Unnamed 11/04/2011

• ScienceDirect - The Lancet : Fabry's disease

  • Fabry's disease
  • X-linked lysosomal storage disorder
  • deficiency in α-galactosidase A.
  • Fabry's disease has been identified in different patient populations who have cardiac, renal, or cerebrovascular disease with no other known causes. Its prevalence in patients with end-stage renal disease who are on haemodialysis ranges between 0·2% and 1·2%; in adult male patients with cryptogenic stroke and male patients with unexplained left ventricular hypertrophy (LVH) or hypertrophic cardiomyopathy it could be as high as 3–4%
  • Deficiency of α-galactosidase A leads to storage of neutral glycosphingolipids, particularly globotriaosylceramid and galactosylceramide,
  • 5–10% of residual enzyme activity seems to be sufficient to prevent clinically significant accumulation of globotriaosylceramid.<!--refPreviewPlaceHolder-->11 JT Clarke, Narrative review: Fabry disease. Ann Intern Med,  146  (2007), pp. 425–433. | | Cited By in Scopus (47)
  • at least partly poor perfusion caused by storage in the vascular endothelium particularly in kidneys, heart, nervous system, and skin alone or in combination with damage from deposits in other cell types
  • Pain and acroparesthesia are believed to be caused by either poor perfusion of the peripheral nerves or lysosomal accumulation of glycosphingolipids in neurons, dorsal root ganglia, and spinal cord,<!--refPreviewPlaceHolder-->¹² which leads to atrophy of the small unmyelinated nerves

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    Figure 1. 

    <!--Comment-->Progression of clinical findings in Fabry's disease with age

  • Cardiac disease is associated with accumulation of globotriaosylceramid in all cellular components of the heart, including cardiomyocytes, conduction system cells, valvular fibroblasts, endothelial cells, and vascular smooth-muscle cells
  • patients with Fabry's disease show a prominent thickening of the common carotid artery intima, abnormalities of cerebrovascular autoregulation and vasoreactivity, and dysfunction of cerebral circulation with substantial cerebral hyperperfusion in the posterior cerebral circulation, all of which seem to have a considerable role in the pathophysiology of neurovascular disease.^{<!--refPreviewPlaceHolder-->  [15]  and <!--refPreviewPlaceHolder-->  [16]}
  • Storage in vascular endothelium leads to vascular occlusion, which leads to glomerulosclerosis and eventually to renal failure.^{<!--refPreviewPlaceHolder-->  [17]  and <!--refPreviewPlaceHolder-->  [18]}  Storage in podocytes is well documented, although it is not completely related to the amount of proteinuria.
  • three consecutive age periods.
  • Early symptoms in children include burning pain in the hands and feet, hypohydrosis, nausea, abdominal pain, postprandial diarrhoea, poor growth, and school difficulties
  • fter age 20 years, these symptoms tend to progress and proteinuria often presents in men.
  • . Other affected organ systems also progress, leading to life-threatening cardiac and cerebrovascular manifestations with substantial morbidit
  •   Cardiac death is most frequent in women, and although the most frequent cause of death in men was end-stage renal failure, cardiac and cerebrovascular complications are more prevalent than previously in the present era of transplants and dialysis.
  • Pain is not only the earliest manifestation of Fabry's disease but also one of the most disabling complications
  • The classic cardiac abnormality is hypertrophic cardiomyopathy rather than restrictive.
  • initially by myocardial hypertrophy and as the disease progresses, interstitial abnormalities and replacement myocardial fibrosis become important.

  • Cardiac manifestations in Fabry's disease

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    • •	<!--listPara-->Valvular disease: valves are thickened and distorted, with mild-to-moderate regurgitation. Changes are most frequently found on left heart valves (mitral insufficiency)

    • •	<!--listPara-->Left ventricular hypertrophy (LVH): concentric remodelling in early stages, which progresses later to concentric hypertrophy, septal and posterior wall thickness

    • •	<!--listPara-->Right ventricular hypertrophy: does not seem to have major functional or clinical consequences

    • •	<!--listPara-->Ischaemia: vasospastic or stenotic coronary artery disease leads to myocardial infarction, angina, and chest pain, particularly in patients with LVH

