Barth Syndrome in Male and Female Siblings Caused by a Novel Mutation in the Taz Gene

INTRODUCTIONBarth syndrome (BTHS MIM 302060) also known as 3-methylglutaconic aciduria type II is an X-linked multisystem disease with an estimated prevalence of about 1/300,000-400,000 births (3,6). It is manifested by varying in severity and not consistently present clinical features, including cardiomyopathy, nonprogressive skeletal muscle weakness, short stature, facial dysmorphism and recurrent infections due to neutropenia (6). The heart disease may encompass dilated cardiomyopathy, left ventricular noncompaction (LVNC), hypertrophic cardiomyopathy, or endocardial fibroelastosis (8). Laboratory findings of BTHS include variable respiratory chain abnormalities, hypocholesterolemia and organic aciduria with elevated excretion of 3-methylglutaconic acid (3-MGCA), 3-methylglutaric acid, or 2-ethylhydracrylic acid, although they are not always present (4). Mutations in the TAZ gene, located at Xq28 cause the disorder (5). Gene product tafazzin is important for remodeling of immature cardiolipin in mitochondrial membranes. Reduced formation of mature cardiolipin results in respiratory chain dysfunction and represents a critical step in apoptosis (10). Previously, it has been thought that heterozygote females have no symptoms of the BTHS due to a nonrandom X chromosome inactivation (9). Only one female infant with clinical findings of BTHS and chromosomal abnormalities engaging the Xq28 region was reported (7). In this paper, we describe first Bulgarian male and female siblings with BTHS associated with a novel TAZ gene mutation.I CLINICAL DATAPATIENT 1A13-year-old girl, first child of healthy parents, was born at term after uncomplicated pregnancy and delivery, except for fetal growth retardation - birth weight and length were 2050 g, and 46 cm, respectively. During infancy she had normal motor development. At age of three months, the patient was found to have mild aortic valve stenosis with increased trabeculations of the left ventricle. Systematic follow up by a paediatric cardiologist showed onset of hypertrophy of the left ventricle, irrelevant to the level of the stenosis. At age 9 years she had noted a mild persistent muscle weakness and easy fatigability which were nonprogressive. Electromyography excluded skeletal myopathy. At the last examination (13 years old) her body weight and height were within normal range (50th percentile). Physical examination was unremarkable except for hypermobility of large joints and mild dysmorphic features - dolichocephaly, elongated face and prominent forehead (Fig. 1). The patient had a normal female karyotype. Laboratory studies showed normal results, including complete blood count, plasma lactate, total cholesterol, triglycerides, blood sugar, CPK, free carnitine, acylcamitine and amino acid profiles. Urine organic acid analyses did not demonstrate any abnormalities repeatedly.PATIENT 2The younger brother of patient 1 was born at term with birth weight of 2500 g and a length of 49 cm. At two months of age he was admitted to another hospital with respiratory distress due to heart failure. Echocardiography demonstrated dilated cardiomyopathy with noncompaction of the left ventricle and endocardial fibroelastosis. He was treated with ACE inhibitors and diuretics for six months. During infancy he was delayed in meeting his motor milestones - development of head control at 6 months and started to walk at 24 months. Throughout childhood he continued to feel weak. Despite exercise intolerance and difficulty to climb stairs his muscle weakness remained stable. Through serial analyses of complete blood count cyclic mild neutropenia was detected although he never experienced any serious infections except for two protracted diarrhea episodes. The patient had recurrent generalized urticarial rashes from 6 years of age. The regular cardiological assessments showed an overcome of dilatation and congestion of the left ventricle and the development of hypertrophy and diastolic dysfunction. …