Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome

doi:10.3969/j.issn.1674-8115.2024.11.007

Abstract

Abstract:

Objective ·To analyze the clinical and genetic characteristics of Chinese pediatric patients with Barth syndrome (BTHS) and provide data to support the prevention and treatment of BTHS. Methods ·Eighteen pediatric patients diagnosed with BTHS at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, from January 2010 to November 2023, were included. Clinical data (age, birth weight, family history, electrocardiogram, echocardiogram, urine tandem mass spectrometry, complete blood count, blood biochemistry, and genetic test results) were collected to analyze the clinical characteristics, genetic findings, and prognoses of the patients. Results ·The study included 18 male patients with BTHS (including 2 monozygotic twins), consisting of one Yi ethnic and 17 Han Chinese patients. The median age at diagnosis was 3.0 (1.0, 5.6) months. Fifteen patients experienced decreased cardiac function at disease onset, with a left ventricular ejection fraction (LVEF) below 50%. Dilated cardiomyopathy (DCM) was observed in 15 patients, left ventricular non-compaction (LVNC) in 12 patients, and myocardial hypertrophy in 9 patients. During the diagnosis and follow-up, QTc interval prolongation occurred in 9 patients, ventricular arrhythmias in 2 patients, neutropenia in 9 patients, and monocytosis in 10 patients. Urine tandem mass spectrometry revealed 3-methylglutaconic aciduria (3-MGCA) in 8 of 13 tested patients. Fifteen types of TAZ gene mutation were identified in the 18 patients, including 5 novel mutations. Genetic testing of the parents of 16 patients indicated maternal inheritance in 15 cases. The median follow-up period was 8.5 (2.6, 29.3) months, during which 12 patients died. The median age at death was 7.5 (6.0, 12.8) months. Causes of death included heart failure (7 cases, with 4 concurrent infections), sudden death (3 cases), ventricular fibrillation (1 case), and accidental death (1 case). Conclusion ·BTHS is a rare genetic disorder with multisystem involvement. Its primary clinical manifestations include cardiomyopathy and neutropenia. The condition typically presents early in life, with severe progression and poor prognosis. Prompt recognition, accurate diagnosis, and early intervention are essential for managing this disease.

Key words: Barth syndrome (BTHS), TAZ gene mutation, cardiomyopathy, neutropenia

CLC Number:

R725.4

ZHAN Tianliu, YAN Zihang, WU Jinjin, CHEN Hao, CHEN Lijun, CHEN Yiwei, FU Lijun. Analysis of clinical and genetic characteristics of 18 pediatric patients with Barth syndrome[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1406-1413.

