Eur J Pediatr DOI 10.1007/s00431-015-2574-9
CASE REPORT
Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein Tiina Ojala 1 & Irmeli Nupponen 1 & Carola Saloranta 2 & Taisto Sarkola 1 & Priya Sekar 3 & Anniina Breilin 1 & Tiina Tyni 1
Received: 20 February 2015 / Revised: 12 May 2015 / Accepted: 26 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks. The fetus was small for gestational age, and long bones were abnormally short. The baby was born severely asphyxiated at 32 gestational weeks by cesarean section. Intensive care was withdrawn due to failure to thrive and suspicion of a severe mitochondrial disorder. Postmortem brain MRI suggested Communicated by Mario Bianchetti * Tiina Ojala [email protected] Irmeli Nupponen [email protected] Carola Saloranta [email protected] Taisto Sarkola [email protected] Priya Sekar [email protected] Anniina Breilin [email protected] Tiina Tyni [email protected] 1
Department on Pediatrics, Children’s Hospital, University Hospital of Helsinki, Stenbackinkatu 11, PL 281, 00029 HUS, Helsinki, Finland
2
Department of Clinical Genetics, Finland and Fetomaternal Center, Helsinki University Hospital, Helsinki, Finland
3
Department of Pediatric Cardiology, The John Hopkins Hospital, Baltimore, MD, USA
microcephaly with a simplified gyral pattern. The lateral cerebral ventricles were normal. Chromosome analysis was normal (46, XX). Fibroblasts cultured from a skin biopsy of the baby revealed the large homozygous deletion c.1109+ 243_1438-703del in the HADHB gene, and heterozygous mutations were detected in both parents. The deletion has not been reported earlier. Conclusion: It is important to differentiate systemic metabolic diseases from disorders that affect only the cardiac muscle. Trifunctional protein deficiency is a relatively rare disorder of the fatty acid β-oxidation cycle. The mutation in the HADHB gene causes a systemic disease with early-onset cardiomyopathy. Understanding the molecular genetic defect of the patient allows appropriate genetic counseling of the family. What is Known: • Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases. What is New: • We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).
Keywords Fetal cardiomyopathy . Echocardiography . Trifunctional protein . Noncompaction cardiomyopathy
Abbreviations AFLP Acute fatty liver pregnancy syndrome syndrome HADHA Gene encoding the α-subunit of long-chain gene hydroxyacyl-CoA dehydrogenase
Eur J Pediatr
HADHB gene HELLP syndrome TFP
Gene encoding the β-subunit of long-chain hydroxyacyl-CoA dehydrogenase Hemolysis, elevated liver enzyme, low platelet syndrome Trifunctional protein
Introduction Mitochondrial trifunctional protein (TFP), an enzyme of fatty acid β-oxidation, is a multienzyme complex composed of four α-subunits (encoded by HADHA) and four β-subunits (encoded by HADHB). The most severe phenotype of TFP deficiency is characterized by severe cardiomyopathy, lactic acidosis, hypoketotic hypoglycemia, and neonatal death [6]. We report a fetal case with fatal outcome having a novel HADHB mutation. This study is part of a larger project aimed at improving the etiologic diagnostics available for Finnish children with cardiomyopathy. Written informed consent was obtained from the patients’ parents, and the study has been approved by the ethical committee of Helsinki University Central Hospital, Helsinki, Finland.
Case presentation A 29-year-old healthy female has had three pregnancies. The first pregnancy ended in a fetus mortus at 32 gestational weeks in 2005. This fetus was autopsied in Turkey, and the postmortem analysis revealed fetal cardiac insufficiency and ascites. Her second pregnancy in 2008 resulted in the birth of a healthy child. The parents of the baby were first cousins. The third pregnancy originated in 2011. In the first trimester ultrasound, a 5.1-mm nuchal translucency was found, but the mother did not opt for placental biopsy at that time point. In the anomaly screening at 22 weeks of gestation, the nuchal fold was 10 mm and the growth of the fetus was 2 weeks behind. Furthermore, cardiac size was increased. Fetal cardiac echocardiography was recommended. Fetal cardiac echocardiogram showed a structurally normal heart with mild cardiac enlargement (cardio/thoracic area ratio over 0.5). Further, significant biventricular cardiac hypertrophy was observed. The findings suggested fetal cardiomyopathy. No diastolic or systolic (fractional shortening (FS) 30 %) cardiac dysfunction was detected. Although there was mild tricuspid regurgitation, the flow profiles in the systemic venous Dopplers were normal (Fig. 1). Amniotic fluid test showed normal female chromosomes (46, XX). Based on the cardiac findings and family history, parents were informed that the prognosis of the fetus was likely to be poor. If the fetus would develop hydrops, there would be a high risk for fetal death. Close pregnancy follow-up was recommended.
