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FABRY DISEASE:
Fabry disease results from abnormal deposits of a particular fatty substance (called globotriaosylcera-mide) in blood vessel walls throughout the body. The primary defect which allows this to occur is the inherited deficiency of the enzyme, alpha galactosidase A, which is normally responsible for the breakdown of globotriaosylceramide.

Pathophysiology:
A deficiency of the enzyme alpha galactosidase A (a-GAL A, encoded by GLA) due to mutation causes a glycolipid known as globotriaosylceramide (abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, other tissues, and organs. This accumulation leads to an impairment of their proper functions.

The DNA mutations which cause the disease are X-linked recessive with incomplete penetrance in heterozygous females. The condition affects hemizygous males (i.e. all males), as well ashomozygous, and in many cases heterozygous females. While males typically experience severe symptoms, women can range from being asymptomatic to having severe symptoms. New research suggests many women suffer from severe symptoms ranging from early cataracts or strokes to hypertrophic left ventricular heart problems and renal failure. This variability is thought to be due to X-inactivation patterns during embryonic development of the female.

DISEASE INHERITANCE:
Fabry disease is an inherited disorder. The defective gene is on the X-chromosome, which is one of the two chromosomes that determine an individual’s sex. Females have two X chromosomes, one inherited from each of their parents. Males have one X chromosome inherited from their mother and one Y chromosome inherited from their father. A female with Fabry receive one X chromosome with a defective gene and one X chromosome with the normal gene, and thus often has some protection from the major manifestations of the disease. This is not always the case though as there is a high degree of variability in females. Males with Fabry disease receive only one abnormal X chromosome that contains the abnormal gene and thus express the disease.

All male and female children of an affected female have a 50% chance of inheriting the defective gene from their mother. If the father is the one carrying the Fabry gene all female children will inherit the defective gene and all male children will not. The inheritance pattern of Fabry disease is called X-linked inheritance. Fabry disease occurs in all ethnic groups. It is estimated that one person in 40,000 has Fabry disease.

Epidemiology:
FD belongs to a group of at least 50 genetically distinct, biochemically related lysosomal storage disorders. Each disorder is caused by an inborn error of metabolism due to a monogenetic defect specifically resulting in the deficiency of lysosomal enzyme(s). FD is pan-ethnic, but due to its rarity, determining an accurate disease frequency is difficult. Reported incidences, ranging from 1 in 476,000 to 1 in 117,000  in the general population, may largely underestimate the true prevalence. Newborn screening initiatives have found an unexpectedly high prevalence of the disease, as high as 1 in ~3,100 newborns in Italy and have identified a surprisingly high frequency of newborn males with FD (approximately 1 in 1,500) in Taiwan, 86% having the IVS4+919G > A cryptic splice mutation previously found in later-onset cardiac phenotype patients. The intronic IVS4+919G > A mutation was also found in a number of Taiwan Chinese adult patients with idiopathic hypertrophic cardiomyopathy.

Symptoms:
You may notice things like: Fabry disease can lead to more serious problems, especially in men. These can include:
 * Pain and burning in you hands and feet that get worse with exercise, fever, and hot weather     or when you are tired
 * Small, dark red spots    usually found between your belly button andknees
 * Cloudy vision
 * Hearing loss
 * Ringing in the ears
 * Sweating less than normal
 * Stomach pain, bowelmovements right after eating
 * Higher chance of heart attack or stroke
 * Serious kidney problems,including kidney failure
 * High blood pressure
 * Heart failure
 * Enlarged heart
 * Osteoporosis

Diagnosis:
Early onset of FD signs and symptoms warrant prompt diagnosis, particularly because ERT is available. However, recognizing the early manifestations in clinical practice may be challenging due to a variety of reasons. The disease presentation is generally heterogeneous, symptoms may resemble more common diseases, and major renal or cardiac dysfunction is uncommon in pediatric patients. Nowadays, diagnostic delays may still be considerable and patients often have to visit several medical specialists before a correct diagnosis is made. Recent data showed that the overall diagnostic delays were ~15 years for both genders. If clinical examination raises a suspicion of FD, appropriate biochemical and/or genetic confirmation is needed.

