A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report

Abstract

Congenital disorders of glycosylation (CDG) are an expanding group of inherited metabolic diseases with multisystem involvement. ALG6-CDG (CDGIc) is an endoplasmatic reticulum defect in N-glycan assembly. It is usually milder than PMM2-CDG (CDG-Ia) and so is its natural course. It is characterized by psychomotor retardation, seizures, ataxia, and hypotonia. In contrast to PMM2-CDG (CDGIa), there is no cerebellar hypoplasia. Cardiomyopathy has been reported in a few CDG types and in a number of patients with unexplained CDG. We report an 11 year old Saudi boy with severe psychomotor retardation, seizures, strabismus, inverted nipples, dilated cardiomyopathy, and a type 1 pattern of serum transferrin isoelectrofocusing. Phosphomannomutase and phosphomannose isomerase activities were normal in fibroblasts. Full gene sequencing of the ALG6 gene revealed a novel mutation namely c.482A>G (p.Y161C) and heterozygosity in the parents. This report highlights the importance to consider CDG in the differential diagnosis of unexplained cardiomyopathy.

ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients

“…The p.A333V mutation is associated with a mild to moderate phenotype which indicates that the novel frameshift mutation (c.1338dupA), which results in the formation of a truncated ALG6 protein, probably explains the severe phenotype and early death of the patient as well as the unusually low serum tetrasialotransferrin. The phenotypic variation from the typical ALG6 deficiency concurs with previous literature of rare ALG6-CDG cases with multiple organ involvement and intestinal abnormality, e.g., PLE (Westphal et al 2000b;Newell et al 2003;Al-Owain et al 2010). Patients 2, 3, 4, and 5 presented with the classical ALG6-CDG phenotype comprising of a variable degree of neurological involvement, including hypotonia and resistant epilepsy.…”

“…It was first reported in 1998 (Burda et al 1998;K€ orner et al 1998) and about 37 patients have been described (Imbach et al 1999Gr€ unewald et al 2000;Hanefeld et al 2000;Westphal et al 2000aWestphal et al , b, 2003de Lonlay et al 2001;Schollen et al 2002;Newell et al 2003;Sun et al 2005;Vuillaumier-Barrot 2005;Eklund et al 2006;Haeuptle and Hennet 2009;Al-Owain et al 2010). The clinical presentation is mainly characterized by feeding problems and a moderately pronounced neurological disorder with psychomotor retardation, hypotonia, epilepsy, and internal strabismus Newell et al 2003).…”

“…Table 1 summarizes clinical and molecular findings in ten ALG6-CDG patients reported since 1998. Twenty-one different mutations have been described but the majority of patients have the c.998C>T (p.A333V) mutation, either in a compound heterozygous or homozygous state (Imbach et al 1999Gr€ unewald et al 2000;Hanefeld et al 2000;Westphal et al 2000aWestphal et al , b, 2003de Lonlay et al 2001;Schollen et al 2002;Newell et al 2003;Sun et al 2005;Vuillaumier-Barrot 2005;Eklund et al 2006;Haeuptle and Hennet 2009;Al-Owain et al 2010). Haeuptle and Hennet (2009) reported that most of the mutations affect amino acids positioned within the 11 TM domains, which compromise the integrity of the protein structure and alter the properties responsible for the binding of dolichol-linked glycans.…”

ALG6‐CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies

“…From this cohort, 35 patients have never been reported, and six were recently reported but the authors offered follow-up data (Al-Owain et al 2010;Dercksen et al 2013). Six patients with insufficient data (no availability of results of mutation analysis but with type I TIEF profile and characteristic LLO abnormalities for ALG6) were excluded from the genotype-phenotype analysis.…”

Insights into complexity of congenital disorders of glycosylation

“…The most common mutation in ALG6 gene causing ALG6-CDG is c.998C>T resulting in p.A333V substitution (23,27). However, recent case of 11-year old Saudi Arabian boy with dilated cardiomyopathy which revealed a novel c.482A>G (p.Y161C) mutation, suggests that CDG should be considered in the diff erential diagnosis of unexplained cardiomyopathy (30). Two point mutations c.391T>C in exon 5 and c.911T>C in exon 10 resulting in p.Y131H and p. F304S, respectively, although assumed being single nucleotide polymorphisms (rs35383149 and rs17856039) (31,32) are particularly interesting.…”