Table 1.
List of patients reported in the literature and their phenotypes.
| Reference | Age/ Sex |
NGLY1 Genotype | Phenotypes |
|---|---|---|---|
| Need et al., 2012 [14] Enns et al., 2014 [11] Lam et al., 2017 [12] Levy et al., 2022 [13] |
12 y/M * | Q631Sfs/R401X | Developmental delay, movement disorder, hypotonia, seizures, EEG abnormalities, epilepsy, corneal ulcerations, liver fibrosis, microcephaly, dysmorphic features, small hands and feet, peripheral neuropathy, alacrima, elevated liver transaminases, constipation |
| Enns et al., 2014 [11] | 5 y/M * | R401X/R401X | Developmental delay, epilepsy, intrauterine growth retardation, movement disorder, hypotonia, dysmorphic features, EEG abnormalities, seizures, alacrima, scoliosis, small hands and feet, elevated liver transaminases, constipation |
| Enns et al., 2014 [11] Lam et al., 2017 [12] Levy et al., 2022 [13] |
9 y/M | R401X/R401X | Developmental delay, epilepsy, intrauterine growth retardation, movement disorder, hypotonia, seizure, corneal ulcerations, EEG abnormalities, alacrima, strabismus, elevated liver transaminases, scoliosis, constipation, liver fibrosis, small hands and feet, neuropathy |
| Enns et al., 2014 [11] Lam et al., 2017 [12] |
4 y/F | R401X/R401X | Developmental delay, hypotonia, microcephaly, movement disorder, elevated liver transaminases, alacrima, strabismus, constipation, dysmorphic features |
| Enns et al., 2014 [11] Lam et al., 2017 [12] |
18 y/F | R401X/R401X | Developmental delay, movement disorder, microcephaly, intrauterine growth retardation, hypotonic, EEG abnormalities, seizure, corneal ulcerations, alacrima, strabismus, elevated lactate, elevated liver transaminases, scoliosis, constipation, dysmorphic features, small hands and feet |
| Enns et al., 2014 [11] | 9 m/F * | R401X/R401X | Developmental delay, microcephaly, hypotonia, movement disorder, intrauterine growth retardation, microcephaly, EEG abnormalities, seizure, alacrima, dysmorphic features |
| Enns et al., 2014 [11] Lam et al., 2017 [12] Levy et al., 2022 [13] |
27 y/F | R458Kfs/R458Kfs | Developmental delay, intrauterine growth retardation, microcephaly, movement disorder, EEG abnormalities, alacrima, corneal ulceration, hypotonia, elevated liver transaminases, elevated lactate, peripheral neuropathy, constipation, scoliosis |
| Enns et al., 2014 [11] Kong et al., 2018 [23] Levy et al., 2022 [13] |
11 y/F | R402del/R524X | Developmental delay, movement disorder, microcephaly, hypotonia, EEG abnormalities, alacrima/hypolacrima, strabismus, elevated lactate, elevated liver transaminases, constipation, small hands and feet, neuropathy |
| Caglayan et al., 2015 [24] | 16 y/M * | N511Kfs/N511Kfs | Developmental delay, hypotonia, feeding problems, peripheral neuropathy, speech impairment, corneal ulcerations, alacrima |
| Caglayan et al., 2015 [24] | 9 y/F | N511Kfs/N511Kfs | Developmental delay, movement disorder, hypotonia, EEG abnormalities, feeding problems, epilepsy, peripheral neuropathy, seizure, strabismus, speech impairment, dysmorphic features, elevated liver transaminase, scoliosis |
| Heeley et al., 2015 [25] Lam et al., 2017 [12] Levy et al., 2022 [13] |
21 y/M | S116X/c.881+5G>T | Developmental delay, movement disorder, hypotonia, seizure, epilepsy, dysmorphic features, alacrima/hypolacrima, strabismus, elevated liver transaminases, liver fibrosis, constipation, scoliosis, neuropathy |
| Bosch et al., 2016 [26] | 3 y/M | R401X/R401X | Developmental delay, movement disorder, alacrima/hypolacrima, hypotonia, peripheral neuropathy, microcephaly, strabismus |
| Lam et al., 2017 [12] | 3 y/M | L318P/R390P | Developmental delay, movement disorder, feeding problems, EEG abnormalities, epilepsy, dysmorphic features, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate |
| Lam et al., 2017 [12] Levy et al., 2022 [13] |
10 y/F | E311K/W244R | Developmental delay, movement disorder, feeding problems, EEG abnormalities, dysmorphic features, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate, neuropathy |
| Lam et al., 2017 [12] Kong et al., 2018 [23] Levy et al., 2022 [13] |
11 y/M | W535X/L637X | Developmental delay, movement disorder, feeding problems, hypotonia, epilepsy, EEG abnormalities, dysmorphic features, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate, neuropathy |
| Lam et al., 2017 [12] Levy et al., 2022 [13] |
13 y/F # | Q208X/c.930C>T (G310G; splice site) | Developmental delay, movement disorder, feeding problems, EEG abnormalities, epilepsy, dysmorphic features, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate |
| Lam et al., 2017 [12] Levy et al., 2022 [13] |