Enzymatic assay
The demonstration of a deficient activity of α-galactosidase activity in plasma or leukocytes is the reference laboratory method which should systematically be used to confirm the clinical diagnosis of FD in males in whom the result will be conclusive. Plasma assay may occasionally lead to false diagnosis and should be confirmed by a leukocyte assay. In contrast, affected girls and adult females may have their enzyme activity falling within the normal range. Therefore, all females should have their status determined by genotyping (analysis of the GLA gene mutation).

A fluorimetric method that uses filter paper cards containing dried blood spots instead of the leukocyte pellet as the enzyme source was recently introduced for enzymatic diagnosis, allowing storage of the samples for up to 6 months due to stability of the enzyme.

Globotriaosylceramide measurement
Plasma Gb3 has also been proposed and used in the biochemical diagnosis of FD, but this method is time-consuming and, in females, plasma Gb3 levels are generally lower than in males and usually in the normal range.

Urinary Gb3 is a more reliable marker allowing diagnosis in the majority of both male and female patients. However urinary Gb3 is not elevated in some patients with late-onset variants and/or particular mutations in the GLA gene (p.Asn215Ser).

The analysis of tissue glycolipid composition and the use of atmospheric pressure photoionization mass spectrometry (APPI-MS) for the analysis of Gb3 molecular species and MALDI-TOF imaging of biomarkers  are not done routinely and are confined to research laboratories.

B. Genotyping
In female heterozygotes, a-galactosidase activity may be within the normal range  and therefore, the definitive diagnostic confirmation should be made by genetic analysis in suspected cases .The publication of the complementary (cDNA) and genomic DNA sequences of the GLA gene (Genbank X14448) has paved the way towards understanding of the molecular basis of FD. Direct molecular analysis is easy because of the small size of the gene and allows the precise characterization of the mutation of the GLAgene. A method that uses filter paper cards containing dried blood spots instead of the leukocytes pellet as the source of DNA was recently developed for sequencing, allowing genotyping from a dried blood spot on filter paper to confirm enzymatic diagnosis  .

Denaturing high-performance liquid chromatography (DHPLC) has been shown to be useful as a screening method. Since direct sequencing limited to exons may miss deletions, the use of Multiplex Ligation-dependent Probe Amplification (MLPA) has been recommended in cases where a decreased enzyme activity is not associated with the identification of a pathogenic point mutation.

C. Screening
Screening individuals with a family history of FD or newborn screening programs are the only practical ways of identifying patients before the development of symptoms. Moreover, screening of patients in high risk groups who may be exhibiting late-onset symptoms of FD but who have not been diagnosed may be key in optimizing the management of disease in these patients.

Any screening requires a reliable and preferably rapid and low-cost method. Measurement of the accumulated urinary Gb3 has been proposed, but its reliability as a biomarker of FD, particularly in females, is unproven. Screening of at-risk groups is often conducted by measuring plasma a-galactosidase A activity, but clinicians should be aware that this can fail to detect all cases of FD. Identification of the deficient enzyme activity in dried blood spots (DBS) may be a more reliable method of screening for FD and this approach has been validated in males  but fails to detect about one third of heterozygous females.

Light microscopy
The observation of biopsies with light microscopy does not usually contribute a great deal to diagnosis but lipid staining of kidney biopsies can reveal storage cells within glomeruli and, when electron microscopy (EM) is not being done or not available, semi-thin sections stained with toluidine blue or Masson's trichrome can allow diagnosis. However, given the number of false negatives and the non specificity of the results, this invasive procedure should not be used for diagnostic purpose.

Electron microscopy
Ultrastructural studies of endomyocardial and kidney biopsies can reveal lysosomal storage in cardiomyocytes or in a variety of kidney cellular types, respectively. The ultrastructural appearance of the inclusions is of whorled layers of alternating dense and pale material ('zebra bodies' or myelin figures). However, due to the invasive nature of the procedure and the availability of reliable biochemical or molecular methods, these procedures should be considered only in the rare instances where there is residual α-galactosidase A activity in males or doubts on the causality of a DNA sequence change in females. Skin biopsy observed by EM may be a useful additional diagnostic test when carefully interpreted by an expert pathologist. However, acquired metabolic disorders, such as the one induced by chloroquine therapy, may result in storage of ultrastructurally similar inclusions in many of the same cells as FD, leading to erroneous interpretation. In addition, skin biopsies are often normal in heterozygous females and therefore not of great utility.

