Difference between revisions of "Fabry Disease 2012"
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| − | == |
+ | == Genetic Background == |
| + | === Inheritance === |
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| − | [[File:Alpha GAL A.png|200px|thumb|right|The protein encoded by the Fabry-associated GLA gene: α-Galactosidase A]] |
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| + | [[File:fabry_inheritance.jpg|400px|thumb|right|Mode of inheritance for a X linked disease like Fabry]] |
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| + | Fabry Disease is inherited in an X-linked manner. Thus there is a 50% change for an affected or a carrier female to pass on Fabry Disease to any of her offspring. Any of her male children will be affected, her female children are obligate carriers and can be affected. |
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| + | Due to the fact that males only have one X chromosome, they do not pass on the disease to any of their male offspring, but all of their female children are obligate carriers and may even be affected. |
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| − | The Fabry disease is a rare X-linked lysomal storage disease. It, or more precisely its symptoms, was first described in 1898 by the german dermatologist Johannes Fabry and independently by William Anderson in the same year. The ICD-10 classifies it as E75.2, which represents 'Other sphingolipidosis' in the group of 'Disorders of sphingolipid metabolismand other lipid storage disorders'. This is, by the way, the same classification as for the [[Gaucher_Disease|Gaucher's disease]]. |
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| + | (see picture on the right) |
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| − | Alternative names include: |
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| − | * Anderson-Fabry disease |
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| − | * Alpha-galactosidase A deficiency |
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| − | * Angiokeratoma corporis diffusum |
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| − | * Ceramide trihexosidosis |
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| + | <br style="clear: both" /> |
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| − | == Phenotype == |
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| − | [[File:fabry_symptoms.jpg|200px|thumb|left|Symptoms, early and late onset]] |
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| − | [[File:heart_attack_stroke.jpg|200px|thumb|right|Built up Gb3 and glycosphingolipids may lead to heart attack and stroke]] |
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| − | As almost each family has its own [http://www.medterms.com/script/main/art.asp?articlekey=5048 private mutation], phenotypes of affected persons can be very variable. In general, with increasing age symptoms become more severe. This effect is due to more and more accumulated glycosphingolipids that cannot be converted by the dysfunctional enzyme. The built up globotriaoslyceramide (Gb3) and related glycosphingolipids in the lysosomes, tissues, blood vessels and organs lead to a malfunction of major organs in the body starting at an age of 30 - 35 (see picture on the right). Thus untreated patients die approximately 10 - 20 years early (females and males, respectively). |
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| + | == Genomic Characteristics == |
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| + | [[File:Fabry Chromosome X.png|200px|thumb|right|The human X-Chromosome. The location of the GLA gene is highlighted in orange.]] |
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| + | The enzyme [[Alpha-galactosidase|α-galactosidase]] is encoded by the gene GLA which is located on the long arm of X chromosome at the locus Xq22.1 (100,652,778 – 100,663,000) (see the figure on the right). It consists of seven exons without any alternate splicing sites and is transcribed on the reverse strand. |
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| + | [[File:Gla Exons.png|600px|thumb|left|The human GLA gene. The green boxes represent the exons. Note the reverse transcription direction.]] |
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| − | |||
| − | |||
| − | |||
| − | === Symptoms (onset) === |
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| − | ==== Childhood ==== |
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| − | * Acroparesthesia (Numbness in extremities) |
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| − | * Hypohidrosis (decreased sweating) |
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| − | * Cornea opacity |
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| − | |||
| − | Acroparesthesia is signaling the clinical onset of Fabry Disease. It is caused by deposited glycosphingolipids in the small blood supplying vessels of the peripheral nerves. |
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| − | Another very typical symptom for Fabry Disease is the whorled streaks and cloudiness of the eye (cornea opacity) resulting from deposits of granular material on the posterior lens capsule. |
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| − | |||
| − | ==== Adolesence ==== |
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| − | * Gastro Intestinal Manifestation - GIM (nausea, vomitting) |
