Prospective and Retrospective Diagnosis of Barth Syndrome Aided by Next-Generation Sequencing

Brión, Marı́a; López, Matı́as; Santori, Montserrat; Pérez-Muñuzuri, Alejandro; Abel, Bernardo López; Souto, Ana Paula Brandão; Soto, María Isabel Martínez; Couce, María L.

doi:10.1093/ajcp/aqw025

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…Females carrying TAZ variants are usually asymptomatic carriers of the disease without revealing any clinical or biochemical abnormalities 45,67. However, owing to the Lion hypothesis, the inactivation of one X-chromosome in females is skewed, resulting theoretically in a wide phenotypic spectrum from asymptomatic carriers to clinical presentations similar to those of males.…”

Section: Resultsmentioning

confidence: 99%

<p>Barth syndrome: mechanisms and management</p>

Finsterer¹

2019

TACG

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Objectives: Barth syndrome is an ultra-rare, infantile-onset, X-linked recessive mitochondrial disorder, primarily affecting males, due to variants in TAZ encoding for the cardiolipin transacylase tafazzin. This review aimed to summarize and discuss recent and earlier findings concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and outcome of Barth syndrome. Method: A literature review was undertaken through a MEDLINE search. Results: The phenotype of Barth syndrome is highly variable but most frequently patients present with hypertrophic/dilated/non-compaction cardiomyopathy, fibroelastosis, arrhythmias, neutropenia, mitochondrial myopathy, growth retardation, dysmorphism, cognitive impairment, and other, rarer features. Lactic acid and creatine kinase, and blood and urine organic acids, particularly 3-methylglutaconic acid and monolysocardiolipin, are often elevated. Cardiolipin is decreased. Biochemical investigations may show decreased activity of various respiratory chain complexes. The diagnosis is confirmed by documentation of a causative TAZ variant. Treatment is symptomatic and directed toward treating heart failure, arrhythmias, neutropenia, and mitochondrial myopathy. Conclusions: Although Barth syndrome is still an orphan disease, with fewer than 200 cases described so far, there is extensive ongoing research with regard to its pathomechanism and new therapeutic approaches. Although most of these approaches are still experimental, it can be expected that causative strategies will be developed in the near future.

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Section: Resultsmentioning

confidence: 99%

<p>Barth syndrome: mechanisms and management</p>

Finsterer¹

2019

TACG

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“…For example, a woman who was the carrier of a de novo tafazzin mutation and the mother of a BTHS patient had mild trabeculations of the left ventricle as revealed by echocardiography, but her total cardiac function and electrocardiogram were normal [ 49 ]. In a different case, examination of the pedigree of a boy with BTHS possessing a newly documented tafazzin mutation revealed a female relative that was diagnosed with Wolff-Parkinson-White syndrome and affected by dilated cardiomyopathy [ 50 ]. This woman lost her son to dilated cardiomyopathy, and the presence of a tafazzin mutation and BTHS diagnosis was suspected but never confirmed due to a lack of sample acquisition prior to death.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Characterization of Female Carrier Mice Heterozygous for Tafazzin Deletion

Tomczewski,

Chan,

Al-Majmaie

et al. 2023

Biology

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Barth syndrome (BTHS) is caused by mutations in tafazzin resulting in deficits in cardiolipin remodeling that alter major metabolic processes. The tafazzin gene is encoded on the X chromosome, and therefore BTHS primarily affects males. Female carriers are typically considered asymptomatic, but age-related changes have been reported in female carriers of other X-linked disorders. Therefore, we examined the phenotype of female mice heterozygous for deletion of the tafazzin gene (Taz-HET) at 3 and 12 months of age. Food intakes, body masses, lean tissue and adipose depot weights, daily activity levels, metabolic measures, and exercise capacity were assessed. Age-related changes in mice resulted in small but significant genotype-specific differences in Taz-HET mice compared with their female Wt littermates. By 12 months, Taz-HET mice weighed less than Wt controls and had smaller gonadal, retroperitoneal, and brown adipose depots and liver and brain masses, despite similar food consumption. Daily movement, respiratory exchange ratio, and total energy expenditure did not vary significantly between the age-matched genotypes. Taz-HET mice displayed improved glucose tolerance and insulin sensitivity at 12 months compared with their Wt littermates but had evidence of slightly reduced exercise capacity. Tafazzin mRNA levels were significantly reduced in the cardiac muscle of 12-month-old Taz-HET mice, which was associated with minor but significant alterations in the heart cardiolipin profile. This work is the first to report the characterization of a model of female carriers of heterozygous tafazzin deficiency and suggests that additional study, particularly with advancing age, is warranted.

