Hypertrophic cardiomyopathy in mitochondrial disorders: description of an uncommon clinical case.

Abstract

The mitochondria are complex organelles responsible for several functions in every cell, including the assembly of ATP molecules that are the final product of the respiratory chain via oxidative phosphorylation,1, 2 as well as heat production, apoptosis, and transmission of maternal genetic traits.3, 4 The respiratory chain, embedded in the inner mitochondrial membrane, is composed of five enzyme complexes (I, II, III, IV, and V) and mitochondrial respiratory chain proteins are under the genetic control of both nuclear and mitochondrial genes. Mutations involving these genes may cause defects in oxidative phosphorylation.5 Such mitochondrial disorders (MIDs) can be caused by defects in either mitochondrial or nuclear DNA, but mitochondrial DNA (mtDNA) mutations are the commonest cause of mitochondrial disease in adults, identified in up to 70% of patients.6 Several clinically distinct subgroups of MIDs exist, and the most frequently identified biochemical abnormalities are deficiencies in NADH-coenzyme Q (CoQ) reductase (complex I).7 The heart is mainly dependent on aerobic respiration for its energy requirements,8, 9 so it is one of the organs most frequently compromised in MIDs.10, 11 The most frequent cardiac manifestation of MIDs is hypertrophic cardiomyopathy (HCM), more frequently reported in association with mtRNA gene mutations, and in deficiencies in NADH-CoQ reductase (complex I respiratory chain). Yet, MIDs can also, more rarely, cause dilated cardiomyopathy, restrictive cardiomyopathy, or left ventricular non-compaction.6 Conduction system disease occurs commonly in patients with mtDNA disease, often progressing to high-grade atrioventricular block.6 Finally, ventricular pre-excitation, Wolff–Parkinson–White syndrome, and supraventricular and ventricular tachyarrhythmias are also more common in patients with mtDNA disease than in the general population.6 The pathogenesis linking mtDNA to cardiac involvement remains poorly understood. One hypothesis calls for a deficit of complex I activity described in cardiomyocytes of end-stage mtDNA-related cardiomyopathy, as well as in non-cardiac tissues of patients with mtDNA disease. In contrast to skeletal muscle, in cardiac muscle, proliferation of intermyofibrillar mitochondria due to oxidative phosphorylation dysfunction interferes with sarcomeric function, promoting adverse cardiac remodelling. In addition, in normal heart, activation of complex I and fatty acid oxidation increase oxygen consumption, whereas in mtDNA cardiomyopathy, cardiac metabolism shift from fatty acid oxidation to glucose oxidation reduces oxygen consumption and promotes left ventricular (LV) hypertrophy.6, 12-15 We report the case of an infant born from a Caesarean section, after 37 weeks of pregnancy, with no perinatal complications, but preventively admitted to the neonatal intensive care unit at Federico II University of Naples (Italy) because of mild prematurity and a history of premature son death due to uncertain cause. On admission body temperature, blood pressure, heart rate, breathing rate and blood oxygen saturation were normal. At clinical examination no cyanosis or clubbing were present and no heart murmurs, wheezing, rhonchi and crackles, or hepatosplenomegaly were present, with normal peripheral pulses. On the second day, blood gas analysis documented metabolic acidosis, with a pH of 7.180, a pCO2 of 34.5 mmHg, a pO2 of 64.3 mmHg, and HCO3− of 12.6 mmol/L, with low base-excess levels and high lactate levels (16.98 mmol/L), that were treated with NaHCO3 administration. The patient underwent cerebral magnetic resonance, which showed high levels of lactate in the white matter of the centrum semiovale, and genetic testing. A blood sample documented a lactic acid value of 1908 mmol/mol of creatinine (normal range 1–25), and elevated pyruvic dehydrogenase complex activity, commonly observed in patients with lactic acidosis. Thus, therapy including vitamin D3, biotin, thiamin, riboflavin, coenzyme Q10, carnitine, and NaHCO3 was initiated. During the hospital stay, the patient also developed electrocardiographic abnormalities, with high voltage in all leads, and a diffuse abnormal repolarization pattern, typical of HCM (Figure 1), followed on the third week by echocardiographic features of HCM, with massive biventricular hypertrophy. Interventricular septum and LV posterior wall were both 10 mm thick (Z-score 4.83 and 6.70, respectively), causing an obliteration of the cardiac cavity, with a septum to cavity ratio of 0.77, documenting advanced HCM16 (Figures 2 and 3), for which propranolol was initiated. After 4 weeks, multi-organ involvement emerged, including loss of amino acids and electrolytes in the urine, neurological involvement with pyramidal signs and axial hypotonia, and involvement of the respiratory muscles, for which non-invasive respiratory support (continuous positive airway pressure, CPAP), and subsequent invasive mechanical ventilation were necessary. However, the clinical course was complicated by two episodes of cardiac arrest treated with cardiopulmonary resuscitation. Regrettably, multi-organ involvement