Mitochondrial DNA haplogroups may influence Fabry disease phenotype.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.

Seborrheic dermatitis and hypertension in adults: a cross-sectional study.

BACKGROUND: Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that shares some features with psoriasis. Previous reports have demonstrated an association between hypertension and psoriasis. Chronic skin inflammation may plays a role in the aetiology of hypertension in both disorders. OBJECTIVE: To evaluate the association between SD and hypertension in an adult large population sample. METHODS: A cross-sectional study was carried out by utilizing the database of Clalit Health Services, a healthcare provider organization for over 4 million enrollees in Israel. All adult patients previously diagnosed with SD were compared with a sample of enrollees without SD regarding the prevalence of hypertension. Patients without SD were frequency matched to SD patients regarding age and sex. Data on other health-related lifestyles and comorbidities were collected. RESULTS: The study included all 9255 patients with SD and 9246 age- and sex-matched patients without SD. The prevalence of hypertension was significantly higher in patients with SD (27.1% vs. 24.7%, P < 0.001, OR = 1.13, 95% CI: 1.05-1.21). A multivariate logistic regression model demonstrated that SD was significantly associated with hypertension after controlling for confounders, including age, sex, socioeconomic status, smoking, diabetes and obesity (multivariate OR = 1.23, 95% CI: 1.12-1.35, P < 0.001). CONCLUSIONS: In this study, an association between SD and hypertension was demonstrated in adults. Many factors can be advocated to explain this association. Genetic predisposition, psychological conditions, lipid abnormalities and chronic inflammation of the skin with a change in cytokine balance should be explored as potential mechanisms.

Systemic complications of esophageal lichen planus.

Lichen planus is an uncommon inflammatory mucocutaneous disorder affecting the skin and its appendages, as well as oral and genital mucosa. Involvement of the esophageal mucosa is rare and causes significant morbidity, with dysphagia and risk of long-term complications, such as esophageal strictures and stenosis. Esophageal lichen planus is an underreported condition in the spectrum of lichenoid tissue reactions, presenting the risk of systemic manifestations. We describe a patient with severe, long-standing esophageal lichen planus, which had led to marked weight-loss, malnutrition syndrome and chronic respiratory distress due to recurrent aspiration pneumonia. Diagnosis was confirmed by the presence of concomitant muco-cutaneous lesions and characteristic endoscopic and histological findings. Systemic therapy with cyclosporine A and micronutrient supplementation led to rapid clinical improvement. Early diagnosis of esophageal lichen planus as well as effective systemic immunosuppressive treatment is crucial in order to prevent short- and long-term complications.

Mutation identification of Fabry disease in families with other lysosomal storage disorders.

Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom FD was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known from other members affected by fucosidosis or mucopolysaccharidosis I Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study shows that the risk for more than one LSDs can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present because of the random X-chromosome inactivation.

Angiokeratoma: decision-making aid for the diagnosis of Fabry disease.

Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene.

Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.

Functional studies of new GLA gene mutations leading to conformational Fabry disease.

Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of alpha-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants in FD patients which lead to alpha-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain. We identified three GLA mutations, c.155G>A (p.C52Y), c.548G>C (p.G183A), c.647A>G (p.Y216C) in as many individuals (two male; one female) and performed in vitro expression studies and Western blot analysis in order to clarify their functional effects. Reduced GAL-A activity and normal or partially reduced mutant proteins were present in all overexpressed mutant systems in which three-dimensional structural analysis showed that the active site was not directly involved. We hypothesize that the three new mutations affect the GAL-A protein, leading to conformational FD. When mutant proteins overexpressed in COS-1 cells and in patients' lymphocytes were tested in the presence of the 1-deoxygalactonojirimicin (DGJ) chaperone, the p.G183A and p.Y216C systems showed increased GAL-A enzyme activities and protein stabilisation while p.C52Y was not responsive. We underline that genetic, biochemical and functional studies are helpful in clarifying the consequences of the missense genetic lesions detected in FD. ERT is the elective therapy for Fabry patients, but it is not always possible to issue the enzyme's active form in all involved organs. Our study endorses the hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects.

