Barth syndrome

Last updated
Barth Syndrome
Other names3-Methylglutaconic aciduria type II,X-linked cardioskeletal myopathy and neutropenia,BTHS,Cardioskeletal myopathy with neutropenia and abnormal mitochondria,Cardioskeletal myopathy-neutropenia syndrome
Cardiolipin.svg
Cardiolipin
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Dilated cardiomyopathy, neutropenia, short stature, muscle weakness. [1]
Complications Heart failure, delayed motor skills, infections. [1]
Usual onsetInfancy. [1]
Causes Genetic mutation. [1]
Prognosis Reduced life expectancy. [1]
Frequency1-9 / 1 000 000 [2]

Barth syndrome (BTHS) is a rare but serious X-linked genetic disorder, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset cardiomyopathy), and is potentially fatal. [3] The syndrome is diagnosed almost exclusively in males.

Contents

Presentation

Neutropenia Neutropenia.JPG
Neutropenia

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), [4] [5] neutropenia (chronic, cyclic, or intermittent), [5] underdeveloped skeletal musculature and muscle weakness, [6] growth delay, [5] exercise intolerance, cardiolipin abnormalities, [7] [8] and 3-methylglutaconic aciduria. [5] It can be associated with stillbirth. [9]

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. [10]

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. [10]

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; [4] in Barth Syndrome patients, however, there are reports of relatively fewer bacterial infections as compared to non-Barth patients with neutropenia. [11]

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. [7] [8] Any type of mutation of TAZ (missense, nonsense, deletion, frameshift, and/or splicing) is closely associated with Barth syndrome. [12]

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. [13] 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. [14]

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; [15] 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. [16]

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).[ citation needed ]

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.[ citation needed ]

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 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. [17] [18]

Epidemiology

Being X-linked, Barth syndrome has been predominantly diagnosed in males (as of July 2009: 120+ males [12] ), although by 2012 a female case had been reported. [19]

The syndrome is believed to be severely under-reported due to the complexity of (early) diagnosis. [20] 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).[ 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).[ 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. [6] He described a pedigree chart, showing that this is an inherited trait and not a 'communicated' (i.e. infectious) disease.[ citation needed ]

See also

Related Research Articles

Malouf syndrome is a congenital disorder that causes one or more of the following symptoms: intellectual disability, ovarian dysgenesis, congestive cardiomyopathy, broad nasal base, blepharoptosis, and bone abnormalities, and occasionally marfanoid habitus.

Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most bacteria. The name "cardiolipin" is derived from the fact that it was first found in animal hearts. It was first isolated from the beef heart in the early 1940s by Mary C. Pangborn. In mammalian cells, but also in plant cells, cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane, where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism.

<span class="mw-page-title-main">Tafazzin</span> Protein found in humans

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 catalyzes remodeling of immature cardiolipin to its mature composition containing a predominance of tetralinoleoyl moieties. Several different isoforms of the tafazzin protein are produced from the TAFAZZIN gene. A long form and a short form of each of these isoforms is produced; the short form lacks a hydrophobic leader sequence and may exist as a cytoplasmic protein rather than being membrane-bound. Other alternatively spliced transcripts have been described but the full-length nature of all these transcripts is not known. Most isoforms are found in all tissues, but some are found only in certain types of cells. Mutations in the TAFAZZIN gene have been associated with mitochondrial deficiency, Barth syndrome, dilated cardiomyopathy (DCM), hypertrophic DCM, endocardial fibroelastosis, left ventricular noncompaction (LVNC), breast cancer, papillary thyroid carcinoma, non-small cell lung cancer, glioma, gastric cancer, thyroid neoplasms, and rectal cancer.

<span class="mw-page-title-main">3-Methylglutaconic aciduria</span> Medical condition

3-Methylglutaconic aciduria (MGA) is any of at least five metabolic disorders that impair the body's ability to make energy in the mitochondria. As a result of this impairment, 3-methylglutaconic acid and 3-methylglutaric acid build up and can be detected in the urine.

