Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III
Abstract
:1. Introduction
2. Materials and Methods
2.1. MPS III Subtype Classification: Enzyme Assays and Genetic Tests
2.2. Statistical Analysis
2.3. Ethics Statement
3. Results
3.1. Clinical Presentation
3.2. Neurodegenerative Symptoms
3.3. Survival Analysis by Subtype
3.4. Genetic Analysis
4. Discussion
Gene | Reference Sequences | DNA Nucleotide Change | Predicted Protein Change | Common [Reference] | Patient Number |
---|---|---|---|---|---|
SGSH | NM_000199.5 NP_000190.1 | c.1129C > T | p.Arg377Cys | Di Natale et al. [37] | 9A |
c.1094A > G | p.Gln365Arg | Novel | 9A | ||
c.1040C > T | p.Ser347Phe | Miyazaki et al. [38] | 1A, 2A 3A, 4A, 7A, 10A £ | ||
c.823G > A | p.Gly275Arg | Heron et al. [8] | 15A | ||
c.812C > T | p.Thr271Met | Heron et al. [8] | 5A | ||
c.703G > A | p.Asp235Asn | Beesley et al. [41] | 1A, 4A, 5A, 12A, 14A, 17A | ||
c.703G > C | p.Asp235His | Novel | 3A, 7A, 12A | ||
c.544C > T | p.Arg192Cys | Di Natale et al. [37] | 2A | ||
c.449G > A | p.Arg150Gln | Bunge et al. [35] | 15A, 17A | ||
c.228C > G | p.Ser76Arg | Novel | 14A | ||
c.69delG | p.Asn24Thrfs*240 | Novel | 8A£ | ||
NAGLU | NM_000263.4 NP_000254.2 | c.1976C > T | p.Ala659Val | Novel | 1B |
c.1694G > C | p.Arg565Pro | Weber et al. [42] | 12B, 14B £ | ||
c.1444C > T | p.Arg482Trp | Bunge et al. [43] | 1B, 2B £, 5B £, 6B, 8B, 11B £, 13B £ | ||
c.775C > T | p.Gln259* | Novel | 12B | ||
c.607C > T | p.Arg203* | Schmidtchen et al. [44] | 8B | ||
c.200T > C | p.Leu67Pro | Novel | 6B | ||
HGSNAT | NM_152419.3 NP_689632.2 | c.234+1G > A | IVS2+1G > A | Canals et al. [45] | 1C, 2C |
c.1150C > T | p.Arg384* | Ruijter et al. [23] | 1C, 2C |
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristic | Total (N = 34) | IIIA (N = 18) | IIIB (N = 14) | p-Value | IIIC (N = 2) |
---|---|---|---|---|---|
Sex | >0.99 | ||||
Male | 20 (58.9%) | 11 (61.1%) | 8 (57.1%) | 1 (50%) | |
Female | 14 (41.1%) | 7 (38.9%) | 6 (42.9%) | 1 (50%) | |
Follow-up period (mean years ± SD) | 12.6 ± 6.1 | 12.3 ± 5.8 | 13.6 ± 6.5 | 0.58 | 11.2 ± 0.6 |
Age at symptom onset (mean years ± SD) | 2.8 ± 0.8 | 3.1 ± 0.9 | 2.6 ± 0.7 | 0.10 | 2.0 ± 0.2 |
Age at diagnosis (mean years ± SD) | 6.3 ± 2.2 | 6.3 ± 2.3 | 6.5 ± 2.0 | 0.77 | 3.7 ± 1.4 |
Diagnosis lag time (mean years ± SD) | 3.6 ± 2.5 | 3.5 ± 2.9 | 3.9 ± 1.9 | 0.29 | 1.7 ± 1.2 |
Cardiac evaluation by TTE (positive finding/test available, %) | NA | ||||
MR | 15/19 (78.9%) | 10/14 (71.4%) | 5/5 (100.0%) | 0.53 | |
TR | 16/19 (84.2%) | 11/14 (78.6%) | 5/5 (100.0%) | 0.53 | |
MV thickening | 13/19 (68.4%) | 9/14 (64.3%) | 4/5 (80.0%) | >0.99 | |
Abdominal US (positive finding / test available, %) | |||||
Hepatosplenomegaly | 17/21 (80.9%) | 9/12 (75%) | 6/7 (85.7%) | >0.99 | 2/2 (100%) |
SMA syndrome | 6/21 (28.6%) | 4/12 (33.3%) | 2/7 (28.6%) | 0.51 | 0 |
Clinical findings | |||||
Age at first walking without assistance, median years (IQR Q1,Q3) | 1.3 (1.23, 1.6) | 1.25 (1, 1.37) | 1.55 (1.42, 1.6) | 0.002 * | 1.3, 1.0 |
Age of first seizure (mean years ± SD) | 10.0 ± 2.9 | 9.8 ± 2.8 | 10.3 ± 3.2 | 0.739 | NA |
History of AEDs medication | 26 (76.5%) | 15 (83.3%) | 11 (78.6%) | >0.99 | 0 |
Gastrostomy | 18 (52.9%) | 9 (50%) | 9 (64.3%) | 0.65 | 0 |
Age at gastrostomy (mean years ± SD) | 17.2 ± 1.9 | 16.8 ± 2.2 | 17.6 ± 1.8 | 0.421 | NA |
Tracheostomy | 6 (17.6%) | 4 (22.2%) | 2 (14.3%) | 0.67 | 0 |
Age at tracheostomy (mean years ± SD) | 17.8 ± 3.7 | 16.3 ± 1.3 | 21 ± 5.7 | 0.24 | NA |
