Fabry Disease and the Heart: A Comprehensive Review.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat.

Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?

BACKGROUND: Fabry disease (FD) is a treatable cause of hypertrophic cardiomyopathy (HCM). We aimed to determine the independent predictors of FD and to define a clinically useful strategy to discriminate FD among HCM. METHODS: Multicenter study including 780 patients with the ESC definition of HCM. FD screening was performed by enzymatic assay in males and genetic testing in females. Multivariate regression analysis identified independent predictors of FD in HCM. A discriminant function analysis defined a score based on the weighted combination of these predictors. RESULTS: FD was found in 37 of 780 patients with HCM (4.7%): 31 with p.F113L mutation due to a founder effect; and 6 with other variants (p.C94S; p.M96V; p.G183V; p.E203X; p.M290I; p.R356Q/p.G360R). FD prevalence in HCM adjusted for the founder effect was 0.9%. Symmetric HCM (OR 3.464, CI95% 1.151-10.430), basal inferolateral late gadolinium enhancement (LGE) (OR 10.677, CI95% 3.633-31.380), bifascicular block (OR 10.909, CI95% 2.377-50.059) and ST-segment depression (OR 4.401, CI95% 1.431-13.533) were independent predictors of FD in HCM. The score ID FABRY-HCM [-0.729 + (2.781xBifascicular block) + (0.590xST depression) + (0.831xSymmetric HCM) + (2.130xbasal inferolateral LGE)] had a negative predictive value of 95.8% for FD, with a cut-off of 1.0, meaning that, in the absence of both bifascicular block and basal inferolateral LGE, FD is a less probable cause of HCM, being more appropriate to perform HCM gene panel than targeted FD screening. CONCLUSION: FD prevalence in HCM was 0.9%. Bifascicular block and basal inferolateral LGE were the most powerful predictors of FD in HCM. In their absence, HCM gene panel is the most appropriate step in etiological study of HCM.

Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype.

BACKGROUND: Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. METHODS AND RESULTS: FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. CONCLUSION: A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

Fabry Disease Therapy: State-of-the-Art and Current Challenges.

Fabry disease (FD) is a lysosomal storage disorder caused by mutations of the GLA gene that lead to a deficiency of the enzymatic activity of α-galactosidase A. Available therapies for FD include enzyme replacement therapy (ERT) (agalsidase alfa and agalsidase beta) and the chaperone migalastat. Despite the large body of literature published about ERT over the years, many issues remain unresolved, such as the optimal dose, the best timing to start therapy, and the clinical impact of anti-drug antibodies. Migalastat was recently approved for FD patients with amenable GLA mutations; however, recent studies have raised concerns that "in vitro" amenability may not always reflect "in vivo" amenability, and some findings on real-life studies have contrasted with the results of the pivotal clinical trials. Moreover, both FD specific therapies present limitations, and the attempt to correct the enzymatic deficiency, either by enzyme exogenous administration or enzyme stabilization with a chaperone, has not shown to be able to fully revert FD pathology and clinical manifestations. Therefore, several new therapies are under research, including new forms of ERT, substrate reduction therapy, mRNA therapy, and gene therapy. In this review, we provide an overview of the state-of-the-art on the currently approved and emerging new therapies for adult patients with FD.

p.G360R Is a Pathogenic GLA Gene Mutation Responsible for a Classic Phenotype of Fabry Disease.

The authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.

High-Resolution Seismocardiogram Acquisition and Analysis System.

Several devices and measurement approaches have recently been developed to perform ballistocardiogram (BCG) and seismocardiogram (SCG) measurements. The development of a wireless acquisition system (hardware and software), incorporating a novel high-resolution micro-electro-mechanical system (MEMS) accelerometer for SCG and BCG signals acquisition and data treatment is presented in this paper. A small accelerometer, with a sensitivity of up to 0.164 µs/µg and a noise density below 6.5 µg/ Hz is presented and used in a wireless acquisition system for BCG and SCG measurement applications. The wireless acquisition system also incorporates electrocardiogram (ECG) signals acquisition, and the developed software enables the real-time acquisition and visualization of SCG and ECG signals (sensor positioned on chest). It then calculates metrics related to cardiac performance as well as the correlation of data from previously performed sessions with echocardiogram (ECHO) parameters. A preliminarily clinical study of over 22 subjects (including healthy subjects and cardiovascular patients) was performed to test the capability of the developed system. Data correlation between this measurement system and echocardiogram exams is also performed. The high resolution of the MEMS accelerometer used provides a better signal for SCG wave recognition, enabling a more consistent study of the diagnostic capability of this technique in clinical analysis.

New biomarkers defining a novel early stage of Fabry nephropathy: A diagnostic test study.

