Clinical awareness and targeted manual urine microscopy enable diagnosis of a fabry disease family missed by routine urinalysis.

backgroundFabry disease (FD) is an X-linked lysosomal storage disorder where early diagnosis is crucial to prevent irreversible organ damage. However, diagnosis is often delayed due to heterogeneous clinical presentations, particularly in heterozygous females and subjectively asymptomatic patients. Urinary mulberry cells and bodies are pathognomonic markers of FD, reflecting globotriaosylceramide (Gb3) accumulation in podocytes and consequent podocyte injury. Despite their diagnostic utility, these subtle morphological features are frequently missed by modern automated urine sediment analyzers and routine manual microscopy performed without specific clinical suspicion of FD. We emphasize the importance of "targeted" manual urine sediment examination triggered by clinical awareness. CASE PRESENTATION: We report a three-generation Japanese family with FD where targeted manual urine sediment examination served as the pivotal cue for diagnosis. The index case, a 61-year-old woman, was referred for incidental electrocardiographic abnormalities suspicious for left ventricular hypertrophy and trace proteinuria. Initial screening with an automated urine sediment analyzer and standard routine microscopy yielded non-specific findings. However, the revelation of a family history of FD during the clinical interview prompted a targeted manual re-evaluation of the urine sediment. This focused review successfully identified characteristic mulberry cells and bodies, triggering the genetic confirmation of a pathogenic GLA variant (c.761_763del). Subsequent screening of her subjectively asymptomatic 32-year-old daughter and 7-year-old grandson initially showed negative results on automated and routine non-targeted microscopy; however, targeted manual review revealed mulberry cells and bodies in the daughter and mulberry bodies in the grandson. These findings provided a compelling rationale for genetic testing in these subjectively asymptomatic relatives, confirming the diagnosis. Furthermore, urinary mulberry cell counts correlated with disease severity across the three family members and decreased following enzyme replacement therapy in the index case, paralleling the reduction in plasma lyso-Gb3.

conclusionsThis family illustrates that laboratory automation and routine non-targeted microscopy may have limitations in detecting Fabry nephropathy. Clinical awareness-the conscious suspicion of FD-serves as the decisive trigger for performing targeted manual urine sediment examination. Close communication between clinicians and laboratory technologists may be beneficial for identifying subtle diagnostic clues like mulberry cells and bodies that automated systems might overlook, ensuring early diagnosis and timely therapeutic intervention.