L-fucose supplementation in a patient with global hypofucosylation and a mono-allelic variant in SLC35C1: Clinical improvement and assessment of biomarkers.

A patient with global hypofucosylation was found to carry a single likely pathogenic mono-allelic variant in SLC35C1 inherited from an unaffected mother.

• The variant identified was SLC35C1 (NM_018389.4):c.503_505delTCT, p.(Phe168del), inherited from an unaffected mother.
• Whole genome sequencing with manual review of raw data did not reveal any second pathogenic variant.
• SLC35C1 mRNA sequencing was negative for changes in the second allele or allelic imbalance.
• This is notable because SLC35C1-CDG is classically described as a bi-allelic disorder.

Biochemical investigations confirmed significant global hypofucosylation in the patient.

• Serum N-glycan profiling demonstrated significant global hypofucosylation.
• Fucosylation-focused whole serum glycoprotein profiling confirmed hypofucosylation.
• Serum lectin blots also showed significant global hypofucosylation.
• All three independent biochemical investigations were concordant in demonstrating hypofucosylation.

The patient presented with a constellation of clinical features including growth faltering, neuroirritability, nystagmus, developmental delays, microcephaly, dysmorphic features, and hypogammaglobulinemia G.

• Clinical features included growth faltering, neuroirritability, nystagmus, developmental delays, microcephaly, and dysmorphic features.
• The patient also had hypogammaglobulinemia G (reduced IgG levels).
• The classical SLC35C1-CDG presentation includes leukocyte adhesion deficiency, dysmorphic features, short stature, and moderate-to-severe developmental and intellectual disabilities.
• Unlike classical SLC35C1-CDG (leukocyte adhesion deficiency type II), hematological abnormalities were not described as a primary feature in this patient.

L-fucose supplementation resulted in clinical improvements including gains in weight and head circumference, normalization of IgG levels, and remarkable developmental catch-up.

• Following L-fucose supplementation, the patient showed improvements in weight and head circumference.
• IgG levels normalized following L-fucose supplementation.
• The authors describe 'remarkable developmental catch-up' following treatment.
• The authors suggest that the early introduction of L-fucose in this patient may have led to the excellent developmental outcomes observed.

L-fucose supplementation was associated with an increase in abundance of previously decreased fucosylated glycan species in serum, particularly Fuc1GlcNAc2Man3.

• There was an increase in abundance of previously decreased fucosylated glycan species in serum following treatment.
• The most notable increase was in Fuc1GlcNAc2Man3, a glycan known to be enriched in neutrophils.
• This biochemical response provides evidence for the mechanism of action of L-fucose supplementation in hypofucosylation disorders.

The authors propose that IgG levels and fucosylated glycan species may serve as useful biomarkers for monitoring L-fucose supplementation therapy in hypofucosylation disorders.

• IgG normalization following L-fucose supplementation suggests its potential utility as a treatment biomarker.
• Changes in fucosylated glycan species, particularly Fuc1GlcNAc2Man3, may serve as biochemical biomarkers.
• The authors note that 'further research is needed to validate them as such.'
• This is presented as a single case report, limiting generalizability.

Recent literature has described cases of SLC35C1 variants with biochemical hypofucosylation but without hematological abnormalities, expanding the phenotypic spectrum of this disorder.

• Classical SLC35C1-CDG (formerly leukocyte adhesion deficiency type II) presents with leukocyte adhesion deficiency, dysmorphic features, short stature, and moderate-to-severe developmental and intellectual disabilities.
• Several cases have been described of individuals with bi-allelic SLC35C1 variants and biochemical proof of hypofucosylation who had short stature, dysmorphic features, and intellectual disability but no hematological abnormalities.
• The current patient adds to this expanding phenotypic spectrum with a mono-allelic variant causing biochemically confirmed hypofucosylation.