Review
Disease names/synonyms
-
Barth Syndrome (BTHS)
-
3-methylglutaconic aciduria type 2
-
X-linked cardioskeletal myopathy and neutropenia
-
Cardioskeletal myopathy with neutropenia and abnormal mitochondria
-
Endocardial fibroelastosis type 2 (EFE2)
Definition
Methods
Epidemiology
Aetiology
Genetics
Pathophysiology
Clinical description
Cardiovascular
| *Dilated Cardiomyopathy (DCM) |
*Left Ventricular Non-compaction (LVNC) | |
*Prolonged corrected QT interval (QTc) | |
Endocardial Fibroelastosis (EFE) | |
Ventricular arrhythmia/Sudden cardiac death | |
Undulating Cardiomyopathy | |
Hypertrophic Cardiomyopathy (HCM) (rarely) | |
Neuromuscular
| *Delayed motor milestones |
*Proximal myopathy | |
*Abnormal fatigability | |
*Exercise intolerance | |
Neurological
| *Mild learning disabilities |
*Attention deficits | |
Strokes (cardiac embolic) | |
Haematological & Infectious
| *Neutropenia |
*Recurrent aphthous ulcers & sore gums | |
*Perianal dermatitis | |
Recurrent bacterial infections | |
Septicaemia | |
Endocrine & Metabolic
| *3-methylglutaconic aciduria |
*Constitutional growth delay with delayed bone age | |
*Delayed puberty | |
Hypocholesterolaemia | |
Hypoglycaemia | |
Lactic acidosis (often accompanies cardiac failure) | |
Osteopenia | |
Gastrointestinal
| *Oromotor feeding problems |
Episodic or chronic diarrhoea | |
Dysmorphic features
| *Deep set eyes |
*Full cheeks | |
*Prominent ears (older boys) | |
Fetal
| Cardiomyopathy |
Fetal hydrops | |
Male miscarriage and stillbirth |
Cardiological aspects
Neutropenia
Neurological aspects & skeletal myopathy
Metabolic aspects
Growth delay
Feeding problems
Miscarriage & stillbirth
Dysmorphology
Diagnosis and diagnostic methods
Recommendations for exclusion of BTHS | Clinical scenario |
---|---|
Consider routinely
| · Fetal Cardiomyopathy |
· Male children with DCM ± EFE, especially those with neonatal / infantile onset | |
· X-linked cardiomyopathy of any type (DCM, LVNC, HCM) | |
· Cardiomyopathy with LVNC or LV modeling defects | |
· Cardiac arrest / cardiac arrhythmia with echocardiographic abnormality consistent with BTHS | |
Consider with relevant accompanying features e.g. X-linked family history, growth failure, feeding problems, delayed motor milestones, lethargy/easy fatigue: | · Multiple male miscarriages / stillbirths / unexplained deaths |
· Neonatal / infantile hypoglycaemia / lactic acidosis | |
· Viral cardiomyopathy | |
· Unexplained neutropenia, mitochondrial disease or proximal myopathy | |
· Serious unexplained bacterial sepsis | |
· Severe feeding problems, persistent episodes of vomiting / diarrhoea | |
· Growth failure / delayed puberty / delayed bone age | |
· Unexplained ventricular arrhythmia or prolonged QTc interval |
Test | Description |
---|---|
Urinary 3-MGCA Testing
| Most cases of BTHS will be suggested by the finding of a 5-20 fold elevation of 3-MGC excretion on quantitative urinary organic acid analysis. As this test is non-specific, confirmation of the diagnosis is required by TAZ mutation/cardiolipin ratio testing. |
N.B. Multiple reports suggest that urinary 3-MGCA levels may be normal on single specimen testing in patients later shown to have BTHS[45, 50, 61, 65‐67]. A negative 3-MGCA test in a candidate patient must therefore be confirmed by cardiolipin ratio testing or TAZ sequencing in order to reliably exclude BTHS. | |
Monolysocardiolipin/Cardiolipin (MLCL:L4-CL) Ratio Testing (where available)
| |
Testing can be performed on blood specimens (sent by routine postal services), stored tissue or dried blood spots. | |
TAZ Gene Sequencing:
| TAZ gene sequencing can be targeted selectively to those with an abnormal cardiolipin ratio test or performed in all candidate patients where cardiolipin testing is not available. It is increasingly being offered as one of the genes sequenced simultaneously in sequencing panels for investigation of cardiomyopathy. It also has an important place in the investigation of patients/families where appropriate samples for biochemical testing are not available from suspected index patients. |
Antenatal diagnosis and genetic counselling
Differential diagnosis
-
Hereditary cardiomyopathy (including autosomal dominant, autosomal recessive, X-linked and mitochondrial forms)
-
Dilated cardiomyopathy of endocrine or metabolic aetiology. The most important differential diagnosis is DCM with ataxia (DCMA) syndrome, an autosomal recessive BTHS-like disorder first described in the Canadian Dariusleut Hutterite population in 2006[82] and more recently diagnosed in a pair of Finnish brothers[83]. This is caused by homozygous mutations in the DNAJC19 gene which encodes a protein previously localised to mitochondria in cardiac myocytes and thought to play a role in mitochondrial matrix protein import[84]. Males and females are affected, with a high incidence of early onset DCM plus noncompaction cardiomyopathy with prolonged QTc interval, skeletal myopathy, microcytic anaemia, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure and 3-MGCA (termed type V methylglutaconic aciduria) and 3-methylglutaric aciduria. Neutropenia has not been described.
-
Nutritional cardiomyopathy (including thiamine, selenium, carnitine and vitamin D deficiency)
-
Idiopathic mitochondrial disease
-
Cyclic or idiopathic neutropenia