<span class="mw-page-title-main">McLeod syndrome</span> Medical condition

McLeod syndrome is an X-linked recessive genetic disorder that may affect the blood, brain, peripheral nerves, muscle, and heart. It is caused by a variety of recessively inherited mutations in the XK gene on the X chromosome. The gene is responsible for producing the Kx protein, a secondary supportive protein for the Kell antigen on the red blood cell surface.

<span class="mw-page-title-main">MERRF syndrome</span> Mitochondrial disorder

MERRF syndrome is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the muscles and nervous system. The signs and symptoms of this disorder appear at an early age, generally childhood or adolescence. The causes of MERRF syndrome are difficult to determine, but because it is a mitochondrial disorder, it can be caused by the mutation of nuclear DNA or mitochondrial DNA. The classification of this disease varies from patient to patient, since many individuals do not fall into one specific disease category. The primary features displayed on a person with MERRF include myoclonus, seizures, cerebellar ataxia, myopathy, and ragged red fibers (RRF) on muscle biopsy, leading to the disease's name. Secondary features include dementia, optic atrophy, bilateral deafness, peripheral neuropathy, spasticity, or multiple lipomata. Mitochondrial disorders, including MERRFS, may present at any age.

<span class="mw-page-title-main">Mitochondrial neurogastrointestinal encephalopathy syndrome</span> Medical condition

Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE) is a rare autosomal recessive mitochondrial disease. It has been previously referred to as polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudoobstruction. The disease presents in childhood, but often goes unnoticed for decades. Unlike typical mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, MNGIE is caused by mutations in the TYMP gene, which encodes the enzyme thymidine phosphorylase. Mutations in this gene result in impaired mitochondrial function, leading to intestinal symptoms as well as neuro-ophthalmologic abnormalities. A secondary form of MNGIE, called MNGIE without leukoencephalopathy, can be caused by mutations in the POLG gene.

<span class="mw-page-title-main">HADHB</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.

<span class="mw-page-title-main">Costeff syndrome</span> Medical condition

Costeff syndrome, or 3-methylglutaconic aciduria type III, is a genetic disorder caused by mutations in the OPA3 gene. It is typically associated with the onset of visual deterioration in early childhood followed by the development of movement problems and motor disability in later childhood, occasionally along with mild cases of cognitive deficiency. The disorder is named after Hanan Costeff, the doctor who first described the syndrome in 1989.

<span class="mw-page-title-main">Fukutin</span> Mammalian protein found in Homo sapiens

Fukutin is a eukaryotic protein necessary for the maintenance of muscle integrity, cortical histogenesis, and normal ocular development. Mutations in the fukutin gene have been shown to result in Fukuyama congenital muscular dystrophy (FCMD) characterised by brain malformation - one of the most common autosomal-recessive disorders in Japan. In humans this protein is encoded by the FCMD gene, located on chromosome 9q31. Human fukutin exhibits a length of 461 amino acids and a predicted molecular mass of 53.7 kDa.

Mitochondrially encoded tRNA histidine, also known as MT-TH, is a transfer RNA which, in humans, is encoded by the mitochondrial MT-TH gene.

<span class="mw-page-title-main">LDB3</span> Protein-coding gene in the species Homo sapiens

LIM domain binding 3 (LDB3), also known as Z-band alternatively spliced PDZ-motif (ZASP), is a protein which in humans is encoded by the LDB3 gene. ZASP belongs to the Enigma subfamily of proteins and stabilizes the sarcomere during contraction, through interactions with actin in cardiac and skeletal muscles. Mutations in the ZASP gene has been associated with several muscular diseases.

<span class="mw-page-title-main">DNAJC19</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM14 is an enzyme that in humans is encoded by the DNAJC19 gene on chromosome 3. TIM14 belongs to the DnaJ family, which has been involved in Hsp40/Hsp70 chaperone systems. As a mitochondrial chaperone, TIM14 functions as part of the TIM23 complex import motor to facilitate the import of nuclear-encoded proteins into the mitochondria. TIM14 also complexes with prohibitin complexes to regulate mitochondrial morphogenesis, and has been implicated in dilated cardiomyopathy with ataxia.

