Discussion

Inborn errors of metabolism may present at any age and often involve multiple organ systems, with prognosis largely influenced by the presence of cardiac involvement. In several metabolic disorders, more than one form of cardiac involvement may coexist, and such manifestations may occur early or later in the disease course, contributing substantially to increased morbidity and mortality. ^{Reference Ferreira and Blau5} Owing to the high metabolic demand of the myocardium, the reported prevalence of cardiac involvement in inborn errors of metabolism ranges from 15% to 60%. ^{Reference Wicks and Elliott6–Reference Evangeliou, Papadopoulou-Legbelou and Daphnis8} In the present study, the prevalence of cardiac involvement was consistent with previously published data.

The predominant pathophysiological mechanism underlying cardiac involvement in lysosomal storage diseases is the progressive accumulation of undegraded substrates within cardiomyocytes, resulting in structural and functional impairment. The timing of disease onset and the pattern of cardiac manifestations vary according to the underlying metabolic defect: lysosomal storage diseases typically present in late infancy or childhood, organic acidaemias in the neonatal period, and carnitine deficiency or fatty acid oxidation defects in early life. ^{Reference Ashworth9} In this cohort, lysosomal storage diseases constituted a substantial proportion of diagnoses, with cardiac involvement occurring more frequently in patients aged over 6 years, consistent with the progressive nature of substrate accumulation.

Lysosomes are intracellular organelles responsible for the degradation and recycling of complex macromolecules, including glycoproteins, sphingolipids, and mucopolysaccharides. ^{Reference Nair, Belanger and Veinot10} In mucopolysaccharidoses, valvular regurgitation is a characteristic finding, predominantly affecting the left-sided valves—particularly the mitral and aortic valves—more severely than the right-sided valves. ^{Reference Braunlin, Harmatz and Scarpa11,Reference Dangel12} Similarly, in sphingolipidoses, substrate accumulation in the connective tissue of the mitral and aortic valves may result in progressive thickening, calcification, and nodular formation. ^{Reference Hoffmann, Zschocke and Nyhan13}

Cardiac involvement varied substantially across diagnostic groups, with lysosomal storage diseases demonstrating the greatest burden of cardiac pathology. Within this group, valvular disease predominated, most frequently affecting the mitral and aortic valves, while right-sided valve involvement was uncommon. This pattern reflects the progressive accumulation of storage material within valvular connective tissue and is consistent with the pathophysiological mechanisms underlying lysosomal storage diseases. The predominance of valvular involvement in this subgroup underscores the importance of early diagnosis and systematic paediatric cardiology follow-up to enable timely detection and management of progressive cardiac complications in patients with inborn errors of metabolism.

Valvular pathology was highly prevalent among patients with mucopolysaccharidoses, with additional cardiac findings typically emerging during follow-up. Mitral valve involvement was the most frequent manifestation, followed by aortic, tricuspid, and pulmonary valve involvement. Mitral and aortic regurgitation predominated, whereas left ventricular hypertrophy was observed less commonly. These findings are consistent with previous reports: Çakar and Karaca described cardiac involvement in 70.2% of patients with mucopolysaccharidoses, predominantly affecting the mitral valve, with mitral and aortic regurgitation being the most common abnormalities; ^{Reference Cakar and Karaca14} similarly, Leal et al. reported mitral valve dysfunction with thickening in 60.8%, aortic valve dysfunction in 35.8%, and left ventricular hypertrophy in 43% of cases. ^{Reference Leal, de Paula, Leone and Kim15} Collectively, these observations align with the published literature and underscore the importance of systematic paediatric cardiology follow-up in patients with mucopolysaccharidoses for early detection and timely intervention in progressive valvular disease.