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| − | * Angiokeratoma |
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| − | * Depression |
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| − | * Heat/cold intolerance |
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| − | * Fatigue |
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| − | |||
| − | The GIM results from accumulated Gb-3 in small intestinal vessels and autonomic ganglia of the intestinal. Eventually this often leads to a weight loss of the patient. From early stages on psychosocial manifestations like depression and fatigue lead to a degression of life quality. |
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| − | In a study [[http://www.ncbi.nlm.nih.gov/pubmed/15025723 Whybra et al 2004]] the occurence of angiokeratomas correlated with the severity of Fabry disease and its systemic manifestation. |
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| − | |||
| − | ==== Adulthood ==== |
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| − | * Renal Disease |
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| − | ** Proteinuria (excess of serum proteins in the urine) |
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| − | ** Progressive renal insufficiency |
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| − | ** End-stage renal disease |
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| − | * Cardiac Disease |
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| − | ** Hypertension (high blood pressure) |
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| − | ** Cardiomyopathy |
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| − | * Central Nervous System Disease |
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| − | ** Headache |
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| − | ** Stroke |
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| − | ** Ischaemic cerebrovascular events |
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| − | ** Binswanger’s Disease (Vascular dementia) |
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| − | |||
| − | According to [http://www.ncbi.nlm.nih.gov/books/NBK11586/ FOS], the most common cause of death were renal failure (males) and cerebrovascular disease (females), whereas [http://www.ncbi.nlm.nih.gov/pubmed/19745746 Waldek et al] claim that the principal cause of death is cardiovascular disease. Most of these diseased patients had received a kidney transplant. |
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| − | Again, all these symptoms are in consequence of progressive glycosphingolipid deposition mostly in vessels and in the lysosomes. |
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| − | |||
| − | === Atypical variants === |
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| − | It is believed that late onset variants mostly with specific mutations are underdiagnosed, because of the missing typical early onset symptoms like acroparesthesia and cornea opacity. According to [http://www.ncbi.nlm.nih.gov/pubmed/16298216 Rolfs et el.] patients with these variants in the majority of cases have missense or splicing mutations leading to a residual α-galactosidase A enzyme activity. |
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| − | |||
| − | '''Cardiac variant''' |
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| − | |||
| − | This variant does not affect patients until their sixth to eighth decade. Usually a hypertrophic cardiomyopathy is diagnosed. Besides from a mild to moderate proteinuria, due to accumulated Gb-3 in the podocytes, no involvement of the kidney is observed. |
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| − | |||
| − | '''Renal variant''' |
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| − | |||
| − | Many patients with this variant are misdiagnosed, because about 80% of them do not show any signs of angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities. However they had moderate to severe left ventricular hypertrophy. |
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| − | |||
| − | === Major manifestations in Classic and atypical Fabry Disease === |
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| − | see [http://www.ncbi.nlm.nih.gov/books/NBK1292/ source] |
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| − | |||
| − | {| class="wikitable" border="1" style="text-align:center; border-spacing:0;" |
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| − | ! scope=col width=200 | Manifestation || scope=col width=270 | Classic || scope=col width=270 | Renal variant || scope=col width=270 | Cardiac variant |
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| − | |- |
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| − | | Age at onset || 4-8 years || > 25 years || > 40 years |
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| − | |- |
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| − | | Average age of death || 41 years || > 60 years || > 60 years |
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| − | |- |
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| − | | Angiokeratoma || ++ || - || - |
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| − | |- |
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| − | | Acroparesthesia || ++ || -/+ || - |
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| − | |- |
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| − | | Hypohidrosis || ++ || -/+ || - |