At 29 gestational weeks, at a routine follow-up visit, cardiac enlargement, biventricular symmetric hypertrophy, and cardiac function remained the same. However, the right pleural cavity contained a mild pleural effusion. The mother was treated with antenatal corticosteroids for fetal lung maturation due to increased risk of preterm labor. Three weeks later (at 32 gestational weeks), the massive pleural effusions, fetal skin edema, and mild cardiac systolic compromise were detected (FS 24 %). Fetal lungs were compressed. Due to hydrops and suspected fetal asphyxia, pleural puncture and delivery were initiated (Fig. 2). After birth, remarkable neonatal lactatemia (fP-lactate 6– 15 mmol/l) and metabolic acidosis (pH 6.95–7.12, BE −15–(−21)) were noted. Acidosis persisted and did not response to any treatment procedures. A neonatal cardiac ultrasound showed symmetric hypertrophy of both ventricles. Furthermore, there was obvious left ventricle noncompaction (an end systolic ratio of noncompacted to compacted layers of >2). Intensive care was withdrawn because of lung and heart failure despite maximal support. Parents declined fetal autopsy. Postmortem brain MRI suggested that the cerebral cortical gyri were poorly formed, particularly in the frontal and temporal region. The cortical structures were poorly developed suggesting microcephaly Bwith simplified gyral pattern,^ particularly in frontal and temporal regions. In diffusion brain imaging, the diffusion was limited to the thalamic and basal ganglia regions. However, this finding might only be a postmortem change. The cerebral ventricle sizes were normal. Suspicion of fatty acid β-oxidation cycle and TFP deficiency was raised after urinary organic acid analysis. Increased concentration of long-chain 3-hydroxyacyl-carnitines was detected suggesting deficiency of long-chain 3-hydroxyacylcarnitine dehydrogenase. As a first step, fibroblasts cultured from a skin biopsy of the baby revealed that the Finnish founder mutation was not found in the HADHA gene. The molecular genetic analysis was continued in the academisch medisch centrum (AMC) laboratory (Amsterdam, Netherlands), and a homozygous gene defect in the HADHB gene, c1109+243_14338-703del, was revealed in the fetus. Both parents were heterozygous carriers of the same mutation. The mutation resulted in the most severe type of TFP defect with a lethal mitochondrial disease, including cardiomyopathy. In this case, there were no therapeutic options. Genetic counseling was offered to the parents. The disease is recessively inherited, and in each pregnancy of the couple, there is a 25 % risk that the baby inherits the mutation in a homozygous state, in which case the baby will get TFP deficiency. Respectively, in each pregnancy, there is a 75 % possibility that the baby is healthy regarding this disease. During pregnancy, the genetic status of the fetus is possible to determine from chorionic villus or amniotic fluid samples. There is a sampling-related miscarriage risk of about 0.5 %. If the fetus
Eur J Pediatr
Fig. 1 Fetal cardiac assessments showed no cardiac diastolic dysfunction or increased central venous pressure. All measurements were normal in systemic venous Dopplers of inferior caval vein, ductus venosus, and umbilical vein. Normal findings throughout the follow-up were
measured also in left or right ventricular inflow Dopplers (biphasic and normal duration). Tricuspid valve had mild regurgitation with 30 mmHg between right ventricle and right atrium suggesting normal right ventricular systolic function at 29 gestational weeks
has inherited the mutation in a homozygous state, and as a result has TFP deficiency, termination of the pregnancy is an option. Fetal TFP deficiency can also induce potentially lifethreatening diseases featuring acute fatty liver (AFLP) or hemolysis, elevated liver enzymes, and low platelets (HELLP) in the mother.