Proinflammatory cytokine production in HaCaT cells treated by eosin: implications for the topical treatment of psoriasis.

Psoriasis is a multifactorial skin dermatosis characterized in its classical form by erythematous and hyperkeratotic plaques on extensor surfaces of the body, that in most cases can be managed therapeutically by topical agents. Hyperproliferation and a marked inflammation in both epidermis and dermis are thought to be driven by interaction of activated type-1 T lymphocytes and antigen-presenting cells and keratinocytes that release several proinflammatory and immunomodulating molecules. The aim of this study is to investigate whether tetrabromofluorecin, commonly know as eosin, a classical compound traditionally topically used in psoriasis for its presumed anti-inflammatory activities, is able to modulate the production of TNF-alpha, IL-6 and IL-8 that are recognized as the most active and characterized cytokines in the pathogenesis of this skin disorder. HaCaT cell line was used to verify the effects on epidermal inflammation by eosin at scalar doses after testing the viability of cells. Two different population of cells, one stimulated by IFNgamma and one non-stimulated, were cultivated in presence of tolerable concentrations. The expression and release of IL-6, IL-8, IL-10, and TNF-alpha were analysed by RT-PCR and ELISA, respectively. Our results show that tolerable concentrations of eosin were 0.05%, 0.02%, and 0.01%. The expression and production of TNFalpha, IL-8 and IL-6 were dramatically reduced in presence of eosin 0.05% and 0.02% and the action of eosin was more pronounced on TNF-alpha. In agreement with clinical data, our results show that in presence of tolerable concentrations, eosin seems to influence remarkably the production of three important cytokines involved in the hyperproliferation and inflammatory process, giving a specific explanation of its efficacy and supporting its topical use in the clinical setting.

Exacerbation of pemphigus after influenza vaccination.

Pemphigus is a rare autoimmune disease characterized by flaccid blisters and erosions on skin and mucous epithelia. A critical event in its pathogenesis is production of antidesmoglein antibodies, which mediate the loss of intercellular adhesion in epithelia, leading to blister formation. Multiple environmental factors (ultraviolet radiation, trauma, drugs, infective agents) have been suggested as possible triggers of pemphigus. Occasionally, the disease has been reported to follow viral and bacterial vaccination. We describe a patient who experienced exacerbation of pemphigus shortly after administration of the influenza vaccination on two separate occasions. We review the literature, suggest possible explanations for a causal relationship, and discuss the administration of vaccination to these patients.

Tannic acid induces in vitro acantholysis of keratinocytes via IL-1alpha and TNF-alpha.

The mechanism of acantholysis in pemphigus vulgaris (PV) is an intriguing argument since several chemical mediators are implicated. We previously reported a central role for IL-1alpha and TNF- alpha, both able to regulate complement activation and plasminogen activators. Very little is known about what triggers the disease (drugs, viruses or food). In this study, we evaluate the molecular role of tannins in acantholysis. By HPLC chromatography we measured tannic acid (TA) and gallic acid (GA) in blister fluid of 4 groups of patients divided according to their dietary habits, including a regular diet, a diet rich in tannins, a diet free of tannins, and a group of pemphigus patients. Blister fluid was obtained from patients using a suction blister apparatus. We show that people with a diet rich in tannins have increased tannin metabolites (TA and GA) in the skin in respect to controls (tannin-rich diet: GA = 194.52+/-2.39 nmol/ml; TA = 348.28+/-1.4 nmol/ml versus tannin-Mediterranean diet: GA = 15.28+/-1.63 nmol/ml; TA = 22.81+/-1.68 nmol/ml). PV patients showed similar values to the Mediterranean diet population (PV patients: GA = 95.8+/-1.97 nmol/ml; TA = 199.09+/-4.15 nmol/ml versus Mediterranean diet: GA = 83.53+/-2.35 nmol/ml; TA = 195.1+/-2.50 nmol/ml). In an in vitro acantholysis system using TA and PV-IgG we show that TA 0.1 mM in NHEK culture is able to induce acantholysis. This effect was able to amplify the acantholytic action of PV-IgG in vitro. A blocking study using anti IL-1 alpha and anti TNF-alpha antibodies showed a reduction in TA-induced acantholysis. Taken together, these results suggest that a diet rich in tannins could be a trigger in genetically predisposed patients. If these data are confirmed, a complementary diet poor in tannins may be useful in patients affected by PV.

