Congenital disorders of glycosylation (CDG) are genetic defects in the synthesis of glycans and their attachment to proteins and lipids to form glycoproteins and glycolipids, respectively. Protein glycosylation defects comprise protein
The large majority of CDG are inherited in an autosomal recessive manner. About 15 CDG show an autosomal dominant or X-linked inheritance, and, interestingly, a few show one or the other inheritance depending on their variant(s) (see, e.g. POFUT1-CDG and COG4-CDG below). This review aims to discuss, mainly from a clinical point of view, a selection of CDG with peculiar features, e.g. an unusual presentation, different phenotypes, a novel biochemical/genetic mechanism, a relatively high frequency or a rather efficient treatment. See recent reviews for complementary information (1, 2, 3, 4).
Phosphomannomutase 2 (PMM2) deficiency is the first clinically described CDG. It is the most frequent protein
Mannosephosphate isomerase (MPI) deficiency belongs to the most common
Guanosine diphosphate-mannose pyrophosphorylase A (GMPPA) deficiency is known as alacrima, achalasia and mental retardation (AAMR) syndrome. It resembles the triple A syndrome, but patients with AAMR do not have adrenal insufficiency. Remarkably, there is no evidence of abnormal
Guanosine-diphosphate-mannose pyrophosphorylase B (GMPPB) deficiency is clinically very different from, and more frequent than, GMPPA-CDG. It is associated with a wide neurological spectrum, ranging from Walker-Warburg syndrome to pseudo-metabolic myopathy, and even congenital myasthenic syndromes. Less frequent features are the asymptomatic increase of serum creatine kinase, arthrogryposis, congenital clubfoot, seizures and autism spectrum disorder. As in GMPPA-CDG patients,
CAD encodes a multi-functional enzyme involved in de novo pyrimidine, and hence uridine diphosphate (UDP) and cytosine monophosphate (CMP), biosynthesis. Its deficiency causes a severe syndrome with global intellectual disability, early infantile epilepsy and dyserythropoietic anaemia. Nearly all UDP-activated sugars, which are donors for glycosylation, have been reported to be decreased, but the serum Tf IEF is normal. Promising results have been obtained by oral uridine supplementation in two children, leading to immediate cessation of seizures and significant improvement of psychomotor development (12).
Phosphoglucomutase 1 (PGM1) deficiency is a multi-system CDG that leads to decreased
Phosphoglucomutase 3 (PGM3) deficiency is a disorder of
Adams-Oliver syndrome is characterised by aplasia cutis congenital of the scalp and is mostly associated with terminal transverse limb defects, besides other abnormalities (neurological, cardiovascular and ocular). There are at least six genes for this syndrome and two modes of inheritance. Autosomal recessive Adams-Oliver syndrome is caused by variants in the
While EOGT-CDG is caused by EGF-domain-specific
Dehydrodolichol diphosphate synthase (DHDDS) deficiency is one of the three known defects in the synthesis of dolichol phosphate, the carrier of the glycan intermediates in the ER. It causes either autosomal recessive non-syndromic retinitis pigmentosa (17) or a de novo encephalopathy comprising epilepsy and other movement disorders, hypotonia and developmental and intellectual disability (18).
Mannosyltransferase 1 deficiency is characterised by a predominant neurological involvement: mostly severe intellectual developmental disability and hypotonia. A majority of patients show dysmorphism, microcephaly, intractable epilepsy, visual disturbances, tremor, ataxia, severe infections and brain abnormalities. Life expectancy ranges from 1 day to >20 years. Serum tTf IEF shows a type 1 pattern, and recently, a novel biomarker was detected in these patients, namely the protein-linked xeno-tetrasaccharide NeuAc–Gal– GlcNAc2 (19).
Glucosyltransferase 1 deficiency is mostly characterised by a mild to moderately severe neurological disorder and feeding problems. Many other symptoms have been reported, the most uncommon being limb anomalies such as brachytelephalangy and short arms. For an unknown reason, blood glycoproteins such as clotting factors XI, antithrombin, protein C and protein S are unusually low, as is serum cholesterol; for a review, see Morava et al. (20).
