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. 2025 Mar 7;26(6):2408.
doi: 10.3390/ijms26062408.

Novel Phenotypical and Biochemical Findings in Mucolipidosis Type II

Eines Monteagudo-Vilavedra  1 , Daniel Rodrigues  1   2 , Giorgia Vella  1 , Susana B Bravo  3 , Carmen Pena  4 , Laura Lopez-Valverde  1   2 , Cristobal Colon  1   2 , Paula Sanchez-Pintos  1   2   5 , Francisco J Otero Espinar  6   7 , Maria L Couce  1   2   3 , J Victor Alvarez  1   2
Affiliations

Novel Phenotypical and Biochemical Findings in Mucolipidosis Type II

Eines Monteagudo-Vilavedra et al. Int J Mol Sci. .

Abstract

Mucolipidosis type II is a very rare lysosomal disease affecting the UDP-GlcNAc N-acetylglucosamine-1-phosphotransferase enzyme, which catalyzes the synthesis of the targeting signal mannose 6-phosphate in lysosomal acid hydrolases. Its deficiency hinders the arrival of lysosomal enzymes to the lysosome, diminishing the multiple degradations of components that cells need to perform. Due to the low prevalence of this condition, available information is scarce. This article aims to deepen the understanding of the disease; clinical, biochemical, and proteomic data are analyzed. Three patients have been identified presenting GNPTAB pathogenic variants using whole exome sequencing. A biochemical profile for these patients has been carried out through quantification of glycosaminoglycans in urine samples and enzymatic analysis in dried blood spot (DBS) samples. Quantitative proteomic studies were performed. Results show how enzymatic assays in DBS can be used to diagnose this disease both during the neonatal period or in patients of more advanced age. Increased levels of acid sphingomyelinase, alpha-iduronidase, iduronidate 2-sulfatase, alpha-N-acetyl glucosaminidase, and beta-glucuronidase are found. Conclusion: this biochemical method could potentially improve early diagnosis. Proteomic data supporting these results reveal disrupted biochemical pathways, including the degradation of dermatan sulfate, heparan sulfate, and cellular cholesterol trafficking.

Keywords: biochemistry; biomarkers; early findings; lysosomal diseases; mucolipidosis II-III; proteomic studies.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Alterations in cranial morphology. Cranial deformity with trigonocephaly and early closure of the metopic suture, patients 1 and 2.
Figure 2
Figure 2
Skeletal findings of the three patients. Deformity of costal arches with widening of the costal metaphysis, patients 1, 2, and 3. AP: anteroposterior protection from X-rays.
Figure 3
Figure 3
Biochemical routes for degradation of Heparan sulfate and Dermatan sulfate. Enzymes analyzed: IDS—iduronidate 2-sulfatase, IDUA—alpha-iduronidase; ARSB—arylsulfatase B, NAGLU alpha-N-acetyl glucosaminidase; GUSB—beta-glucuronidase. Enzymes not analyzed: Heparanase—HSPE, N-sulfoglucosamine sulfohydrolase—SGSH, N-acetylglucosamine-6-sulfatase—GNS, Hyaluronidase—HYAL.
Figure 4
Figure 4
Volcano plot obtained from SWATH-MS quantitative proteomics analysis. The red dots represent proteins upregulated in ML II patients vs. neonatal healthy samples and green dots represent proteins upregulated in neonatal healthy samples vs. ML II patient samples.
Figure 5
Figure 5
Volcano plot obtained from SWATH-MS quantitative proteomics analysis. The red dots represent proteins upregulated in ML II patients at diagnosis vs. neonatal healthy samples and green dots represent proteins upregulated in neonatal healthy vs. ML II patients.
Figure 6
Figure 6
Volcano plot obtained from SWATH-MS quantitative proteomics analysis. The red dots represent proteins upregulated in healthy vs. disease samples and green dots represent proteins upregulated in disease ML II patients.
Figure 7
Figure 7
Venn diagram between the dysregulated proteins in different comparisons.
See this image and copyright information in PMC

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