Expanding the phenotype, genotype and biochemical knowledge of <scp>ALG3‐CDG</scp>

Alsharhan, Hind; Ng, Bobby G.; Daniel, Earnest James Paul; Friedman, Jennifer; Pivnick, Enikö K.; Alhashem, Amal; Faqeih, Eissa; Liu, Pengfei; Engelhardt, Nicole; Keller, Kierstin; Chen, Jie; Mazzeo, Pamela A.; Rosenfeld, Jill A.; Bamshad, Michael J.; Nickerson, Deborah A.; Raymond, Kimiyo; Freeze, Hudson H.; He, Miao; Edmondson, Andrew C.; Lam, Christina

doi:10.1002/jimd.12367

Cited by 9 publications

(11 citation statements)

References 36 publications

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“…Our case adds to the previously published phenotype data several novel aspects. In earlier reports pale or small optic disc was observed in 12 patients suggesting optic nerve atrophy or hypoplasia [2,5,6,8,9,11,14,18]. Our case report is however the first clearly documenting optic nerve and retinal layers pathology by ocular imaging methods.…”

Section: Discussionsupporting

confidence: 54%

“…Out of the 43 reported individuals 17 had a lethal phenotype with prenatal manifestation, medical termination of pregnancy and/or early neonatal death. Three further patients died of respiratory failure during pneumonia in childhood (aged 1.8; 3.5 and 6 years) [11,12,14] and one of multiorgan failure (aged 1 year) [18]. Neurological symptoms have recently been summarized in 26 patients, and a ketogenic diet was suggested as a therapeutic option for intracrable epilepsy [16].…”

Section: Clinical Coursementioning

confidence: 99%

“…The longest living patient is 38 years-old male suffering from moderate intellectual disability, intractable seizures, feeding difficulties, facial dysmorphism, hearing loss, cardiac abnormalities, osteopenia/osteoporosis, nocturnal apnoea, scoliosis, hypothyroidism [18].…”

Section: Clinical Coursementioning

confidence: 99%

“…Most subjects carried a unique disease-causing variant(s), only three mutations have been identified recurrently. Homozygous variants were mainly linked to consanguinity when this information was available [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Disease-causing Variantsmentioning

confidence: 99%

“…ALG3-CDG patients show various combinations of cardiac defects (obstructive cardiomyopathy, dilatation of aorta), lung hypoplasia, hepatomegaly, neurological impairment (cerebral and cerebellar atrophy, agenesis of corpus callosum, epilepsy) with developmental delay, musculoskeletal involvement (ulnar deviation, joint contractures, skeletal dysplasia, scoliosis), urogenital abnormalities (nephrocalcinosis, renal cysts, hydronephrosis), microcephaly, visual impairment and dysmorphic features (down slanting palpebral fissures, hypertelorism, high nasal bridge, anteverted nares, large and thick lowset ears with abnormal pinnae, micrognathia, thin lips, inverted nipples). Forty-two cases of ALG3-CDG have been reported to date [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings

et al. 2021

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Background ALG3-CDG is a rare autosomal recessive disease. It is characterized by deficiency of alpha-1,3-mannosyltransferase caused by pathogenic variants in the ALG3 gene. Patients manifest with severe neurologic, cardiac, musculoskeletal and ophthalmic phenotype in combination with dysmorphic features, and almost half of them die before or during the neonatal period. Case presentation A 23 months-old girl presented with severe developmental delay, epilepsy, cortical atrophy, cerebellar vermis hypoplasia and ocular impairment. Facial dysmorphism, clubfeet and multiple joint contractures were observed already at birth. Transferrin isoelectric focusing revealed a type 1 pattern. Funduscopy showed hypopigmentation and optic disc pallor. Profound retinal ganglion cell loss and inner retinal layer thinning was documented on spectral-domain optical coherence tomography imaging. The presence of optic nerve hypoplasia was also supported by magnetic resonance imaging. A gene panel based next-generation sequencing and subsequent Sanger sequencing identified compound heterozygosity for two novel variants c.116del p.(Pro39Argfs*40) and c.1060 C > T p.(Arg354Cys) in ALG3. Conclusions Our study expands the spectrum of pathogenic variants identified in ALG3. Thirty-three variants in 43 subjects with ALG3-CDG have been reported. Literature review shows that visual impairment in ALG3-CDG is most commonly linked to optic nerve hypoplasia.

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Section: Discussionsupporting

confidence: 54%

Section: Clinical Coursementioning

confidence: 99%

Section: Clinical Coursementioning

confidence: 99%

Section: Disease-causing Variantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings

et al. 2021

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Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1

Bakar

Ashikov

Brum

et al. 2022

J of Inher Metab Disea

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Deficient glycan extension and endoplasmic reticulum stresses in ALG3‐CDG

Daniel,

Edmondson,

Argon

et al. 2024

J of Inher Metab Disea

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ALG3‐CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol‐P‐Man to Dol‐PP‐Man5GlcNAc2 (Man5) forming Dol‐PP‐Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3‐CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER‐associated degradation activities are increased in ALG3‐CDG patient‐derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1‐α pathway. In addition, we show that N‐linked Man3‐4 glycans are increased in cellular glycoproteins and secreted plasma glycoproteins with hepatic or non‐hepatic origin. We found that like other CDGs such as ALG1‐ or PMM2‐CDG, in transferrin, the assembling intermediate Man5 in ALG3‐CDG, are likely further processed into a distinct glycan, NeuAc1Gal1GlcNAc1Man3GlcNAc2, probably by Golgi mannosidases and glycosyltransferases. We predict it to be a mono‐antennary glycan with the same molecular weight as the truncated glycan described in MGAT2‐CDG. In summary, this study elucidates multiple previously unrecognized biochemical consequences of the glycan extension deficiency in ALG3‐CDG which will have important implications in the pathogenesis of CDG.

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Expanding the phenotype, genotype and biochemical knowledge of ALG3‐CDG

Cited by 9 publications

References 36 publications

ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings

ALG3-CDG: a patient with novel variants and review of the genetic and ophthalmic findings

Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1

Deficient glycan extension and endoplasmic reticulum stresses in ALG3‐CDG

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