Mucopolysaccharidosis Type I
Abstract
:1. Introduction
2. Clinical Picture
2.1. Severe Phenotype (Hurler Syndrome)
2.2. Attenuated Phenotypes
3. Laboratory Diagnosis
3.1. Glycosaminoglycans
3.2. Enzyme Assay
3.3. Molecular Diagnosis
4. Therapeutic Approaches
4.1. Hematopoietic Stem Cell Transplantation
4.2. Intravenous Enzyme Replacement Therapy
4.3. Intravenous Enzyme Replacement Therapy with Fusion Proteins
4.4. Intrathecal Enzyme Replacement Therapy
4.5. Gene Therapy, Gene Editing, and Stop Codon Read Through
4.6. Small Molecules
5. Newborn Screening
6. Genotype–Phenotype Correlation
7. Prospects and Conclusions
Funding
Conflicts of Interest
References
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Variant a | Combined Frequency (%) |
---|---|
p.Trp402 * | 31.5 |
p.Pro533Arg | 25.8 |
p.Gln70 * | 21.5 |
c.56_47del12 | 6.3 |
p.Arg89Gln | 6.3 |
p.Arg628 * | 5.5 |
p.Gln380Arg | 5.1 |
p.Ala327Pro | 4.9 |
p.Glu178Lys | 3.4 |
Therapy | Category | Delivery | Current Status of Development | ClinicalTrials.Gov Identifier |
---|---|---|---|---|
Laronidase (Aldurazyme®) | Enzyme replacement therapy | I.V. infusion | Approved | NA |
Stem cell transplantation | Stem cell transplantation | I.V. infusion | Approved | NA |
Intrathecal Laronidase | Intrathecal Enzyme replacement therapy | Intrathecal administration | Phase I | NCT00638547, NCT00852358 |
SB-318 | Genome editing | I.V. infusion | Phase I/II | NCT02702115 |
RGX-111 | Gene therapy | Intracisternal injection | Phase I | NCT03580083 |
AGT-181 | Enzyme replacement therapy with fusion protein | I.V. infusion | Phase I/II | NCT02597114, NCT03071341, NCT02371226, NCT03053089 |
Genetically modified autologous hematopoietic stem cells | Ex vivo gene therapy | I.V. infusion | Phase I/II | NCT03488394 |
Genotype | Severe Phenotype (n = 380) | Attenuated Phenotype (n = 158) |
---|---|---|
c.1403-1G> T;p.[Gln400*] | 2 (0.5%) | 0 |
c.1524+1G>T;p.[Trp402*] | 2 (0.5%) | 0 |
c.1650+5G>A;p.[Trp402*] | 3 (0.8%) | 0 |
c.1727+5G>C;p.[Asn348Lys] | 0 | 2 (1.3%) |
c.386-2A>G;c.386-2A>G | 2 (0.5%) | 0 |
c.386-2A>G;p.[Trp402*] | 2 (0.5%) | 0 |
p.[Ala327Pro];[Ala327Pro] | 3 (0.8%) | 2 (1.3%) |
p.[Ala327Pro];[Arg383His] | 0 | 1 (0.6%) |
p.[Ala327Pro];[Arg89Trp] | 0 | 1 (0.6%) |
p.[Ala327Pro];[Gln380Arg] | 0 | 1 (0.6%) |
p.[Ala327Pro];[Gln70*] | 5 (1.3%) | 0 |
p.[Ala327Pro];[Ser423Arg] | 1 (0.2%) | 0 |
p.[Ala327Pro];[Thr374Asn] | 0 | 1 (0.6%) |
p.[Ala327Pro];c.1190-1G>C | 1 (0.2%) | 0 |
p.[Ala327Pro];[Ala327Pro] | 0 | 2 (1.3%) |
p.[Ala327Pro];[Trp402*] | 14 (3.7%) | 0 |
p.[Ala36Glu];[Gln70*] | 0 | 2 (1.3%) |
p.[Ala75Thr];[Gln70*] | 2 (0.5%) | 0 |
p.[Ala75Thr];[Trp402*] | 2 (0.5%) | 0 |
p.[Arg383His]; c.386-2A>G | 0 | 3 (1.9%) |
p.[Arg383His];[Gln70*] | 0 | 2 (1.3%) |
p.[Arg383His];[Trp402*] | 0 | 2 (1.3%) |
p.[Arg619*];[Trp402*] | 5 (1.3%) | 0 |
