Intrafamilial variability for novel TAZ gene mutation: Barth syndrome with dilated cardiomyopathy and heart failure in an infant and left ventricular noncompaction in his great-uncle

Abstract

Background The tafazzin gene (TAZ) is located at Xq28 and encodes a protein involved in the transacylation of cardiolipin, an essential mitochondrial phospholipid. Mutations in TAZ are associated with Barth syndrome (BTHS), the X-linked recessive condition with dilated cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and organic aciduria. TAZ mutations also contribute to left ventricular noncompaction (LVNC), a cardiomyopathy characterized by loose, trabeculated myocardium. Case report We report a family with a novel TAZ mutation and the clinical spectrum from severe BTHS in an infant to skeletal myopathy with LVNC in an adult, the oldest individual with BTHS reported. The proband is a 51-year-old male with muscle weakness since early childhood. He remained stable until the age of 43. His initial evaluations found LVNC and borderline neutropenia with no elevation of urine 3-methylglutaconic acid. The proband’s great nephew is a 3-year-old who presented at birth with poor feeding, hypotonia, lactic acidosis and hypoglycemia. At three months he was admitted with failure to thrive, lethargy and respiratory distress due to heart failure. Cardiac studies revealed dilated cardiomyopathy with a spongiform trabeculated pattern of the left ventricle. Laboratory studies showed cyclic neutropenia and elevated urine 3-methylglutaconic and 3-methylglutaric acid. At age 11 months the patient had a heart transplant. We conducted sequence analysis of the TAZ gene for two affected individuals, the proband first and then his great-nephew. A novel, hemizygous nonsense mutation in TAZ exon 7 (c.583G>T, p.Gly195X) was detected. Conclusion At his current age of 51 years-old, the proband is the oldest surviving individual reported with a confirmed molecular diagnosis and features of Barth syndrome. Further studies will be conducted to identify the genetic modifying factor(s) associated with the wide phenotypic range seen in this family.

Barth syndrome

“…No genotype/phenotype correlations have so far been identified and there may be marked phenotypic variation between males within a family (e.g. those described in [17]).…”

“…Patients with BTHS are able to walk but often find normal activities, such as kicking a ball or running, difficult. The evolution of disabling myopathy has been described at between 43 and 50 years in one man subsequently diagnosed with BTHS; his electromyogram was consistent with severe, chronic myopathy and creatine phosphokinase was slightly elevated [17]. …”

“…Diagnostic investigations for BTHS should therefore be considered in any boy with idiopathic myopathy or “mitochondrial disease” where no cause can be found on routine screening of relevant genes. Investigation of myopathy by invasive muscle biopsy has yielded a variety of results including increased fat vacuolisation/atrophy of type I fibres and increased subsarcolemmal spaces, normal or abnormal mitochondria, and variable changes in respiratory chain complexes [1,11,17,60-62]. It is, however, important to note that muscle biopsy has no role in the elective diagnosis of a patient with suspected BTHS.…”

Barth syndrome associated with triple mutation

“…Barth syndrome has a much broader phenotype. Because the family had significant variability in the age of presentation and severity of the cardiac disease, additional genetic factors must be involved in the complete clinical expression of Barth syndrome . Hypertrophic cardiomyopathy with multiple mutations has a more severe phenotype than that with a single mutation .…”

The Mitochondrial Quality Control Protein Yme1 Is Necessary to Prevent Defective Mitophagy in a Yeast Model of Barth Syndrome

“…Indeed, it is difficult to predict the severity of Barth syndrome due to a lack of known genotype-phenotype correlations. Clinical manifestation of the disease has been shown to vary within the same family containing the same TAZ mutation, implying that modifier genes exist that contribute to disease severity (19,20). To further understand the molecular basis of Barth syndrome, we sought to identify modifier genes whose inactivation affected the fitness of yeast cells lacking tafazzin function.…”