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“…In a large cohort study of BTHS, ninety percent of patients had a clinical history of cardiomyopathy diagnosed at an average age of 5.5 months, but the genetic diagnosis of BTHS was not made until an average age of 4.6 years [ 13 ]. The use of NGS has recently been reported as a possible diagnostic strategy in BTHS, but not yet been widely implemented [ 22 ]. The present study demonstrates that target NGS provides a novel, rapid, simple, and highly sensitive screening method for the early detection of this disease.…”

Section: Discussionmentioning

confidence: 99%

Identification of TAZ mutations in pediatric patients with cardiomyopathy by targeted next-generation sequencing in a Chinese cohort

Wang

Guo

Huang

et al. 2017

Orphanet J Rare Dis

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BackgroundBarth syndrome (BTHS) is a rare X-linked recessive disease characterized by cardiomyopathy, neutropenia, skeletal myopathy and growth delay. Early diagnosis and appropriate treatment may improve the prognosis of this disease. The purpose of this study is to determine the role of targeted next-generation sequencing (NGS) in the early diagnosis of BTHS in children with cardiomyopathy.MethodsDuring the period between 2012 and 2015, a gene panel-based NGS approach was used to search for potentially disease-causing genetic variants in all patients referred to our institution with a clinical diagnosis of primary cardiomyopathy. NGS was performed using the Illumina sequencing system.ResultsA total of 180 Chinese pediatric patients (114 males and 66 females) diagnosed with primary cardiomyopathy were enrolled in this study. TAZ mutations were identified in four of the male index patients, including two novel mutations (c.527A > G, p.H176R and c.134_136delinsCC, p.H45PfsX38). All four probands and two additional affected male family members were born at full term with a median birth weight of 2350 g (range, 2000–2850 g). The median age at diagnosis of cardiomyopathy was 3.0 months (range, 1.0–20.0 months). The baseline echocardiography revealed prominent dilation and trabeculations of the left ventricle with impaired systolic function in the six patients, four of which fulfilled the diagnostic criteria of left ventricular noncompaction. Other aspects of their clinical presentations included hypotonia (6/6), growth delay (6/6), neutropenia (3/6) and 3-methylglutaconic aciduria (4/5). Five patients died at a median age of 7.5 months (range, 7.0–12.0 months). The cause of death was heart failure associated with infection in three patients and cardiac arrhythmia in two patients. The remaining one patient survived beyond infancy but had fallen into a persistent vegetative state after suffering from cardiac arrest.ConclusionsThis is the first report of systematic mutation screening of TAZ in a large cohort of pediatric patients with primary cardiomyopathy using the NGS approach. TAZ mutations were found in 4/114 (3.5%) male patients with primary cardiomyopathy. Our findings indicate that the inclusion of TAZ gene testing in cardiomyopathy genetic testing panels may contribute to the early diagnosis of BTHS.

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Prospective and Retrospective Diagnosis of Barth Syndrome Aided by Next-Generation Sequencing

Cited by 7 publications

References 23 publications

<p>Barth syndrome: mechanisms and management</p>

<p>Barth syndrome: mechanisms and management</p>

Phenotypic Characterization of Female Carrier Mice Heterozygous for Tafazzin Deletion

Identification of TAZ mutations in pediatric patients with cardiomyopathy by targeted next-generation sequencing in a Chinese cohort

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