Table 2.
Clinical severity scores based on system adapted from Al Teneiji et al. (2017)
| Patient ID | Variant type | Amino acid change | First seizure/movement episode score | GDD/ID score | B6 response score | Severity score sum | Protein effect |
|---|---|---|---|---|---|---|---|
| Patients reported in this study | |||||||
| 1 | Homozygous missense | p.Thr116Ile; | 3 | 2 | 2 | Severe (7) | Predicted LOF - variant likely impacts PLP binding |
| Homozygous missense | p.His275Asp | Variant of unknown significance: variant likely impacts PLP binding | |||||
| 2 | Homozygous missense | p.Arg41Gln | 2 | 0 | 0 | Mild (2) | Predicted to still bind PLP, but stability is reduced |
| 3 | Homozygous missense | p.Glu67Lys | 3 | 3 | 2 | Severe (8) | Predicted LOF - variant likely impacts PLP binding |
| 4 | Compound heterozygous nonsense and missense | c.320–2A>G; | 3 | NAa | NAa | Deceased: Severe (9) | LOF - Truncated proteine |
| p.Gly224Ala | Predicted LOF - Variant likely disrupts loop 15 structure and orientation of several PLP binding residues | ||||||
| 5 | Homozygous nonsense | p.Asp124Lys fs*2 | 3 | NAb | NAb | Deceased: Severe (9) | LOF - Truncated protein (band absent as in Supplementary Fig 1) |
| 6 | Homozygous missense | p.Thr116Ile | 3 | 2 | 3 | Severe (8) | Predicted LOF - variant likely impacts PLP binding |
| 7 | Homozygous missense | p.Ile94Phe | 1 | 1 | 1 | Mild (3) | Predicted LOF? Variant likely impacts PLP binding, but it is possible Phe could still establish aromatic/hydrophobic contacts with PLP; |
| 8 | Homozygous missense | p.Arg41Gln | 3 | 0 | 0 | Mild (3) | Predicted to still bind PLP, but stability is reduced |
| 9 | Homozygous missense | p.Arg41Gln | 3 | 0 | 0 | Mild (3) | Predicted to still bind PLP, but stability is reduced |
| 10 | Homozygous missense | p.Glu67Lys | 3 | 2 | 2 | Severe (7) | Predicted LOF - variant likely impacts PLP binding |
| 11 | Homozygous missense | p.Glu67Lys | 3 | 2 | 2 | Severe (7) | Predicted LOF - variant likely impacts PLP binding |
| 12 | Homozygous deletion | p.Asp124Lys fs*2 | 3 | NAd | 2 | NAd | LOF - Truncated protein (band absent as in Supplementary Fig 1) |
| Patients reported by Darin et al. (2016) | |||||||
| 1 | Homozygous nonsense | p.Ser78Ter | 3 | NAc | NAc | Deceased: Severe (9) | LOF - Truncated proteine |
| 2 | Homozygous nonsense | p.Ser78Ter | 3 | 2 | 3 | Severe (8) | LOF - Truncated proteine |
| 3 | Homozygous nonsense | p.Ser78Ter | 3 | 3 | 3 | Severe (9) | LOF - Truncated proteine |
| 4 | Homozygous missense | p.Leu175Pro | 3 | 3 | 2 | Severe (8) | LOF - Misfolded proteine,g |
| 5 | Compound heterozygous missense and missense | c.207+1G>A; | 3 | 3 | 2 | Severe (8) | LOF - Truncated proteine; absent band in western blote |
| c.320–2A>G; | |||||||
| 6 | Homozygous nonsense | p.Gln71Ter | 3 | 2 | 3 | Severe (8) | LOF - Truncated proteine |
| 7 | Compound heterozygous missense | p.Pro87Leu; | 1 | 1 | 1 | Mild (3) | Lower solubility and some precipitated; folded forms still binds to PLPg |
| p.Arg241Gln | LOF - variant abolishes PLP bindingg, drastic reduction in stability (Tm shift −14°C)g | ||||||
| Patients reported by Plecko et al. (2017) | |||||||
| 1 | Compound heterozygous missense and missense | p.Pro40Leu; | 2 | 0 | 1 | Mild (3) | Reduced stability (Tm shift −6°C); Still binds to PLPg |
| p.Arg241Gln | LOF - variant abolishes PLP binding, drastic reduction in stability (Tm shift −14°C)g | ||||||
| 2 | Compound heterozygous truncating and missense | p.Ser84Cysfs*21; | 2 | 1 | 1 | Moderate (4) | LOF - Truncated proteinf |
| p.Arg205Gln | Reduced stability (Tm shift −7°C); Still binds to PLPg | ||||||
| 3 | Homozygous missense | p.Pro87Leu | 3 | 3 | 1 | Severe (7) | Lower solubility and some precipitated; Folded forms still binds to PLPg |
| 4 | Homozygous missense | p.Tyr69Cys | 2 | 0 | 2 | Moderate (4) | Cys forms disulfide bridges, which creates an artificial dimer that hides PLP. Decreased PLP binding in 30%g |
Variants are organized by whether seen homozygously versus compound heterozygous, then based on variant type (missense, truncating, splicing). Note that truncating variants are associated with the most severe phenotypes. aNA, bNA , cNA: full clinical scores could not be calculated due to early death of these patients but assumed severe based on lethality. dNA full clinical score could not yet be calculated due to early age of patient, so GDD/ID cannot yet be assessed. eVariant reported by Darin et al. (2016).f Variant reported by Plecko et al. (2017). gVariant experimentally studied by Tremino et al. (2018). LOF = loss-of-function.