What causes pseudoxanthoma elasticum defect ?

 PSEUDOXANTHOMA ELASTICUM :



Pseudoxanthoma elasticum (PXE) is a genetic disease that causes mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes  and later in blood vessels in the form of premature atherosclerosis.  PXE is caused by autosomal recessive mutation in the ABCC6 gene on the short arm of chromosome 16. 

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.

WHAT ARE THE  SIGNS AND SYMPTOMS OF PSEUDOXANTHOMA ELASTICUM ?

PXE first affects the retina through a dimpling of the Bruch membrane (a thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina), that is only visible during ophthalmologic examinations This is called peau d'orange (a French term meaning "skin of the orange"). Eventually the mineralization of the elastic fibers in the Bruch membrane create cracks called angioid streaks that radiate out from the optic nerve. Angioid streaks themselves do not cause distortion of vision, even if they cross into the foveal area. This symptom is present in almost all PXE patients and is usually noticed a few years after the onset of cutaneous lesions. These cracks may allow small blood vessels that were originally held back by Bruch's membrane to penetrate the retina. These blood vessels sometimes leak, and these retinal hemorrhages may lead to the loss of central vision. Vision loss is a major issue in many PXE patients.



PXE may affect the gastrointestinal and cardiovascular systems. Gastrointestinal bleeding is a rare symptom and usually involved bleeding from the stomach. In the circulatory system, intermittent claudication, a condition in which cramping pain in the leg is induced by exercise, is a prominent feature. At later stages, coronary artery disease may develop, leading to angina and myocardial infarction (heart attack). Cerebral ischemia in PXE is caused by small vessel occlusive disease.

Other rare neurological complications may include intracranial aneurysms, subarachnoid and intracerebral hemorrhages. Usually, pseudoxanthoma elasticum affects the skin first, often in childhood or early adolescence.Small, yellowish papular lesions form and cutaneous laxity mainly affect the neck, axillae (armpits), groin, and flexural creases (the inside parts of the elbows and knees). Skin may become lax and redundant. Many individuals have "oblique mental creases" (horizontal grooves of the chin.


HOW IS PSEUDOXANTHOMA ELASTICUM DIAGNOSIS ?

The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks  in the retina. Criteria were established by consensus of clinicians and researchers at the 2010 biennial research meeting of the PXE Research Consortium. and confirmed at the 2014 meeting. These consensus criteria state that definitive PXE is characterized by two pathogenic mutations in the ABCC6 or ocular findings – angioid streaks > 1 DD or peau d’orange in an individual <20 years of age together with skin findings:

  • Characteristic pseudoxanthomatous papules and plaques on the neck or flexural creases.
  • Diagnostic histopathological changes in lesional skin: Calcified elastic fibers in the mid and lower dermis, confirmed by positive calcium stain

HOW TO TREAT PSEUDOXANTHOMA ELASTICUM ?

Cosmetic surgery to remove excessive skin has been used to improve aesthetic appearance in PXE patients but because of the non-life-threatening nature of these symptoms, should be used with caution.




To limit cardiovascular symptoms, reduction of cardiovascular risk factors through lifestyle changes is recommended. Generally clinicians recommend avoidance of non-steroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen to prevent eye and gastrointestinal bleeding.

Formerly, dietary restriction of calcium was tried with no benefit, and in fact accelerated mineralization in mice. There are a number of potential treatments that are currently being tested or have just undergone testing including magnesium, etidronate, PPi, and tissue-nonspecific alkaline phosphatase inhibitors.

Given that ABCC6 heterozygous mutations result in few symptoms of PXE, this disease is a candidate for gene therapy. Some initial proof-of-principle experiments have been done in mice that have relieved some of symptoms of PXE, but as with all gene therapy treatments, there are many hurdles that must be over come including insuring that the treatment will be long-lasting and reducing the risk of insertional mutagenesis and severe immune reactions


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