Figures/Tables 4

TrendMD

References 26

1	BARTH P G, SCHOLTE H R, BERDEN J A, et al. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes[J]. J Neurol Sci, 1983, 62(1/2/3): 327-355.
2	MILLER P C, REN M D, SCHLAME M, et al. A Bayesian analysis to determine the prevalence of Barth syndrome in the pediatric population[J]. J Pediatr, 2020, 217: 139-144.
3	ROBERTS A E, NIXON C, STEWARD C G, et al. The Barth Syndrome Registry: distinguishing disease characteristics and growth data from a longitudinal study[J]. Am J Med Genet A, 2012, 158A(11): 2726-2732.
4	LIPSHULTZ S E, LAW Y M, ASANTE-KORANG A, et al. Cardiomyopathy in children: classification and diagnosis: a scientific statement from the American Heart Association[J]. Circulation, 2019, 140(1): e9-e68.
5	JENNI R, OECHSLIN E, SCHNEIDER J, et al. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy[J]. Heart, 2001, 86(6): 666-671.
6	STEWARD C G, GROVES S J, TAYLOR C T, et al. Neutropenia in Barth syndrome: characteristics, risks, and management[J]. Curr Opin Hematol, 2019, 26(1): 6-15.
7	CLARKE S L, BOWRON A, GONZALEZ I L, et al. Barth syndrome[J]. Orphanet J Rare Dis, 2013, 8(1): 23.
8	KANG S L, FORSEY J, DUDLEY D, et al. Clinical characteristics and outcomes of cardiomyopathy in Barth syndrome: the UK experience[J]. Pediatr Cardiol, 2016, 37(1): 167-176.
9	SPENCER C T, BRYANT R M, DAY J, et al. Cardiac and clinical phenotype in Barth syndrome[J]. Pediatrics, 2006, 118(2): e337-e346.
10	PANG J, BAO Y, MITCHELL-SILBAUGH K, et al. Barth syndrome cardiomyopathy: an update [J]. Genes (Basel), 2022, 13(4): 231-241.
11	GARLID A O, SCHAFFER C T, KIM J, et al. TAZ encodes tafazzin, a transacylase essential for cardiolipin formation and central to the etiology of Barth syndrome[J]. Gene, 2020, 726: 144148.
12	CONSORTIUM U. UniProt: the universal protein knowledgebase in 2023[J]. Nucleic Acids Res, 2023, 51(D1): D523-D531.
13	IMAI-OKAZAKI A, KISHITA Y, KOHDA M, et al. Barth syndrome: different approaches to diagnosis[J]. J Pediatr, 2018, 193: 256-260.
14	D'ADAMO P, FASSONE L, GEDEON A, et al. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies[J]. Am J Hum Genet, 1997, 61(4): 862-867.
15	CANTLAY A M, SHOKROLLAHI K, ALLEN J T, et al. Genetic analysis of the G4.5 gene in families with suspected Barth syndrome[J]. J Pediatr, 1999, 135(3): 311-315.
16	RIGAUD C, LEBRE A S, TOURAINE R, et al. Natural history of Barth syndrome: a national cohort study of 22 patients[J]. Orphanet J Rare Dis, 2013, 8: 70.
17	HIRONO K, HATA Y, NAKAZAWA M, et al. Clinical and echocardiographic impact of tafazzin variants on dilated cardiomyopathy phenotype in left ventricular non-compaction patients in early infancy[J]. Circ J, 2018, 82(10): 2609-2618.
18	SABBAH H N. Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide[J]. Heart Fail Rev, 2021, 26(2): 237-253.
19	THOMPSON W R, MANUEL R, ABBRUSCATO A, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER[J]. Genet Med, 2024, 26(7): 101138.
20	HORNBY B, THOMPSON W R, ALMUQBIL M, et al. Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome[J]. Orphanet J Rare Dis, 2022, 17(1): 336.
21	SCHAFER C, MOORE V, DASGUPTA N, et al. The effects of PPAR stimulation on cardiac metabolic pathways in Barth syndrome mice[J]. Front Pharmacol, 2018, 9: 318.
22	HUANG Y, POWERS C, MOORE V, et al. The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome[J]. Orphanet J Rare Dis, 2017, 12(1): 49.
23	DABNER L, PIELES G E, STEWARD C G, et al. Treatment of Barth syndrome by cardiolipin manipulation (CARDIOMAN) with bezafibrate: protocol for a randomized placebo-controlled pilot trial conducted in the nationally commissioned Barth syndrome service[J]. JMIR Res Protoc, 2021, 10(5): e22533.
24	ZEGALLAI H M, HATCH G M. Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets[J]. Mol Cell Biochem, 2021, 476(3): 1605-1629.
25	THOMPSON R, JEFFERIES J, WANG S Y, et al. Current and future treatment approaches for Barth syndrome[J]. J Inherit Metab Dis, 2022, 45(1): 17-28.
26	LI Y, GODOWN J, TAYLOR C L, et al. Favorable outcomes after heart transplantation in Barth syndrome[J]. J Heart Lung Transplant, 2021, 40(10): 1191-1198.

