Almost all types of congenital disorders of glycosylation (CDG) present in infancy. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in broad multisystem clinical manifestations [Varki 1993] that may include one or more of the following: failure to thrive, developmental delay, hepatopathy, hypotonia/neurologic abnormalities, hypoglycemia, protein-losing enteropathy, eye abnormalities, immunologic findings, skin abnormalities, and skeletal findings [Rymen & Jaeken 2014]. It is becoming increasingly clear that the clinical spectrum can involve individual or multiple organ systems and may or may not affect neurodevelopment. CDG is increasingly being considered in the differential diagnosis for varied symptoms across multiple age groups and clinical specialties.
For many types of CDG, the phenotype is not completely known because only a few affected individuals have been reported.
Note: In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not italicized) followed by "-CDG." If the type has a known letter name, it is added in parentheses as shown for CDG type 1a; new nomenclature: PMM2-CDG (CDG-Ia) [Jaeken et al 2009a].
CDG N-Linked
PMM2-CDG (CDG-Ia). The typical clinical course of PMM2-CDG (CDG-Ia) has been divided into an infantile multisystem stage, late-infantile and childhood ataxia-intellectual disability stage, and adult stable disability stage; see PMM2-CDG (CDG-Ia). The phenotypic spectrum includes hydrops fetalis at the severe end [van de Kamp et al 2007] and a mild neurologic phenotype in adults with multisystemic involvement at the mild end [Barone et al 2007, Coman et al 2007].
The infantile multisystem stage, the most commonly seen stage, is characterized by failure to thrive, inverted nipples, abnormal subcutaneous fat distribution, and cerebellar hypoplasia, in combination with facial dysmorphism and developmental delay.
Neuroimaging may demonstrate the following:
An enlarged cisterna magna and superior cerebellar cistern in late infancy to early childhood
In 13 affected individuals, the extent of cerebellar involvement on brain imaging correlated with functional and cognitive assessments [
Serrano et al 2015].
Occasionally both infratentorial and supratentorial changes compatible with atrophy
Dandy-Walker malformations and small white matter cysts
Myelination that varies from normal to insufficient or delayed maturation
Areas of ischemia or edema followed by focal necrosis in those who have had a recent stroke-like episode [
Ishikawa et al 2009]
MPI-CDG (CDG-Ib). Cyclic vomiting, profound hypoglycemia, failure to thrive, liver fibrosis, and protein-losing enteropathy, occasionally associated with coagulation disturbances without neurologic involvement, are characteristic [de Koning et al 1998, Jaeken et al 1998, Niehues et al 1998, Babovic-Vuksanovic et al 1999, de Lonlay et al 1999, Adamowicz et al 2000, de Lonlay & Seta 2009]. The clinical course is variable even within families.
ALG6-CDG (CDG-Ic) is now considered to be a common type of CDG [Jaeken et al 2015]. The characteristic clinical phenotype of ALG6-CDG (CDG-Ic) (previously carbohydrate-deficient glycoprotein syndrome type V) includes hypotonia, developmental delay, ataxia and epilepsy [Morava et al 2016].
ALG3-CDG (CDG-Id). A total of 11 affected individuals have been described; features include severe neurologic involvement, microcephaly, seizures, dysmorphic facial features, skeletal anomalies (arthrogryposis multiplex congenita, chondrodysplasia punctata), and eye anomalies (cataract, corneal opacities, iris coloboma) [Lepais et al 2015].
DPM1-CDG (CDG-Ie). Features may include severe developmental delay, microcephaly, seizures, ataxia, peripheral neuropathy, eye abnormalities (retinopathy, nystagmus, strabismus), and severe gastrointestinal involvement [Dancourt et al 2006, Bursle et al 2017]. One infant presented with congenital muscular dystrophy similar to that seen in the dystroglycanopathies [Yang et al 2013].
MPDU1-CDG (CDG-If). Five individuals had severe developmental delay, generalized scaly, erythematous skin, and attacks of hypertonia [Jaeken et al 2000, Kranz et al 2001, Schenk et al 2001].
ALG12-CDG (CDG-Ig). Features may include generalized hypotonia, feeding difficulties, moderate to severe developmental delay, progressive microcephaly, seizures, dysmorphic facial features, frequent upper respiratory tract infections, hypogonadism with or without hypospadias, impaired immunity with decreased immunoglobulin levels, cardiac anomalies, and decreased coagulation factors [Chantret et al 2002, Grubenmann et al 2002, Thiel et al 2002, Zdebska et al 2003, Di Rocco et al 2005, Eklund et al 2005a, Eklund et al 2005b, Kranz et al 2007a].
ALG8-CDG (CDG-Ih) is characterized by severe multisystem involvement with seizures, distinctive facial features, protein-losing enteropathy, and hematopoietic issues (anemia, thrombocytopenia, decreased levels of factor XI, protein C, and antithrombin III) [Chantret et al 2003, Schollen et al 2004a, Eklund et al 2005b, Höck et al 2015].