Atypical multifocal cutaneous leishmaniasis in an immunocompetent patient treated by liposomal amphotericin B.

Multifocal cutaneous leishmaniasis (MCL) is an extremely rare disease in South Europe, and it mainly affects immunosuppressed patients. We report a case of MCL in an immunocompetent patient affected by type II diabetes mellitus that clinically presented with three large ulcers on the legs with a non-linear distribution and several months later with an erythematous-crusty lesion on the left cheek. Diagnosis of leishmaniasis due to Leishmania infantum was formulated by PCR analysis. Given the diffuse and wide lesions, the unresponsiveness to previous local and systemic treatments, a parenteral i.v. therapy with liposomal amphotericin B at a dosage of 3mg/kg/day for 5 days was started and then repeated on the 14th and 21st days, leading to a clear improvement in the clinical picture. The different clinical expression and the evolution of leishmaniasis depend on both the parasite subtype and the host's immunity status. L. infantum manifests with an atypical clinical feature more frequently than other species. The differential diagnosis for multiple ulcers must include several skin diseases, such as cutaneous TBC, bacterial ulcers, traumatic ulcers, deep mycoses, and sarcoidosis. However, an MCL should always be considered in subjects coming from endemic areas. In our case, the multifocality, the size of the lesions and the unresponsiveness to other treatment indicate a short course treatment with liposomal B amphotericin that proved to be a suitable alternative to traditional drugs used in MCL.

Correlation between bacterial population and axillary and plantar bromidrosis: study of 30 patients.

Although studies on the chemistry of odors are expanding to identify the chemical structures of odorous substances, there are no universal standards as yet to measure odor and intensity of bromidrosis. Clinical evaluation can be made on a subjective scoring from 0 to 3 prior to prescription of an antiseptic soap. In order to appreciate the correlation between the intensity of bromidrosis (BI) and bacterial activity, a study was carried out with both clinical and bacterial assessment in thirty patients with axillary or plantar BI. Odor intensity was evaluated by two physicians using a score from 0 to 3 (i.e. absent, minor, moderate, major), meanwhile bacterial composition and density were assessed before and after 10 days of hygiene using an antiseptic detergent (trichlocarbanilide) provided on the first visit. Baseline count of diphtheroids/cm2 was 35.104 and baseline micrococci average was 32.104/cm2. At the end of the study, the reduction of odor intensity was observed in 20 patients (67%) without any change in sweat production. The clinical improvement correlated with a reduction of both micrococci (70%) or diphtheroids (73%) as compared with initial data. In patients presenting persistant bromidrosis, the bacterial count/cm2 did not significantly decrease and remained above 104 diphtheroids/cm2. Thus, this study suggests that body odor may be at least indirectly correlated to microbia counts with a bacteria threshold of BI ranging around and above 104.

Polymerase chain reaction-reverse cross-blot hybridization assay in the diagnosis of sporotrichoid Mycobacterium marinum infection.

In this paper, we report a patient in whom Mycobacterium marinum sporotrichoid infection was diagnosed using polymerase chain reaction (PCR) amplification of the 16S rRNA gene and subsequent analysis of the amplified product in a reverse cross-blot hybridization assay with mycobacterial species-specific probes. This molecular method allowed us rapidly to detect and identify this organism directly in the patient's lesional skin biopsy rather than in cultures in conventional media. The identification provided by PCR-reverse cross-blot hybridization assay was confirmed by examination of the morphological and biochemical features and by high-performance liquid chromatography analysis of mycolic acid from the clinical isolate, suggesting the validity of our molecular approach.