15 y/M # | Q208X/c.930C>T (G310G; splice site) | Developmental delay, movement disorder, feeding problems, EEG abnormalities, epilepsy, dysmorphic features, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate |
| Lam et al., 2017 [12] Levy et al., 2022 [13] |
22 y/F * | R401X/R401X | Developmental delay, movement disorder, feeding problems, EEG abnormalities, epilepsy, dysmorphic features, corneal ulcerations, alacrima/hypolacrima, microcephaly, elevated liver transaminases, elevated lactate, neuropathy |
| Van Keulen et al., 2019 [27] Panneman et al., 2020 [28] |
9 y/F | Q613fs/Q613fs | Developmental delay, movement disorder, seizures, scoliosis, adrenal insufficiency |
| Chang et al., 2019 [29] Levy et al., 2022 [13] |
7 y/F | R469X/R469X | Developmental delay, microcephaly, dysmorphic features, feeding problems, constipation, hypotonia, alacrima/hypolacrima, elevated liver transaminases, liver fibrosis, neuropathy, movement disorder |
| Haijes et al., 2019 [30] | 18 y/M | c.247-2A>G/c.247-2A>G | Developmental delay, movement disorder |
| Haijes et al., 2019 [30] | 26 y/F | c.247-2A>G/c.247-2A>G | Developmental delay, movement disorder, alacrima/hypolacrima, corneal ulcerations |
| Haijes et al., 2019 [30] | 11 y/M | R586X/R586X | Developmental delay, intrauterine growth retardation, EEG abnormalities, alacrima, corneal ulceration, elevated liver transaminases, constipation, scoliosis |
| Haijes et al., 2019 [30] | 6 y/F | R586X/R586X | Developmental delay, epilepsy, alacrima, EEG abnormalities, corneal ulceration, elevated liver transaminases, constipation |
| Haijes et al., 2019 [30] | 15 y/F | L618X/Y539Gfs | Developmental delay, epilepsy, EEG abnormalities, intrauterine growth retardation, microcephaly, constipation, elevated liver transaminases, strabismus |
| Panneman et al., 2020 [28] | 8 yr */? | R401X/C283W | Developmental delay, movement disorder, hypotonia, seizures, EEG abnormalities, peripheral neuropathy, dysmorphic features, small hands and feet, corneal ulceration, liver fibrosis, elevated liver transaminases, elevated lactate, epilepsy |
| Panneman et al., 2020 [28] | ?/? | R401X/R401X | Developmental delay, hypotonia, peripheral neuropathy, dysmorphic features, small hands and feet, alacrima/hypolacrima, strabismus, elevated liver transaminases |
| Panneman et al., 2020 [28] | ?/F | R401X/E356G | Developmental delay, movement disorder, hypotonia, seizure, EEG abnormalities, peripheral neuropathy, dysmorphic features, small hands and feet, strabismus, elevated lactate |
| Abuduxikuer et al., 2020 [20] | 17 m/M | Y342C/R411X | Developmental delay, movement disorder, hypotonia, alacrima/hypolacrima, microcephaly, epilepsy, feeding problems, elevated liver transaminases, seizures, speech impairment |
| Abuduxikuer et al., 2020 [20] | 5 y/F | Y342C/R411X | Developmental delay, movement disorder, hypotonia, alacrima/hypolacrima, epilepsy, microcephaly, feeding problems, elevated liver transaminases, constipation, seizures, speech impairment |
| Abuduxikuer et al., 2020 [20] | 19 m/F | Y342C/R411X | Developmental delay, movement disorder, hypotonia, intrauterine growth retardation, epilepsy, alacrima/hypolacrima, feeding problems, microcephaly, elevated liver transaminases, seizures, speech impairment, dysmorphic features, elevated lactate |
| Abuduxikuer et al., 2020 [20] | 8 m/F | S546Ffs/c.1003+3A>G | Developmental delay, hypotonia, intrauterine growth retardation, alacrima/hypolacrima, strabismus, microcephaly, small hands and feet, feeding problems, elevated liver transaminases, speech impairment, dysmorphic features |
| Abuduxikuer et al., 2020 [20] | 4 y/F | S546Ffs/c.1003+3A>G | Developmental delay, movement disorder, hypotonia, intrauterine growth retardation, alacrima/hypolacrima, microcephaly, scoliosis, small hands and feet, feeding problems, elevated liver transaminases, speech impairment, dysmorphic features |
| Abuduxikuer et al., 2020 [20] | 10 m/M | R328G/R328G | Developmental delay, movement disorder, hypotonia, intrauterine growth retardation, alacrima/hypolacrima, microcephaly, small hands and feet, feeding problems, elevated liver transaminases, constipation, peripheral neuropathy, dysmorphic features |
| Lipiński et al., 2020 [31] | 7 y/M | c.1789+1G>A/c.1063T>C | Elevated liver transaminases, liver steatosis, global developmental delay, movement disorder, hypolacrima |
| Lipiński et al., 2020 [19] | 1.5 y/? | E84X/R401X | Developmental delay, movement disorder, alacrima, elevated liver transaminases, hypotonia, hypolipidemia |
| Ge et al., 2020 [32] | 10 m/F | R390X/D386Y | Developmental delay, intrauterine growth retardation, alacrima/hypolacrima, elevated liver transaminases, elevated lactate, EEG abnormalities, seizures, constipation |
