Clinical Overview

Symptoms

• Dilated cardiomyopathy (DCM) (and sometimes hypertrophic cardiomyopathy [HOCM]), congestive cardiac failure, left ventricular noncompaction (LVNC), endocardial fibroelastosis (EFE), ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation), fetal cardiomyopathy causing miscarriage and stillbirth, neonatal cardiomyopathy
• Skeletal myopathy, delayed motor milestones, waddling gait, exercise intolerance
• Feeding problems and Growth Delay: often requiring nasogastric tube feeding or gastrostomy feeding; savoury food fads, vomiting, episodic diarrhoea, rapid growth in late adolescence
• Neutropenia: low numbers of the white cells which fight bacterial and fungal infections). Neutropenia may be chronic, cyclical or intermittent, mild to severe, and may not be present at all in some cases. Symptoms associated with neutropenia include mouth ulcers, malaise and infections
• Hypoglycaemia (low blood sugar) and /or lactic acidosis: particularly in babies and infants
• Cardiolipin abnormalities and Organic aciduria

Prevalence

Prevalence is estimated to be 1 in million based on analysis conducted in the US.

Clinical presentation

Clinical presentation is highly variable. Most children will develop DCM during the first decade, generally during the first year of life, which may be accompanied by endocardial fibroelastosis (EFE) and/or left ventricular noncompaction (LVNC). It may start in utero, causing cardiac failure, fetal hydrops and miscarriage or stillbirth during the 2nd/3rd trimester of pregnancy. Ventricular arrhythmia, especially during adolescence, can lead to sudden cardiac death. There is a significant risk of stroke. Skeletal (mostly proximal) myopathy causes delayed motor milestones, hypotonia, severe lethargy or exercise intolerance. There is a tendency to hypoglycemia during the neonatal period. Ninety percent of patients show mild to severe intermittent or persistent neutropenia with a risk of septicaemia, severe bacterial sepsis, mouth ulcers and painful gums. Lactic acidosis and mild anaemia may occur. Affected children usually show delayed puberty and growth delay that is observed until the late teens or early 20s, when a substantial growth spurt often occurs. Patients may also present severe difficulties with adequate food intake. Episodic diarrhoea is common. Many patients have a similar facial appearance with chubby cheeks, deep-set eyes and prominent ears.

Testing for Barth syndrome

Diagnosis was historically based on metabolic screening of urine showing elevated excretion of organic acids (typically 3-methylglutaconic acid (3-MGCA)), followed by TAZ gene sequencing. However, 3-MGC excretion may be normal even in severe cases.

Analysis of the ratio of monolysocardiolipin (MLCL) / cardiolipin (CL) on blood, tissue, fibroblasts or stored neonatal bloodspots is therefore the diagnostic test of choice. Testing is free – click here for details.

Differential diagnosis includes hereditary, dilated and nutritional cardiomyopathy and idiopathic/cyclic neutropenia.

Prenatal diagnosis (chorionic villus biopsy and/or amniocentesis) is possible in families in which the mutation is known.

Transmission is X-linked recessive. A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected.

Treatment

Treatment is essentially supportive and multidisciplinary. Cardiac failure is treated with conventional drugs or by cardiac transplantation if refractory. The risk of bacterial sepsis in cases of intermittent neutropenia can be reduced by the use of prophylactic antibiotics and/or intermittent use of granulocyte-colony stimulating factor (G-CSF). Difficulties in feeding may necessitate nasogastric or gastrostomy tube feeding. Prognosis has greatly improved with early detection and improvements in treatment and management. Patients are already surviving into their 50s and are expected to live beyond this age.

Written by

Dr Colin Steward, PhD, FRCP, FRCPCH, Royal Hospital for Children, Bristol, England.

Clinical trials

Our mission is to save lives through education, advances in treatments, and finding a cure for Barth syndrome. We know that we need new, safe, and effective treatments to help people with Barth syndrome live better lives at the same time as we invest in research towards one day finding a cure for Barth syndrome.

A vital step towards achieving this goal is providing our community opportunities to take part in new clinical studies and trials. And although we encourage participation in research, we stress that it is always the individual's choice to engage and participate in research.

BSF, along with its affiliates, is actively supporting research into exciting new prospects like:

• Gene therapy
• Elamipretide/TazPower clinical trial
• Enzyme replacement Therapy

The UK was where the first ever clinical trial for a repurposed drug for Barth syndrome was done. This drug is called bezafibrate and the trial was called the CARDIOMAN clinical trial. While the end results of the actual drug were not what we hoped, we learned much from this trial, including how committed our community is to taking part in clinical trials and what we know works (and doesn’t work) going forward. And who knew taking part in a clinical trial could also be so much fun?! Watch our CARDIOMAN video created by the talented Oliver Baxter-Smith

Details of new, international clinical trials are regularly posted on the BSF site here: Clinical Trials : Clinical Trials : Research : Barth Syndrome Foundation

Genetic and Biochemical Background

BTHS is caused by mutations in the TAZ gene (tafazzin; Xq28) which encodes _Taz_1p acyltransferase involved in the metabolism of cardiolipin, a major phospholipid in inner mitochondrial membranes. Defective _Taz_1p function results in abnormal remodelling of cardiolipin which ultimately compromises mitochondrial structure or respiratory chain function.