Alternative titles; symbols
SNOMEDCT: 768846004; ORPHA: 404454; DO: 0060728;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p24.2 | Congenital disorder of deglycosylation 1 | 615273 | Autosomal recessive | 3 | NGLY1 | 610661 |
A number sign (#) is used with this entry because congenital disorder of deglycosylation-1 (CDDG1) is caused by homozygous or compound heterozygous mutation in the NGLY1 gene (610661) on chromosome 3p24.
Congenital disorder of deglycosylation-1 (CDDG1) is an autosomal recessive multisystem disorder characterized by global developmental delay, hypotonia, abnormal involuntary movements, and alacrima or poor tear production. Other common features include microcephaly, intractable seizures, abnormal eye movements, and evidence of liver dysfunction. Liver biopsy shows cytoplasmic accumulation of storage material in vacuoles (summary by Enns et al., 2014).
Genetic Heterogeneity of Congenital Disorder of Deglycosylation
See also CDDG2 (619775), caused by mutation in the MAN2C1 gene (154580).
For a discussion of the classification of congenital disorders of glycosylation, see CDG1A (212065).
Need et al. (2012) and Shashi (2013) reported a boy with a phenotype consistent with a congenital disorder of glycosylation. He presented with developmental delay, hypotonia, involuntary movements, intractable multifocal epilepsy, abnormal liver function, congenital absence of tears, peripheral neuropathy, and small hands and feet. At age 15 months he showed regression of motor development. At age 5 years he was able to sit up, reach for objects, transfer them from hand to hand, but never developed speech. Liver biopsy showed evidence of inflammatory changes with an amorphous substance in the cytoplasm. Urine oligosaccharides were abnormal, showing keratan sulfate, heparan sulfate, and chondroitin sulfate. Brain MRI showed prominent perivascular spaces with surrounding gliosis in periatrial white matter and mildly delayed myelination. Testing for congenital disorders of glycosylation had been normal by transferrin isoelectric focusing and N-glycan analysis.
Enns et al. (2014) reported 7 patients from 5 families with CDDG. Global developmental delay and hypotonia became apparent in the first months of life, followed by abnormal involuntary movements. A notable feature was poor tear production with subsequent corneal ulceration and scarring. All patients had EEG abnormalities, and 4 patients developed seizures, usually intractable, consisting of staring spells or myoclonic jerks. Additional features included microcephaly, constipation, hyporeflexia, strabismus, ocular apraxia, and small hands and feet. Laboratory studies showed abnormally increased liver enzymes, and some patients had elevated alpha-fetoprotein. Liver biopsy showed cytoplasmic accumulation of storage material in vacuoles. Brain MRI tended to show enlarged ventricles and delayed myelination, and neuropathologic examination of several patients showed axonal loss and gliosis, suggestive of hypoxic-ischemic encephalopathy.
Lam et al. (2017) studied 12 individuals, aged 2 to 21 years, with confirmed biallelic pathogenic NGLY1 mutations and identified previously unreported clinical features, including optic atrophy and retinal pigmentary changes/cone dystrophy, delayed bone age, joint hypermobility, and lower than predicted resting energy expenditure. Novel laboratory findings included low CSF total protein and albumin and unusually high antibody titers toward rubella and/or rubeola following vaccination. Lam et al. (2017) also confirmed and further quantified previously reported findings, noting that decreased tear production, transient transaminitis, small feet, a complex hyperkinetic movement disorder, and varying degrees of global developmental delay with relatively preserved socialization are the most consistent features. Lam et al. (2017) reported that most individuals had hypotonic facies, and while the majority (10 of 12) were born at term with normal growth parameters, individuals grew poorly after midchildhood, with weight affected more than height. Acquired microcephaly was documented in the 4 oldest subjects. Total foot length was less than the 3rd percentile for all 12 individuals. All 12 subjects had at least some developmental delay or intellectual disability. Seven had profound intellectual disability. Two individuals with an IQ below average were verbally fluent. The remainder were nonverbal or used only single words or phrase speech. Seven of 12 patients had seizures. All 12 had hyperkinetic movement disorders characterized by choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements, which were more severe in younger individuals. Brain MRIs were not clinically striking. Nerve conduction studies were performed in 11 individuals, of whom 8 were found to have an axonal sensorimotor polyneuropathy, with additional demyelinating features in 6.
Haijes et al. (2019) identified aspartylglycosamine as a biomarker for CDDG caused by mutation in the NGLY1 gene. In 7 dried blood spots from 4 CDDG1 patients, compared with 125 dried blood spots from healthy controls and 238 dried blood spots from patients with other diseases, Haijes et al. (2019) identified aspartylglycosamine as the only significantly increased compound, with a median Z-score of 4.8 (range, 3.8-8.5), compared to a median Z-score of -0.1 (range, -2.1-4.0) in dried blood spots of healthy controls and patients with other diseases.
Panneman et al. (2020) described 4 patients with moderately to severely impaired intellectual development, developmental delay, hypotonia, and extrapyramidal movements of the limbs. Biochemical laboratory studies showed evidence for mitochondrial dysfunction including mildly elevated serum lactate levels in 2 patients, elevated serum alanine in 1 patient, elevated urine 3-methylglutaconic acid in 2 patients, and elevated urine lactate in 2 patients.