marriage is common. This is well in line with the fact that both parents carried the same mutation. Mitochondrial TFP deficiency is a rare genetic disorder of the fatty acid β-oxidation cycle. The human TFP is an enzymatic complex consisting of four α-subunits (encoded by HADHA) and four β-subunits (encoded by HADHB) located in association with the inner mitochondrial membrane. The alpha subunit contains the 2.3-long-chain enoyl-CoA hydratase and the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) domains, and the beta-subunit harbors the long-chain 3-ketoacyl-CoA thiolase (LKAT) domain. These enzymes catalyze the last steps of the β-oxidation spiral of long-chain fatty acids. Mutations resulting in TFP deficiency in one subunit reduce activities of all three enzymes for an unclear reason. The TFP subunits are coded by separate nuclear genes located in the same region of chromosome 2p23 [9]. The most common defect of the TFP complex is LCHAD deficiency caused by mutations in HADHA. Mutations in HADHB are rarer. Both alpha and beta subunits are equally essential for stabilizing the TFP complex. Because the mechanism of the disease is the same in both HADHA- and HADHB-related TPF deficiency, the clinical phenotype is similar in both groups. Three different phenotypes have been described: the lethal phenotype, the infant-onset hepatic phenotype, and the later-onset neuromyopathic phenotype. The lethal phenotype is characterized by severe cardiomyopathy, lactic acidosis, hypoketotic hypoglycemia, and neonatal death [1, 6]. The phenotype of our patient was the most severe form of TFP deficiency and was caused by a new mutation in the HADHB gene. Cardiac involvements with cardiomyopathy and arrhythmias are frequent findings in TFP deficiency. The pathogenic mechanisms involved in heart function in these patients are still not fully established. Recently, it has been suggested that
Discussion We report a case with severe fetal left ventricular noncompaction and hypertrophic cardiomyopathy caused by a homozygous c.1109+243_1438-703del mutation in the HADHB gene. Based on our knowledge, this deletion of our patient has not been reported earlier. The parents were first cousins and also belong to a culture were consanguineous
Fig. 2 A massive pleural effusion was noticed at 32 weeks of gestation, resulting in mild decrease of biventricular systolic function. Intrauterine pleural puncture and delivery were planned. After birth, hypertrophic cardiomyopathy with left ventricular noncompaction was confirmed
Eur J Pediatr
impairment of heart energy homeostasis is due to accumulation of mitochondrial oxidative metabolites and thereby increased mitochondrial resting respiration in these patients. It has further been suggested that mitochondrial permeability inhibitors may be potentially interesting as therapeutic candidates for the heart alterations in these patients [7]. The etiologic spectrum of fetal cardiomyopathy is broad, and the disease is associated with substantial mortality [4, 8], particularly for hydroptic fetuses [5]. It has recently been shown that despite of etiological heterogeneity, the prognosis of fetal cardiomyopathy is closely associated with the phenotypic. Hypertrophic cardiomyopathy carries worse prognosis and has very high risk for perinatal demise in comparison to nonhypertrophic ones [8]. As shown in our patient, left ventricular noncompaction should be suspected especially if ventricular walls are thickened [2]. Early echocardiographic findings appear useful in predicting adverse outcomes [8]. Fetal cardiac diastolic dysfunction with increased ventricular filling pressure leading to high central venous pressure is especially poorly tolerated and carries the greatest risk of mortality in these cases [3]. However, extracardiac conditions can impact myocardial function negatively, as was the case in our patient. Fetal hydrops developed, not because of increased central venous pressure reflected by normal systemic venous Doppler, but because of metabolic abnormality and massive pleural effusion suggesting primary lymphatic abnormalities. Finally, it is important to differentiate systemic diseases from disorders that affect only the cardiac muscle in order to provide accurate counseling regarding pregnancy prognosis and for planning of the most appropriate perinatal management. In conclusion, TFP deficiency is a relatively rare disorder. The mutation in HADHB causes a systemic disorder with cardiomyopathy originating already in fetal life. Detailed fetal assessment for both structural and functional pathology and for arrhythmias is of critical importance in these patients. Understanding the molecular genetic defect behind the disease allows for genetic counseling of the family, and earlier prenatal diagnosis can be offered in future pregnancies. The specific diagnosis in this case was made even though autopsy was withheld. Acknowledgments The manuscript was supported by grants from the Finnish Pediatric Research Foundation. Conflict of interest The authors declare that they have no competing interests.
