X-linked cardioskeletal myopathy and neutropenia (Barth syndrome)—MIM 302060
1999; Elsevier BV; Volume: 135; Issue: 3 Linguagem: Inglês
10.1016/s0022-3476(99)70118-6
ISSN1097-6833
AutoresP. G. Barth, Ronald J. A. Wanders, P. Vreken,
Tópico(s)Blood disorders and treatments
ResumoSee related article, p. 311 . In this issue of The Journal, Cantlay et al1Cantlay AM Shokrollahi K Allen JT Lunt PW Newbury-Ecob RA Steward CG. Genetic analysis of the G4.5 gene in families with suspected Barth syndrome.J Pediatr. 1999; 135: 311-315Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar focus on a rare, distinct metabolic disorder, X-linked cardioskeletal myopathy and neutropenia or Barth syndrome.2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar Findings in typical cases include (1) cardiomyopathy of the dilated type, (2) neutropenia, (3) skeletal myopathy, (4) diminished statural growth, and (5) 3-methylglutaconicaciduria. Cantlay et al1Cantlay AM Shokrollahi K Allen JT Lunt PW Newbury-Ecob RA Steward CG. Genetic analysis of the G4.5 gene in families with suspected Barth syndrome.J Pediatr. 1999; 135: 311-315Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar identified 5 unrelated families within 5 years in the area of Bristol (United Kingdom). Molecular analysis revealed 4 different mutations in the BTHS-associated G4,5 gene. These findings raise the question of whether BTHS is underdiagnosed. In order to resolve this important question, BTHS must be excluded vigorously in all suspected cases, taking into account its variable clinical expression. A number of families studied in Europe, North America, and Australia present essentially the same picture with some variation.1Cantlay AM Shokrollahi K Allen JT Lunt PW Newbury-Ecob RA Steward CG. Genetic analysis of the G4.5 gene in families with suspected Barth syndrome.J Pediatr. 1999; 135: 311-315Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar, 3Ino T Sherwood WG Cutz E Benson LN Rose V Freedom RM. Dilated cardiomyopathy with neutropenia, short stature, and abnormal carnitine metabolism.J Pediatr. 1988; 113: 511-514Abstract Full Text PDF PubMed Scopus (35) Google Scholar, 4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar, 5Bolhuis PA Hensels GW Hulsebos TJM Baas F Barth PG. Mapping of the locus for X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria (Barth syndrome) to Xq28.Am J Hum Genet. 1991; 48: 481-485PubMed Google Scholar, 6Adès LC Gedeon AK Wilson MJ Latham M Partington MW Mulley JC et al.Barth syndrome: clinical features and confirmation of gene localization to distal Xq28.Am J Med Genet. 1993; 45: 327-334Crossref PubMed Scopus (95) Google Scholar The most common presentation is that of a young, moderately growth-retarded male infant with cardiac failure caused by dilated cardiomyopathy. Presentation may be slowly progressive or precipitous. In most patients cardiomyopathy becomes manifest in infancy. Screening for neutropenia should be performed and repeated several times, especially during infections, because normal neutrophil counts may occur during periods of relative well-being; and the effects of neutropenia, although occasionally leading to life-threatening bacterial infections, are more often limited to mild involvement, such as persistent oral infections. Mild or moderate proximal muscle weakness should be specifically excluded by somatic investigation. This part of the clinical picture is usually non-progressive and only in a minority results in gross physical impairment. Growth charts usually reveal moderately retarded somatic growth, often just below the –2 SD line. Metabolic screening by gas chromatography–mass spectrometry will show elevated excretion of several organic acids, especially 3-methylglutaconic acid but also 3-methylglutaric acid and 2-ethyl-hydracrylic acid, in addition to a low serum cholesterol level. Chances are high that a pediatric cardiologist will take care of an infant or child affected by BTHS. Developments in the last decade have made it increasingly clear that metabolic investigation in any infant or child with cardiomyopathy is of utmost importance for the diagnosis of such treatable disorders as systemic carnitine deficiency, very-long-chain acyl