    • •	<!--listPara-->Electrocardiogram abnormalities: voltage criteria for LVH and repolarisation changes. Short PR interval, bundle branch block, atrioventricular conduction delay, and progressive sinus node dysfunction

    • •	<!--listPara-->Arrhythmias: bradycardia, supraventricular tachycardias, atrial fibrillation, atrial flutter, and cardiac sudden death

  • earliest manifestation of abnormal rhythm is bradycardia
  • frequency of stroke in men aged 25–44 years can be 12 times higher than that expected in the general population,
  • Gastrointestinal disturbance is the second most common symptom reported in childhood and tends to persist into adulthood
  • Symptoms include nausea, vomiting, abdominal pain, and diarrhoea, especially associated with meals.^{<!--refPreviewPlaceHolder-->} 
  • Angiokeratomas (characteristic reddish-purple skin lesions, <!--refPreviewPlaceHolder-->figure 2) are commonly seen at presentation when physicians carefully search for them, but are easily overlooked and rarely associated with substantial medical problems. They will develop in about 40% of male adolescents with classic Fabry's disease at a median age of onset of 14–16 years
  • hey tend to increase in number and size with age, and tend to cluster around the umbilicus and swimming trunk regions
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    Figure 2. 

    <!--Comment-->Typical angiokeratomas

  • Decreased sweating (hypohidrosis) is another common problem in men, which has been attributed to both a main effect on the sweat glands and to autonomic neuropathy. More than 50% of men and 25% of women have proved to have decreased sweating or heat intolerance, or both, in childhood
  • pohidrosis leads to heat intolerance and decreased ability to exercise, and both tend to worsen with age.^{<!--refPreviewPlaceHolder-->  [2]  and <!--refPreviewPlaceHolder-->  [37]}  It might affect employability and limit young patients from participation in sports or other physical activities. Hyperhidrosis (excessive sweating) has also been described. It is frequently exacerbated by stress, fever, and changes in temperature, and typically affects the palms of the hands and soles of the feet. Hypohidrosis is more frequent than hyperhidrosis is and affects more men than women, although hyperhidrosis is more prevalent in women than in men
  • Distinctive corneal opacities (cornea verticillata and a specific diagnostic sign, which is characterised by one or more lines that irradiate from a point near the centre of the cornea) are seen in most patients
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    Figure 3. 

  • Hoigne and others<!--refPreviewPlaceHolder-->⁸¹ reported that the combination of four criteria in patients with LVH at baseline—acroparesthesia or polyneuropathy, anhydrosis, absence of hypertension, and presence of Sokolow criteria for LVH—were useful to distinguish Fabry's disease from other disorders.
  • Pieroni and others<!--refPreviewPlaceHolder-->82 M Pieroni, C Chimenti and F De Cobelli, et al. Fabry's disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol,  47  (2006), pp. 1663–1671. Article | PDF (440 K) | | | Cited By in Scopus (35)⁸² noted that Fabry's cardiomyopathy could be identified with echocardiography by observation of a hypoechogenic line described as a subendocardial binary appearance, which was absent in controls and those with hypertrophic cardiomyopathy.

  • Gold-standard methods to diagnose Fabry's disease

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    • •	<!--listPara-->α-galactosidase A activity in peripheral leucocytes or plasma if leucocyte analysis is unavailable

    • •	<!--listPara-->α-galactosidase A gene sequencing and identification of disease-causing mutation or testing for all known familial mutations

    • •	<!--listPara-->α-galactosidase A gene sequencing and identification of disease-causing mutation or testing for a known familial mutation (α-galactosidase A activity in peripheral leucocytes is not preferred and plasma levels are unreliable)

    • •	<!--listPara-->α-galactosidase A gene sequencing assessing for a known familial mutation