<span class="mw-page-title-main">CLPB</span> Protein-coding gene in the species Homo sapiens

Caseinolytic peptidase B protein homolog (CLPB), also known as Skd3, is a mitochondrial AAA ATPase chaperone that in humans is encoded by the gene CLPB, which encodes an adenosine triphosphate-(ATP) dependent chaperone. Skd3 is localized in mitochondria and widely expressed in human tissues. High expression in adult brain and low expression in granulocyte is found. It is a potent protein disaggregase that chaperones the mitochondrial intermembrane space. Mutations in the CLPB gene could cause autosomal recessive metabolic disorder with intellectual disability/developmental delay, congenital neutropenia, progressive brain atrophy, movement disorder, cataracts, and 3-methylglutaconic aciduria. Recently, heterozygous, dominant negative mutations in CLPB have been identified as a cause of severe congenital neutropenia (SCN).

Danon disease is a metabolic disorder. Danon disease is an X-linked lysosomal and glycogen storage disorder associated with hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability. It is inherited in an X-linked dominant pattern.

Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.

<span class="mw-page-title-main">SERAC1</span> Protein-coding gene in the species Homo sapiens

Serine active site-containing protein 1, or Protein SERAC1 is a protein in humans that is encoded by the SERAC1 gene. The protein encoded by this gene is a phosphatidylglycerol remodeling protein found at the interface of mitochondria and endoplasmic reticula, where it mediates phospholipid exchange. The encoded protein plays a major role in mitochondrial function and intracellular cholesterol trafficking. Defects in this gene are a cause of 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL). Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene.

Acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT1) is a polyglycerophospholipid acyltransferase of the endoplasmic reticulum which is primarily known for catalyzing the acylation of monolysocardiolipin back into cardiolipin, although it does catalyze the acylation of other polyglycerophospholipids.

<span class="mw-page-title-main">Sengers syndrome</span> Medical condition

Sengers syndrome is a rare autosomal recessive mitochondrial disease characterised by congenital cataract, hypertrophic cardiomyopathy, muscle weakness and lactic acidosis after exercise. Biallelic pathogenic mutations in the AGK gene, which encodes the acylglycerol kinase enzyme, cause Sengers syndrome. In addition, heart disease and muscle disease are prevalent, meaning that life expectancy is short for many patients.

<span class="mw-page-title-main">TMEM70</span> Protein-coding gene in the species Homo sapiens

Transmembrane protein 70 is a protein that in humans is encoded by the TMEM70 gene. It is a transmembrane protein located in the mitochondrial inner membrane involved in the assembly of the F1 and Fo structural subunits of ATP synthase. Mutations in this gene have been associated with neonatal mitochondrial encephalo-cardiomyopathy due to ATP synthase deficiency, causing a wide variety of symptoms including 3-methylglutaconic aciduria, lactic acidosis, mitochondrial myopathy, and cardiomyopathy.