Biomarkers:
One of the most urgent research needs is for (a) reliable and validated biomarker(s) with which to assess disease progression and treatment response. Ideally, measurement of such (a) surrogate marker(s) would involve non-invasive testing. Although various imaging techniques have shown promising results, the clinical relevance of what they reveal in patients with FD has yet to be evaluated for its correlation with clinical endpoints. There is currently no proper plasma or urinary biomarker for FD.

Mildly elevated plasma chitotriosidase levels have been reported in male patients but not in heterozygous females.

Globotriaosylsphingosine or lyso-Gb3 has been reported to be elevated in FD patients. This analyte is elevated in the plasma of hemizygous males and to a lesser extent in that of adult females with classical FD and lyso-Gb3 appears interesting to monitor enzyme replacement therapy. Lyso-Gb3 was shown to be an independent risk factor for the development of cerebrovascular white matter lesions in male patients with FD while, in females, plasma lyso-Gb3 concentration correlated with overall disease severity.

Lyso-Gb3 could be a potential biomarker since plasma lyso-Gb3 level in Fabry patients who had received ERT was shown to be elevated at baseline and to fall more dramatically on ERT than that of Gb3. Urinary lyso-Gb3 may also prove a potential biomarker. Lyso-Gb3may have a role in glomerular injury in FD by promoting the release of secondary mediators of glomerular injury (Transforming growth factor-beta1 (TGF-β 1) and the macrophage inhibitory factor receptor CD74) common to diabetic nephropathy.

Sphingosine-1-phosphate (S1P) was recently identified as a biologically active growth-promoting factor involved in cardiovascular remodelling in both males and females with FD. Male patients had significantly higher plasma S1P levels compared with healthy controls. Moreover, there was a strong correlation between plasma S1P levels and LVM index, and increased common carotide artery IMT in patients with FD. Sphingosine-1 phosphate has been shown to induce in vitro vascular smooth muscle cells proliferation by a variety of signal transduction pathways.

In the interest of future research, biobanking of plasma, serum and urine samples remains highly recommended in all patients affected with FD prior to initiation of ERT.

TREATEMENT:
Pain and discomfort -

episodes of pain are nearly always linked to certain triggers, such as exposure to heat, temperature changes, sun exposure, exercise, and fever. The patient must learn to avoid these pain triggers.For patients with severe and    frequent episodes of pain, the doctor may prescribe an anticonvulsant,     such as carbamazepine (Tegretol, Tegretol XR, Equetro, Carbatrol) or     diphenylhydantoin (Dilantin). They should be taken daily.

Enzyme replacement therapy (ERT) 

- ERT is a medical treatment that replaces an enzyme which is either absent or deficient in patients.In Fabry disease patients' cases, the missing enzyme is alpha galactosidase A (a-GAL A).

There are two recombinant GLA preparations for ERT on the market today:

1. agalsidase alfa (Replagal, Shire Human Genetic Therapies, Cambridge, MA, 0.2 mg/kg per infusion).

2. agalsidase beta    (Fabrazyme, Genzyme Corporation, Cambridge, MA, 1 mg/kg per infusion).

In the USA, only Fabrazyme is FDA approved. Genzyme Corp. writes on its website "The lowering of GL-3 suggests that Fabrazyme may improve how Fabry disease affects your body; however a relationship of lower GL-3 to specific signs and symptoms of Fabry disease has not been proven."

ERT has one serious drawback - it is extremely expensive.

What is the life expectancy for somebody with Fabry disease?

Patients who are diagnosed early and can receive treatments promptly have longer lifespans. According to the Genzyme Corporation, new treatments have lengthened life expectancy from 41 to 50 years.

Researchers published an article in Genetics in Medicine saying that "The life expectancy of males with Fabry disease was 58.2 years, compared with 74.7 years in the general population of the United States. The life expectancy of females with Fabry disease was 75.4 years, compared with 80.0 years in the United States."

REFERENCES:
http://www.webmd.com/a-to-z-guides/fabry-disease#1

http://www.uptodate.com/contents/treatment-of-fabry-disease

http://www.fabry.org/fsig.nsf/pages/fabry

https://www.ncbi.nlm.nih.gov/books/NBK11605/

https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-30