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Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation

Vajro, Pietro; Zielinska, Katarzyna LU ; Ng, Bobby G.; Maccarana, Marco LU ; Bengtson, Per LU ; Poeta, Marco; Mandato, Claudia; D'Acunto, Elisa; Freeze, Hudson H. and Eklund, Erik A. LU (2018) In Orphanet Journal of Rare Diseases 13(1).
Abstract

Background: TMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no information on the long-term outcome in this disorder. Results: We here present three novel patients with TMEM199-CDG. All three patients carried the same set of mutations (c.13-14delTT (p.Ser4Serfs∗30) and c.92G > C (p.Arg31Pro), despite only two were related (siblings). One mutation (c.92G > C) was described previously whereas the other was deemed pathogenic due to its early frameshift. Western Blot analysis confirmed a reduced level of TMEM199 protein in patient fibroblasts and all patients showed a similar... (More)

Background: TMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no information on the long-term outcome in this disorder. Results: We here present three novel patients with TMEM199-CDG. All three patients carried the same set of mutations (c.13-14delTT (p.Ser4Serfs∗30) and c.92G > C (p.Arg31Pro), despite only two were related (siblings). One mutation (c.92G > C) was described previously whereas the other was deemed pathogenic due to its early frameshift. Western Blot analysis confirmed a reduced level of TMEM199 protein in patient fibroblasts and all patients showed a similar glycosylation defect. The patients presented with a very similar clinical and biochemical phenotype to the initial publication, confirming that TMEM199-CDG is a non-encephalopathic liver disorder. Two of the patients were clinically assessed over two decades without deterioration. Conclusion: A rising number of disorders affecting Golgi homeostasis have been published over the last few years. A hallmark finding is deficiency in protein glycosylation, both in N- and O-linked types. Most of these disorders have signs of both liver and brain involvement. However, the present and the four previously reported patients do not show encephalopathy but a chronic, non-progressive (over decades) liver disease with hypertransaminasemia and steatosis. This information is crucial for the patient/families and clinician at diagnosis, as it distinguishes it from other Golgi homeostasis disorders, in having a much more favorable course.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CDG, Ceruloplasmin, Glycosylation, Liver disease, TMEM199, Transaminase, Transferrin
in
Orphanet Journal of Rare Diseases
volume
13
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85040378003
ISSN
1750-1172
DOI
10.1186/s13023-017-0757-3
language
English
LU publication?
yes
id
21fdfa62-7fe2-43a8-99cb-46441a4aab7c
date added to LUP
2018-02-23 18:40:57
date last changed
2018-07-16 12:28:18
@article{21fdfa62-7fe2-43a8-99cb-46441a4aab7c,
  abstract     = {<p>Background: TMEM199 deficiency was recently shown in four patients to cause liver disease with steatosis, elevated serum transaminases, cholesterol and alkaline phosphatase and abnormal protein glycosylation. There is no information on the long-term outcome in this disorder. Results: We here present three novel patients with TMEM199-CDG. All three patients carried the same set of mutations (c.13-14delTT (p.Ser4Serfs∗30) and c.92G &gt; C (p.Arg31Pro), despite only two were related (siblings). One mutation (c.92G &gt; C) was described previously whereas the other was deemed pathogenic due to its early frameshift. Western Blot analysis confirmed a reduced level of TMEM199 protein in patient fibroblasts and all patients showed a similar glycosylation defect. The patients presented with a very similar clinical and biochemical phenotype to the initial publication, confirming that TMEM199-CDG is a non-encephalopathic liver disorder. Two of the patients were clinically assessed over two decades without deterioration. Conclusion: A rising number of disorders affecting Golgi homeostasis have been published over the last few years. A hallmark finding is deficiency in protein glycosylation, both in N- and O-linked types. Most of these disorders have signs of both liver and brain involvement. However, the present and the four previously reported patients do not show encephalopathy but a chronic, non-progressive (over decades) liver disease with hypertransaminasemia and steatosis. This information is crucial for the patient/families and clinician at diagnosis, as it distinguishes it from other Golgi homeostasis disorders, in having a much more favorable course.</p>},
  articleno    = {4},
  author       = {Vajro, Pietro and Zielinska, Katarzyna and Ng, Bobby G. and Maccarana, Marco and Bengtson, Per and Poeta, Marco and Mandato, Claudia and D'Acunto, Elisa and Freeze, Hudson H. and Eklund, Erik A.},
  issn         = {1750-1172},
  keyword      = {CDG,Ceruloplasmin,Glycosylation,Liver disease,TMEM199,Transaminase,Transferrin},
  language     = {eng},
  month        = {01},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Orphanet Journal of Rare Diseases},
  title        = {Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation},
  url          = {http://dx.doi.org/10.1186/s13023-017-0757-3},
  volume       = {13},
  year         = {2018},
}