Compliance with ethical standards All procedures performed in study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the parents. Authors Contributions Dr Tiina Ojala and Tiina Tyni are primary responsibility for data collection and data analysis and writing the manuscript. Dr Tiina Ojala, Tiina Tyni, Taisto Sarkola, Irmeli Nupponen and Carola Saloranta contributed to the clinical treatment of the patients and the writing of the manuscript. Dr Priya Sekar and Dr Anniina Breilin contributed to the interpretation of the analysis and writing of the manuscript.
References 1.
2.
3. 4.
5.
6.
7.
8.
9.
Grunewald S, Bakkeren J, Wanders RA, Wendel U (1997) Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect. J Inherit Metab Dis 20:835–836 Menon SC, O’Leary PW, Wright GB, Rios R, MacLellan-Tobert SG, Cabalka AK (2007) Fetal and neonatal presentation of noncompacted ventricular myocardium: expanding the clinical spectrum. J Am Soc Echocardiogr 20:1344–1350 Ojala TH, Hornberger LK (2010) Fetal heart failure. Front Biosci (Schol Ed) 2:891–906 Pedra SR, Smallhorn JF, Ryan G, Chitayat D, Taylor GP, Khan R, Abdolell M, Hornberger LK (2002) Fetal cardiomyopathies: pathogenic mechanisms, hemodynamic findings, and clinical outcome. Circulation 106:585–591 Sivasankaran S, Sharland GK, Simpson JM (2005) Dilated cardiomyopathy presenting during fetal life. Cardiol Young 15:409–416 Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW (2004) General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 55:190–196 Tonin AM, Amaral AU, Busanello EN, Grings M, Castilho RF, Wajner M (2013) Long-chain 3-hydroxy fatty acids accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies uncouple oxidative phosphorylation in heart mitochondria. J Bioenerg Biomembr 45:47–57 Weber R, Kantor P, Chitayat D, Friedberg MK, Golding F, Mertens L, Nield LE, Ryan G, Seed M, Yoo SJ, Manlhiot C, Jaeggi E (2014) Spectrum and outcome of primary cardiomyopathies diagnosed during fetal life. JACC Heart Fail 2:403–411 Yang BZ, Heng HH, Ding JH, Roe CR (1996) The genes for the alpha and beta subunits of the mitochondrial trifunctional protein are both located in the same region of human chromosome 2p23. Genomics 37:141–143
CASE REPORT
Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein Tiina Ojala 1 & Irmeli Nupponen 1 & Carola Saloranta 2 & Taisto Sarkola 1 & Priya Sekar 3 & Anniina Breilin 1 & Tiina Tyni 1
Received: 20 February 2015 / Revised: 12 May 2015 / Accepted: 26 May 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks. The fetus was small for gestational age, and long bones were abnormally short. The baby was born severely asphyxiated at 32 gestational weeks by cesarean section. Intensive care was withdrawn due to failure to thrive and suspicion of a severe mitochondrial disorder. Postmortem brain MRI suggested Communicated by Mario Bianchetti * Tiina Ojala [email protected] Irmeli Nupponen [email protected] Carola Saloranta [email protected] Taisto Sarkola [email protected] Priya Sekar [email protected] Anniina Breilin [email protected] Tiina Tyni [email protected] 1
Department on Pediatrics, Children’s Hospital, University Hospital of Helsinki, Stenbackinkatu 11, PL 281, 00029 HUS, Helsinki, Finland
2
Department of Clinical Genetics, Finland and Fetomaternal Center, Helsinki University Hospital, Helsinki, Finland
3
Department of Pediatric Cardiology, The John Hopkins Hospital, Baltimore, MD, USA
microcephaly with a simplified gyral pattern. The lateral cerebral ventricles were normal. Chromosome analysis was normal (46, XX). Fibroblasts cultured from a skin biopsy of the baby revealed the large homozygous deletion c.1109+ 243_1438-703del in the HADHB gene, and heterozygous mutations were detected in both parents. The deletion has not been reported earlier. Conclusion: It is important to differentiate systemic metabolic diseases from disorders that affect only the cardiac muscle. Trifunctional protein deficiency is a relatively rare disorder of the fatty acid β-oxidation cycle. The mutation in the HADHB gene causes a systemic disease with early-onset cardiomyopathy. Understanding the molecular genetic defect of the patient allows appropriate genetic counseling of the family. What is Known: • Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases. What is New: • We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).
