Dr. Struk Reports on PXE-Related
Cardiovascular Manifestations

Listen

Click to listen (3 MB)

As written by Dr. F. Benham, L. Austin, & Dr. G. Jolly

Disorder & Epidemiology
PXE is a heritable systemic disorder affecting the elastic tissue, characterized by clinical manifestations, typically first in the skin, then in the eyes and cardiovascular system. The development of the disorder involves accelerated aging of the organ systems.

PXE is prevalent in approximately 1 in 50,000 to 1 in 100,000, and has no racial predilection. Although it has a mean onset age of 13 years and has been diagnosed as young as 2 years old, it is generally under-diagnosed.

 

PXE Cardiovascular System
The PXE patient may acquire coronary artery disease, endocardial thickening or mitral valve prolapse.

Peripheral artery disease can affect carotid arteries, gastrointestinal arteries, or arteries of upper and lower extremities. Small vessel disease may affect the brain, the gut or the kidneys for example.

 

PXE Cardiovascular Phenotype
The defining physical characteristics or appearance of PXE (its phenotype) affect a fraction of patients. Identifiable characteristics include:
§ Intermittent claudication (20-30% of patients)
§ Hypertension, angina pectoris, heart attacks, stroke (20%)
§ Gastrointestinal hemorrhage (5-13%)

Intermittent claudication and angina pectoris in PXE become prevalent 10 to 20 years earlier than in the general population.

 

PXE Pathology
Calcification of elastic fibers (above left), increases in the elastic fibers of the skin's elastic tissue (above right) and increases in sugars (glycosaminoglycans) commonly found on the surface of cells in the eyes, connective tissue and heart valves, are responsible for the development of PXE phenotypes. Calcification of elastic fibers, shown as the dark "spots" of calcium (above right), accumulate gradually leading to loss of function and the eventual destruction of the fiber.

PXE IVUS
The build up of calcium in blood vessels can be observed using intravascular ultrasound (right).

PXE Mutation Analysis
Mutations cause loss of protein function. Previous investigations have examined the molecular genetics of PXE and the type of frequency of mutations including a paper (see research abstract published in this newsletter):
Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, Ramesar RK, Lebwohl M, Hohl D, Neldner KH, Lindpaintner K, Richards RI, Struk B. "Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6." Hum Mutat. 2005 Sep;26(3):235-48.

This investigation involved 89 PXE-affected individuals belonging to 81 families and representing 170 distinct PXE chromosomes. Of these individuals there were:
§ 61 families (75%) with PXE in a sibling pair of 1 generation (recessive inheritance)
§ 11 families (13.5%) with PXE in 1 person of a single generation (sporadic inheritance)
§ 9 families (11%) with PXE either in first degree cousins, or two or three family generations (possible dominant inheritance).

Mutation Detection Rate
Potentially disease causing mutations were identified in 97% of the disease chromosomes analyzed, including one disease causing mutation found in all 89 patients examined.

Mutation Spectrum & Distribution in ABCC6
In the 170 PXE chromosomes identified so far, the following mutations were recorded (illustrated in the figure below):
§ 5 distinct large deletions
§ 32 mis-sense mutations
§ 8 non-sense mutations
§ 1 small insertion
§ 7 small deletions
§ 6 splice site mutations

 

The five most frequent mutations account for close to 50% of mutations. The following table of the founder alleles was published in the research article.

 

PXE From Bench to Bedside
Examining the genetic mark up of the individuals in the study (their genomes) in the current set of families reveals two things. First, all affected individuals according to category I diagnostic criteria always carry two mutation alleles (homozygotes, compound heterozygotes). Second, all affected individuals according to category II diagnostic criteria always carry one mutation allele (heterozygotes).

Homozygotes and compound heterozygotes show the full expression of the disorder according to category I diagnostic criteria:
§ Characteristic flexural skin lesions
§ Elastic fiber calcification of lesional skin
§ Ocular disease in adults (retinal hemorrhages with subsequent central visual field loss).

Heterozygotes can show the expression of a forme fruste of PXE that is characterized by category II diagnostic criteria, but not by long-term complications of the disorder:
§ Angioid streaks
§ Elastic fiber calcification of non-lesional skin
§ Family history of PXE in first degree relatives
§ No retinal bleeding and no central visual field loss.

Therefore, PXE (full phenotype expression with long term complications) is solely recessively inherited. This finding has profound consequences for the correct genetic counseling of families with PXE.

Bench to Bedside Conclusions
The Famillial PXE mutation analysis in ABCC6 that was undertaken has enhanced and refined the clinical diagnostic criteria of the disorder. It has demonstrated a recessive-only mode of inheritance of the full phenotype expression against the forme fruste. And therefore, it has allowed early individual risk prediction with regard to potential long-term disabling disease complications.

Simply, molecular analysis of PXE confirms that:
§ The skin tells it all.
§ You see it or you don't.
§ However, the clinically blind will be safely guided by molecular tools.

The study has established that there is no PXE inheritance to the next generation through a single parent.

Personal Cardiovascular Risk Control
It is important for a PXE patient to adjust her lifestyle to minimize cardiovascular risk factors including regular monitoring for cardiovascular disease manifestations of PXE. To reduce the impact of PXE, an affected individual should aim to keep the body weight within normal range (body mass index, BMI, of less than 26 for males and 25 for females). Regular exercise and a healthy diet are also important mitigations.

To calculate your BMI :
1. Measure your body weight in kilograms (kg).
2. Measure your height in centimeters (cm), divide it by 100 to get your height in meters (m) and square it (mxm = m^2).
3. Divide your weight (kg) by the calculated square meters of your height (m^2).

BMI = body weight (kg) / [height (m)]^2

You can also use the chart (nomogram) below to determine your BMI. Place a ruler between the body weight in kilograms or pounds (on the left-hand line scale) and the height in centimeters or in inches (on the right-hand scale). The BMI is read from the middle of the chart and is in metric units.

Dr. Struk is interested in getting a sense of the BMI of PXE patients, so please email your current BMI to him at bstruk@mdc-berlin.de or mail it by post to the NAPE office. Thank you.

 

Professional Medical Cardiovascular Risk Management
A physician providing care to a PXE patient should ensure the following levels are tested annually:
§ Cholesterol (HDL, LDL, VLDL, Chylomicrons)
§ Triglycerid
§ Lipoprotein a [Lp (a)]
§ Homocystein
§ C-reactive Protein

Regular cardiological monitoring should include annual echocardiography and stress testing. In addition, 24-hour blood pressure monitoring should be conducted twice a year. Diabetes mellitus is an additional risk factor that requires testing and careful management if tested positive.

There is no causal treatment available for PXE. Treatment of hyperlipidemia is recommended to keep low-density lipoprotein (LDL) below 100 mg/dl. High blood pressure should also be treated with blood pressure lowering drugs.

______________________

Please refer to the original research article for more detailed medical information. Hum Mutat. 2005 Sep; 26(3):235-48. You can also request a copy of this article by email from the NAPE office ( NAPEStLouis@sbcglobal.net).