Barth syndrome (BTHS) is a rare but serious

X-linked Sex linkage describes the sex-specific patterns of inheritance and expression when a gene is present on a sex chromosome (allosome) rather than a non-sex chromosome ( autosome). Genes situated on the X-chromosome are thus termed X-linked, and ...

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset

cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

), and is potentially fatal. The syndrome is diagnosed almost exclusively in males.

Presentation

Though not always present, the cardinal characteristics of this multi-system disorder include:

(dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis),

neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

(chronic, cyclic, irregular, or intermittent), underdeveloped skeletal musculature and

muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includ ...

, growth delay,

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe pos ...

, cardiolipin abnormalities, and 3-methylglutaconic aciduria. It can be associated with

stillbirth Stillbirth is typically defined as fetus, fetal death at or after 20 or 28 weeks of pregnancy, depending on the source. It results in a baby born without vital signs, signs of life. A stillbirth can often result in the feeling of guilt (emotio ...

. 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.Kelley RI, ited 6 Dec 2011 "Barth Syndrome - X-linked Cardiomyopathy and Neutropenia". Department of Pediatrics, Johns Hopkins Medical Institutions. Available from:

Cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

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 Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number. Although hypertro ...

). While cardiomyopathy can be life-threatening, it is commonly resolved or substantially improved in Barth Syndrome patients after puberty.

Neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...

, 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; in Barth Syndrome patients, however, there are reports of relatively fewer bacterial infections as compared to non-Barth patients with neutropenia.

Cause

The

tafazzin Tafazzin is a protein that in humans is encoded by the ''TAFAZZIN'' gene. Tafazzin is highly expressed in cardiac and skeletal muscle, and functions as a phospholipid- lysophospholipid transacylase (it belongs to phospholipid:diacylglycerol acylt ...

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

(''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 Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

. Any type of

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

of TAZ (missense, nonsense, deletion, frameshift, and/or splicing) is closely associated with Barth syndrome. 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. Cardiolipin is intimately connected with the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

proteins and the membrane structure of the

mitochondrion A mitochondrion () is an organelle found in the cell (biology), cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosine tri ...

, the energy-producing organelle of the cell. iPLA2-VIA has been suggested as a target for treatment. 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; the long arm of the X chromosome. This explains the

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.

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 Urinalysis, a portmanteau of the words ''urine'' and ''analysis'', is a Test panel, panel of medical tests that includes physical (macroscopic) examination of the urine, chemical evaluation using urine test strips, and #Microscopic examination, m ...

(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).

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.

Treatment

Currently, there is no treatment for Barth syndrome, although some of the symptoms can be successfully managed. Clinical trials for possible treatments are ongoing, and preliminary research into AAV9-mediated ''TAZ'' gene replacement by the

University of Florida The University of Florida (Florida or UF) is a public university, public land-grant university, land-grant research university in Gainesville, Florida, United States. It is a senior member of the State University System of Florida and a preem ...

has been promising. However, more research and (pre-)clinical testing is needed before the gene therapy is eligible for approval by the FDA as a treatment modality. In the fall of 2024 the Cardiovascular and Renal Drugs Advisory Committee voted 10-6 that elamipretide is effective for this rare disease caused by TAFAZZIN gene mutations. Elamipretide is proposed as a first-in-class mitochondrial protective agent that theoretically improves the function of cardiolipin-deficient mitochondria in patients with Barth syndrome.

Epidemiology

Being X-linked, Barth syndrome has been predominantly diagnosed in males (as of July 2009: 120+ males), although by 2012 a female case had been reported. The syndrome is believed to be severely under-reported due to the complexity of (early) diagnosis. Reports on its incidence and

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

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). 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).

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. He described a

pedigree chart A pedigree chart is a diagram that shows the occurrence of certain traits through different generations of a family, most commonly for humans, show dogs, and race horses. Definition The word pedigree is a corruption of the Anglo-Norman French ''p ...

, showing that this is an inherited trait and not a 'communicated' (i.e. infectious) disease.

References

External links

* {{X-linked disorders Phospholipid metabolism disorders Syndromes affecting the heart Syndromes affecting blood Rare syndromes