References

  1. 1 2 3 4 5 "Barth syndrome: MedlinePlus Genetics". medlineplus.gov. Retrieved 2023-08-13.
  2. ↑ "Orphanet: Barth syndrome". orpha.net. Retrieved 2023-08-13.
  3. ↑ Claypool SM, Boontheung P, McCaffery JM, Loo JA, Koehler CM (December 2008). "The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome". Mol. Biol. Cell. 19 (12): 5143–55. doi:10.1091/mbc.E08-09-0896. PMC   2592642 . PMID   18799610.
  4. 1 2 Spencer CT, Bryant RM, Day J, et al. (August 2006). "Cardiac and clinical phenotype in Barth syndrome". Pediatrics. 118 (2): e337–46. doi:10.1542/peds.2005-2667. PMID   16847078. S2CID   23163528.
  5. 1 2 3 4 Kelley RI, Cheatham JP, Clark BJ, et al. (November 1991). "X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria". The Journal of Pediatrics. 119 (5): 738–47. doi: 10.1016/S0022-3476(05)80289-6 . PMID   1719174.
  6. 1 2 Barth PG, Scholte HR, Berden JA, et al. (December 1983). "An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes". Journal of the Neurological Sciences. 62 (1–3): 327–55. doi:10.1016/0022-510X(83)90209-5. PMID   6142097. S2CID   22790290.
  7. 1 2 Schlame M, Kelley RI, Feigenbaum A, et al. (December 2003). "Phospholipid abnormalities in children with Barth syndrome". Journal of the American College of Cardiology. 42 (11): 1994–9. doi: 10.1016/j.jacc.2003.06.015 . PMID   14662265.
  8. 1 2 Vreken P, Valianpour F, Nijtmans LG, et al. (December 2000). "Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome". Biochemical and Biophysical Research Communications. 279 (2): 378–82. doi:10.1006/bbrc.2000.3952. PMID   11118295.
  9. ↑ Steward CG, Newbury-Ecob RA, Hastings R, et al. (October 2010). "Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth". Prenat. Diagn. 30 (10): 970–6. doi:10.1002/pd.2599. PMC   2995309 . PMID   20812380.
  10. 1 2 Kelley RI, [cited 6 Dec 2011]. "Barth Syndrome - X-linked Cardiomyopathy and Neutropenia". Department of Pediatrics, Johns Hopkins Medical Institutions. Available from: "Barth Syndrome - X-linked Cardiomyopathy and Neutropenia". Archived from the original on 2004-12-14. Retrieved 2004-12-19.
  11. ↑ Barth Syndrome Foundation, 28 Jun 2011. "Diagnosis of Barth Syndrome". Available from: "Barth Syndrome Foundation : Home". Archived from the original on 2012-04-26. Retrieved 2011-12-06.
  12. 1 2 "Barth Syndrome Foundation : Home". Archived from the original on 2009-09-23. Retrieved 2009-04-17.
  13. ↑ Kulik W, van Lenthe H, Stet FS, et al. (February 2008). "Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome". Clinical Chemistry. 54 (2): 371–8. doi: 10.1373/clinchem.2007.095711 . PMID   18070816.
  14. ↑ Malhotra A, Edelman-Novemsky I, Xu Y, et al. (February 2009). "Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome". Proc. Natl. Acad. Sci. U.S.A. 106 (7): 2337–41. Bibcode:2009PNAS..106.2337M. doi: 10.1073/pnas.0811224106 . PMC   2650157 . PMID   19164547.
  15. ↑ Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D (April 1996). "A novel X-linked gene, G4.5. is responsible for Barth syndrome". Nature Genetics. 12 (4): 385–9. doi:10.1038/ng0496-385. PMID   8630491. S2CID   23539265.
  16. ↑ Ferreira, Carlos; Pierre, Germaine; Thompson, Reid; Vernon, Hilary (July 9, 2020). "Barth Syndrome". University of Washington, Seattle. PMID   25299040 . Retrieved November 28, 2023.
  17. ↑ Suzuki-Hatano, Silveli; Saha, Madhurima; Rizzo, Skylar A.; Witko, Rachael L.; Gosiker, Bennett J.; Ramanathan, Manashwi; Soustek, Meghan S.; Jones, Michael D.; Kang, Peter B. (2018-08-02). "AAV-Mediated TAZ Gene Replacement Restores Mitochondrial and Cardioskeletal Function in Barth Syndrome". Human Gene Therapy. 30 (2): 139–154. doi:10.1089/hum.2018.020. ISSN   1043-0342. PMC   6383582 . PMID   30070157.
  18. ↑ "Gene therapy for heart, skeletal muscle disorder shows promise in preclinical model | UF Health, University of Florida Health". 13 December 2018.
  19. ↑ Cosson L, Toutain A, Simard G, Kulik W, Matyas G, Guichet A, Blasco H, Maakaroun-Vermesse Z, Vaillant MC, Le Caignec C, Chantepie A, Labarthe F (May 2012). "Barth syndrome in a female patient". Mol Genet Metab. 106 (1): 115–20. doi:10.1016/j.ymgme.2012.01.015. PMID   22410210.
  20. ↑ Cantlay AM, Shokrollahi K, Allen JT, Lunt PW, Newbury-Ecob RA, Steward CG (September 1999). "Genetic analysis of the G4.5 gene in families with suspected Barth syndrome". The Journal of Pediatrics. 135 (3): 311–5. doi:10.1016/S0022-3476(99)70126-5. PMID   10484795.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.