Barth syndrome
Template:Short description Template:Distinguish Template:Infobox medical condition Barth syndrome (BTHS) is an ultra-rare, but serious X-linked genetic disorder, caused by pathogenic variants in the TAFAZZIN gene, which leads to an inborn error of lipid metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset cardiomyopathy), and is potentially fatal.<ref name="pmid18799610">Template:Cite journal</ref> The syndrome is diagnosed almost exclusively in males.
Signs and symptoms
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Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy (dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis),<ref name="pmid16847078">Template:Cite journal</ref><ref name="pmid1719174">Template:Cite journal</ref> neutropenia (chronic, cyclic, irregular, or intermittent),<ref name = "pmid6392059">Template:Cite journal</ref><ref name=pmid1719174/> underdeveloped skeletal musculature and muscle weakness,<ref name="pmid6142097">Template:Cite journal</ref> growth delay,<ref name=pmid1719174/> exercise intolerance, cardiolipin abnormalities,<ref name="pmid14662265">Template:Cite journal</ref><ref name="pmid11118295">Template:Cite journal</ref> and 3-methylglutaconic aciduria.<ref name=pmid1719174/> It can be associated with stillbirth.<ref name="pmid20812380">Template:Cite journal</ref>
Barth syndrome is manifested in a variety of ways at birth. A majority of patients are hypotonic at birth; show signs of cardiomyopathy within the first few months of life; and experience a deceleration in growth in the first year, despite adequate nutrition. As patients progress into childhood, their height and weight lag significantly behind average. While most patients express normal intelligence, a significant proportion of patients also express mild or moderate learning disabilities. Physical activity is also hindered due to diminished muscular development and muscular hypotonia. Many of these disorders are resolved after puberty. Growth accelerates during puberty, and many patients reach a normal adult height.<ref name="hopkinsmedicine.org">Kelley RI, [cited 6 Dec 2011]. "Barth syndrome - X-linked Cardiomyopathy and Neutropenia". Department of Pediatrics, Johns Hopkins Medical Institutions. Available from: Template:Cite web</ref>
Cardiomyopathy is one of the more severe manifestations of Barth syndrome. The myocardium is dilated, reducing the systolic pump of the ventricles. For this reason, most patients have left myocardial thickening (hypertrophy). While cardiomyopathy can be life-threatening, it is commonly resolved or substantially improved in Barth syndrome patients after puberty.<ref name="hopkinsmedicine.org" />
Neutropenia, a granulocyte disorder that results in a low production of neutrophils, the body's primary defenders against bacterial infections, is another severe manifestation of Barth syndrome. In general, lower levels of neutrophils render a patient more vulnerable to bacterial infections;<ref name="pmid16847078" /> in Barth syndrome patients, however, there are reports of relatively fewer bacterial infections as compared to non-Barth patients with neutropenia.<ref>Barth syndrome Foundation, 28 Jun 2011. "Diagnosis of Barth syndrome". Available from: Template:Cite web</ref>
Cause
The tafazzin gene (TAZ, also called G4.5 or NG_009634) is highly expressed in cardiac and skeletal muscle; its gene product, Taz1p, functions as an acyltransferase in complex lipid metabolism.<ref name=pmid14662265/><ref name=pmid11118295/> Any type of mutation of TAZ (missense, nonsense, deletion, frameshift, and/or splicing) is closely associated with Barth syndrome.<ref name=bs1357/>
In 2008, Dr. Kulik found that every patient with Barth syndrome that he tested had abnormalities in their cardiolipin, a lipid found inside the mitochondria of cells.<ref>Template:Cite journal</ref> Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondrion, the energy-producing organelle of the cell. iPLA2-VIA has been suggested as a target for treatment.<ref name="pmid19164547">Template:Cite journal</ref>
The human tafazzin gene is over 10,000 base pairs in length, the full-length mRNA, NM_000116, being 1919 nucleotides long, encoding 11 exons with a predicted protein length of 292 amino acids and a molecular weight of 33.5 kDa. It is located at Xq28;<ref>Template:Cite journal</ref> the long arm of the X chromosome. This explains the X-linked nature of Barth syndrome.
There are some case reports of women who are asymptomatic carriers of the TAZ mutation. Any of their children might inherit the modified gene with a 50% probability, with the males developing Barth syndrome and the females going on to be carriers themselves. Thus, it is vitally important to take familial histories of Barth syndrome patients to determine genetic risk. Ideally, any male who is matrilineally related to an individual with Barth syndrome should be tested for TAZ mutation(s). Because the phenotype can vary widely, even among affected siblings, symptomatology (or lack thereof) by itself is insufficient for diagnosis.<ref name="Ferreira Pierre Thompson Vernon 2020 x110">Template:Cite web</ref>
Diagnosis
Early diagnosis of the syndrome is complicated, but of critical importance. Clinical presentation in Barth syndrome is highly variable, with the only common denominator being early-onset and pronounced cardiomyopathy. Diagnosis is established based upon several tests, among which can be blood tests (neutropenia, white blood cell count), urinalysis (increased urinary organic acid levels), echocardiography (cardiac ultrasound, to assess (and detect abnormalities in) the heart's structure, function and condition), and, with reasonable suspicion of Barth syndrome, DNA sequencing (to verify TAZ gene status).Template:Cn
Differential diagnosis
Based on symptoms at time of presentation, the differential diagnosis may include other hereditary and/or nutritional causes of (dilated) cardiomyopathy and (cyclic or idiopathic) neutropenia.Template:Cn
Treatment
Elamipretide (Forzinity) was approved for medical use in the United States in September 2025.<ref>Template:Cite press release</ref>
Epidemiology
Being X-linked, Barth syndrome has been predominantly diagnosed in males (as of July 2009: 120+ males<ref name="bs1357">Template:Cite web</ref>), although by 2012 a female case had been reported.<ref>Template:Cite journal</ref>
The syndrome is believed to be severely under-reported due to the complexity of (early) diagnosis.<ref>Template:Cite journal</ref> Reports on its incidence and prevalence in the international literature vary; around 1 in every 454,000 individuals are thought to suffer from Barth syndrome. Incidence has been estimated at anywhere between 1:140,000 (South West England, South Wales) and 1:300,000 – 1:400,000 live births (United States).Template:Citation needed Geographical distribution is homogenous, with patients (and their family members) on every continent (with known cases in, for example, the US, Canada, Europe, Japan, South Africa, Kuwait, and Australia).Template:Citation needed
History
The syndrome was named for Dr. Peter Barth (b. 1932), a Dutch pediatric neurologist, for his research into and the discovery of the syndrome in 1983.<ref name=pmid6142097/> He described a pedigree chart, showing that this is an inherited trait and not a 'communicated' (i.e. infectious) disease.Template:Citation needed
See also
- 3-Methylglutaconic aciduria
- noncompaction cardiomyopathy: mutations to the affected genes in Barth syndrome are also present here.
References
External links
Template:Phospholipid metabolism disorders Template:X-linked disorders