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ALG3-congenital disorder of glycosylation(CDGId; CDG1D; CDGS4, FORMERLY)

MedGen UID:
322026
Concept ID:
C1832736
Disease or Syndrome
Synonyms: ALG3-CDG; ALG3-CDG (CDG-Id); Carbohydrate-deficient glycoprotein syndrome type IV (formerly); CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE IV; CDG 1D; CDG Id; CDGS, TYPE IV; CDGS4 (formerly); Congenital disorder of glycosylation type 1D; CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Id
SNOMED CT: Asparagine-linked glycosylation 3 congenital disorder of glycosylation (720976009); ALG3 congenital disorder of glycosylation (720976009); Carbohydrate deficient glycoprotein syndrome type Id (720976009); Congenital disorder of glycosylation type 1d (720976009); Congenital disorder of glycosylation type Id (720976009); Mannosyltransferase 6 deficiency (720976009); ALG3-CDG - asparagine-linked glycosylation 3 congenital disorder of glycosylation (720976009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): ALG3 (3q27.1)
 
Monarch Initiative: MONDO:0010998
OMIM®: 601110
Orphanet: ORPHA79321

Definition

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). CDG1D is a type I CDG that generally presents with severe neurologic involvement associated with dysmorphism and visual impairment. Liver involvement is sometimes present (summary by Marques-da-Silva et al., 2017). For a discussion of the classification of CDGs, see CDG1A (212065). [from OMIM]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
Long fingers
MedGen UID:
346836
Concept ID:
C1858091
Finding
The middle finger is more than 2 SD above the mean for newborns 27 to 41 weeks EGA or above the 97th centile for children from birth to 16 years of age AND the five digits retain their normal length proportions relative to each other (i.e., it is not the case that the middle finger is the only lengthened digit), or, Fingers that appear disproportionately long compared to the palm of the hand.
Clinodactyly of the 5th toe
MedGen UID:
871256
Concept ID:
C4025741
Anatomical Abnormality
Bending or curvature of a fifth toe in the tibial direction (i.e., towards the big toe).
Clinodactyly
MedGen UID:
1644094
Concept ID:
C4551485
Congenital Abnormality
An angulation of a digit at an interphalangeal joint in the plane of the palm (finger) or sole (toe).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Villous atrophy
MedGen UID:
154306
Concept ID:
C0554101
Finding
The enteric villi are atrophic or absent.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Joint contracture of the hand
MedGen UID:
56382
Concept ID:
C0158113
Finding
Contractures of one ore more joints of the hands meaning chronic loss of joint motion due to structural changes in non-bony tissue.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
Food intolerance
MedGen UID:
57440
Concept ID:
C0149696
Finding
A detrimental reaction to a food, beverage, food additive, or compound found in foods that produces symptoms in one or more body organs and systems that is not mediated by an immune reaction.
Type I transferrin isoform profile
MedGen UID:
324900
Concept ID:
C1837899
Finding
Abnormal transferrin isoform profile consistent with a type I congenital disorder of glycosylation. In the traditional nomenclature for congenital disorders of glycosylation, absence of entire glycans was designated type I, and loss of one or more monosaccharides as type II.
Bulbous nose
MedGen UID:
66013
Concept ID:
C0240543
Finding
Increased volume and globular shape of the anteroinferior aspect of the nose.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Depressed nasal bridge
MedGen UID:
373112
Concept ID:
C1836542
Finding
Posterior positioning of the nasal root in relation to the overall facial profile for age.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.
Nail dysplasia
MedGen UID:
331737
Concept ID:
C1834405
Congenital Abnormality
The presence of developmental dysplasia of the nail.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Iris coloboma
MedGen UID:
116097
Concept ID:
C0240063
Anatomical Abnormality
A coloboma of the iris.
Severely reduced visual acuity
MedGen UID:
226987
Concept ID:
C1301509
Disease or Syndrome
Severe reduction of the ability to see. On the 6m visual acuity scale, severe reduction is defined as less than 6/60 but at least 3/60. On the 20ft visual acuity scale, severe reduction is defined as less than 20/200 but at least 20/400. On the decimal visual acuity scale, severe reduction is defined as less than 0.1 but at least 0.05.
Decreased light- and dark-adapted electroretinogram amplitude
MedGen UID:
326793
Concept ID:
C1839025
Finding
Decreased amplitude of eletrical response upon electroretinography.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for ALG3-congenital disorder of glycosylation in Orphanet.

