TABLE 3.
Molecular analysis results shows the PLP and PN responsiveness as well as the clinical outcome of each variant
| Effect | Mutation | Clinical observations | Molecular basis | Reference |
|---|---|---|---|---|
| Normal | D33V | Normal neurodevelopmental outcome at 11 y | Non‐homologous substitution in disordered N‐terminal extension | 11 , 21 , 22 |
| D33V | Normal neurodevelopmental outcome at 11 mo | Non‐homologous substitution in disordered N‐terminal extension | 28 | |
| D33V | Normal neurodevelopmental outcome at 7 y | Non‐homologous substitution in disordered N‐terminal extension | 21 | |
| R116Q | Normal neurodevelopmental outcome at 3 y and 7 mo | Destabilizing FMN, loss of inter‐molecular ionic bond with E143 | 7 | |
| G118R | Normal neurodevelopmental outcome at 6 y | Severe destabilizing clashes with surrounding | 20 | |
| R141C | Normal IQ, recurrent breakthrough seizure and SE, seizure free at the age of 26 y for the last 4 y (cp hetero) | Loss of FMN phosphate coordination | 16 | |
| P213S | Normal neurodevelopmental outcome at 5 y | Loss of minor hydrophobic interactions | 21 | |
| R225H | Normal neurocognitive development at 3 y and 10 mo | Loss of PLP coordination | 16 | |
| R225H | Normal neuro‐cognitive outcome at 6 years and 10 months | Loss of PLP coordination | 16 | |
| R225C | Normal neurodevelopmental status, and improved axial tone | Loss of PLP coordination | 16 | |
| Mild to Moderate | R116Q | Moderate GDD at 12 y | Destabilizing FMN, loss of inter‐molecular ionic bond with E143 | 7 |
| R116Q | Mild GDD at 6 y | Destabilizing FMN, loss of inter‐molecular ionic bond with E143 | 7 | |
| G118R | GDD | Severe destabilizing clashes with surrounding | 9 | |
| G118R | GDD | Severe destabilizing clashes with surrounding | 9 | |
| G118R | Mild hypotonia and GDD at 28 mo | Severe destabilizing clashes with surrounding | 12 | |
| R141H | Normal growth and development patterns neurological at 4 mo | Loss of FMN phosphate coordination | 30 | |
| P150Rfs*27 | Normal neurodevelopmental outcome at the age of 12 mo | Non‐functional fragment | 27 | |
| R161C | Normal neurodevelopmental outcome at the age of 14 mo | Loss of PLP phosphate coordination | 29 | |
| R225H | ASD | Loss of PLP coordination | 13 | |
| R225H | Normal neurocognitive development and seizure free at 1 y and 8 mo. Unsteady gait | Loss of PLP coordination | 16 | |
| R225H | Normal neurocognitive development and seizure free at 1 y and 5 mo. Unsteady gait | Loss of PLP coordination | 16 | |
| R225H | GDD, seizure free at 9 y and 9 mo | Loss of PLP coordination | 16 | |
| R225H | GDD, recurrent breakthrough seizure | Loss of PLP coordination | 16 | |
| R225L | GDD | Loss of PLP coordination | 9 | |
| R225L | GDD | Loss of PLP coordination | 9 | |
| R225L | GDD | Loss of PLP coordination | 9 | |
| R225L | GDD | Loss of PLP coordination | 9 | |
| Severe | E50K | Severe DD, microcephaly, spasticity at 2 y | Loss of minor stabilizing interactions | 1 , 15 |
| E50K | Died at 6 wk | Loss of minor stabilizing interactions | 1 , 15 | |
| R95C | Died at 7 mo | Loss of FMN phosphate coordination | 11 | |
| R95C | Severe psychomotor delay at 2 y and 5 mo | Loss of FMN phosphate coordination | 11 | |
| R95C | Died | Loss of FMN phosphate coordination | 11 | |
| R95C | Died | Loss of FMN phosphate coordination | 11 | |
| R95C | Severe psychomotor delay | Loss of FMN phosphate coordination | 11 | |
| R95C | Death at 47 DOL | Loss of FMN phosphate coordination | 36 | |
| R95C | Died at 31 d | Loss of FMN phosphate coordination | 26 | |
| R95C | Psychomotor development was severely delayed and epileptic phenomena were almost constantly present at 3 y old | Loss of FMN phosphate coordination | 26 | |
| P150Rfs*27/R161G (cp heteroz) | Neurodevelopmental outcome was poor with severe developmental delay, cortical visual impairment and autistic features | Non‐functional fragment/loss of PLP phosphate coordination | 19 | |
| A174X | Died at 48 d of life (DOL) | Non‐functional fragment | 35 | |
| R225H | Died at 14 mo | Loss of PLP coordination | 18 | |
| R225H | Psychomotor retardation with autonomous gait at 2.5 y and a slight intellectual disability | Loss of PLP coordination | 30 | |
| R225H | Severe GDD, spastic tetraplegia, progressive microcephaly, recurrent breakthrough seizure at 8 y | Loss of PLP coordination | 16 | |
| R225H | Severe GDD, spastic tetraplegia, progressive microcephaly, recurrent breakthrough seizure while on PN | Loss of PLP coordination | 16 | |
| R225C | Global psychomotor delay at the age of 3 y | Loss of PLP coordination | 17 | |
| R229Q | Normal head growth, pigmentary retinopathy, diffuse hypotonia, and hyperkinetic movements | Loss of FMN phosphate coordination | 14 | |
| R229Q | Hemiparesis at 21 mo after middle cerebral artery ischemic stroke | Loss of FMN phosphate coordination | 13 | |
| R229W | Died at 21 DOL | Loss of FMN phosphate coordination | 1 , 2 | |
| R229W | Died on first DOL | Loss of FMN phosphate coordination | 1 , 2 | |
| R229W | Died at 6 mo | Loss of FMN phosphate coordination | 1 , 2 | |
| R229W | Died at 17 DOL | Loss of FMN phosphate coordination | 1 , 2 | |
| R229W | Died at 19 DOL | Loss of FMN phosphate coordination | 1 , 2 | |
| X262Q | Died at 23 DOL | Additional residues disrupt ligand binding and 3D‐fold | 1 | |
| X262Q | Died at 15 DOL | Additional residues disrupt ligand binding and 3D‐fold | 1 |
Abbreviations: DD, developmental delay; FMN. flavin mononucleotide; PLP, pyridoxal 5′‐phosphate; PN, pyridoxine.