Keywords Fetal cardiomyopathy . Echocardiography . Trifunctional protein . Noncompaction cardiomyopathy
Abbreviations AFLP Acute fatty liver pregnancy syndrome syndrome HADHA Gene encoding the α-subunit of long-chain gene hydroxyacyl-CoA dehydrogenase
Eur J Pediatr
HADHB gene HELLP syndrome TFP
Gene encoding the β-subunit of long-chain hydroxyacyl-CoA dehydrogenase Hemolysis, elevated liver enzyme, low platelet syndrome Trifunctional protein
Introduction Mitochondrial trifunctional protein (TFP), an enzyme of fatty acid β-oxidation, is a multienzyme complex composed of four α-subunits (encoded by HADHA) and four β-subunits (encoded by HADHB). The most severe phenotype of TFP deficiency is characterized by severe cardiomyopathy, lactic acidosis, hypoketotic hypoglycemia, and neonatal death [6]. We report a fetal case with fatal outcome having a novel HADHB mutation. This study is part of a larger project aimed at improving the etiologic diagnostics available for Finnish children with cardiomyopathy. Written informed consent was obtained from the patients’ parents, and the study has been approved by the ethical committee of Helsinki University Central Hospital, Helsinki, Finland.
Case presentation A 29-year-old healthy female has had three pregnancies. The first pregnancy ended in a fetus mortus at 32 gestational weeks in 2005. This fetus was autopsied in Turkey, and the postmortem analysis revealed fetal cardiac insufficiency and ascites. Her second pregnancy in 2008 resulted in the birth of a healthy child. The parents of the baby were first cousins. The third pregnancy originated in 2011. In the first trimester ultrasound, a 5.1-mm nuchal translucency was found, but the mother did not opt for placental biopsy at that time point. In the anomaly screening at 22 weeks of gestation, the nuchal fold was 10 mm and the growth of the fetus was 2 weeks behind. Furthermore, cardiac size was increased. Fetal cardiac echocardiography was recommended. Fetal cardiac echocardiogram showed a structurally normal heart with mild cardiac enlargement (cardio/thoracic area ratio over 0.5). Further, significant biventricular cardiac hypertrophy was observed. The findings suggested fetal cardiomyopathy. No diastolic or systolic (fractional shortening (FS) 30 %) cardiac dysfunction was detected. Although there was mild tricuspid regurgitation, the flow profiles in the systemic venous Dopplers were normal (Fig. 1). Amniotic fluid test showed normal female chromosomes (46, XX). Based on the cardiac findings and family history, parents were informed that the prognosis of the fetus was likely to be poor. If the fetus would develop hydrops, there would be a high risk for fetal death. Close pregnancy follow-up was recommended.
At 29 gestational weeks, at a routine follow-up visit, cardiac enlargement, biventricular symmetric hypertrophy, and cardiac function remained the same. However, the right pleural cavity contained a mild pleural effusion. The mother was treated with antenatal corticosteroids for fetal lung maturation due to increased risk of preterm labor. Three weeks later (at 32 gestational weeks), the massive pleural effusions, fetal skin edema, and mild cardiac systolic compromise were detected (FS 24 %). Fetal lungs were compressed. Due to hydrops and suspected fetal asphyxia, pleural puncture and delivery were initiated (Fig. 2). After birth, remarkable neonatal lactatemia (fP-lactate 6– 15 mmol/l) and metabolic acidosis (pH 6.95–7.12, BE −15–(−21)) were noted. Acidosis persisted and did not response to any treatment procedures. A neonatal cardiac ultrasound showed symmetric hypertrophy of both ventricles. Furthermore, there was obvious left ventricle noncompaction (an end systolic ratio of noncompacted to compacted layers of >2). Intensive care was withdrawn because of lung and heart failure despite maximal support. Parents declined fetal autopsy. Postmortem brain MRI suggested that the cerebral cortical gyri were poorly formed, particularly in the frontal and temporal region. The cortical structures were poorly developed suggesting microcephaly Bwith simplified gyral pattern,^ particularly in frontal and temporal regions. In diffusion brain imaging, the diffusion was limited to the thalamic and basal ganglia regions. However, this finding might only be a postmortem change. The cerebral ventricle sizes were normal. Suspicion of fatty acid β-oxidation cycle and TFP deficiency was raised after urinary organic acid analysis. Increased concentration of long-chain 3-hydroxyacyl-carnitines was detected suggesting deficiency of long-chain 3-hydroxyacylcarnitine dehydrogenase. As a first step, fibroblasts cultured from a skin