Mucopolysaccharidosis-Plus: From Molecular Defects to Therapeutic Strategies

Dear Colleagues,

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders characterized by the absence or markedly reduced activity of lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). This enzymatic deficiency leads to the progressive accumulation of GAGs within lysosomes, ultimately resulting in cellular, tissue, and organ dysfunction. Thirteen distinct types and subtypes of MPS have been identified, classified according to the specific deficient or partially functioning enzyme or the type of accumulated GAG.

An MPS-like disease has recently been described and called mucopolysaccharidosis-plus syndrome (MPSPS). MPSPS represents one of the rarest diseases, with only a few dozen cases reported worldwide. The clinical phenotype of MPSPS patients resembles Hurler syndrome, the severe form of MPS I. The term "plus" reflects the presence of additional symptoms beyond those typically observed in classical MPS types/subtypes, including congenital heart defects, renal abnormalities, and hematopoietic system disorders.

The primary pathogenic mechanism in MPS involves the accumulation of GAGs within lysosomes. In MPSPS, a similar accumulation occurs—specifically of heparan sulfate and dermatan sulfate—yet, to date, no studies have demonstrated reduced activity of any known lysosomal enzymes. In contrast, mutations in the VPS33A gene were found in MPSPS patients, though only two pathogenic variants have been identified as causative for MPSPS. The c.1492C>T (p.Arg498Trp) variant has been found in the homozygous state in patients from Yakutia and Turkey, while the c.599G>C (p.Arg200Pro) variant has been reported, also in homozygous form, in two patients from the Mediterranean region and Poland. Due to the markedly shortened lifespan of affected individuals and the complex pathomechanism of the disease, no effective treatment has been developed for patients with MPSPS. Current therapeutic approaches are limited to symptomatic management and aim to alleviate clinical manifestations and improve the patients’ quality of life.

Due to the unclear pathomechanism of MPSPS and the above-mentioned lack of treatment, studies on this disease and development of therapeutic approaches are highly desirable. This Special Issue is, therefore, devoted to any kind of studies on MPSPS, ranging from basic to clinical studies, from diagnostic to translational works, and from subjects related to patients’ care to development of novel therapies. Both original and review manuscripts are welcome, provided they are directly or indirectly related to MPSPS.

We look forward to your contributions.

Dr. Zuzanna Cyske
Guest Editor

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• mucopolysaccharidosis
• mucopolysaccharidosis-plus syndrome
• MPSPS
• VPS33A
• therapy
• patomechanism
• diagnostic
• patients’ care