Sample	Age of onset /month	Age at diagnosis /month	Birth weight/g	Age at death /month	Cause of death	First presentation	Genotype	LVEF/LVFS /%	LVEDd Z score	LVPWd Z score	NC/C	Prolonged QTc	Neutropenia
BTHS 1	2.5	3	2 000	7	Heart failure with fever	Pneumonia	c.527A>G	45.6/22.1	5.7	0.45	1.58	-	-
BTHS 2	2.5	3	2 400	7.5	Heart failure with fever	Heart failure	c.527A>G	36.2/16.7	3.8	-0.12	2.2	-	-
BTHS 3	6	20	2 850	77	Accidental asphyxiation in a vegetative state	Muscle weakness	c.367C>T	40.1/19.1	3.3	1.96	2.11	-	+
BTHS 4	6.5	6.5	2 300	7.5	Ventricular fibrillation	Pneumonia	c.710_711delTG	36.8/17.3	5.3	2.18	2.75	-	+
BTHS 5	1	1	2 650	12	Heart failure and respiratory infection	Heart failure	c.134_136delinsCC	40.1/18.9	5.7	0.9	4	+	+
BTHS 6	0	6	3 620	Alive	-	Cardiomyopathy	c.324_325insCACTCC	62/31	0.24	1.54	2.19	+	+
BTHS 7	4	6	2 500	6	Sudden death	Growth delay	del TAZ	48.1/23.2	2.24	4.24	2.09	-	+
BTHS 8	0	1	3 100	Alive	-	Cardiomyopathy	c.718G>A	46.2/21.5	1.51	1.84	2.68	+	+
BTHS 9	1	1	3 250	13	Heart failure and respiratory infection	Diarrhea	c.589G>A	41.1/19.2	3.56	NA	1.95	+	-
BTHS 10	In utero	2	2 550	Alive	-	Cardiomyopathy	c.193A>G	35/15	4.46	-0.65	2.85	+	+
BTHS 11	4	4	2 400	5	Heart failure	Heart failure	c.226C>T	47.5/23.2	5.38	3.57	2.47	-	-
BTHS 12	5.5	5.5	2 500	Alive	-	Pneumonia	c.207C>A	44/21	4.65	2.27	2.4	+	-
BTHS 13	2	2	3 550	alive	-	Heart failure	c.85G>A	32.6/15	5.93	3.09	1.9	+	-
BTHS 14	1	1	3 050	7.5	Sudden death	Cardiomyopathy	Del exon 3‒5	50.8/24.9	2.64	2.17	2	-	-
BTHS 15	5	5	3 210	17	Sudden death	Diarrhea	c.777+1G>A	20/8.6	5.22	2.84	1.63	+	-
BTHS 16	In utero	0	2 315	0.1	Heart failure	Cardiomyopathy	c.699+1G>A	26.4/11.7	6.28	0.92	2	-	-
BTHS 17	3	3	2 800	Alive	-	Cardiomyopathy	c.589G>A	61.4/31.3	-0.02	4.41	1.94	NA	+
BTHS 18	4	4	4 150	6	Heart failure	Feeding difficulties	c.367C>T	41/19	4.93	4.22	1.5	+	+