prevented cardiac transplantation, leading to fatal ventricular arrhythmia at 3 months after birth. Based on the clinical suspicion of a mitochondrial defect, the patient had undergone muscular biopsy, which confirmed the diagnosis of MID, with substantial improvement of the activity of the respiratory chain complex I (NADH CoQ1) (0.6 nmol/min/mg, normal value 17–34 nmol/min/mg), normal activity of complexes II, III, IV, and V, and increased pyruvic dehydrogenase complex activity (7.3 nmol/min/mg, normal value 0.50–2.50 nmol/min/mg). Thus, genetic screening was performed for the patient and his parents. Genetic analysis of the patient documented two different nuclear DNA mutations, inherited in heterozygosis, involving the acyl-CoA dehydrogenase 9 (ACAD9) gene, on chromosome 3q21.3. In particular, the mother had the mutation c.555-2A > G in intron 5 of the ACAD9 gene, present in heterozygosis, and the father had the mutation c.1168G > A in exon 12 of the ACAD9 gene, present in heterozygosis. The child inherited the two variants in heterozygosis of the ACAD9 gene: in the splicing accepting site of intron 5, the change c.555-2A > G; in exon 12, the change c.1168G > A, causing the substitution p.Ala390Thr. This genotype could be associated with the phenotype of the patient. The present case was characterized by a compound heterozygosity mutation in the ACAD9 gene not previously described. The ACAD9 gene encodes a protein involved in the assembly of complex I of the respiratory chain, and it is known that mutations in this gene could be associated with HCM. ACAD9 deficiency is an autosomal recessive multisystemic disorder, often characterized by infantile onset of acute metabolic acidosis, HCM, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblast cells.17 Haack et al.17 reported four patients carrying mutations in ACAD9. The first patient had an early onset, with cardiorespiratory depression, HCM, encephalopathy, and lactic acidosis, and died at 46 days of age. The other patients had an onset of HCM and lactic acidosis, with longer survival. The authors identified compound heterozygosity for two mutations in the ACAD9 gene, different from the mutations of the current case. In addition, Haack et al.18 also reported a family in which three patients had HCM, hypotonia, lactic acidosis, and exercise intolerance associated with complex I deficiency associated with a homozygous mutation in the ACAD9 gene. Leslie et al.,19 in an autopsy study of a fatal neonatal lethal lactic acidosis due to mutations in ACAD9 that reduced complex I activity, identified compound heterozygous variants in the ACAD9 gene: c.187G > T and c.941 T > C, also different from our case. Collet et al.,20 in a retrospective analysis of 20 children with cardiac hypertrophy and isolated complex I deficiency, identified compound heterozygosity for missense, splice site, or frame shift ACAD9 variants in eight patients (40%). Age at onset ranged from neonatal period to 9 years and 5/8 died in infancy. Heart transplantation was possible in 3/8 patients. Finally, Dewulf et al.21 reported nine patients from three unrelated families with a wide spectrum of cardiac involvement among families and patients within the same families. All patients exhibited elevated lactate levels, and ACAD9 mutations were identified in all patients. The pathomechanism that links genotype to phenotype of ACAD9 deficiency was investigated by Schiff et al.22 who assessed, using in vitro functional expression assays in Escherichia coli, the ACAD enzymatic dehydrogenase activity of 16 pathogenic ACAD9 mutations from 24 patients with complex I deficiency. In this study, a significant inverse correlation between residual ACAD enzymatic dehydrogenase activity and phenotypic severity (P = 0.034) was observed. These results indicate that ACAD9 regulates fatty acid oxidation in cells where it is strongly expressed and suggest that fatty acid oxidation defect contributes to the severity of phenotype in ACAD9-deficient patients. The first therapeutic approach in MIDs is symptomatic, treating lactic acidosis when present with carnitine, vitamin D3, NaHCO3, and riboflavin supplementation (Figure 4).23 Conventional pharmacological and device therapy, according to general guidelines, is indicated in HCM and dilated cardiomyopathy phenotypes (Figure 4),24, 25 pacemaker implantation in patients with an early stage of conduction system dysfunction is recommended,6, 26 whereas heart transplantation is the last reasonable chance for patients at end-stage disease. In patients with one of these phenotypes, it should be considered the diagnosis of a MID. In fact, as shown in our case, it is important to evaluate in a newborn with lactic acidosis and HCM the activity of the pyruvic dehydrogenase complex, muscular biopsy, and genetic testing (Figure 4).6, 17-20 However, heart transplantation could only be considered in patients without multi-organ engagement, and has been performed successfully in patients with mtDNA disease.27 Conflict of interest: F.M. was supported by a research grant provided by the Cardiovascular Pathophysiology and Therapeutics PhD programme of the University of Naples Federico II, Italy. The other authors declare no conflict of interests.