Valvular involvement was a prominent feature among lysosomal storage diseases, particularly in patients with mucopolysaccharidoses. In this subgroup, valvular pathology most frequently affected the mitral valve, followed by the aortic valve, whereas right-sided valve involvement was uncommon. The high prevalence of valvular disease observed in mucopolysaccharidoses is consistent with previous reports, although slightly higher rates have been described in some paediatric cohorts. Mueller et al. reported valvular involvement in approximately three-quarters of patients with mucopolysaccharidoses and a lower prevalence in other lysosomal storage diseases, ^{Reference Mueller, Attenhofer-Jost and Rohrbach16} while Sestito et al. demonstrated substantial variability in cardiac involvement across mucopolysaccharidoses subtypes at the time of diagnosis. ^{Reference Sestito, Rinninella and Rampazzo17}

The high prevalence of valvular involvement observed in patients with mucopolysaccharidoses I is likely influenced by the small sample size but remains consistent with previous paediatric series. Schroeder et al. reported left-sided valve thickening in 96% of infants with severe (Hurler) mucopolysaccharidoses I; Dangel reported cardiac involvement in 92% of children, predominantly affecting the mitral and aortic valves. ^{Reference Dangel12,Reference Schroeder, Orchard and Whitley18} All patients in our cohort were receiving weekly enzyme replacement therapy with iduronidase, which has been shown to improve ventricular hypertrophy, preserve ventricular function, and reduce mortality and morbidity. ^{Reference Spranger, Kliegman, St Geme, Stanton and Schor19}

Hunter syndrome (mucopolysaccharidoses type II) is inherited in an X-linked recessive manner due to iduronate-2-sulphatase deficiency, resulting in dermatan sulphate and heparan sulphate accumulation. ^{Reference Wraith, Scarpa and Beck20} Its cardiac phenotype resembles that of mucopolysaccharidoses type I, including predominant cardiomyopathy and valvular involvement, and has been associated with reports of sudden death related to atrioventricular block. ^{Reference Hishitani, Wakita and Isoda21,Reference Mohan, Hay, Cleary, Wraith and Patel22} In the present cohort, valvular involvement in mucopolysaccharidoses type II was frequent, consistent with previously described patterns.

Valvular pathology was also highly prevalent in patients with mucopolysaccharidoses type VI, predominantly affecting the mitral and aortic valves, with less frequent tricuspid involvement. The higher rates observed in this cohort compared with those reported by Kampmann et al. highlight the variability of cardiac involvement across different patient populations and reinforce the need for systematic cardiological follow-up in mucopolysaccharidoses type VI. ^{Reference Kampmann, Lampe and Whybra-Trümpler23}

The absence of cardiac involvement in patients with Pompe disease may be explained by early diagnosis and prompt initiation of enzyme replacement therapy with recombinant human alpha-glucosidase. Previous studies have demonstrated substantial regression of ventricular hypertrophy following early treatment. Levine et al. reported nearly complete reversal of ventricular hypertrophy within 1 year of therapy initiation in early-treated infants, while Forsha et al. described low rates of cardiac involvement at diagnosis in patients with late-onset Pompe disease. ^{Reference Levine, Kishnani, Chen, Herlong and Li24,Reference Forsha, Li and Smith25} These findings support the concept that timely diagnosis and early therapeutic intervention can effectively mitigate cardiac manifestations in paediatric Pompe disease.

Gaucher disease, the most prevalent lysosomal storage disorder, is characterised by glucocerebrosidase (β-glucosidase) deficiency leading to glycosphingolipid accumulation in multiple organs, with cardiac involvement reported less frequently. Deposition within valvular connective tissues has been associated with thickening, calcification, and nodular changes, predominantly affecting the mitral and aortic valves. ^{Reference Hoffmann, Zschocke and Nyhan13,Reference Bohra and Nair26} The limited valvular involvement observed in this cohort is consistent with previously reported patterns.

In Fabry disease, cardiac valve involvement predominantly affects the mitral and aortic valves, with mitral valve pathology often manifesting earlier in the disease course, while aortic root dilatation may occur at more advanced stages. ^{Reference Linhart, Magage, Palecek and Bultas27} These cardiac manifestations are clinically significant and contribute substantially to morbidity and mortality. The pattern of mitral valve involvement is consistent with previously published reports.

Cardiac involvement in vitamin-responsive metabolic diseases appears to be heterogeneous and infrequently reported. Available evidence suggests that cardiomyopathy and structural cardiac abnormalities may occur in selected conditions, such as biotinidase deficiency; however, overall data on cardiac manifestations in this subgroup remain limited, underscoring the need for further studies.