BACKGROUND: Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2. METHODS: In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria<30mg/g; 2) albuminuria 30-299mg/g; 3) albuminuria>300mg/g; 4) glomerular filtration rate (GFR)<60mL/min/1.73m2. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-ß-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria). RESULTS: Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ=-0.289; p=0.003) or N-acetyl-ß-glucosaminidase (ρ=-0.448; p<0.001), which were stronger than with albumin (ρ=-0.274; p=0.019). There was also better diagnostic accuracy of N-acetyl-ß-glucosaminidase to predict CKD stage≥2. CONCLUSIONS: These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.

Mild Left Ventricular Hypertrophy Unravels a Novel Nonsense Mutation of the GLA Gene Associated with the Classical Phenotype of Fabry Disease.

We report on the clinical, biochemical, and genetic findings of a large family with the classical phenotype of Fabry disease due to the novel nonsense mutation c.607G>T (p.E203X) of the GLA gene, which occurs in the active site of the α-galactosidase A enzyme. This report highlights that (i) Fabry disease diagnosis should be considered in all cases of unexplained left ventricular hypertrophy (LVH), even in its milder forms; (ii) a complete evaluation of patients with unexplained LVH is important to find diagnostic red flags of treatable causes of LVH, such as Fabry disease; (iii) cascade family screening is paramount to the earlier diagnosis and treatment of other affected family members; and (iv) the Fabry disease phenotype is highly variable in heterozygote females, even within the same family.

Arrhythmogenic right ventricular cardiomyopathy with left ventricular involvement: a novel splice site mutation in the DSG2 gene.

We report the case of a 37-year-old male patient admitted to the cardiac intensive care unit for acute pulmonary edema. He had a history of excessive alcoholic consumption and had had a viral syndrome in the preceding 10 days. A transthoracic echocardiogram revealed severe biventricular dysfunction, mild dilatation of the left heart chambers, and severe dilatation of the right chambers. Nonsustained ventricular tachycardia with a left bundle branch block morphology was detected during electrocardiographic monitoring. In the follow-up, he underwent a contrast-enhanced transthoracic echocardiogram and a cardiac resonance which were compatible with the diagnosis of arrhythmogenic right ventricular cardiomyopathy with biventricular involvement. Molecular analysis detected the mutation c.1423+2T>G (IVS10 ds +2T>G) in intron 10 of the gene DSG2 (desmoglein-2) in heterozygosity. To our knowledge, this mutation has not been previously described in arrhythmogenic right ventricular cardiomyopathy.

Inflammation and Exosomes in Fabry Disease Pathogenesis.

Fabry Disease (FD) is one of the most prevalent lysosomal storage disorders, resulting from mutations in the GLA gene located on the X chromosome. This genetic mutation triggers glo-botriaosylceramide (Gb-3) buildup within lysosomes, ultimately impairing cellular functions. Given the role of lysosomes in immune cell physiology, FD has been suggested to have a profound impact on immunological responses. During the past years, research has been focusing on this topic, and pooled evidence strengthens the hypothesis that Gb-3 accumulation potentiates the production of pro-inflammatory mediators, revealing the existence of an acute inflammatory process in FD that possibly develops to a chronic state due to stimulus persistency. In parallel, extracellular vesicles (EVs) have gained attention due to their function as intercellular communicators. Considering EVs' capacity to convey cargo from parent to distant cells, they emerge as potential inflammatory intermediaries capable of transporting cytokines and other immunomodulatory molecules. In this review, we revisit the evidence underlying the association between FD and altered immune responses and explore the potential of EVs to function as inflammatory vehicles.

Invariant natural killer T cells are phenotypically and functionally altered in Fabry disease.

Fabry disease is a lysosomal storage disease belonging to the group of sphingolipidoses. In Fabry disease there is accumulation of mainly globotriaosylceramide due to deficiency of the lysosomal enzyme α-galactosidase A. The lysosome is an important compartment for the activity of invariant natural killer T (iNKT) cells. iNKT cells are lipid-specific T cells that were shown to be important in infection, autoimmunity and tumor surveillance. In several mouse models of lysosomal storage disorders there is a decrease in iNKT cell numbers. Furthermore, alterations on iNKT cell subsets have been recently described in the Fabry disease mouse model. Herein, we analyzed iNKT cells and their subsets in Fabry disease patients. Although there were no differences in the percentage of iNKT cells between Fabry disease patients and control subjects, Fabry disease patients presented a reduction in the iNKT CD4(+) cells accompanied by an increase in the iNKT DN cells. Since iNKT cell subsets produce different quantities of pro-inflammatory and anti-inflammatory cytokines, we analyzed IFN-γ and IL-4 production by iNKT cells of Fabry disease patients and mice. We found a significant reduction in the production of IL-4 by mice splenic iNKT cells and human iNKT cell subsets, but no significant alterations in the production of IFN-γ. Altogether, our results suggest a bias towards a pro-inflammatory phenotype in Fabry disease iNKT cells.

