mucopolysaccharidosis-plus syndrome

Mucopolysaccharidosis-plus syndrome is a very rare, multisystem condition that affects several organ systems including the respiratory, musculoskeletal, and hematologic systems, as well as neurodevelopment. It is caused by pathogenic variants in the VPS33A gene, which plays a critical role in cellular trafficking and lysosomal function. This condition typically presents in early childhood with a combination of recurrent respiratory infections, developmental delays, and distinct facial and skeletal features. Given its very rare prevalence, it affects fewer than 1 in 1,000,000 individuals.

Individuals with mucopolysaccharidosis-plus syndrome frequently present with a complex array of symptoms affecting multiple organ systems. Respiratory manifestations are prominent, with recurrent pneumonia, recurrent bronchopulmonary infections, and respiratory distress reported in all cases. Neurodevelopmental challenges are also a key feature, evidenced by global developmental delay, motor delay, and absent speech, while musculoskeletal issues such as flexion contractures, hypotonia, and dysostosis multiplex are consistently observed. Additionally, distinct facial features including epicanthus, wide nose, telecanthus, and a prominent forehead are common, alongside systemic findings such as anemia, hypoalbuminemia, proteinuria, thrombocytopenia, and signs of organ involvement like hepatomegaly, splenomegaly, and nephrotic syndrome. Not all individuals experience all features, and severity varies considerably.

The genetic basis of mucopolysaccharidosis-plus syndrome lies in pathogenic variants in the VPS33A gene. This gene is essential for proper intracellular trafficking and lysosomal function, and its disruption is believed to affect multiple tissues and organ systems. The condition is inherited in an autosomal recessive pattern, meaning that an affected individual has received one altered copy of the gene from each parent. This also implies that parents sharing a common ancestor have a higher chance of both carrying the same rare variant, and genetic counseling is recommended for families to understand the implications for future pregnancies.

Currently, management of mucopolysaccharidosis-plus syndrome focuses on supportive care and tailored symptom management, as there are no FDA-approved or established foundational therapies for this condition. Treatment involves a multidisciplinary approach, with regular surveillance to monitor respiratory status, cardiac function, growth, and overall development. Approaches such as physical therapy, occupational therapy, and respiratory support are incorporated to address specific symptoms, and families are encouraged to discuss all treatment options with their care team and seek genetic counseling for guidance on inheritance and future family planning.

The clinical course of mucopolysaccharidosis-plus syndrome is highly variable, with outcomes that depend on the severity of symptoms, the age at which the condition is diagnosed, and the availability of specialized care. While many individuals face significant challenges such as developmental delays and recurrent infections, advances in supportive care and regular monitoring have the potential to improve quality of life over time. Outcomes described in medical literature continue to evolve as standards of care improve, and families are encouraged to connect with specialists and genetic counselors to better understand the potential long-term trajectory for their loved ones. Severity and symptoms vary widely between individuals.

Mucopolysaccharidosis-plus syndrome is an active area of research, with a considerable number of clinical trials currently investigating new treatment approaches. Individuals interested in clinical trials are encouraged to search ClinicalTrials.gov or consult their care team to learn more about eligibility and available research opportunities.