Fatty acid oxidation disorders arise from defects in mitochondrial β-oxidation or carnitine-dependent fatty acid transport and are commonly associated with cardiomyopathy, particularly dilated cardiomyopathy in carnitine transport defects, although hypertrophic cardiomyopathy and tachyarrhythmias have also been reported. ^{Reference Hoffmann, Zschocke and Nyhan13} In this cohort, myocardial and valvular involvement was observed; notably, in patients with primary carnitine deficiency or carnitine transport defect, dilated cardiomyopathy constituted the initial clinical manifestation. In these cases, subsequent aetiological evaluation enabled carnitine supplementation, which was associated with improvement in cardiac findings. These observations are consistent with previously reported reversible cardiac phenotypes in fatty acid oxidation disorders.

Cardiomyopathies are well recognised in mitochondrial diseases, most frequently presenting as hypertrophic cardiomyopathy, while dilated cardiomyopathy and left ventricular non-compaction have also been described. ^{Reference Bates, Bourke, Giordano, d’Amati, Turnbull and Taylor28} Although valvular abnormalities were identified in a subset of patients in this cohort, cardiomyopathy was not observed. This finding may reflect phenotypic heterogeneity and underscores the importance of continued cardiological surveillance, as cardiac manifestations may evolve over time in mitochondrial diseases.

In addition to structural abnormalities, conduction disturbances have been described in organic acidaemias. The identification of a prolonged QT interval in a patient with propionic acidaemia in this cohort is consistent with previous reports and supports the association between this metabolic disorder and cardiac repolarisation abnormalities.

Isolated reports have described dilated cardiomyopathy as an initial manifestation in malonic aciduria, a pattern also observed in this cohort and consistent with published observations. In addition, conduction abnormalities have been reported in organic acidaemias; Ferreira et al. identified prolonged QT intervals in patients with propionic acidaemia, further supporting this association. ^{Reference Ferreira and Blau5}

Patients with lipoprotein metabolism disorders are at increased risk of long-term atherosclerotic vascular disease affecting the arterial vasculature. Although valvular involvement was identified in this subgroup, the relatively older age of these patients suggests that progressive atherosclerotic complications may emerge during follow-up, in keeping with existing literature.

Cardiac involvement has been reported in the majority of congenital disorders of glycosylation, most commonly presenting within the first 2 years of life. ^{Reference Footitt, Karimova and Burch29} Reported manifestations include pericardial effusion, rhythm disturbances, valvular and septal defects, hypertrophic cardiomyopathy, and dilated cardiomyopathy. ^{Reference Marques-da-Silva, Francisco, Webster, Dos Reis Ferreira, Jaeken and Pulinilkunnil30} The identification of hypertrophic cardiomyopathy in a patient with congenital disorders of glycosylation-I in this cohort is consistent with previously published findings.

In this single-centre retrospective cohort, cardiac involvement was identified in 34.3% of paediatric patients with inborn errors of metabolism, a prevalence that lies within the range reported in previous studies. Given the well-established impact of cardiac involvement on prognosis, morbidity, and mortality, comprehensive cardiovascular evaluation should be considered an integral component of the diagnostic approach. Cardiac manifestations may represent the initial clinical presentation in a subset of patients, and selected cases of dilated cardiomyopathy may reflect underlying primary carnitine deficiency, underscoring the potential for reversibility with timely diagnosis and appropriate treatment.

A multidisciplinary approach involving Paediatric Metabolism and Paediatric Cardiology Clinics is particularly important in patients with an as-yet unclear metabolic aetiology. In regions with high rates of consanguinity, including our country, families of patients diagnosed with inborn errors of metabolism should be offered genetic counselling. High-risk groups should undergo annual cardiology assessments, including electrocardiography and echocardiography, with 24-hour Holter monitoring for those at risk of rhythm disturbance and more frequent follow-up when clinically indicated.

Overall, our findings are largely consistent with the existing literature, although certain limitations should be acknowledged, particularly the small sample sizes within some inborn error of metabolism subgroups. Importantly, cardiac involvement may also emerge during follow-up even in patients without abnormalities at initial evaluation.

In conclusion, coordinated multidisciplinary follow-up and management are likely to play a key role in the early detection and optimal management of cardiac involvement, thereby contributing to improved clinical outcomes in paediatric patients with inborn errors of metabolism.