Aims Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by defects in two proteins (VPS33B and VIPAR), involved in regulation of intracellular protein trafficking. ARC patients usually die by 2 years of age, often secondary to infective complications. It was previously thought that the defect affects the proximal tubule in the kidney, as well as the liver and the musculoskeletal system. We have recently managed three cases with varying clinical presentations and found that in addition to commonly described features, they all demonstrated marked albuminuria suggesting the glomerulus is also involved in this syndrome.
Methods Case-note review of the three cases of ARC syndrome and glomerular mapping of the VPS33B expression using western blotting in conditionally immortalised cells of the glomerulus (Podocytes, Glomerular Endothelial cells and Mesangial cells).
Results All cases had severe failure to thrive, arthrogryposis, renal tubular acidosis, nephrotic range albuminuria, conjugated hyperbilirubinaemia with normal γ GT, gastro-oesophageal reflux with difficulty establishing well tolerated feed regimens, metabolic bone disease with fractures and recurrent septic episodes. The primary case had a confirmed VPS33B mutation and died of overwhelming sepsis at the age of 4 months. The subsequent two cases have a clinical diagnosis of ARC, but negative initial VPS33B mutation analysis. These children are still alive at five and 6 months of age respectively. We are currently analysing the expression of VPS33B in the cells of the glomerulus to identify the mechanism of action of this mutation in this site. The initial experiments showed that VPS33B was highly expressed in human glomerular endothelium but much less in podocyte and mesangial cell lines. Review of the literature suggests ARC syndrome has an expanding clinical spectrum and may be more common than previously thought. Nephrotic range albuminuria as a feature of ARC syndrome has only been previously described in a small number of cases.
Conclusion The cases demonstrate severe failure to thrive and nephrotic range albuminuria as common features of ARC syndrome. Nephrotic range albuminuria may contribute to the infective complications of this condition.