Barth syndrome
01 Dec 2013-
TL;DR: The Barth syndrome (BTHS) is a rare X-linked genetic disease characterized by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA) as mentioned in this paper.
Abstract: First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
Citations
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TL;DR: The intent of this American Heart Association (AHA) scientific statement is to summarize the current understanding of dilated cardiomyopathies, with special emphasis on recent developments in diagnostic approaches and therapies for specific cardiologyopathies.
Abstract: The intent of this American Heart Association (AHA) scientific statement is to summarize our current understanding of dilated cardiomyopathies. There is special emphasis on recent developments in diagnostic approaches and therapies for specific cardiomyopathies. Recommendations in this document are based on published studies, published practice guidelines from the American College of Cardiology (ACC)/AHA1 and other organizations,2,3 and the multidisciplinary expertise of the writing group. Existing evidence in epidemiology, classification, diagnosis, and management of specific cardiomyopathies is usually derived from nonrandomized observational studies, registries, case reports, or expert opinion based on clinical experience, not large-scale randomized clinical trials or systematic reviews. Therefore, in this document, rather than using the standard ACC/AHA classification schema of recommendations and level of evidence,4 we have included key management strategies at the end of each section and categorized our recommendations according to the level of consensus. Although the format of our recommendations might resemble the ACC/AHA classification of recommendations used in the ACC/AHA practice guidelines, because of the preponderance of expert opinion or level of evidence C evidence in our document, we elected to use different terminology to provide a distinction from the practice guidelines, in which stronger levels and quality of evidence with randomized clinical trials or meta-analyses are usually present.4 The levels of evidence follow the AHA and ACC methods of classifying the level of certainty of the treatment effect.4
The term dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders that are characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease.5
In clinical practice, the pathogenesis of heart failure (HF) has often been placed into 2 categories: ischemic and nonischemic cardiomyopathy. The term nonischemic cardiomyopathy has been interchangeably used with DCM. Although this …
497 citations
TL;DR: The formation, the migration, and the degradation of cardiolipin are described and how cardiolIPin affects mitochondrial function is discussed, which gives an overview of the various phenotypes of cardiolaipin deficiency in different organisms.
253 citations
TL;DR: Recent progress in this field contributes to understanding how and why membrane glycerophospholipid diversity is organized and maintained.
237 citations
TL;DR: The role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction are focused on.
Abstract: In eukaryotic cells, mitochondria are involved in a large array of metabolic and bioenergetic processes that are vital for cell survival. Phospholipids are the main building blocks of mitochondrial membranes. Cardiolipin (CL) is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM). It is now widely accepted that CL plays a central role in many reactions and processes involved in mitochondrial function and dynamics. Cardiolipin interacts with and is required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into supercomplexes. Moreover, CL plays an important role in mitochondrial membrane morphology, stability and dynamics, in mitochondrial biogenesis and protein import, in mitophagy, and in different mitochondrial steps of the apoptotic process. It is conceivable that abnormalities in CL content, composition and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of pathophysiological situations and diseases. In this review, we focus on the role played by CL in mitochondrial function and dynamics in health and diseases and on the potential of pharmacological modulation of CL through several agents in attenuating mitochondrial dysfunction.
208 citations
TL;DR: The prevalence of LVNC in healthy athletes, its possible reversibility, and increasing diagnosis in healthy subjects suggests cautious use of the term LVNC cardiomyopathy, which describes the morphology but not the functional profile of the cardiopathy.
194 citations
References
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772 citations
TL;DR: The results suggest that G4.5 is the genetic locus responsible for the Barth syndrome, and introduces stop codons in the open reading frame interrupting translation of most of the putative proteins.
Abstract: Barth syndrome is a severe inherited disorder, often fatal in childhood, characterized by cardiac and skeletal myopathy, short stature and neutropenia. The disease has been mapped to a very gene-rich region in distal portion of Xq28. We now report the identification of unique mutations in one of the genes in this region, termed G4.5, expressed at high level in cardiac and skeletal muscle. Different mRNAs can be produced by alternative splicing of the primary G4.5 transcript, encoding novel proteins that differ at the N terminus and in the central region. The mutations introduce stop codons in the open reading frame interrupting translation of most of the putative proteins (which we term 'tafazzins'). Our results suggest that G4.5 is the genetic locus responsible for the Barth syndrome.
686 citations
TL;DR: Biochemical studies and haematological abnormalities (neutropenia) are reported for the first time in an X-linked recessive disease reported in a large pedigree of boys.
646 citations
TL;DR: The timing and severity of presentation in children with cardiomyopathy are related to the type of cardiomeopathy, as well as to genetic and ethnic factors.
Abstract: Background The incidence and age distribution of primary cardiomyopathy in children are not well defined. We undertook a population-based, retrospective cohort study in Australia to document the epidemiology of childhood cardiomyopathy. Methods We analyzed all cases of primary cardiomyopathy in children who presented between 1987 and 1996 and who were younger than 10 years of age. Children were recruited from multiple sources, and cases of cardiomyopathy were classified according to World Health Organization guidelines. Results Over the 10-year period, 314 new cases of primary cardiomyopathy were identified, for an annual incidence of 1.24 per 100,000 children younger than 10 years of age (95 percent confidence interval, 1.11 to 1.38). Dilated cardiomyopathy made up 58.6 percent of cases, hypertrophic cardiomyopathy 25.5 percent, restrictive cardiomyopathy 2.5 percent, and left ventricular noncompaction 9.2 percent of cases. The incidence of all types of cardiomyopathy except restrictive declined rapidly ...
621 citations
TL;DR: A significant number of patients with LVNC have transient recovery of function followed by later deterioration, which may account for many patients presenting as adults, some manifesting an “undulating” phenotype.
Abstract: Background— Left ventricular noncompaction (LVNC) is a reportedly uncommon genetic disorder of endocardial morphogenesis with a reportedly high mortality rate. The purpose of this study was to identify the clinical characteristics of children with LVNC. Methods and Results— We retrospectively reviewed 36 children with LVNC evaluated at Texas Children’s Hospital (TCH) from January 1997 to December 2002. Five children had associated cardiac lesions. There were 16 girls and 20 boys. The median age at presentation was 90 days (range, 1 day to 17 years). The median duration of follow-up was 3.2 years (range, 0.5 to 12 years). Twenty-seven patients (75%) had ECG abnormalities, most commonly biventricular hypertrophy (10 patients, 28%). Both ventricles were involved in 8 patients (22%) and only the left ventricle in 28 patients (78%). Left ventricular systolic function was depressed in 30 patients (83%), with a median ejection fraction of 30% (range, 15% to 66%) at diagnosis. Nine patients presenting in the firs...
614 citations