Action myoclonus-renal failure syndrome: diagnostic applications of activity-based probes and lipid analysis

Area of Science:

• Biochemistry
• Genetics
• Lysosomal Storage Disorders

Background:

• Lysosomal integral membrane protein-2 (LIMP2) is crucial for glucocerebrosidase (GBA) lysosomal trafficking.
• LIMP2 deficiency leads to action myoclonus-renal failure (AMRF) syndrome, characterized by absent GBA in lysosomes.
• Gaucher disease (GD), caused by GBA mutations, presents with glucosylceramide-laden macrophages, unlike AMRF.

Purpose of the Study:

• To investigate the fate of GBA in LIMP2-deficient cells and its clinical implications.
• To differentiate AMRF from GD based on molecular and biochemical markers.
• To explore plasma glycosphingolipid profiles in AMRF patients and LIMP2-deficient models.

Main Methods:

• Utilized activity-based probes to label active GBA molecules.
• Analyzed GBA levels in lysosomes and white blood cells of AMRF fibroblasts.
• Measured plasma chitotriosidase and glycosphingolipid levels (glucosylceramide, glucosylsphingosine) in AMRF patients and LIMP2-deficient mice.

Main Results:

• GBA was virtually absent in AMRF fibroblast lysosomes, but residual enzyme was found in white blood cells.
• AMRF patients did not develop lipid-laden macrophages or show elevated plasma chitotriosidase, distinguishing them from GD patients.
• Plasma glucosylceramide was normal in AMRF, but glucosylsphingosine levels were significantly increased in both AMRF patients and LIMP2-deficient mice.

Conclusions:

• LIMP2 deficiency affects GBA trafficking, leading to AMRF without the characteristic GD macrophage accumulation.
• Elevated plasma glucosylsphingosine is a key indicator in LIMP2 deficiency.
• Combined measurement of chitotriosidase and glucosylsphingosine offers a diagnostic tool to differentiate GD and AMRF.