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| − | |- |
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| − | | Corneal opacity || ++ || - || - |
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| − | |- |
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| − | | Heart || Left ventricular hypertrophy, Ischemia || Left ventricular hypertrophy || Left ventricular hypertrophy, myopathy |
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| − | |- |
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| − | | Brain || Transient ischemic attack || - || - |
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| − | |- |
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| − | | Kidney || End stage renal disease || End stage renal disease || Proteinuria |
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| − | |- |
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| − | | Residual α-Gal A activity || < 1% || > 1% || > 1% |
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| − | |} |
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| − | |||
| − | + = Present, - = Absent |
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| − | |||
| − | === Cross-references === |
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| − | * [http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GLA HGMD] |
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| − | * [http://www.genome.jp/dbget-bin/www_bget?ds:H00125 KEGG Disease] |
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| − | * [http://omim.org/entry/301500 OMIM] |
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| − | * [https://en.wikipedia.org/wiki/Fabry_disease Wikipedia] |
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| − | * [https://www.lsdregistry.net/fabryregistry/ Fabry Registry] |
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| − | * [http://www.ncbi.nlm.nih.gov/books/NBK1292/ NCBI Bookshelf, Fabry Disease, A. Mehta and D. Hughes] |
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| − | * [http://www.ncbi.nlm.nih.gov/books/NBK11586/ Fabry Outcome Survey FOS] |
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| − | * [http://www.ncbi.nlm.nih.gov/pubmed/19745746 Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11:790–6.] |
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| − | * [http://www.ncbi.nlm.nih.gov/pubmed/16298216 Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Lohr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R. Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet. 2005;366:1794–6.] |
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| − | * [http://www.ncbi.nlm.nih.gov/pubmed/15025723 Whybra C, Kampmann C, Krummenauer F, Ries M, Mengel E, Miebach E, Baehner F, Kim K, Bajbouj M, Schwarting A, Gal A, Beck M. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet. 2004;65:299–307.] |
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| − | |||
| − | == Diagnosis == |
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| − | As described in [[Fabry_Disease#Symptoms_.28onset.29|Symptoms]], the diversity of symptoms and especially the lack of early onset ones in the atypical variants make Fabry desease hard to diagnose. Thus it is believed that the number of patients suffering from Fabry Disease is underestimated. |
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| − | |||
| − | === Presumptive Diagnosis === |
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| − | Most cases of Fabry Disease are revealed due to a family member being diagnosed. Also, in a lot of cases observation of early onset symptoms like angiokeratoma and acroparesthesia lead to further testing and eventually to the diagnosis Fabry Disease. Other symptoms that are associated with the disease may also be initiation of further examination. |
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| − | |||
| − | * Observation of symptoms |
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| − | * Family history |
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| − | * Lab findings |
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| − | ** Kidney biopsy (Renal disease) |
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| − | ** Oculist findings (Cornea Opacity) |
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| − | ** MRI (Cardiac disease) |
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| − | ** Echocardiography (Cardiac disease) |
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| − | |||
| − | === Definitive Diagnosis === |
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| − | After a presumptive diagnosis, there is a demand in substantiating this suspicion. The first step would be an enzyme assay. Usually a fluorometric assay is performed, where the difference in the fluorescence of substrate (4-methylumbelliferyl-α-D-galactopyranoside) and product is measured. Thereby, the enzymatic activity of α-Gal A may be measured. Less than 1% of normal enzyme activity is an indication of classic Fabry Disease, more than 1%, but still decreased activity, indicates atypical variants (see section [[Fabry_Disease#Major manifestations in Classic and atypical Fabry Disease|Major manifestations in Classic and atypical Fabry Disease]]). This method is not sufficient for female carrier detection. Due to [http://en.wikipedia.org/wiki/X-inactivation random X Chromosome inactivation] some females have a normal or only little decreased enzyme activity. |