coenzyme A dehydrogenase deficiency and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Also, various mitochondrial respiratory chain disorders, various lysosomal disorders, carbohydrate-deficient glycoprotein syndrome type I, and D-2-hydroxyglutaric aciduria may cause cardiomyopathy. BTHS is another reason for the pediatrician or pediatric cardiologist to initiate metabolic investigation in an infant or child with cardiomyopathy. The last decade has seen several new developments in BTHS. After its clinical and biochemical characterization,2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar, 3Ino T Sherwood WG Cutz E Benson LN Rose V Freedom RM. Dilated cardiomyopathy with neutropenia, short stature, and abnormal carnitine metabolism.J Pediatr. 1988; 113: 511-514Abstract Full Text PDF PubMed Scopus (35) Google Scholar, 4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar the gene was mapped to Xq28,5Bolhuis PA Hensels GW Hulsebos TJM Baas F Barth PG. Mapping of the locus for X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria (Barth syndrome) to Xq28.Am J Hum Genet. 1991; 48: 481-485PubMed Google Scholar, 6Adès LC Gedeon AK Wilson MJ Latham M Partington MW Mulley JC et al.Barth syndrome: clinical features and confirmation of gene localization to distal Xq28.Am J Med Genet. 1993; 45: 327-334Crossref PubMed Scopus (95) Google Scholar, 7Christodoulou J McInnes RR Jay V Wilson G Becker LE Lehotay DC et al.Barth syndrome: clinical observations and genetic linkage studies.Am J Med Genet. 1994; 50: 255-264Crossref PubMed Scopus (82) Google Scholar followed by positional cloning of the G4,5 gene8Bione S D'Adamo P Maestrini E Gedeon AK Bolhuis PA Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome.Nat Genet. 1996; 12: 385-389Crossref PubMed Scopus (593) Google Scholar and mutational analysis.9D'Adamo P Fassone L Gedeon A Janssen EAM Bione S Bolhuis PA et al.The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies.Am J Hum Genet. 1997; 61: 862-867Abstract Full Text PDF PubMed Scopus (200) Google Scholar, 10Johnston J Kelley RI Feigenbaum A Cox GF Iyer GS Funanage VL et al.Mutation characterization and genotype-phenotype correlation in Barth syndrome.Am J Hum Genet. 1997; 61: 1053-1058Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar This latter result has made it possible to make a definite diagnosis and to offer antenatal diagnostics for future pregnancies in an affected family. The G4,5 gene located on Xq28 has 11 exons. Differential splicing produces 5 different messenger RNAs, dependent on alternate splicing of exons 5, 6, and 7. There are 2 transcription initiation sites, on exons 1 and 3. Because of the two 5 ́ ends together with the various splice variants, up to 10 different mRNAs can be detected. Together these predict a total of 10 proteins, for which the name tafazzins was proposed.8Bione S D'Adamo P Maestrini E Gedeon AK Bolhuis PA Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome.Nat Genet. 1996; 12: 385-389Crossref PubMed Scopus (593) Google Scholar Most important is the fact that translation may start at 2 sites. When it starts at the first ATG initiation site, the result is a protein that carries an N-terminal hydrophobic stretch of 30 residues expected to function as a membrane anchor. When translation starts at the second downstream ATG site, it skips exons 1 and 2 and produces a protein without the hydrophobic stretch, which is predicted to be a soluble, cytoplasmic protein. The meaning of 2 fundamentally different gene products, one membrane-bound and the other cytosolic, is not clear. Twenty-five mutations of the G4,5 gene were published by 2 groups in 1997; the mutations involved exons 1-3 and 6-10 and some adjacent intron sequences, resulting in a variety of gene alterations including missense and nonsense mutations, splice site mutations, and various deletions of one or more base pairs resulting in frame shifts, some in highly conserved regions. Patients with a mutation that produces a stop codon in exons 1 and 2 are enigmatic, because the site of their mutation predicts absence of the membrane-bound protein. These patients do not appear to have more severe involvement than those with a mutation in one of the