Tachypnea of Infancy as the First Sign of Sanfilippo Syndrome

Discussion

MPS III, also known as Sanfilippo syndrome, is an autosomal recessive lysosomal storage disease resulting in mucopolysacchariduria and accumulation of glycosaminoglycan heparan sulfate in the tissues.³ Compared with other mucopolysaccharidoses, the central nervous system appears to be the major organ affected in MPS III.⁴ MPS III has 4 variants, based on the respective deficiency of the catalytic enzymes, which all lead to the same phenotype: MPS IIIA (heparin N-sulphatase), MPS IIIB (α-N-acetylglucosaminidase), MPS IIIC (acetyl-coenzyme A: α-glucosaminide acetyltransferase), and MPS IIID (N-acetylglucosamine 6-sulfatase).

In the majority of patients who have MPS IIIA, the first signs and symptoms of disease appear at 2 to 3 years of age, with a median age of diagnosis of 4.5 years.⁵ Initial symptoms consist of developmental delay (primarily speech) and/or behavioral problems (hyperactivity, aggression, or destructive behavior). Progressive mental deterioration eventually culminates in severe dementia and death by a median age of 18 years.^3,4 Other medical problems include hearing and vision abnormalities, seizures, diarrhea, and sleep disturbances.³ Respiratory disease is not reported in association with MPS III.⁶

The typical clinical phenotype of MPS IIIA was not displayed in this case, likely owing to his unusually young age at diagnosis. His initial symptoms were primarily respiratory. The simplified, over-expanded alveoli evident on lung biopsy could potentially be attributed to MPS and its deleterious effects on lung development, and may have influenced the clinical presentation. It is also possible that the compound heterozygous ABCA3 mutations found in our patient may have contributed to his respiratory symptoms. ABCA3 plays a role in surfactant lipid transport into lamellar bodies, and mutations in this gene have been shown to cause interstitial lung disease owing to surfactant deficiency.⁷ The classic lung pathology findings include desquamative interstitial pneumonia-like picture with or without alveolar proteinosis and abnormal lamellar bodies with dense inclusion bodies observed on electron microscopy, which were not evident in our case.⁸ Lung disease caused by ABCA3 mutations requires mutations in both alleles as it is inherited as an autosomal recessive disorder.⁹ The ABCA3 sequence variants in our patient were likely not disease-causing, as his unaffected father was shown to carry the same variants. However, previous studies have shown that heterozygous ABCA3 mutations can modify the severity of lung disease associated with surfactant protein C mutations.¹⁰ Single ABCA3 mutations have also been found to increase the risk for neonatal respiratory distress syndrome in infants 34 weeks’ gestation and older.¹¹ It is therefore plausible that heterozygous ABCA3 mutations may sufficiently exacerbate lung disease associated with mucopolysaccharide deposition to produce clinically apparent respiratory symptoms.

Currently all the MPS disorders remain incurable, but a variety of therapies have become available in the last decade. These include exogenous enzyme replacement therapy, with phase II trials completed for MPS IIIA,¹² and other specific therapies under development.¹³ Maximal therapeutic benefit will likely require early diagnosis and treatment initiation. This case demonstrates that respiratory symptoms may herald the diagnosis of MPS III before neurologic deterioration.

It is imperative that any infant who has chronic tachypnea and diffuse parenchymal abnormalities on lung imaging have prompt and appropriate investigations to help elucidate an etiology (Table 1). In this case, flexible bronchoscopy with bronchoalveolar lavage was not performed but is usually recommended to exclude infection or airway abnormalities as possible causes of diffuse lung disease.¹⁴ Lung biopsy, although invasive, should be considered for those in whom the diagnosis is uncertain. In particular, electron microscopy should be part of routine handling for all pediatric lung biopsies, as ultrastructural studies play a significant role in the diagnosis of respiratory disorders in young children.¹⁵ Furthermore, all metabolic storage diseases, including MPS IIIA, should be included in the differential diagnosis of diffuse lung disease.¹⁴ Infants should be carefully examined for features of metabolic storage diseases (including coarse facial features and hepatosplenomegaly) and, if present, consultation with a metabolic specialist should be requested to guide further investigations, such as urine for mucopolysaccharidoses.