Discussion

Sialidosis, a rare autosomal recessive disorder (Incidence: 1/5,000,000–1/1,500,000 live births; ~210 patients reported till date, Supplementary Table 1), is caused by a deficiency of the enzyme alpha-N-acetyl neuraminidase (encoded by NEU1) and is characterised by progressive lysosomal storage of sialylated glycopeptides and oligosaccharides. ^{Reference Lowden and O’Brien5,Reference Gultekin, Bayramov, Karaca and Acer6} Based on the clinical presentation, patients with sialidosis have been broadly divided into two groups – type I sialidosis is characterised by older age at presentation, normal intellect, normal skeletal anatomy and body proportions, appearance of cherry red spots in the macular region of fundus, occasional cataracts, and myoclonus. In contrast, type II sialidosis is characterised by early-onset disease with prominent skeletal abnormalities, dysmorphic features, growth retardation, cataracts, and visceromegaly. Neonatal, infantile, and juvenile-onset forms of type II sialidosis have been described. ^{Reference Lowden and O’Brien5}

Animal models have helped elucidate expression patterns of alpha-N-acetyl neuraminidase in vivo. Mouse neuraminidase shares 80% homology with the human enzyme and is expressed not only in the kidney, brain, spinal cord, liver, lung, and spleen but also in the heart. ^{Reference Doura, Gafuik and Mertineit7} Similar expression patterns have been noted in humans. ^{Reference Sergi, Penzel and Uhl8,Reference Hale, van de Ven, Wenger, Bradford and Kahler9,Reference Pueschel, O’Shea and Alroy10,Reference Godra, Kim and D’Cruz11} Consistent with these expression patterns, abdominal visceral, renal, neurological, ophthalmological, and hematopoietic system involvement is common in humans with sialidosis (Supplementary Table 1). Despite evidence of expression of neuraminidase in the heart in both murine models and humans, cardiac involvement in patients with sialidosis is poorly characterised.

Early-onset cardiac involvement was noted in our patient. A comprehensive review of published literature revealed that cardiac involvement occurs in approximately 10% of patients and is exclusive to type II neonatal or infantile-onset phenotype (Supplementary Table 1). It can present as cardiomegaly and left ventricular dysfunction with or without overt heart failure. A single patient has been reported with mitral valve thickening, prolapse, and regurgitation. ^{Reference Ranganath, Sharma, Danda, Nandineni and Dalal12} Cardiac involvement was a significant contributor to morbidity in the majority and was the direct cause of mortality in at least one. ^{Reference Lemyre, Russo, Melançon, Gagné, Potier and Lambert13}

The mechanisms underlying cardiac involvement in patients with sialidosis are not well elucidated. Cardiac histopathology of autopsy specimens from patients with type II sialidosis has revealed vacuolated appearance of cardiomyocytes suggesting that storage of sialylated glycopeptides and oligosaccharides in cytoplasm could play a role. ^{Reference Hale, van de Ven, Wenger, Bradford and Kahler9,Reference Pueschel, O’Shea and Alroy10,Reference Godra, Kim and D’Cruz11} Till date, for reasons that are not understood, cardiovascular involvement has not been reported in patients with late-onset type 1 sialidosis. In fact, the incidence of cardiovascular involvement in patients with sialidosis is inversely proportional to the age of onset of symptoms. The younger the age of onset, the more likely they are to have cardiovascular involvement.

Given the overall paucity of patients with sialidosis, the optimal therapeutic strategy for cardiac dysfunction in such patients is unknown. Patients with neonatal or infantile-onset type II sialidosis have markedly decreased lifespan (death in infancy or the first few years of life) due to progressive multisystem involvement and therefore are unlikely to be candidates for mechanical support or cardiac transplantation. We maintained our patient on an age appropriate dose of enalapril. Further deterioration of left ventricular function was not noted after the initiation of enalapril.

In summary, cardiac involvement is common in patients with sialidosis, particularly in those with neonatal or infantile-onset type II disease. The time of onset of cardiac involvement and its symptomatology can be variable; therefore, serial clinical cardiovascular evaluation is warranted with electrocardiographic and echocardiographic monitoring. The optimal therapy for cardiac dysfunction in patients with sialidosis is not known. Patients with early-onset type II multisystem disease are unlikely to be candidates for aggressive mechanical support or cardiac transplant due to shortened lifespan.