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| − | |||
| − | Thus molecular genetic testing is necessary. This method is also useful for early detection and thus treatment at an early stage if family history is known. Most of the times full '''gene sequencing''' is needed, where the mutation in the GLA gene is detected. Almost 100 % of affected males, but less than 100% of affected females can be detected. Mutations in heterozygous females may not be detected, as well as deletion or duplications in the gene of both sexes (PCR fails in this case). Thus targeted mutation analysis can be performed, if the private mutation of the respective family is known. Otherwise, if a partial or whole gene deletion is suspected, several methods, including quantitativ PCR and [http://en.wikipedia.org/wiki/Multiplex_ligation-dependent_probe_amplification multiplex ligation-dependant probe amplification], can be applied. |
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| − | |||
| − | * Enzyme Assay (Plasma, leukocytes, tissue, urine) |
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| − | * Gene Mutation Analysis |
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| − | ** Sequence analysis |
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| − | ** Targeted mutation analysis |
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| − | ** Deletion testing |
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| − | |||
| − | All listed diagnosis methods may be performed prenatal. |
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| − | |||
| − | === Cross-references === |
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| − | * [http://www.ncbi.nlm.nih.gov/books/NBK1292/ NCBI Bookshelf, Fabry Disease, A. Mehta and D. Hughes] |
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| − | |||
| − | == Treatment == |
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| − | === Symptom management === |
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| − | Usually, Fabry Disease is diagnosed after the onset of symptoms. Thus, manifestations need to be treated individually. Some examples: |
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| − | '''Acroparesthesia:''' The pain in the extremities is reduced by administering agents that interfere with the sodium channel, such as Diphenylhydantoin. |
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| − | |||
| − | '''Renal Disease:''' ACE inhibitors (angiotensin-converting-enzyme inhibitor) are used to prevent proteinuria. If the kidney is already damaged, renal transplantation can correct the organ's function. |
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| − | |||
| − | === Prevention of early symptoms === |
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| − | '''Enzyme Replacement Therapy''' (ERT) should be initiated as soon as possible in each patient. By administering synthetic α-galactosidase A an almost normal metabolism may be ensured. Thus cerebrovascular, cardiac and neurological complications can be prevented. Drawbacks of this treatment are the high costs and the need for an infusion at the hospital every two weeks. |
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| − | === Prevention of late onset symptoms === |
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| − | It is important to undergo prophylaxis of heart, renovascular and cerebrovascular disease. These are essentially the same as for patients without Fabry Disease. Usually the blood pressure and cholesterol need to be normalized. Acetylsalicylic acid may be applied to prevent stroke. Also smoking should be avoided, because it has been shown that obstructive lung disease is more severe in smokers. |
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| − | === Future prospects === |
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| − | '''Substrate Reduction Therapy''' is already an approved therapy for other lysosomal storage diseases like [[Gaucher_Disease |Gaucher Disease]] and thus was also considered as therapy for Fabry Disease by inhibiting the addition of glucose to ceramide (e.g. with a glucosylceramide synthase inhibitor like Miglustat) and therefore blocking the formation of Gb3. |
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| − | '''Gene Therapy''' currently is under research without major longterm benefit. Although the amount of built up glycosphingolipids is reduced up to 60 - 85 % in the major organs after one injection of a viral vector containing a modified α-actin promoter, the Gb3 level had not been significantly reduced after 6 months anymore. [http://www.ncbi.nlm.nih.gov/pubmed/12624185 see] Researcher hope that new self-inactivating lentival vectors may be of help in the future. |
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| − | '''Chaperon Therapy:''' Chaperons assist the non-covalent folding or unfolding and the assembly or disassembly of macromolecular structures. In the body a certain type of these proteins can increase the catalytic activity of some misfolded forms of α-galactosidase A. A hindrance is the large amount of patients with nonsense mutations who are excluded from this therapy of Fabry Disease due to the lack of a detectable residual enzyme. Therefore it is necessary to determine the type of mutation before starting the treatment. |
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| − | |||