Mannosyltransferase 7/9 is one of the three ‘dual’ mannosyltransferases (together with ALG2 and ALG11) that attaches two mannose residues to the growing ER glycan. Its deficiency causes one of two phenotypes: a syndrome with failure to thrive, dysmorphism, epilepsy and hepatic and/or renal cysts; and on the other hand, a lethal skeletal dysplasia in affected foetuses (21). Moreover,
UDP–GlcNAc:Dol–P–GlcNAc–P transferase deficiency presents as one of two different phenotypes: a usually severe encephalopathy with early death in the context of a multi-system disorder, or a congenital myasthenic syndrome. A few cases of adults with a milder, stable disease, have been reported. Serum Tf IEF shows a type 1 pattern in all patients with multi-system presentation but in only half of the patients with congenital myasthenic syndrome. Patients with the latter presentation responded favourably to acetylcholinesterase inhibitors such as pyridostigmine; see review by Ng et al. (23).
Phosphatidylinositol glycan anchor biosynthesis class M protein transfers the first mannose from dolichol phosphate mannose to phosphatidylinositol, initiating the synthesis of the trimannosyl core of the glycosylphosphatidylinositol (GPI) membrane anchor. Deficient patients show a unique syndrome of portal/cerebrovascular vein thrombosis and absence seizures. They have the same
Dolichol kinase catalyses the final step in the synthesis of dolichol phosphate. Its deficiency causes an unusual association of symptoms, mainly dilated cardiomyopathy and ichthyosis. The cardiopathy is apparently isolated in some patients. Half of the reported patients died (at 8 days to 11 years). In some patients, there is neurological, hepatic and/or endocrinological involvement. An unusual symptom is truncation of distal phalanges. Cardiac transplantation has been performed in three patients, and two of them survived; see review by Rush et al. (25).
Protein
SEC23B is a COPII component. Its deficiency affects only the red blood cell lineage, causing ineffective erythropoiesis, haemolysis, erythroblast morphological abnormalities, hypoglycosylation of some red blood cell proteins (particularly band 3) and secondary abnormalities such as splenomegaly (28). It is one of the few CDG affecting only one organ/tissue. Other examples are EXT1-CDG (cartilage involvement), LFNG-CDG (vertebral column), POFUT1-CDG (skin), PRKCSH-CDG (liver), ST3GAL3-CDG and TUSC3-CDG (brain).
The protein complex exostosin-1/exostosin-2 catalyses the attachment of glucuronic acid and
This defect of the polypeptide
The conserved oligomeric Golgi (COG) complex, involved in vesicular transport, is composed of eight subunits distributed between two lobes: lobe A (COG1–4) and lobe B (COG5–8). Defects have been reported in each lobe except COG3. COG4-CDG is caused by biallelic loss-of-function variants and is mainly characterised by epileptic encephalopathy. In 2018, Ferreira et al. (34) showed that a novel heterozygous de novo COG4 variant is responsible for the Saul-Wilson syndrome described in 1990, a rare skeletal dysplasia with dwarfism, facial dysmorphism (progeria-like), hearing loss, cataracts and developmental delay. Contrary to the type 2 serum Tf IEF pattern in ‘classical’ COG4-CDG, this variant shows a normal Tf IEF pattern.
XYLT1 deficiency causes Desbuquois dysplasia type 2, a skeletal disorder comprising short stature, dislocation of the large joints, flat face and prominent eyes (35). In 2019, LaCroix et al. identified a GGC repeat expansion and exon 1 methylation of
The
This CDG disrupts the function of ZIP8, a major manganese transport protein, thus causing manganese deficiency. The phenotype mainly comprises cranial synostoses with lacunar skull, severe psychomotor disability, epilepsy, vision and hearing impairment, and cerebral and cerebellar atrophy. Malfunction of the manganese-dependent β-1,4-galactosyltransferase causes hypogalactosylation, and galactose supplementation has been reported to have a favourable effect on both clinical features and glycosylation in a severely affected child. Two children treated with oral MnSO4 have reportedly shown considerable clinical improvement and normalisation of enzymatic activities (38).
TMEM5 is a ribitol β1,4-xylosyltransferase that transfers xylose to the ribitol 5-phosphate tandem in the
No other metabolic disease family presents such a broad spectrum of signs and symptoms, as well as disease severity, as the CDG. A few CDG show very different phenotypes depending on the variant involved, and on the other hand, there are several CDG phenotypes caused by different genetic defects. Regarding treatment, MPI-CDG is still the only rather efficiently treatable CDG (oral mannose). A few other CDG partially respond to nutritional therapy (fucose, galactose, manganese, ketogenic diet and uridine), medication (acetazolamide) or transplantation (heart, liver and haematopoietic stem cells). For PMM2-CDG, treatments with chaperones, morpholino oligonucleotides, mannose-1-phosphate encapsulated in liposomes and gene therapy are under development. The number of CDG continues to rise exponentially mainly due to next-generation sequencing.