A pair of sibs who had a milder presentation with pseudo-gynecomastia, hypotonia, intellectual disability, and ataxia were described [Stölting et al 2009].
ALG2-CDG (CDG-Ii). An individual age six years had bilateral iris colobomas, unilateral cataract, infantile spasms beginning at age four months, and severe developmental delay; coagulation factors were abnormal [Thiel et al 2003].
DPAGT1-CDG (CDG-Ij) is characterized by hypotonia, intractable seizures, developmental delay, skeletal anomalies, and microcephaly [Carrera et al 2012, Timal et al 2012, Würde et al 2012].
ALG1-CDG (CDG-Ik). The phenotypic spectrum ranges from mild intellectual disability to death in the first few weeks of life [Ng et al 2016]. Features may include severe developmental delay, rapidly progressive microcephaly, hypotonia, early-onset seizures, severe coagulation defects, immunodeficiency, nephrotic syndrome, liver dysfunction, and cardiomyopathy [Schwarz et al 2004, Dupré et al 2010].
ALG9-CDG (CDG-IL). Features may include microcephaly, hypotonia, developmental delay, seizures, hepatomegaly, pericardial effusion, renal cysts, and skeletal dysplasia. Brain MRI may demonstrate cerebral atrophy and delayed myelination [Frank et al 2004, Weinstein et al 2005, AlSubhi et al 2016].
DOLK-CDG (CDG-Im). Dilated cardiomyopathy in combination with a muscular dystrophy phenotype [Lefeber et al 2011], a purely neurologic phenotype [Helander et al 2013], and a severe fatal multiple system syndrome have been described [Lieu et al 2013]. Features may include hypotonia, ichthyosis, seizures, and progressive microcephaly.
RFT1-CDG (CDG-In). Common features include severe developmental delay, hypotonia, visual disturbances, seizures, feeding difficulties, sensorineural hearing loss, inverted nipples, and microcephaly [Jaeken et al 2009b, Vleugels et al 2009]. Two adult sibs had severe cognitive impairment and controlled seizures; neither had visual impairment [Ondruskova et al 2012].
DPM3-CDG (CDG-Io). A single described individual diagnosed at age 27 years had a low normal IQ and mild muscle weakness. She presented initially at age 11 years with mild muscle weakness and waddling gait. She had dilated cardiomyopathy without signs of cardiac muscle hypertrophy at age 20 years followed by a stroke-like episode at age 21 years [Lefeber et al 2009].
ALG11-CDG (CDG-Ip). Features include developmental delay, strabismus, and seizures [Thiel et al 2012]. One infant developed an unusual fat pattern around age six months [Rind et al 2010]; she had persistent vomiting and gastric bleeding and died at age two years.
SRD5A3-CDG (CDG-Iq). Common features including congenital eye malformations (ocular coloboma, optic nerve hypoplasia, and variable degree of visual loss), nystagmus, hypotonia, developmental delay/intellectual disability, and cerebellar ataxia. Less commonly affected individuals have dermatologic complications and/or congenital heart defects [Cantagrel et al 2010, Morava et al 2010].
Note: Biallelic pathogenic variants in SRD5A3 have also been identified in people with Kahrizi syndrome, an allelic disorder characterized by coloboma, cataract, kyphosis, and intellectual disability [Kahrizi et al 2011].
DDOST-CDG (CDG-Ir). A single child was described, presenting with failure to thrive, developmental delay, hypotonia, strabismus and hepatic dysfunction. At three years the child walked but continued to have fine motor delays and minimal speech development. Brain MRI showed dysmyelination [Jones et al 2012].
MAGT1-CDG was reported in a family with two girls with mild cognitive impairment and two boys with more severe cognitive involvement. The mother is reported to have mild cognitive impairment [Molinari et al 2008].
TUSC3-CDG has been described in 12 individuals (including 2 French sibs and 3 Iranian sibs) with nonsyndromic moderate-to-severe cognitive impairment and normal brain MRI [Garshasbi et al 2011].
ALG13-CDG was described in one child with microcephaly, hepatomegaly, edema of the extremities, intractable seizures, recurrent infections and increased bleeding tendency who died at age one year [Timal et al 2012].
PGM1-CDG. Features may include dilated cardiomyopathy, chronic hepatitis, fatigue, and Pierre Robin sequence with cleft palate [Timal et al 2012].
Note: Biallelic pathogenic variants in PGM1 have also been described in an individual with a clinical diagnosis of glycogen storage disease type 14 with recurrent rhabdomyolysis [Stojkovic et al 2009].
STT3A-CDG (CDG-Iw). Two sibs have been described with microcephaly, cognitive impairment, failure to thrive, seizures, and cerebellar atrophy [Shrimal et al 2013].
STT3B-CDG (CDG-Ix). A single individual with microcephaly, severe developmental delay, failure to thrive, seizure disorder, and liver and genitourinary abnormalities has been described [Shrimal et al 2013].