Challenges in Fabry disease: the combination of two individually amenable GLA variants may be nonamenable to migalastat.

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or absent α-Gal A activity. Migalastat is an oral chaperone therapy for Fabry patients with amenable GLA variants. We previously reported a case of a 60-year-old male patient with a classic phenotype of Fabry disease, presenting with two GLA variants: p.R356Q and p.G360R. Herein, we report that, although these two missense variants are individually classified as amenable to migalastat in the validated in vitro human embryonic kidney-293 cell-based assay, their combination precludes the patient to be treated with this oral chaperone. This case illustrates how therapeutic decisions may be challenging and how a good genotypic characterization of Fabry patients is critical for the selection of the correct therapeutic strategy.

Fabry disease is a rare genetic disease that is part of a group of conditions called lysosomal storage diseases. It is characterized by an abnormal accumulation of glycosphingolipids, a subclass of glycolipids which are important components of the body's cell membranes. This accumulation is caused by a reduction in, or absence of, enzyme α-Gal A activity, which normally breaks glycosphingolipids down into smaller units, avoiding their accumulation. The absence or reduction in the α-Gal A enzyme activity is caused by mutations (changes in the normal DNA sequence) in the GLA gene. Migalastat is an oral treatment for Fabry patients with GLA mutations that respond to this treatment. We report a case of a 60-year-old male patient with Fabry disease, presenting with two GLA mutations (p.R356Q and p.G360R). Although these mutations are individually amenable to migalastat, their combination and interaction in the same chromosome precludes response to this treatment. This case illustrates how therapeutic decisions for treating Fabry disease can be challenging depending on the mutations causing the disease and how genetic material is decisive for therapy selection.

Left ventricular noncompaction associated with a pathogenic mutation in the MYH7 gene: Known mutation, different phenotype.

Left ventricular noncompaction (LVNC) is a genetically heterogeneous cardiomyopathy, with familial and sporadic forms, but genetic testing only identifies a pathogenic mutation in a minority of cases. The main complications are heart failure, embolism and dysrhythmias. Herein we report a familial case of LVNC associated with a mutation in the MYH7 gene and review the literature regarding controversies in LVNC. A 50-year-old woman was referred to the cardiology clinic for palpitations. She underwent echocardiography and cardiac magnetic resonance imaging that revealed mild left ventricular systolic dysfunction and LVNC criteria. She had several episodes of non-sustained ventricular tachycardia and received an implantable cardioverter-defibrillator (ICD). Genetic testing revealed the c.1003G>C (p.Ala335Pro) mutation in the MYH7 gene. Familial screening showed clear genotype-phenotype cosegregation, which provided strong evidence for the pathogenic role of this mutation. To the best of our knowledge, this is the first report of LVNC associated with the p.Ala335Pro mutation in the MYH7 gene. This mutation has been described in hypertrophic cardiomyopathy, suggesting that the same pathogenic sarcomere mutation may be associated with different cardiomyopathies. This case also highlights the current difficulties regarding decisions on ICD implantation for primary prevention of sudden cardiac death in LVNC.

Sex Differences in the Individual Behaviour of Bait-Attracted White Sharks (Carcharodon carcharias, Linnaeus, 1758) Are Linked to Different Environmental Factors in South Africa.

The white shark (Carcharodon carcharias) is a charismatic species and, consequently, one of the most studied and protected sharks. This species can be found in a wide range of temperatures and depths, showing site fidelity and migrating across the oceans. This offers a challenge to understanding the processes influencing their lifecycle and, more importantly, assessing anthropogenic disturbances to their populations. These predators' behaviour has been linked to diverse abiotic factors. Here, an ethological approach was used to understand the influence of environmental variables on white shark behaviour. A different environmental impact was found between the activity of females and males toward the bait. Females performed a higher number of behaviours under daylight, lower sea surface temperatures, short wavelets, clear and cloudy skies, under La Niña events, elevated moonlight and high tides. Males behaved with more complexity at dawn, medium sea surface temperatures, large wavelets, few clouds, high tides, and elevated moonlight. The world's aquatic habitats are experiencing significant physiochemical shifts due to human-induced climate change. Knowledge about how white sharks respond to environmental factors is essential to guide management and conservation actions.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Left ventricular noncompaction in a patient with fabry disease: overdiagnosis, morphological manifestation of fabry disease or two unrelated rare conditions in the same patient?

We report a clinical case of a young female with Fabry disease but without left ventricular hypertrophy, which fulfills the diagnostic criteria of left ventricular noncompaction (LVNC). To our knowledge, this is the first report of LVNC in a patient with Fabry disease. The possibility of an overdiagnosis of LVNC is discussed based on the limitations of the current diagnostic criteria. This case was further investigated by genetic analysis, which came to demonstrate the limited usefulness of genetic testing in the diagnosis of LVNC. Assuming a true trabecular pattern of LVNC, the hypothesis that the same patient has two unrelated and rare conditions, although possible, is unlikely. The genetic and clinical heterogeneity of LVNC is discussed and supports, along with this clinical case, the hypothesis that LVNC is a morphological expression of different diseases rather than a distinct cardiomyopathy. Accordingly, LVNC could be a rare cardiac manifestation of Fabry disease.