| Rios-Flores et al., 2020 [33] Levy et al., 2022 [13] |
8 y/M | Q631Sfs/N178Qfs | Developmental delay, movement disorder, hypotonia, intrauterine growth retardation, alacrima/hypolacrima, constipation, dysmorphic features, elevated liver transaminases, liver fibrosis, feeding problems, epilepsy |
| Lipari-Pinto et al., 2020 [34] | 8 y/M | Q631Sfs/Q631Sfs | Developmental delay, hypotonia, elevated liver transaminases, small hands and feet |
| Kariminejad et al., 2021 [21] | 30 y/M | W236C/W236C | Developmental delay, hypotonia, scoliosis, EEG abnormalities |
| Kariminejad et al., 2021 [21] | 34 y/M | W236C/W236C | Developmental delay, hypotonia, movement disorder, seizures, scoliosis, constipation |
| Kariminejad et al., 2021 [21] | 35 y/F | W236C/W236C | Developmental delay, hypotonia, scoliosis, constipation |
| Kariminejad et al., 2021 [21] | 14 y/F | R390Q/R390Q | Developmental delay, movement disorder, epilepsy, liver fibrosis, EEG abnormalities, seizures, elevated liver transaminases, scoliosis |
| Kariminejad et al., 2021 [21] | 29 y/F | R390Q/R390Q | Developmental delay, movement disorder, liver fibrosis, elevated liver transaminases, scoliosis |
| Stuut et al., 2021 [22] | 5 y/M * | R401X/R401X | Developmental delay, alacrima/hypolacrima, movement disorder, epilepsy, intrauterine growth retardation, feeding problems, elevated liver transaminases |
| Dabaj et al., 2021 [35] | 6.5 y/F * | R328C/R328C | Developmental delay, alacrima/hypolacrima, feeding problems, hypotonia, dysmorphic features, seizures, microcephaly, intrauterine growth retardation, elevated liver transaminases |
| Kalfon et al., 2022 [18] | 6 m/F * | E432X/E432X | Developmental delay, feeding problems, hypotonia, alacrima/hypolacrima |
| Kalfon et al., 2022 [18] | 3 y/M * | E432X/E432X | Developmental delay, hypotonia, movement disorder, EEG abnormalities, elevated lactate, elevated liver transaminases, peripheral neuropathy, seizure, feeding problems |
| Kalfon et al., 2022 [18] | 12 y/F | E432X/E432X | Developmental delay, alacrima, movement disorder, hypotonia, EEG abnormalities, elevated lactate, elevated liver transaminases, seizure, feeding problems, peripheral neuropathy, microcephaly, scoliosis |
| Levy et al., 2022 [13] | 17 y/F | N415Mfs/c.658+1G>A | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities |
| Levy et al., 2022 [13] | 15 y/M | R401X/deletion of at least exon 1–3 | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 17 y/M | S169X/R383X | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy |
| Levy et al., 2022 [13] | 8 y/M | S169X/R383X | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy |
| Levy et al., 2022 [13] | 16 y/M * | R321X/Q631Sfs | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 4 y/M | R308W/c.1789+1G>T | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 7 y/F | R401X/c.1150-1G>C | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 3 y/F | R401X/c.1150-1G>C | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 6 y/F | R401X/C283W | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 5 y/M | R401X/deletion of intron3 and exon 3 splice junction | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities |
| Levy et al., 2022 [13] | 4 y/F | R401X/S607Ffs | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, no EEG abnormalities |
| Levy et al., 2022 [13] | 17 y/F | W369X/R469X | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities, epilepsy |
| Levy et al., 2022 [13] | 9 y/M | C355Y/R469X | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy |
| Levy et al., 2022 [13] | 11 y/M | Q191X/Q191X | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, epilepsy |
| Levy et al., 2022 [13] | 9 y/F | Q631Sfs/Q631Sfs | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, epilepsy |
| Levy et al., 2022 [13] | 3 y/M | R401X/N511Kfs | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy |
| Levy et al., 2022 [13] | 13 y/F | R469X/D597Sfs | Developmental delay, elevated liver transaminases, alacrima/hypolacrima, movement disorder, neuropathy, EEG abnormalities |
* Deceased patients; ?, not reported; y, years; m, months; M, male; F, female; EEG, electroencephalography. Note that not all patient cohorts were examined for all the symptoms/phenotypes. The table summarizes only those phenotypes that were examined in the published reports. The siblings marked with # (first reported by Lam and colleagues [12]) exhibit significantly milder intellectual disability compared to other patients examined in that study, likely because the c.930C>T (G310G) splice site variant does not fully impair the splicing of the NGLY1 mRNA and can lead to the expression of low levels of functional NGLY1 protein.