Considering Fabry, but Diagnosing MPS I: Difficulties in the Diagnostic Process

Recent studies have indicated that a proportion of patients with renal failure, left ventricular hypertrophy, or cryptogenic stroke have sequence variants in their aGal A gene (Fabry disease), which has resulted in an increase in diagnostic activities for this disorder. The diagnostic process for lysosomal storage disorders may result in findings of unknown clinical significance. Here we report such an unexpected outcome.

A 32-year-old male presented at the emergency department because of a transient ischemic attack. Extensive investigations revealed no cause and an initial diagnosis of cryptogenic stroke was made. Subsequently, aGal A activity was measured in a bloodspot and was shown to be normal, but the activity of alpha-L-iduronidase (IDUA), used as reference enzyme, was unexpectedly low: 0.5 umol/L (ref = 1.7-14.3). A diagnosis of IDUA deficiency, mucopolysaccharidosis type 1S or Scheie disease was considered. IDUA gene analysis revealed two homozygous sequence alterations: a silent sequence change (979C > T) in exon 7 (N297N) and an unknown missense mutation 875A > T (R263W). Physical examination was completely normal, without clinical signs of mucopolysaccharidosis type I (MPS I). Leukocyte IDUA activity was also low: 2.1 nmol/mg prot/h (ref = 14-40 nmol prot/h), but higher than the patient range of <0.1 nmol/mg prot/h. Urinary glycosaminoglycan levels were normal both quantitatively and qualitatively. It was concluded that there was low IDUA activity without clinical symptoms and the diagnosis of mucopolysaccharidosis I was discarded.

The diagnostic process for lysosomal storage disorders may result in biochemical abnormalities of unknown clinical significance. Early evaluation by a specialist in inborn errors of metabolism may help to avoid anxiety in patients and unnecessary additional analyses.