Sample	Age of onset /month	Age at diagnosis /month	Birth weight/g	Age at death /month	Cause of death	First presentation	Genotype	LVEF/LVFS /%	LVEDd Z score	LVPWd Z score	NC/C	Prolonged QTc	Neutropenia
BTHS 1	2.5	3	2 000	7	Heart failure with fever	Pneumonia	c.527A>G	45.6/22.1	5.7	0.45	1.58	-	-
BTHS 2	2.5	3	2 400	7.5	Heart failure with fever	Heart failure	c.527A>G	36.2/16.7	3.8	-0.12	2.2	-	-
BTHS 3	6	20	2 850	77	Accidental asphyxiation in a vegetative state	Muscle weakness	c.367C>T	40.1/19.1	3.3	1.96	2.11	-	+
BTHS 4	6.5	6.5	2 300	7.5	Ventricular fibrillation	Pneumonia	c.710_711delTG	36.8/17.3	5.3	2.18	2.75	-	+
BTHS 5	1	1	2 650	12	Heart failure and respiratory infection	Heart failure	c.134_136delinsCC	40.1/18.9	5.7	0.9	4	+	+
BTHS 6	0	6	3 620	Alive	-	Cardiomyopathy	c.324_325insCACTCC	62/31	0.24	1.54	2.19	+	+
BTHS 7	4	6	2 500	6	Sudden death	Growth delay	del TAZ	48.1/23.2	2.24	4.24	2.09	-	+
BTHS 8	0	1	3 100	Alive	-	Cardiomyopathy	c.718G>A	46.2/21.5	1.51	1.84	2.68	+	+
BTHS 9	1	1	3 250	13	Heart failure and respiratory infection	Diarrhea	c.589G>A	41.1/19.2	3.56	NA	1.95	+	-
BTHS 10	In utero	2	2 550	Alive	-	Cardiomyopathy	c.193A>G	35/15	4.46	-0.65	2.85	+	+
BTHS 11	4	4	2 400	5	Heart failure	Heart failure	c.226C>T	47.5/23.2	5.38	3.57	2.47	-	-
BTHS 12	5.5	5.5	2 500	Alive	-	Pneumonia	c.207C>A	44/21	4.65	2.27	2.4	+	-
BTHS 13	2	2	3 550	alive	-	Heart failure	c.85G>A	32.6/15	5.93	3.09	1.9	+	-
BTHS 14	1	1	3 050	7.5	Sudden death	Cardiomyopathy	Del exon 3‒5	50.8/24.9	2.64	2.17	2	-	-
BTHS 15	5	5	3 210	17	Sudden death	Diarrhea	c.777+1G>A	20/8.6	5.22	2.84	1.63	+	-
BTHS 16	In utero	0	2 315	0.1	Heart failure	Cardiomyopathy	c.699+1G>A	26.4/11.7	6.28	0.92	2	-	-
BTHS 17	3	3	2 800	Alive	-	Cardiomyopathy	c.589G>A	61.4/31.3	-0.02	4.41	1.94	NA	+
BTHS 18	4	4	4 150	6	Heart failure	Feeding difficulties	c.367C>T	41/19	4.93	4.22	1.5	+	+

Item	M (Q₁, Q₃)
LVEF/%	41.1 (35.9, 47.7)
LVFS/%	19.2 (16.3, 23.2)
LVEDd Z score	4.56 (2.54, 5.46)
LVPWd Z score	2.17 (0.91, 3.33)
NC/C	2.10 (1.93, 2.52)

Item	M (Q₁, Q₃)
LVEF/%	41.1 (35.9, 47.7)
LVFS/%	19.2 (16.3, 23.2)
LVEDd Z score	4.56 (2.54, 5.46)
LVPWd Z score	2.17 (0.91, 3.33)
NC/C	2.10 (1.93, 2.52)

Location	Nucleotide change	Amino acid change	Type of mutation	Number of pedigree	Mother with proven TAZ mutation
Exon 1	c.85G>A	p.G29S	Missense mutation	1	Yes
Exon 2	c.134_136delinsCC	p.H45PfsX38	Frameshift mutation	1	Yes
Exon 2	c.193A>G	p.T65A	Missense mutation	1	Yes
Exon 2	c.207C>A	p.H69Q	Missense mutation	1	Yes
Exon 2	c.226C>T	p.P76S	Missense mutation	1	Yes
Exon 3‒5	Del exon 3‒5		Exon deletions	1	Yes
Exon 4	c.324_325insCACTCC	p.111_112insSH	Inframe mutation	1	Not mutated
Exon 4	c.367C>T	p.R123X	Nonsense mutation	2	Yes
Exon 6	c.527A>G	p.H176R	Missense mutation	2	Yes
Exon 8	c.589G>A	p.G197R	Missense mutation	2	Yes
Exon 10	c.710_711delTG	p.V237AfsX73	Frameshift mutation	1	Yes
Exon 10	c.718G>A	p.G240R	Missense mutation	1	Yes
Intron 9	c.699+1G>A	p.?	Splicing defect	1	Not available
Intron 10	c.777+1G>A	p.?	Splicing defect	1	Yes
TAZ gene	Del TAZ gene		Gene deletion	1	Not available