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

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Increased Fabry disease testing due to gene variants in renal failure, hypertrophy, or stroke patients.
• Lysosomal storage disorder diagnostics can yield results of unknown clinical significance.
• This case presents an unexpected outcome during diagnostic evaluation.

Purpose of the Study:

• To report an unexpected biochemical finding during the diagnostic workup for a patient presenting with stroke-like symptoms.
• To investigate the clinical significance of low alpha-L-iduronidase (IDUA) activity in the absence of clinical signs of mucopolysaccharidosis type I (MPS I).

Main Methods:

• A 32-year-old male with transient ischemic attack underwent extensive investigations.
• Alpha-L-iduronidase (IDUA) activity was measured in bloodspots and leukocytes.
• IDUA gene sequencing was performed, identifying homozygous sequence alterations.
• Urinary glycosaminoglycan levels were assessed quantitatively and qualitatively.

Main Results:

• Initial diagnosis of cryptogenic stroke was made; aGal A activity was normal.
• Low IDUA activity (0.5 umol/L) was detected, prompting consideration of mucopolysaccharidosis type 1S (Scheie disease).
• Genetic analysis revealed a silent variant (979C>T) and a missense mutation (875A>T, R263W).
• Leukocyte IDUA activity was low (2.1 nmol/mg prot/h) but above the patient range; urinary glycosaminoglycans were normal.
• No clinical signs of MPS I were present.

Conclusions:

• Low IDUA activity was observed in a patient without clinical manifestations of MPS I.
• The diagnostic process for lysosomal storage disorders can lead to biochemical abnormalities of unknown clinical significance.
• Early specialist evaluation is recommended to manage patient anxiety and avoid unnecessary tests.