biopsy of the baby revealed that the Finnish founder mutation was not found in the HADHA gene. The molecular genetic analysis was continued in the academisch medisch centrum (AMC) laboratory (Amsterdam, Netherlands), and a homozygous gene defect in the HADHB gene, c1109+243_14338-703del, was revealed in the fetus. Both parents were heterozygous carriers of the same mutation. The mutation resulted in the most severe type of TFP defect with a lethal mitochondrial disease, including cardiomyopathy. In this case, there were no therapeutic options. Genetic counseling was offered to the parents. The disease is recessively inherited, and in each pregnancy of the couple, there is a 25 % risk that the baby inherits the mutation in a homozygous state, in which case the baby will get TFP deficiency. Respectively, in each pregnancy, there is a 75 % possibility that the baby is healthy regarding this disease. During pregnancy, the genetic status of the fetus is possible to determine from chorionic villus or amniotic fluid samples. There is a sampling-related miscarriage risk of about 0.5 %. If the fetus
Eur J Pediatr
Fig. 1 Fetal cardiac assessments showed no cardiac diastolic dysfunction or increased central venous pressure. All measurements were normal in systemic venous Dopplers of inferior caval vein, ductus venosus, and umbilical vein. Normal findings throughout the follow-up were
measured also in left or right ventricular inflow Dopplers (biphasic and normal duration). Tricuspid valve had mild regurgitation with 30 mmHg between right ventricle and right atrium suggesting normal right ventricular systolic function at 29 gestational weeks
has inherited the mutation in a homozygous state, and as a result has TFP deficiency, termination of the pregnancy is an option. Fetal TFP deficiency can also induce potentially lifethreatening diseases featuring acute fatty liver (AFLP) or hemolysis, elevated liver enzymes, and low platelets (HELLP) in the mother.
marriage is common. This is well in line with the fact that both parents carried the same mutation. Mitochondrial TFP deficiency is a rare genetic disorder of the fatty acid β-oxidation cycle. The human TFP is an enzymatic complex consisting of four α-subunits (encoded by HADHA) and four β-subunits (encoded by HADHB) located in association with the inner mitochondrial membrane. The alpha subunit contains the 2.3-long-chain enoyl-CoA hydratase and the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) domains, and the beta-subunit harbors the long-chain 3-ketoacyl-CoA thiolase (LKAT) domain. These enzymes catalyze the last steps of the β-oxidation spiral of long-chain fatty acids. Mutations resulting in TFP deficiency in one subunit reduce activities of all three enzymes for an unclear reason. The TFP subunits are coded by separate nuclear genes located in the same region of chromosome 2p23 [9]. The most common defect of the TFP complex is LCHAD deficiency caused by mutations in HADHA. Mutations in HADHB are rarer. Both alpha and beta subunits are equally essential for stabilizing the TFP complex. Because the mechanism of the disease is the same in both HADHA- and HADHB-related TPF deficiency, the clinical phenotype is similar in both groups. Three different phenotypes have been described: the lethal phenotype, the infant-onset hepatic phenotype, and the later-onset neuromyopathic phenotype. The lethal phenotype is characterized by severe cardiomyopathy, lactic acidosis, hypoketotic hypoglycemia, and neonatal death [1, 6]. The phenotype of our patient was the most severe form of TFP deficiency and was caused by a new mutation in the HADHB gene. Cardiac involvements with cardiomyopathy and arrhythmias are frequent findings in TFP deficiency. The pathogenic mechanisms involved in heart function in these patients are still not fully established. Recently, it has been suggested that
Discussion We report a case with severe fetal left ventricular noncompaction and hypertrophic cardiomyopathy caused by a homozygous c.1109+243_1438-703del mutation in the HADHB gene. Based on our knowledge, this deletion of our patient has not been reported earlier. The parents were first cousins and also belong to a culture were consanguineous
Fig. 2 A massive pleural effusion was noticed at 32 weeks of gestation, resulting in mild decrease of biventricular systolic function. Intrauterine pleural puncture and delivery were planned. After birth, hypertrophic cardiomyopathy with left ventricular noncompaction was confirmed
Eur J Pediatr
