Hematopoietic Disorders, Renal Impairment and Growth in Mucopolysaccharidosis-Plus Syndrome

Abstract

Mucopolysaccharidoses (MPS) are rare lysosomal storage disorders (LSD) characterized by the excessive accumulation of glycosaminoglycans (GAG). Conventional MPS, caused by inborn deficiencies of lysosomal enzymes involved in GAG degradation, display various multisystemic symptoms—including progressive neurological complications, ophthalmological disorders, hearing loss, gastrointestinal and hepatobiliary issues, cardiorespiratory problems, bone and joint abnormalities, dwarfism, and coarse facial features. Mucopolysaccharidosis-Plus Syndrome (MPSPS), an autosomal recessive disease caused by a mutation in the endo-lysosomal tethering protein VPS33A, shows additional renal and hematopoietic abnormalities (“Plus symptoms”) uncommon in conventional MPS. Here, we analyze data from biochemical, histological, and physical examinations—particularly of blood counts and kidney function—to further characterize the clinical phenotype of MPSPS. A series of blood tests indicate hematopoietic symptoms including progressive anemia and thrombocytopenia, which correlate with histological observations of hypoplastic bone marrow. High urinary excretion of protein (caused by impairments in renal filtration), hypoalbuminemia, and elevated levels of creatinine, cholesterol, and uric acid indicate renal dysfunction. Histological analyses of MPSPS kidneys similarly suggest the extensive destruction of glomerular structures by foamy podocytes. Height and weight did not significantly deviate from the average, but in some cases, growth began to decline at around six months or one year of age.

Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients

“…Sofronova et al recently reported on progressive hematopoietic abnormalities noted in MPS-PS patients, especially in the red blood cells and platelets; however, we did not observe any of them [ 14 ]. They also observed that most patients experienced elevated levels of uric acid in the blood as a manifestation of kidney failure.…”

“…Growth retardation, as well as poor weight gain, were also observed in several patients reported by Sofronova et al [ 14 ]. Contrary to that, our patient had normal growth (see Figure 2 ) and was overweight (visceral obesity).…”

“…Up to now, 39 patients with MPS-PS have been described [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Notably, a detailed clinical presentation and follow-up was not available in some of the reported cases, especially in the first report of 11 Yakut children authored by Gurinova et al [ 8 ].…”

“…The name of the disease stems from the presence of only some clinical or biochemical features resembling MPS (including dysostosis multiplex in some cases, thickened facial features, valvular disease, psychomotor retardation, slightly increased urinary GAGs excretion), and additional signs and symptoms. Up to now, a total number of 38 patients have been reported [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. In all of them, the disease was caused by the NM_022916.6:c.1492C>T (p.Arg498Trp) variant of the VPS33A gene, coding for the vacuolar protein sorting-associated protein 33A.…”

Juvenile Mucopolysaccharidosis plus disease caused by a missense mutation inVPS33A

“…Immune deficiency caused by impaired development of NK cells and cytotoxic T cells has been documented in lysosomal biogenesis defects and abnormal endosomal-lysosomal trafficking (Ham, 2014; Orange, 2008; Ballabio, 2020). Finally, the severe nephritis with glomerular sclerosis and proteinuria is likely to be related to vacuolation and effacement of podocytes in which active endocytosis is impaired (Chen, 2013; Bechtel, 2013; Sofronova, 2022).…”