p.[Arg628*];[Arg628*] | 6 (1.6%) | 0 |
p.[Arg89Gln];[Trp402*] | 0 | 4 (2.5%) |
p.[Arg89Trp];[Trp402*] | 0 | 3 (1.9%) |
p.[Asn110Asp];[Gln70*] | 2 (0.5%) | 0 |
p.[Asn348Lys];[Trp402*] | 0 | 2 (1.3%) |
p.[Gln380*];[Arg654*] | 0 | 2 (1.3%) |
p.[Gln380Arg];[Gln380Arg] | 0 | 4 (2.5%) |
p.[Gln380Arg];[Thr388Arg] | 0 | 2 (1.3%) |
p.[Gln380Arg];[Trp402*] | 0 | 2 (1.3%) |
p.[Gln70*];[Gln70*] | 24 (6.3%) | 0 |
p.[Gly265Arg];[Trp402*] | 0 | 2 (1.3%) |
p.[Gly51Asp];[Gly51Asp] | 2 (0.5%) | 0 |
p.[Leu18Pro];[Thr388Lys] | 2 (0.5%) | 0 |
p.[Leu218P];[Gln70*] | 5 (1.3%) | 0 |
p.[Leu218P];[Leu218P] | 2 (0.5%) | 0 |
p.[Leu218P];[Trp402*] | 3 (0.8%) | 0 |
p.[Leu238Gln];[Gln70*] | 0 | 2 (1.3%) |
p.[Leu238Gln];[Trp402*] | 0 | 6 (3.8%) |
p.[Leu490Pro];[Leu490Pro] | 0 | 21 (13.3%) |
p.[Leu535Phe];[Trp402*] | 0 | 2 (1.3%) |
p.[Lys153*];[Trp402*] | 2 (0.5%) | 0 |
p.[Pro21fs];[Trp402*] | 3 (0.8%) | 0 |
p.[Pro496Arg];[Gln70*] | 4 (1.1%) | 0 |
p.[Pro533Arg];[Arg363Leu] | 2 (0.5%) | 0 |
p.[Pro533Arg];[Arg621*] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Arg89Gln] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Asp184Val] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Asp301Glu] | 2 (0.5%) | 0 |
p.[Pro533Arg];[Gln70*] | 0 | 2 (1.3%) |
p.[Pro533Arg];[Gly197Asp] | 0 | 1 (0.6%) |
p.[Pro533Arg];[His425Profs*84] | 1 (0.2%) | 0 |
p.[Pro533Arg];[IleI259Asn] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Lys153*] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Pro533Arg] | 7 (1.8%) | 17 (10.8%) |
p.[Pro533Arg];[Ser633Leu] | 0 | 1 (0.6%) |
p.[Pro533Arg];[Trp402*] | 5 (1.3%) | 3 (1.9%) |
p.[Pro533Arg];[Trp402*] | 0 | 3 (1.9%) |
p.[Ser16del];[Glu178Lys] | 0 | 2 (1.3%) |
p.[Ser16del];[Trp402*] | 6 (1.6%) | 0 |
p.[Ser633Leu];[Trp402*] | 0 | 3 (1.9%) |
p.[Ser633Leu];[S16_A19del] | 0 | 3 (1.9%) |
p.[Thr388Arg];[Trp402*] | 5 (1.3%) | 0 |
p.[Trp402*];[Gln70*] | 61 (16.1%) | 0 |
p.[Trp402*];[Trp402*] | 109 (28.7%) | 0 |
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Share and Cite
Kubaski, F.; de Oliveira Poswar, F.; Michelin-Tirelli, K.; Matte, U.d.S.; Horovitz, D.D.; Barth, A.L.; Baldo, G.; Vairo, F.; Giugliani, R. Mucopolysaccharidosis Type I. Diagnostics 2020, 10, 161. https://doi.org/10.3390/diagnostics10030161
Kubaski F, de Oliveira Poswar F, Michelin-Tirelli K, Matte UdS, Horovitz DD, Barth AL, Baldo G, Vairo F, Giugliani R. Mucopolysaccharidosis Type I. Diagnostics. 2020; 10(3):161. https://doi.org/10.3390/diagnostics10030161
Chicago/Turabian StyleKubaski, Francyne, Fabiano de Oliveira Poswar, Kristiane Michelin-Tirelli, Ursula da Silveira Matte, Dafne D. Horovitz, Anneliese Lopes Barth, Guilherme Baldo, Filippo Vairo, and Roberto Giugliani. 2020. "Mucopolysaccharidosis Type I" Diagnostics 10, no. 3: 161. https://doi.org/10.3390/diagnostics10030161