Cerium uptake, translocation and toxicity in the salt marsh halophyte Halimione portulacoides (L.), Aellen.

Halimione portulacoides plants were exposed to dissolved cerium (Ce) in a hydroponic medium for five days. Ce accumulation in plants followed the metal's increase in the medium although with a very low translocation factor (TF < 0.01) between roots and shoots. Ce median concentrations in roots were 586, 988 and 1103 µg/g (dry wt.), while in shoots the median values reached 1.9, 3.5 and 10.0 µg/g (dry wt.), for plants exposed to 300, 600 and 1200 µg/L of Ce, respectively. No significant differences occurred in the length of roots and shoots among treatment groups, albeit plants exposed to the highest Ce concentration showed a clear loss of turgor pressure on the fifth day. An increase of hydrogen peroxide and malondialdehyde levels were observed in the plant shoots at 1200 µg/L of Ce. The highest concentration also triggered an answer by the shoots' antioxidant enzymes with a decrease in the activity of superoxide dismutase and an increase in peroxidase. However, no significant change in catalase activity was observed, compared to the control group, which may indicate that peroxidase played a more crucial role against the oxidative stress than catalase. Combined results indicate that H. portulacoides was actively responding to a toxic effect imposed by this higher Ce concentration. Nevertheless, changes in normal environmental conditions, may increase the bioavailability of Ce, while in areas where acid mine drainage may occur, the highest Ce concentration tested in this study may be largely exceeded, placing the sustainability of halophytes and estuarine marshes at risk.

Tissue and gender-related differences in the elemental composition of juvenile ocean sunfish (Mola spp.).

Trace elements are potentially critical contaminants of aquatic environments and fish, occupying upper trophic levels, are especially vulnerable to bioaccumulation. Due to public health concerns, however, data on the elemental composition of non-commercially important marine species are particularly lacking. Ocean sunfish (Mola spp.) attain a low commercial value worldwide and information on their elemental composition is limited. In this context, we examined the concentration of 11 trace elements (V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Cd and Pb) in eight tissues [brain, gills, gelatin (subcutaneous white gelatinous layer), gonads, spleen, liver, white muscle and red muscle] of 20 juvenile specimens (37.5-85.5 cm TL). Gender-related differences were solely found in the gonads and chiefly for essential elements possibly as a result of their importance in embryo development. Overall, Zn and As were the elements observed in greatest concentrations in body tissues. The considerably high presence of As should be related to the dietary preferences of juvenile ocean sunfish. Considerable inter-individual variability in the concentration of each element in any given tissue was observed, especially in the liver, likely originating from the inclusion of both benthic and pelagic prey in the diet of analysed fish. Greatest elemental loads were found in the liver and gills whereas lowest loads were observed in white muscle, brain and gelatin. Moreover, a clear distinction in elemental load and elemental composition was observed between white and red muscles, likely deriving from existing divergent metabolism-related physiological adaptations linked to their different roles in locomotion.

Screening of Fabry Disease in Patients with Chest Pain Without Obstructive Coronary Artery Disease.

Identification of Anderson-Fabry disease (AFD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Coronary microvascular dysfunction has been described in AFD with and without cardiac hypertrophy and may represent the only manifestation in AFD patients, offering a possible earlier diagnosis. We studied the prevalence of AFD in 663 patients with chest pain with normal or non-obstructive coronary arteries. The overall prevalence of AFD in this cohort was only 0.15% (1/663). AFD is not a frequent cause of chest pain without obstructive coronary artery disease and screening efforts should not be conducted in this patient population.

Cardiomyopathy and kidney disease in a patient with maternally inherited diabetes and deafness caused by the 3243A>G mutation of mitochondrial DNA.

Cardiomyopathy is a manifestation of mitochondrial cytopathies, but rarely constitutes the dominant feature, especially in adults. We report the case of a 59-year-old male with a personal and maternal history of diabetes and deafness, who presented with cardiomyopathy and kidney disease. We diagnosed the patient as having a mitochondrial cytopathy resulting from the 3243A>G mutation on the tRNA(Leu(UUR)) gene in the mitochondrial DNA. The family history, broad spectrum of clinical manifestations and fluctuant clinical course provided clues to the diagnosis. We discuss the possible mechanisms underlying the phenotypic variability and fluctuant clinical course of mitochondrial disorders and the potential usefulness of coenzyme Q10 and L-carnitine in 3243A>G mutation patients.