Final Diagnosis -- Congenital Disorder of Glycosylation SRD5A3-CDG (CDG-1q) Associated with Retinitis Pigmentosa

DIAGNOSIS

Congenital disorder of glycosylation SRD5A3-CDG (CDG-1q) associated with retinitis pigmentosa

DISCUSSION

Glycosylation of secreted and membrane-bound proteins on asparagine residues (e.g. N-linked glycosylation) is common in eukaryotic cells [1]. Disruption of N-linked glycosylation is the most common mechanism whereby Congenital Disorders of Glycosylation (CDG) are realized. In eukaryotic cells, this posttranslational modification is involved in protein folding and trafficking with implications for cell-cell and cell-matrix interactions and intra-cellular signaling [1, 2]. SRD5A3 is located in the endoplasmic reticulum (ER) membrane and catalyzes the conversion of polyprenol to dolichol. Dolichol-specific kinase transfers a phosphate from cytidine triphosphate to dolichol, and synthesis of dolichol phosphate is the step proximal to the start of N-glycosylation and O-and C-mannosylation [3]. Assembly of an oligosaccharide precursor, transfer of the precursor to asparagine residues and modification of the N-linked glycan are the three phases of N-linked glycosylation. Defects in the maturation and transfer of the glycan precursor were categorized as CDG type I, and disorders affecting the subsequent N-glycan processing steps were categorized as CDG type II [1]. A recent nomenclature modification uses the approved gene abbreviation together with a CDG suffix [4].

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is one of a growing number of congenital disorders of glycosylation (CDG). These disorders disrupt protein and lipid ].glycosylation. Most CDG are multisystem disorders with predominant neurological involvement [3]. SRD5A3-CDG is an autosomal recessive, severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor [3, 5]. SRD5A3-CDG also presents with early onset retinal dystrophy [6]. Within SRD5A3-CDG presentation is variable; however, nearly every reported case includes cognitive delays, nystagmus/optic atrophy/optic hypoplasia, and ataxia (some with documented vermis hypoplasia). The cerebellum and optic tract seem especially vulnerable to the deficiency of SRD5A3. In addition to optic nerve hypoplasia/atrophy, multiple individuals have been reported with colobomas of the optic nerve and iris and later in life development of retinal abnormalities including retinitis pigmentosa as well as glaucoma and cataracts [7].

SRD5A3-CDG generates subtle abnormality in the serum transferrin pattern. Classically a so-called Type 1 CDG pattern is characterized by increased disialotransferrin and/or asialotransferrin [8]. Figure 1 displaying the sialotransferrin pattern of this patient identifies only a modest increase in disialo species and asialo species are not present. High order sialated species are normally represented. The overall representation of sialotransferrins varies widely between patients; however, the pattern of representation between alternatively glycated species is exceedingly consistent. These data demonstrate that any profile with even subtle alteration within the overall pattern should trigger further follow-up in the form of MS/MS based sialotransferrin assessment or DNA testing (CGD specific gene panels, exome). Carbohydrate-deficient transferrin (CDT) is also a biomarker for chronic alcohol intake [9]. However, the patient has no history of alcohol use.

REFERENCES

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Contributed by Gaurav Kattel, MBBS, MD and Steven F. Dobrowolski, PhD