impairment of heart energy homeostasis is due to accumulation of mitochondrial oxidative metabolites and thereby increased mitochondrial resting respiration in these patients. It has further been suggested that mitochondrial permeability inhibitors may be potentially interesting as therapeutic candidates for the heart alterations in these patients [7]. The etiologic spectrum of fetal cardiomyopathy is broad, and the disease is associated with substantial mortality [4, 8], particularly for hydroptic fetuses [5]. It has recently been shown that despite of etiological heterogeneity, the prognosis of fetal cardiomyopathy is closely associated with the phenotypic. Hypertrophic cardiomyopathy carries worse prognosis and has very high risk for perinatal demise in comparison to nonhypertrophic ones [8]. As shown in our patient, left ventricular noncompaction should be suspected especially if ventricular walls are thickened [2]. Early echocardiographic findings appear useful in predicting adverse outcomes [8]. Fetal cardiac diastolic dysfunction with increased ventricular filling pressure leading to high central venous pressure is especially poorly tolerated and carries the greatest risk of mortality in these cases [3]. However, extracardiac conditions can impact myocardial function negatively, as was the case in our patient. Fetal hydrops developed, not because of increased central venous pressure reflected by normal systemic venous Doppler, but because of metabolic abnormality and massive pleural effusion suggesting primary lymphatic abnormalities. Finally, it is important to differentiate systemic diseases from disorders that affect only the cardiac muscle in order to provide accurate counseling regarding pregnancy prognosis and for planning of the most appropriate perinatal management. In conclusion, TFP deficiency is a relatively rare disorder. The mutation in HADHB causes a systemic disorder with cardiomyopathy originating already in fetal life. Detailed fetal assessment for both structural and functional pathology and for arrhythmias is of critical importance in these patients. Understanding the molecular genetic defect behind the disease allows for genetic counseling of the family, and earlier prenatal diagnosis can be offered in future pregnancies. The specific diagnosis in this case was made even though autopsy was withheld. Acknowledgments The manuscript was supported by grants from the Finnish Pediatric Research Foundation. Conflict of interest The authors declare that they have no competing interests.
Compliance with ethical standards All procedures performed in study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the parents. Authors Contributions Dr Tiina Ojala and Tiina Tyni are primary responsibility for data collection and data analysis and writing the manuscript. Dr Tiina Ojala, Tiina Tyni, Taisto Sarkola, Irmeli Nupponen and Carola Saloranta contributed to the clinical treatment of the patients and the writing of the manuscript. Dr Priya Sekar and Dr Anniina Breilin contributed to the interpretation of the analysis and writing of the manuscript.
References 1.
2.
3. 4.
5.
6.
7.
8.
9.
Grunewald S, Bakkeren J, Wanders RA, Wendel U (1997) Neonatal lethal mitochondrial trifunctional protein deficiency mimicking a respiratory chain defect. J Inherit Metab Dis 20:835–836 Menon SC, O’Leary PW, Wright GB, Rios R, MacLellan-Tobert SG, Cabalka AK (2007) Fetal and neonatal presentation of noncompacted ventricular myocardium: expanding the clinical spectrum. J Am Soc Echocardiogr 20:1344–1350 Ojala TH, Hornberger LK (2010) Fetal heart failure. Front Biosci (Schol Ed) 2:891–906 Pedra SR, Smallhorn JF, Ryan G, Chitayat D, Taylor GP, Khan R, Abdolell M, Hornberger LK (2002) Fetal cardiomyopathies: pathogenic mechanisms, hemodynamic findings, and clinical outcome. Circulation 106:585–591 Sivasankaran S, Sharland GK, Simpson JM (2005) Dilated cardiomyopathy presenting during fetal life. Cardiol Young 15:409–416 Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW (2004) General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover. Pediatr Res 55:190–196 Tonin AM, Amaral AU, Busanello EN, Grings M, Castilho RF, Wajner M (2013) Long-chain 3-hydroxy fatty acids accumulating in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies uncouple oxidative phosphorylation in heart mitochondria. J Bioenerg Biomembr 45:47–57 Weber R, Kantor P, Chitayat D, Friedberg MK, Golding F, Mertens L, Nield LE, Ryan G, Seed M, Yoo SJ, Manlhiot C, Jaeggi E (2014) Spectrum and outcome of primary cardiomyopathies diagnosed during fetal life. JACC Heart Fail 2:403–411 Yang BZ, Heng HH, Ding JH, Roe CR (1996) The genes for the alpha and beta subunits of the mitochondrial trifunctional protein are both located in the same region of human chromosome 2p23. Genomics 37:141–143
