ALG8-CDG: novel patients and review of the literature

Abstract

Background: Since 1980, about 100 types of congenital disorders of glycosylation (CDG) have been reported representing an expanding group of inherited disorders. ALG8-CDG (= CDG-Ih) is one of the less frequently reported types of CDG, maybe due to its severe multi-organ involvement with coagulation disturbances, edema, massive gastrointestinal protein loosing enteropathy, cataracts, and often early death. We report three additional patients, provide an update on two previously reported, and summarize features of ten patients reported in literature.

Results: Of 15 ALG8-CDG patients, three were homozygous and 12 compound heterozygous. There were multiple prenatal abnormalities in 6/12 patients. In 13/15, there were symptoms at birth, 9/15 died within 12 months. Birth weight was appropriate in 11/12, only one was small for gestational age. Prematurity was reported in 7/12. Hydrops fetalis was noticed in 3, edemas in 11/13; gastrointestinal symptoms in 9/14; structural brain pathology, psychomental retardation, seizures, ataxia in 12/13, muscle hypotonia in 13/14. Common dysmorphic signs were: low set ears, macroglossia, hypertelorism, pes equinovarus, campto- and brachydactyly (13/15). In 10/11, there was coagulopathy, in 8/11 elevated transaminases; thrombocytopenia was present in 9/9. Eye involvement was reported in 9/14. CDG typical skin involvement was reported in 8/13.

Conclusion: In ALG8-CDG, isoelectric focusing of transferrin in serum or plasma shows an abnormal sialotransferrin pattern. The diagnosis is confirmed by mutation analysis in ALG8; all patients reported so far had point mutations or small deletions. The prognosis is generally poor. Thus, a timely and correct diagnosis is important for counselling.

Fig. 1

a,b Patient 4 at the age of 10 months - floppy infant, with multiple dysmorphic features such as a prominent forehead, wide fontanelle, macroglossia, dysplastic ears, high palate, inverted nipples, short fingers and toes and a pale mottled skin, “fat pads” on arms and thighs [11]

Fig. 2

a,b Patient 5 at the age of 20 days - floppy infant, with intermittent dystonic posturing, and multiple dysmorphic features such as an abnormal fat distribution on arms and thighs, macroglossia, low-set ears, additionally, cataracts and persisting primary vitreous artery were present

Fig. 3

Ocular sonography of Patient 5 at the age of 10 days - Persistent hyperplastic primary vitreous artery. A thin y-shaped membrane extends from the optic disc to the posterior aspect of the opacified lens representing a remnant of the hyaloid vasculary system