| − | '''ERT with α-N-acetylgalactosiminidase''' essentially works equivalent to the usual ERT. It has the benefit of not being immunogen in Fabry Disease patients. In the active site modified α-N-acetylgalactosiminidase is able to convert Gb3. |
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| − | |||
| − | === Cross-references === |
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| − | * [http://www.ncbi.nlm.nih.gov/books/NBK1292/ NCBI Bookshelf, Fabry Disease, A. Mehta and D. Hughes] |
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| − | * [http://www.ncbi.nlm.nih.gov/books/NBK11576/#A1138 Treatment issues] |
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| − | * [http://books.google.de/books?id=GAwHNttd8McC&pg=PR24&lpg=PR24&dq=Substrate%2Breduction%2Btherapy%2Bfabry&source=bl&ots=HP2BxxiD2Z&sig=L1Mkx7M4aPjXVj7Hio28QD4bLxI&hl=de&sa=X&ei=GraST8beEO6Q4gSut9HQDw&redir_esc=y#v=onepage&q=Substrate%2Breduction%2Btherapy%2Bfabry&f=false Google Books: Deborah Elstein, Gheona Altarescu, Michael Beck, "Fabry Disease"] |
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| − | * [http://en.wikipedia.org/wiki/Chaperone_%28protein%29 Chaperone (protein)] |
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| − | * [http://www.ncbi.nlm.nih.gov/pubmed/12624185 Park J, Murray GJ, Limaye A, Quirk JM, Gelderman MP, Brady RO, Qasba P. ,"Long-term correction of globotriaosylceramide storage in Fabry mice by recombinant adeno-associated virus-mediated gene transfer."; Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3450-4. Epub 2003 Mar 6.] |
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| − | |||
| − | == Biochemical disease mechanism == |
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| − | |||
| − | [[File:Fabry-glycosphingolipid biosynthesis globoseries.png]] |
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<br style="clear: both" /> |
<br style="clear: both" /> |
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| − | === Cross-references === |
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| − | * [http://www.genome.jp/dbget-bin/www_bget?hsa:2717 KEGG] |
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| − | * [http://metacyc.org/HUMAN/NEW-IMAGE?type=GENE&object=HS02389 MetaCyc] |
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| − | * [http://www.rcsb.org/pdb/explore/explore.do?pdbId=1r46 PDB] |
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| − | |||
| − | == Genetic Background == |
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| − | |||
| − | === Inheritance === |
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| − | [[File:fabry_inheritance.jpg|400px|thumb|right|Mode of inheritance for a X linked disease like Fabry]] |
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| − | Fabry Disease is inherited in an X-linked manner. Thus there is a 50% change for an affected or a carrier female to pass on Fabry Disease to any of her offspring. Any of her male children will be affected, her female children are obligate carriers and can be affected. |
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| − | |||
| − | Due to the fact that males only have one X chromosome, they do not pass on the disease to any of their male offspring, but all of their female children are obligate carriers and may even be affected. |
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| − | |||
| − | (see picture on the right) |
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=== Reference sequence === |
=== Reference sequence === |
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Revision as of 19:25, 21 April 2012
Contents
Genetic Background
Inheritance
Fabry Disease is inherited in an X-linked manner. Thus there is a 50% change for an affected or a carrier female to pass on Fabry Disease to any of her offspring. Any of her male children will be affected, her female children are obligate carriers and can be affected.
Due to the fact that males only have one X chromosome, they do not pass on the disease to any of their male offspring, but all of their female children are obligate carriers and may even be affected.
(see picture on the right)
Genomic Characteristics
The enzyme α-galactosidase is encoded by the gene GLA which is located on the long arm of X chromosome at the locus Xq22.1 (100,652,778 – 100,663,000) (see the figure on the right). It consists of seven exons without any alternate splicing sites and is transcribed on the reverse strand.
Reference sequence
Reference Sequence of α-galactosidase A from Uniprot entry P06280
>gi|4504009|ref|NP_000160.1| alpha-galactosidase A precursor [Homo sapiens] MQLRNPELHLGCALALRFLALVSWDIPGARALDNGLARTPTMGWLHWERFMCNLDCQEEPDSCISEKLFM EMAELMVSEGWKDAGYEYLCIDDCWMAPQRDSEGRLQADPQRFPHGIRQLANYVHSKGLKLGIYADVGNK TCAGFPGSFGYYDIDAQTFADWGVDLLKFDGCYCDSLENLADGYKHMSLALNRTGRSIVYSCEWPLYMWP FQKPNYTEIRQYCNHWRNFADIDDSWKSIKSILDWTSFNQERIVDVAGPGGWNDPDMLVIGNFGLSWNQQ VTQMALWAIMAAPLFMSNDLRHISPQAKALLQDKDVIAINQDPLGKQGYQLRQGDNFEVWERPLSGLAWA VAMINRQEIGGPRSYTIAVASLGKGVACNPACFITQLLPVKRKLGFYEWTSRLRSHINPTGTVLLQLENT MQMSLKDLL
Mutations
| Mutation type | # of public mutations | # of commerical mutations |
|---|---|---|
| Missense/nonsense | 354 | 441 |
| Small deletions | 74 | 97 |
| Small insertions | 29 | 32 |
| Splicing | 28 | 34 |
| Gross deletions | 16 | 27 |
| Small indels | 8 | 10 |
| Complex rearrangements | 3 | 6 |
| Gross insertions/duplications | 1 | 4 |
| Regulatory | 1 | 2 |
| Repeat variations | 0 | 0 |
| Total | 514 | 653 |
