One known pathogenic ALG1 variant
Emma has ALG1 p.Ser258Leu. A second causal ALG1 event has not been found yet.
Importantly: p.Ser258Leu has published functional evidence of impaired ALG1 activity in patient cells.
Can restoring normal ALG1 correct Emma's fibroblast glycosylation defect?
Emma has a severe neurodevelopmental disorder. Her fibroblasts show abnormal glycosylation, but the usual blood tests are not clearly diagnostic. The main question is whether ALG1 is truly causing the cell phenotype.
What we know
Four facts define the case.
The page is intentionally short. The goal is fast orientation and one obvious next step.
The fibroblasts are abnormal
LAMP2 hypoglycosylation was reported. ADAMTS13 was also repeatedly abnormal.
Blood tests are not classical for ALG1-CDG
Transferrin was normal / once borderline. Serum MALDI-TOF was not typical, although one possible biomarker appeared at low level.
The case is still open
RNA analysis did not show an ALG1 splice defect. CHAMP1 remains only a mosaic VUS.
Why this is interesting
There is a real cell signal, but the blood signal is weak.
That makes the case unusual and worth studying. It is not just a broad phenotype story — it is a concrete experimental problem.
Why a lab might care
- The fibroblast phenotype is already there.
- The next experiment is clear: wild-type ALG1 rescue.
- The case may reflect an atypical ALG1 mechanism.
- The missing second ALG1 event is still unresolved.
How a lab could help
Three useful directions.
The Bratislava fibroblast glycomics are still pending. The clearest causal experiment after that — or in parallel where feasible — is wild-type ALG1 rescue.
Material available
Patient-derived fibroblasts already exist.
The fibroblast culture is available and reported to be in good condition. Clinical, genetic and biochemical documentation can be shared with serious research collaborators, subject to the appropriate clinical and research arrangements.
A. Do the key rescue experiment
Add normal ALG1 to Emma's fibroblasts and measure whether glycosylation improves.
B. Look for the hidden second ALG1 event
Use deeper genomic analysis of ALG1 and the surrounding locus.
C. Test 4-PBA in fibroblasts
Use 4-PBA as a controlled in-vitro rescue experiment and ask whether the glycosylation phenotype improves. This is a cell experiment, not a treatment claim.
What has happened so far
Research timeline.
The key findings, what each test showed, and what is still outstanding.
2020–2024
Genetic testing did not give a complete diagnosis.
Exome-based testing found a de novo mosaic CHAMP1 p.Arg548Cys VUS and one pathogenic ALG1 variant. No second pathogenic ALG1 allele was identified.
2025
Fibroblasts produced the clearest glycosylation signal.
LAMP2 hypoglycosylation was demonstrated in Emma's fibroblasts. ALG1 protein quantity appeared preserved, while ADAMTS13-related abnormalities had also been repeatedly observed.
Nov 2025
Bratislava glycomics was arranged.
The metabolic team arranged research glycomic analysis, including the search for an ALG1-associated biomarker. A 4-PBA fibroblast experiment was considered feasible, but the team preferred to obtain RNA results and a better biomarker first.
Dec 2025
RNA-seq did not reveal an ALG1 splice defect.
The known pathogenic ALG1 c.773C>T (p.Ser258Leu) variant was detected in fibroblast RNA, but no altered ALG1 mRNA splicing was found.
Mar 2026
Serum glycomics was not typical for classical ALG1-CDG.
MALDI-TOF detected only one of four potential ALG1 biomarkers, and only at low level. The Bratislava team still planned to analyse the fibroblasts separately.
May–Aug 2026 · waiting
PendingFibroblast glycomics from Bratislava is still pending.
The fibroblast culture is available and reported to be in good condition, but the research result has not yet returned. The pending work is best described as fibroblast glycomics / ALG1 biomarker analysis, including interest in the ALG1-associated N-tetrasaccharide. This matters because published ALG1 cases show that fibroblast abnormalities can be detectable despite normal blood-based testing.
Next
ProposedTest causality with wild-type ALG1 rescue.
The clearest next experiment is to add normal ALG1 to Emma's fibroblasts and ask whether the abnormal glycosylation phenotype moves toward control cells. Deeper analysis for a hidden second ALG1 event can proceed in parallel.