SSR4-CDG (CDG-Iy) is an X-linked disorder in which males have microcephaly, cognitive impairment, and seizure disorder. Other features may include feeding issues with oral aversion, failure to thrive, and distinctive facial features. Less commonly, skeletal, hematologic, cardiac, and renal abnormalities have been described [Ng et al 2015].
MGAT2-CDG (CDG-IIa). Individuals have facial dysmorphism, stereotypic hand movements, seizures, and varying degrees of developmental delay, but no peripheral neuropathy or cerebellar hypoplasia. A bleeding disorder is caused by diminished platelet aggregation [Van Geet et al 2001].
MOGS-CDG (CDG-IIb). Findings include distinctive facial features, generalized hypotonia, cognitive impairment, seizures, abnormal brain imaging, hearing loss, and recurrent infections along with hypogammaglobulinemia [Sadat et al 2014]. One infant also had hypoplastic genitalia, feeding difficulties, hypoventilation, and generalized edema [De Praeter et al 2000].
SLC35C1-CDG (CDG-IIc). Severe growth and developmental delay, microcephaly, hypotonia, distinctive facial l features, and recurrent bacterial infections with persistent, highly elevated peripheral blood leukocyte count are characteristic [Etzioni et al 2002].
B4GALT1-CDG (CDG-IId). Mild developmental delay, Dandy-Walker malformation, progressive hydrocephalus, coagulation abnormalities, and elevated serum creatine kinase concentration have been observed [Peters et al 2002].
SLC35A2-CDG is an X-linked disorder leading to severe early-onset encephalopathy [Kodera et al 2013].
GMPPA-CDG was identified in several individuals with cognitive impairment and autonomic dysfunction including achalasia and alacrima. Gait abnormalities were also seen [Koehler et al 2013].
Multiple-Pathway Disorders
COG7-CDG (CDG-IIe). Features include dysmorphic facies with a small mouth (although one had full lips), micro- and retrognathia, short neck, wrinkled and loose skin, adducted thumbs, overlapping long fingers, hypotonia, hepatosplenomegaly and progressive jaundice, seizures, and early death [Wu et al 2004, Spaapen et al 2005, Morava et al 2007, Ng et al 2007].
SLC35A1-CDG (CDG-IIf). One affected infant presented at age four months with macrothrombocytopenia, neutropenia, and immunodeficiency, and died at age 37 months of complications from bone marrow transplantation [Martinez-Duncker et al 2005].
COG1-CDG (CDG-IIg). An affected infant presented in the first month of life with feeding difficulties, failure to thrive, and hypotonia. She had mild developmental delays, rhizomelic short stature, and progressive microcephaly with slight cerebral and cerebellar atrophy on brain MRI, as well as cardiac abnormalities and hepatosplenomegaly [Foulquier et al 2006].
COG2-CDG. A single individual was described with acquired microcephaly, cognitive impairment, seizures and liver dysfunction [Kodera et al 2015].
COG8-CDG (CDG-IIh). Two affected infants with severe developmental delay, hypotonia, seizures, esotropia, failure to thrive, and progressive microcephaly were reported [Foulquier et al 2007, Kranz et al 2007b].
COG5-CDG (CDG-Iii). Features may include peripheral neuropathy, hepatic dysfunction, and mild cognitive impairment, although more severe cognitive impairment with blindness and deafness has also been described [Paesold-Burda et al 2009, Rymen et al 2012].
COG4-CDG (CDG-IIj). Features include severe cognitive impairment, seizures, hypotonia, liver cirrhosis, recurrent infections and early death. Less common features may include microcephaly, ataxia, and brisk uncoordinated movements [Reynders et al 2009, Ng et al 2011].
TMEM165-CDG (CDGIIk). Sibs with a skeletal dysplasia affecting the epiphyses, metaphyses, and diaphyse were described. Additional features included abnormal white matter and pituitary hypoplasia on brain MRI [Foulquier et al 2012].
COG6-CDG (CDG-IIL). Features include microcephaly, cognitive impairment, seizures, liver abnormalities, recurrent infections, and ectodermal involvement with hypohidrosis and hyperkeratosis [Lübbehusen et al 2010, Rymen & Jaeken 2014].
DHDDS-CDG. Features may include microcephaly, severe developmental delay, liver and renal dysfunction, and severe seizures or retinitis pigmentosa as an isolated finding [Willer et al 2012, Sabry et al 2016].
DPM2-CDG. Failure to thrive, developmental delay, osteopenia, hypotonia, liver dysfunction, increased creatine kinase, and early death have been observed [Barone et al 2012].
MAN1B1-CDG is characterized by nonsyndromic intellectual disability [Rafiq et al 2011].
PGM3-CDG. Eight individuals with severe atopic dermatitis, recurrent infections due to immunodeficiency, and renal involvement have been described [Zhang et al 2014].