other exons. The production of non-membrane-bound, soluble tafazzin protein is still possible when transcription starts from the second initiation site at exon 3, which is downstream from a mutation in exon 1 or exon 2. In the other cases with a mutation downstream from the second ATG site, an altered or truncated protein would be predicted. This must be confirmed by studies in which the expression of the protein in tissues obtained from patients is examined. The finding of the gene associated with BTHS has allowed the expansion of the phenotype to X-linked noncompaction of the left ventricular myocardium, a cardiac malformation with an early lethal course. Other findings common to BTHS are either absent or inconstant. A missense mutation in exon 8 was found.11Bleyl SB Mumford BR Brown-Harrison MC Pagotto LT Carey JC Pysher TJ et al.Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals.Am J Med Genet. 1997; 72: 257-265Crossref PubMed Scopus (288) Google Scholar, 12Bleyl SB Mumford BR Thompson V Carey JC Pysher TJ Chin TK et al.Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome.Am J Hum Genet. 1997; 61: 868-872Abstract Full Text PDF PubMed Scopus (257) Google Scholar Another, possibly distinct phenotype, with early severe cardiomyopathy without 3-methylglutaconicaciduria has been described in a family13Gedeon AK Wilson MJ Colley AC Sillence DO Mulley JC. X linked fatal cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome.J Med Genet. 1995; 32: 383-388Crossref PubMed Scopus (49) Google Scholar carrying a frameshift deletion in exon 8 resulting in a stop codon.9D'Adamo P Fassone L Gedeon A Janssen EAM Bione S Bolhuis PA et al.The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies.Am J Hum Genet. 1997; 61: 862-867Abstract Full Text PDF PubMed Scopus (200) Google Scholar It may be significant that the 2 more severe phenotypes are associated with exon 8, which represents a highly conserved part that is common to all tafazzins. Obligate female carriers of BTHS do not show clinical symptoms. Ørstavik et al14Ørstavik KH Ørstavik RE Naumova AK D'Adamo P Gedeon A Bolhuis PA et al.X chromosome inactivation in carriers of Barth syndrome.Am J Hum Genet. 1998; 63: 1457-1463Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar studied X-inactivation patterns in female carriers with BTHS and found skewed X inactivation, likely to be the result of a selection against cells that have the mutated gene on the active X chromosome. This fits well with the absence of clinical symptoms. Neuwald,15Neuwald AF. Barth syndrome may be due to an acyltransferase deficiency.Curr Biol. 1997; 7: R465-R466Abstract Full Text Full Text PDF PubMed Google Scholar using a genomic database approach to the gene sequence, has demonstrated that homologues of the G4,5 gene are conserved throughout many species including yeast and Caenorhabditis elegans and that they show sequence homology to a superfamily of acyltransferases. This surprising homology led to the speculation that the product of the G4,5 gene is involved in the synthesis or turnover of one or more complex lipids. Further studies must settle the mechanism involved. Previous results or biochemical studies came from 2 fundamentally different approaches. In their early studies Kelley et al,4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar after excluding leucine breakdown as a major source of 3-methylglutaconic acid excretion in BTHS, suggested a block in the anabolic pathway, which leads to isoprenes and cholesterol. This would explain both the low cholesterol and the elevated 3-methylglutaconic acid levels. So far, this hypothesis has not been experimentally verified. In vitro studies excluded an enzymatic block in the route from leucine to 3-hydroxy-3-methyl-glutaric acid and between 3-hydroxy-3-methyl-glutaric acid and sterols, ubiquinone and dolichol.16Gibson KM Sherwood WG Hoffmann GF Stumpf DA Dianzani I Schutgens RBH et al.Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria.J Pediatr. 