Hall et al. (2018) identified elevated levels of Neu5Ac1Hex1GlcNAc1-Asn (Asn-N) in the urine of 14 patients with CDDG by urine oligosaccharide profiling via MALDI-TOF mass spectrometry. By evaluating urine oligosaccharides in 250 additional clinical samples submitted for laboratory testing, Hall et al. (2018) identified elevated Asn-N in a sample from a 7-year-old girl who was found to be homozygous for a previously identified mutation in the NGLY1 gene. The authors stated that this was the first patient diagnosed with CDDG by a biochemical screening method. Based on their studies, Hall et al. (2018) estimated that a qualitative elevation of Asn-N in urine had a 92.3% sensitivity and a 99.6% specificity for the diagnosis of CDDG, with a positive predictive value of 96% and a negative predictive value of 99.2%.
By whole-exome sequencing, Need et al. (2012) identified compound heterozygous mutations in the NGLY1 gene in a boy with CDDG1: a frameshift mutation in exon 12 (610661.0001) inherited from his mother, and a nonsense mutation in exon 8 (R401X; 610661.0002) inherited from his father. Need et al. (2012) compared NGLY1 protein expression in leukocytes extracted from blood from the patient, his parents, and 3 controls. Both parents showed reduced expression compared with controls, and the patient had barely discernible levels of NGLY1.
Enns et al. (2014) identified a homozygous R401X mutation in 5 patients from 3 families with CDDG1. All of the patients were Caucasian and of European descent, suggesting the possibility of a founder mutation. Two additional patients were found to carry biallelic NGLY1 mutations (610661.0003-610661.0005).
Lam et al. (2017) reported 12 individuals from 10 families with CDDG1 with biallelic mutations in the NGLY1 gene. Thirteen mutations were identified: 5 missense, 5 nonsense, 2 splice site, and 1 frameshift. R401X was the most common mutation, occurring in 7 alleles.
By whole-exome sequencing, Panneman et al. (2020) identified homozygous or compound heterozygous mutations in the NGYL1 gene (610661.0002; 610661.0006-610661.0008) in 4 patients with CDDG1. Evidence for mitochondrial dysfunction was found in patient fibroblasts and muscle tissue. In patients 2 and 4, fibroblast mitochondria were smaller and less branched compared to controls, and maximal respiration and basal respiration were reduced in fibroblasts from patient 4 compared to controls. Biochemical evaluation in muscle tissue from all 4 patients showed reduced mitochondrial ATP production from oxidation of pyruvate and malate.
In a review, Freeze (2013) noted that NGLY1 deficiency represents the first described congenital disorder of deglycosylation. The enzyme deficiency is predicted to cause accumulation of N-glycosylated proteins in the cytoplasm and possible ER stress. Accumulation of the undegraded material in the cytoplasm may have additional toxic effects.
Enns, G. M., Shashi, V., Bainbridge, M., Gambello, M. J., Zahir, F. R., Bast, T., Crimian, R., Schoch, K., Platt, J., Cox, R., Bernstein, J. A., Scavina, M., and 22 others. Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet. Med. 16: 751-758, 2014. Note: Erratum: Genet. Med. 16: 568 only, 2014. [PubMed: 24651605] [Full Text: https://doi.org/10.1038/gim.2014.22]
Freeze, H. H. Understanding human glycosylation disorders: biochemistry leads the charge. J. Biol. Chem. 288: 6936-6945, 2013. [PubMed: 23329837] [Full Text: https://doi.org/10.1074/jbc.R112.429274]
Haijes, H. A., de Sain-van der Velden, M. G. M., Prinsen, H. C. M. T., Willems, A. P., van der Ham, M., Gerrits, J., Couse, M. H., Friedman, J. M., van Karnebeek, C. D. M., Selby, K. A., van Hasselt, P. M., Verhoeven-Duif, N. M., Jans, J. J. M. Aspartylglycosamine is a biomarker for NGLY1-CDDG, a congenital disorder of deglycosylation. Molec. Genet. Metab. 127: 368-372, 2019. [PubMed: 31311714] [Full Text: https://doi.org/10.1016/j.ymgme.2019.07.001]
Hall, P. L., Lam, C., Alexander, J. J., Asif, G., Berry, G. T., Ferreira, C., Freeze, H. H., Gahl, W. A., Nickander, K. K., Sharer, J. D., Watson, C. M., Wolfe, L., Raymond, K. M. Urine oligosaccharide screening by MALDI-TOF for the identification of NGLY1 deficiency. Molec. Genet. Metab. 124: 82-86, 2018. [PubMed: 29550355] [Full Text: https://doi.org/10.1016/j.ymgme.2018.03.002]
Lam, C., Ferreira, C., Krasnewich, D., Toro, C., Latham, L., Zein, W. M., Lehky, T., Brewer, C., Baker, E. H., Thurm, A., Farmer, C. A., Rosenzweig, S. D., and 12 others. Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation. Genet. Med. 19: 160-168, 2017. [PubMed: 27388694] [Full Text: https://doi.org/10.1038/gim.2016.75]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100819]
Panneman, D. M., Wortmann, S. B., Haaxma, C. A., van Hasselt, P. M., Wolf, N. I., Hendriks, Y., Kusters, B., van Emst-deVries, S., van de Westerlo, E., Koopman, W. J. H., Wintjes, L., van den Brandt, F., de Vries, M., Lefeber, D. J., Smeitink, J. A. M., Rodenburg, R. J. Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction. Clin. Genet. 97: 556-566, 2020. [PubMed: 31957011] [Full Text: https://doi.org/10.1111/cge.13706]
Shashi, V. Personal Communication. Durham, N.C. 6/11/2013.