense mutation|Non-sense point mutations]],[[Splicing (genetics)|splicing mutations]], [[Deletion (genetics)|small deletion]]/[[Genetic insertion|Insertion]], and [[Deletion mutation|large deletions]]. | |||
*585 [[mutations]] have been recorded for [[Fabry's disease]]. | |||
Gross pathology | |||
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==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
Revision as of 17:36, 24 July 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Physiology
- GLA gene - stores information for enzyme alpha- galactosidase.
- Normal function of the enzyme alpha-galactosidase is to breakdown globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) into glucocerebroside in lysosomes which serve as recycling centers.
Pathophysiology
- Fabry disease is an X-linked recessive inherited lysosomal storage disorder that is caused by a deficiency of alpha-galactosidase.
- .
- Alpha-galactosidase is a lysosomal protein responsible for breaking down globotriaosylceramide(Gb3) a fatty substance stored in various types of cardiac and renal cells.
- Mutations to the GLA gene encoding α-GAL may result in complete loss of function of the enzyme.
- When globotriaosylceramide (Gb3) is not properly catabolized, it is accumulated in cells lining blood vessels in the skin, cells in the kidney, heart, and nervous system. As a result, signs, and symptoms of Fabry disease begin to manifests.[1]
- Accumulation of globotriaosylceramide (Gb3) in different tissues leads to cellular death, compromised energy metabolism, small vessel injury, potassium-calcium channel dysfunction in the endothelial cells, oxidative stress, impaired autophagosome maturation, tissue ischemia, irreversible cardiac and renal tissue fibrosis.
- The threshold level of alpha- Gal A is 30-35% of the mean normal. uptodate (16).
Genetics
- Fabry's disease follows an X-linked inheritance pattern. Since it is also manifests in women who are heterozygous in different severity due to X chromosome inactivation it being called X linked recessive disease is misleading.
- Since its an X linked inheritance males are homozygous and pass the disease to all daughters but not son.
- Females are heterozygous with 50% chance of passing the gene to daughter and sons.
- Females can present with a varied type of presentation from being asymptomatic to having severe symptoms like in the classic form of the disease seen in males due to skewed non random X chromosome inactivation.
- Gene location: GLA gene encodes information for alpha-Gal-A
- Locus: Long arm of chromosome X
- Position: Xq22
- GLA has 7 exons over 12,436 base pairs.
- Extensive allelic heterogenity but no genetic locus heterogenity.
- Mutations comprise of Missense, Non-sense point mutations,splicing mutations, small deletion/Insertion, and large deletions.
- 585 mutations have been recorded for Fabry's disease.
Gross pathology