ALG8-CDG: novel patients and review of the literature

Michaela Höck,Christine Fauth,Sabine Scholl-Bürgi,Liesbeth Keldermans,Johannes Zschocke,Dirk J Lefeber,Karin Pichler,Gert Matthjis,Karina Wegleiter,Daniela Karall,Kathrin Maurer,Elisabeth Ralser,Ursula Kiechl-Kohlendorfer,Elisabeth Steichen

doi:10.1186/s13023-015-0289-7

Abstract

BackgroundSince 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.ResultsOf 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.ConclusionIn 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.

Highlights

Since 1980, about 100 types of congenital disorders of glycosylation (CDG) have been reported representing an expanding group of inherited disorders
Congenital disorders of glycosylation (CDG) involve a rapidly growing group of metabolic diseases that are caused by genetic defects in the synthesis of glycoproteins [1]
Some 100 CDG have been identified [1, 3], and about 50 of these can be identified via isoelectric focusing of transferrin [1, 3,4,5]

Summary

Results

In all our 5 patients, the plasma isoelectric focusing of transferrin showed a type 1 pattern (CDG-I) and confirmed the clinical suspicion of an underlying CDG. In Patient 4, sialotransferrins showed a type 1 pattern (CDG-Ix). In Patient 2 with prenatal hydrops, edema and cataract, the serum transferrin type 1 pattern prompted us to investigate ALG8 gene as a candidate. Two heterozygous mutations in the ALG8 gene were found in DNA extracted from fibroblasts of Patient 2 (c.139A>C in exon 2, p.Thr47Pro, and c.1090C>T in exon 10, p.Arg364Ter), confirming the diagnosis of ALG8-CDG. The clinical similarity and plasma transferring type I pattern prompted analysis of ALG8 gene in Patient 5. This showed compound heterozygosity for the known. Eye involvement (especially cataracts) was reported in 9/ 14 patients and skin involvement like fat pads, wrinkly skin, cutis laxa and inverted nipples was reported in 8/13 patients

Conclusion

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