Professional guidelines

PubMed

Simpson TC, Clarkson JE, Worthington HV, MacDonald L, Weldon JC, Needleman I, Iheozor-Ejiofor Z, Wild SH, Qureshi A, Walker A, Patel VA, Boyers D, Twigg J
Cochrane Database Syst Rev 2022 Apr 14;4(4):CD004714. doi: 10.1002/14651858.CD004714.pub4. PMID: 35420698Free PMC Article
Dashti HM, Mathew TC, Al-Zaid NS
Med Princ Pract 2021;30(3):223-235. Epub 2020 Oct 9 doi: 10.1159/000512142. PMID: 33040057Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
Lancet Neurol 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7. PMID: 25792100Free PMC Article

Recent clinical studies

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Altassan R, Péanne R, Jaeken J, Barone R, Bidet M, Borgel D, Brasil S, Cassiman D, Cechova A, Coman D, Corral J, Correia J, de la Morena-Barrio ME, de Lonlay P, Dos Reis V, Ferreira CR, Fiumara A, Francisco R, Freeze H, Funke S, Gardeitchik T, Gert M, Girad M, Giros M, Grünewald S, Hernández-Caselles T, Honzik T, Hutter M, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-de-Silva D, Martinez AF, Moravej H, Õunap K, Pascoal C, Pascreau T, Patterson M, Quelhas D, Raymond K, Sarkhail P, Schiff M, Seroczyńska M, Serrano M, Seta N, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Witters P, Zeevaert R, Morava E
J Inherit Metab Dis 2019 Jan;42(1):5-28. doi: 10.1002/jimd.12024. PMID: 30740725
Jaeken J, Péanne R
J Inherit Metab Dis 2017 Jul;40(4):569-586. Epub 2017 May 8 doi: 10.1007/s10545-017-0050-6. PMID: 28484880
Jaeken J
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Diagnosis

He M, Zhou X, Wang X
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Prognosis

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Biochim Biophys Acta Rev Cancer 2021 Apr;1875(2):188409. Epub 2020 Aug 19 doi: 10.1016/j.bbcan.2020.188409. PMID: 32827580
Altassan R, Péanne R, Jaeken J, Barone R, Bidet M, Borgel D, Brasil S, Cassiman D, Cechova A, Coman D, Corral J, Correia J, de la Morena-Barrio ME, de Lonlay P, Dos Reis V, Ferreira CR, Fiumara A, Francisco R, Freeze H, Funke S, Gardeitchik T, Gert M, Girad M, Giros M, Grünewald S, Hernández-Caselles T, Honzik T, Hutter M, Krasnewich D, Lam C, Lee J, Lefeber D, Marques-de-Silva D, Martinez AF, Moravej H, Õunap K, Pascoal C, Pascreau T, Patterson M, Quelhas D, Raymond K, Sarkhail P, Schiff M, Seroczyńska M, Serrano M, Seta N, Sykut-Cegielska J, Thiel C, Tort F, Vals MA, Videira P, Witters P, Zeevaert R, Morava E
J Inherit Metab Dis 2019 Jan;42(1):5-28. doi: 10.1002/jimd.12024. PMID: 30740725

Clinical prediction guides

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Hanić M, Trbojević-Akmačić I, Lauc G
Biochim Biophys Acta Gen Subj 2019 Oct;1863(10):1595-1601. Epub 2019 Jul 2 doi: 10.1016/j.bbagen.2019.07.001. PMID: 31276732
Duarte HO, Freitas D, Gomes C, Gomes J, Magalhães A, Reis CA
Biomolecules 2016 Jul 11;6(3) doi: 10.3390/biom6030033. PMID: 27409642Free PMC Article
Vogt G, Vogt B, Chuzhanova N, Julenius K, Cooper DN, Casanova JL
Curr Opin Genet Dev 2007 Jun;17(3):245-51. Epub 2007 Apr 30 doi: 10.1016/j.gde.2007.04.008. PMID: 17467977

Recent systematic reviews

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