ALG8-CDG: novel patients and review of the literature

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.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…ALG8 is the only one of the ERassociated PCLD genes for which a recessive genotype is reported to be compatible with life. Fifteen cases of congenital disorder of glycosylation 1H (CDG1H) have been reported in the literature, caused by homozygous or compound heterozygous combinations of loss-of-function and deleterious missense mutations in ALG8 (49). The CDG1H phenotype has been reported to include renal failure and hepatomegaly with at least 1 report of bile duct dilation and bile duct cysts (50).…”

DMP1-CDG (CDG1e) with Significant Gastrointestinal Manifestations; Phenotype and Genotype Expansion

“…Previously reported gastrointestinal manifestations (GIT) of the congenital glycosylation disorders include deranged liver function with elevated transaminases, hepatomegaly, liver fibrosis, steatosis and protein-losing enteropathy, as well as non-specific feeding problems, vomiting, diarrhoea and failure-to-thrive (Scott et al 2014). Protein-losing enteropathy is common in children with MPI-CDG (OMIM 602579, CDG-1b) and has also been reported in types PMM2-CDG (OMIM601785, CDG-1a), ALG6-CDG (OMIM 603147, CDG-1c), ALG12-CDG (OMIM 607143, CDG-1g), ALG8-CDG (OMIM 608104, CDG-1h), as well as in several cases of unclassified CDG (CDG-1x) (H€ ock et al 2015;Damen et al 2004;Agarwal et al 2007;McKenzie et al 2007;Kranz et al 2007;Krasnewich 2014).…”

Hyperkinetic movement disorders in congenital disorders of glycosylation

“…Unsteady ataxic gait with normal brain and cerebellar imaging was described in two siblings with a mild ALG8‐CDG phenotype . About half of 15 ALG8‐CDG patients reported so far died precociously . Our patient #6 was affected by a childhood‐onset epileptic encephalopathy associated with severe intellectual disability, ataxia and pure generalized chorea.…”

“…Asparagine‐linked glycosylation 8 CDG is characterized by distinct facial dysmorphisms, brachy‐camptodactyly and usually severe systemic involvement including liver disease, enteropathy, renal tubulopathy and ocular pathology . Neurological manifestations are variable but usually include severe psychomotor disability, seizures and hypotonia . Unsteady ataxic gait with normal brain and cerebellar imaging was described in two siblings with a mild ALG8‐CDG phenotype .…”