1991; 118: 885-890Abstract Full Text PDF PubMed Scopus (51) Google Scholar Furthermore, this interpretation does not account for the other abnormality consistently found in BTHS, that is, the increased levels of the branched chain organic acid 2-ethyl-hydracrylic acid, which is known to be a product of the catabolism of isoleucine and allo-isoleucine.4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar, 14Ørstavik KH Ørstavik RE Naumova AK D'Adamo P Gedeon A Bolhuis PA et al.X chromosome inactivation in carriers of Barth syndrome.Am J Hum Genet. 1998; 63: 1457-1463Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar The other approach has been directed toward mitochondrial respiratory chain dysfunction. Abnormal mitochondria were found in myocardial specimens.2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar, 17Neustein HB Lurie PR Dahms B Takahashi M. An X-linked recessive cardiomyopathy with abnormal mitochondria.Pediatrics. 1979; 64: 24-29PubMed Google Scholar Variable lactic aciduria2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar, 4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar and excess excretion of citric acid cycle intermediates were observed.4Kelley RI Cheatham JP Clark BJ Nigro MA Powell BR Sherwood GW et al.X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.J Pediatr. 1991; 119: 737-738Abstract Full Text PDF Scopus (214) Google Scholar Mitochondrial respiratory chain studies in BTHS provide variable results, indicating involvement of more than a single complex in muscle biopsy specimens.2Barth PG Scholte HR Berden JA van der Klei-van Moorsel JM Luyt-Houwen IEM van 't Veer-Korthof ETh et al.An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.J Neurol Sci. 1983; 62: 327-355Abstract Full Text PDF PubMed Scopus (536) Google Scholar, 6Adès LC Gedeon AK Wilson MJ Latham M Partington MW Mulley JC et al.Barth syndrome: clinical features and confirmation of gene localization to distal Xq28.Am J Med Genet. 1993; 45: 327-334Crossref PubMed Scopus (95) Google Scholar, 7Christodoulou J McInnes RR Jay V Wilson G Becker LE Lehotay DC et al.Barth syndrome: clinical observations and genetic linkage studies.Am J Med Genet. 1994; 50: 255-264Crossref PubMed Scopus (82) Google Scholar Published results in fibroblasts are normal7Christodoulou J McInnes RR Jay V Wilson G Becker LE Lehotay DC et al.Barth syndrome: clinical observations and genetic linkage studies.Am J Med Genet. 1994; 50: 255-264Crossref PubMed Scopus (82) Google Scholar or indicate multiple involvement.18Barth PG Van den Bogert C Bolhuis PA Scholte HR van Gennip AH Schutgens RBH et al.X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): respiratory chain abnormalities in cultured fibroblasts.J Inherit Metab Dis. 1996; 19: 157-160Crossref PubMed Scopus (84) Google Scholar 3-Methylglutaconicaciduria may not indicate a specific enzyme defect because it has been found in patients with a variety of different respiratory chain disorders. No deletions or rearrangements have been found in mitochondrial DNA, excluding nuclear DNA–driven mitochondrial DNA abnormalities as a mechanism. A remaining possibility to explain the findings in BTHS is an abnormality in the inner mitochondrial membrane, which impairs the functioning of more than one of the complexes. Membrane structure of the mitochondria, especially the inner membrane that carries the respiratory complexes, may be altered by an abnormal lipid structure. Prompted by the Neuwald hypothesis, this interesting possibility now leads to attempts in various laboratories, including our own, to characterize the lipid membrane structure of the mitochondria in BTHS.15Neuwald AF. Barth syndrome may be due to an acyltransferase deficiency.Curr Biol. 1997; 7: R465-R466Abstract Full Text Full Text PDF PubMed Google Scholar For the moment, therapeutic prospects are limited. Myocardial failure is amenable to standard treatment. In severe cases of progressive myocardial failure, cardiac transplantation has been performed.19Adwani SS Whitehead BF Rees PG Whitmore P Fabre JW Elliott MJ et al.Heart transplantation for dilated cardiomyopathy.Arch Dis Child. 1995; 73: 447-452Crossref PubMed Scopus (16) Google Scholar Several therapies have been offered on the basis of suspected metabolic derangement, but none has been a singular success so far, probably because none has addressed the basic molecular defect of BTHS.
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