Deafness | 17 (50%) | 11 (64.7%) | 4 (30.8%) | 0.14 | 2 (100%) |
Bed-ridden status | 21 (61.8%) | 12 (57.1%) | 9 (42.9%) | >0.99 | NA |
Age at onset of bed-ridden state (mean years ± SD) | 15.1 ± 1.9 | 15.3 ± 1.6 | 14.9 ± 2.4 | 0.667 | NA |
First Symptom a | Total, N (%) | IIIA, N (%) | IIIB, N (%) | p-Value | IIIC, N (%) | |
---|---|---|---|---|---|---|
Language retardation | 30 (88.2) | 18 (100) | 11 (78.6) | 0.073 | 1 (50) | |
Motor retardation | 26 (76.5) | 11 (61.1) | 14 (100) | 0.010 * | 1 (50) | |
Language and motor retardation | 22 (64.7) | 11 (61.1) | 11 (78.6) | 0.721 | 0 (0) | |
Behavioural abnormalities | 14 (41.2) | 8 (44.4) | 6 (42.9) | >0.99 | 0 (0) | |
Coarse facial features | 6 (17.6) | 3 (16.7) | 2 (14.3) | >0.99 | 1 (50) | |
Skeletal abnormalities | 4 (11.7) | 2 (16.7) | 1 (7.1) | >0.99 | 1 (50) | |
Hearing loss | 4 (11.7) | 1 (5.6) | 2 (14.3) | 0.568 | 1 (50) | |
Associated Symptom a after Diagnosis | N (%) | Median Age, Year (Range) | ||||
Impairment of speech | 33 (97.1) | 3.9 (1.5–5.0) | ||||
Behavioural abnormalities | 32 (94.2) | 4.0 (0.5–7.0) | ||||
Clumsy walking | 31 (91.2) | 10.0 (4.6–15.0) | ||||
Macrocephaly and coarse face | 30 (88.2) | 3.0 (1.0–4.0) | ||||
Sleep disorder | 30 (88.2) | 3.7 (0.5–6.6) | ||||
Hirsutism | 29 (85.3) | |||||
Mongolian spots | 22 (64.7) | |||||
Hearing loss | 17 (50.0) | 5.0 (0–8.5) | ||||
Recurrent otitis | 13 (38.2) | 2.5 (1.0–4.0) | ||||
Recurrent diarrhoea | 8 (23.5) | 3.5 (0.5–5.5) | ||||
Hernia | 8 (23.5) | 0.6 (0–1.2) |
Characteristic | Survivor (N = 21) | Non-Survivor (N = 13) | p-Value |
---|---|---|---|
Sex | >0.99 | ||
Male | 12(57.2%) | 8 (61.5%) | |
Female | 9 (42.8%) | 5 (38.5%) | |
Type | 0.68 | ||
IIIA | 12 (57.2%) | 6 (46.2%) | |
IIIB | 7 (33.3%) | 7 (53.8%) | |
IIIC | 2 (9.5%) | 0 (0%) | |
Age at death (mean years ± SD) | 14.4 ± 4.1 | ||
Age at diagnosis (mean years ± SD) | 5.6 ± 2.3 | 7.3 ± 1.8 | 0.029 * |
Age at symptom onset (mean years ± SD) | 2.8 ± 0.8 | 2.9 ± 0.9 | 0.69 |
Lag time to diagnosis (mean years ± SD) | 2.8 ± 1.8 | 4.8 ± 3.0 | 0.045 * |
Cardiac evaluation by TTE | 11 (100%) | 8 (100%) | |
MR | 8 (72.7%) | 7 (87.5%) | 0.60 |
TR | 9 (81.8%) | 7 (87.5%) | >0.99 |
MV thickening | 6 (54.6%) | 7 (87.5%) | 0.18 |
Abdominal US | 14 (100%) | 7 (100%) | |
Hepatosplenomegaly | 11 (78.6%) | 6 (85.7%) | >0.99 |
SMA syndrome | 2 (14.3%) | 4 (57.1%) | 0.52 |
Clinical findings | |||
History of AEDs medication | 13 (61.9%) | 13 (100%) | 0.027 * |
Gastrostomy | 9 (42.9%) | 9 (69.2%) | 0.31 |
Tracheostomy | 4 (19%) | 2 (15.4%) | >0.99 |
Deafness | 12 (57.1%) | 5 (45.5%) | >0.99 |
Bed-ridden status | 10 (47.6%) | 11 (78.6%) | 0.26 |
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Kim, M.-S.; Yang, A.; Noh, E.-s.; Kim, C.; Bae, G.Y.; Lim, H.H.; Park, H.-D.; Cho, S.Y.; Jin, D.-K. Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III. J. Pers. Med. 2022, 12, 665. https://doi.org/10.3390/jpm12050665
Kim M-S, Yang A, Noh E-s, Kim C, Bae GY, Lim HH, Park H-D, Cho SY, Jin D-K. Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III. Journal of Personalized Medicine. 2022; 12(5):665. https://doi.org/10.3390/jpm12050665
Chicago/Turabian StyleKim, Min-Sun, Aram Yang, Eu-seon Noh, Chiwoo Kim, Ga Young Bae, Han Hyuk Lim, Hyung-Doo Park, Sung Yoon Cho, and Dong-Kyu Jin. 2022. "Natural History and Molecular Characteristics of Korean Patients with Mucopolysaccharidosis Type III" Journal of Personalized Medicine 12, no. 5: 665. https://doi.org/10.3390/jpm12050665