• Calcium Handling in the Failing Heart and SUMO — Weighing the Evidence — NEJM

  • Calcium Handling in the Failing Heart and SUMO — Weighing the Evidence
  • First, extracellular calcium enters the cell through L-type calcium channel
  • resultant increase in intracellular calcium concentration leads to type 2 ryanodine receptor opening and release of calcium from the sarcoplasmic reticulum
  • reversal of these changes occurs during cardiac relaxation (diastole),
  • emoval occurs by means of calcium extrusion through the sodium–calcium exchanger and reuptake of calcium into the sarcoplasmic reticulum through ryanodine receptor 2 closing and, most important of all, through activation of isoform 2a of sarcoendoplasmic reticulum calcium ATPase (SERCA2a)
  • Reduced expression and activity of SERCA2a have been shown in animal models of heart failure and in cardiomyocytes isolated from hearts explanted from patients undergoing transplantation
  • increasing SERCA2a expression is associated with improved inotropy and lusitropy of isolated cardiomyocytes and with improved cardiac function in experimental models of heart failure.
  • levels and activity of SERCA2a in cardiomyocytes are modulated in parallel with the levels of a cytoplasmic protein, small ubiquitin-like modifier type 1 (SUMO1
  • sumoylation appeared to prolong the lifetime of SERCA2a in the cell as well as increase the intrinsic activity of SERCA2a ATPase.

• Ulcerative Colitis — NEJM

  • When inflammatory bowel disease is identified in a new population, ulcerative colitis invariably precedes Crohn's disease and has a higher incidence
  • Among children, however, ulcerative colitis is less prevalent than Crohn's disease
  • A westernized environment and lifestyle is linked to the appearance of inflammatory bowel disease, which is associated with smoking, diets high in fat and sugar, medication use, stress, and high socioeconomic status.13 Inflammatory bowel disease has also been associated with appendectomy.13 Of these factors, only cigarette smoking and appendectomy are reproducibly linked to ulcerative colitis. Smoking is associated with milder disease, fewer hospitalizations, and a reduced need for medications.14 Removal of an inflamed appendix in early life is associated with a decreased incidence of ulcerative colitis,15 whereas the opposite is true for Crohn's disease.
  • Risk loci for ECM1, HNF4A, CDH1, and LAMB1 implicate dysfunction of the epithelial barrier; an association with DAP suggests a link to apoptosis and autophagy; and associations with PRDM1, IRF5, and NKX2-3 suggest defects in transcriptional regulation. In addition, multiple genes in the interleukin-23 signaling pathway overlap in ulcerative colitis and Crohn's disease (e.g., IL23R, JAK2, STAT3, IL12B, and PTPN2)
  • In both ulcerative colitis and Crohn's disease, epithelial cells have a decreased ability to activate suppressor CD8+ T ce
  • Autoimmunity may play a role in ulcerative colitis. In addition to pANCA, this disease is characterized by circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium41; since these are the sites of extraintestinal manifestations in ulcerative colitis, it is possible that cross-reacting antibodies against the colon cause organ-specific damage. Tropomyosin 5, a structural protein, is the putative target autoantigen of the IgG1 antibodies,42 but evidence of classical antibody-mediated autoimmunity in ulcerative colitis is still lacking.
  • In ulcerative colitis, inflammation is characteristically restricted to the mucosal layer, with infiltrates varying in density and composition during active disease or stages of remission
  • Sulfasalazine and 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), given orally, rectally (by means of suppository or enema), or both, represent first-line treatment for ulcerative colitis, with an expected remission rate of about 50%
  • Mild-to-moderate proctitis can be treated with mesalamine suppositories (1 g per day) or enemas (2 to 4 g per day); clinical remission occurs in most patients within 2 weeks, with repeated treatments as needed. If this fails, 5-aminosalicylate enemas (2 to 4 g per day) or glucocorticoid enemas (hydrocortisone at a dose of 100 mg per day, or new preparations such as budesonide or beclomethasone) are a next step.61-63 Patients who do not have a response to rectally administered agents may be given oral glucocorticoids (up to 40 mg of prednisone or its equivalent).
  • Patients with mild-to-moderate ulcerative colitis that is refractory to rectal therapies and to oral 5-aminosalicylate are candidates for oral glucocorticoids or immunosuppressive agents (azathioprine or 6-mercaptopurine);
  • ontinue to require glucocorticoid therapy and for those who do not have a response to it, a good therapeutic option appears to be infliximab
  • Unlike Crohn's disease, ulcerative colitis may respond to probiotic therapy. For example, Escherichia coli strain Nissle 1917 (200 mg per day) is not less effective than 5-aminosalicylate (1.5 g per day) for maintaining remission,80 and the probiotic VSL#3 (3600 billion colony-forming units per day for 8 weeks) in conjunction with 5-aminosalicylate can help induce remission in mild-to-moderate ulcerative colitis

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