Table 1.
Clinical features of PLPHP-deficient patients
| Patient’s ID Sex, current age | Patient 1 Male, 3 11/12 y | Patient 2 Male, 14 y | Patient 3 Female, 5 2/12 y | Patient 4 Female, died at 2 w | Patient 5 Female, died at 8 w | Patient 6 Male, 4 3/12 y | Patient 7 Male, 23 mo | Patient 8 Male, 8 1/12 y | Patient 9 Male, 14 mo | Patient 10 Female, 10 6/12 y (sister of Patient 11) | Patient 11 Female, 6 10/12 y (sister of Patient 10) | Patient 12 Female, 5 mo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ancestry (domicile) | Arab (Oman) | Arab (Oman) | African/Creole (Curacao) | Dutch (Netherlands) | Cree First Nation (Canada) | Arab (United Arab Emirates) | Hispanic (Guatemala) | Arab (Oman) | Arab (Oman) | Kurdish (USA) | Kurdish (USA) | African American (USA) |
| Consanguinity (degree) | + (first cousin) | + (first cousin) | + (degree NA) | – | + (second cousin) | + (second cousin) | – | + (first cousin) | + (first cousin) | + (first cousins) | + (first cousin) | 1st degree relatives |
| PLPBP cDNA change (NM–007198) | 347C>T (homozygous) 823C>G (homozygous VUS) | 122G>A (homozygous) | 199G>A (homozygous) | 320–2A>G; 671G>C | 370–373del (homozygous) | 347C>T (homozygous) | 280A>T (homozygous) | 122G>A (homozygous) | 122G>A (homozygous) | 199G>A (homozygous) | 199G>A (homozygous) | 370–373del (homozygous) |
| Amino acid change | p.Thr116Ile; p.His275Asp (VUS) | p.Arg41Gln | p.Glu67Lys | Splicing; p.Gly224Ala | p.Asp124Lysfs*2 | p.Thr116Ile | p.Ile94Phe | p.Arg41Gln | p.Arg41Gln | p.Glu67Lys | p.Glu67Lys | p.Asp124Lysfs*2 |
| Pregnancy/delivery complications | Abnormal foetal movements | – | C-section due to foetal distress | DCDA-gemelli pregnancy | C-section due to foetal distress | Abnormal foetal movements | – | – | – | C-section due to foetal decelerations and meconium stained amniotic fluid | – | – |
| Birth HC percentile | 66th centile | 10th centile | <2nd centile | 1st centile | 82nd centile | NA | 12.5th centile | 50th centile | 50th centile | NA | 2nd centile | 22nd centile |
| Lactic acidosis | – | – | + | + | + | NA | + | – a | NA | – b | NA | + |
| Seizure onset | Day 5 | Day 7 | Day 2 | Day 1 | Day 1 | Day 4 | 2 mo | 1st w | Day 5 | Day 1 | Day 1 | Day 1 |
| Seizure typee: myoclonic | – | – | – | – | + | – | – f | + | – | + | + | |
| Seizure type: tonic | – | – | + | + | + | – | – | – | + | – | – | + |
| Seizure type: clonic | – | – | – | – | – | + | – | – | – | – | + | – |
| Seizure type: tonic-clonic | + | + | + | – | – | – | – | – | – | – | – | – |
| Seizure type: infantile spasms | – | – | – | + | – | + | – | – | – | + | + | – |
| Initial EEG pattern (at age) | Burst suppression (1 w) | NA | Discontinuous with tendency to burst suppression (5 days) | Discontinuous (Day 1) | Burst suppression (age NA) | Multifocal epileptiform activity (4 mo) | Continuously disorganized background with bursts of higher-amplitude activity (2 mo) | Burst suppression (3 w) | Burst suppression (10 days) | Discontinuous (2 days) | Discontinuous with multifocal sharps (age NA) | Burst suppression (2 days) |
| Response to initial AED treatmentc | Partial response | No response | NA | Partial response | Partial response | Partial response | Partial response | No response | Not tried | Partial response | No response | Partial response |
| Initial B6 treatment (age/responsec) | PN (5 w) PLP (2 y, 6 mo/partial response) | PN (<1 mo/ (seizure free) | PLP (5 days) PN (3 y, 10 mo/good response) | Not tried | Not tried | PN (6 mo/seizure freed) | PN and PLP (2.5 mo/seizure free) | PN (25 days/seizure free) | PN (2nd week/seizure free) | PN (2nd week/ seizure freed) | PN (age NA/ good response) | PN (age NA/no response) PLP (1 mo/seizure free) |
| B6 withdrawal (vitamer/response) | – | – | + (PLP/ seizure relapsed) | Not applicable | Not applicable | + (PN/ seizure relapsed) | – | – | – | + (PN/ seizure relapsed) | + (PN/ increased seizures) | – |
| B6 vitamer switch (type/response) | + (PN→PLP/ no improvement) | – | + (PLP→PN/ no improvement) | Not applicable | Not applicable | – | – | – | – | – | – | + (PN→PLP/ complete response) |
| Current treatment (dose) | PLP (58 mg/kg/day) Folinic acid (2 mg/kg/day) | PN (5 mg/kg/day) | PN (9 mg/kg/day) Midazolam (used during seizures only) | Not applicable | Not applicable | PN (12.8 mg/kg/day) Oxcarbazepine (53.8 mg/kg/day) | PN (23 mg/kg/day) PLP (30 mg/kg/day) | PN (6 mg/kg/day) | PN (8.5 mg/kg/day) | PN (4.7 mg/kg/day) Lamotrigine (3.5 mg/kg/day) Clobazam (0.75 mg/kg/day) | PN (7.8 mg/kg/day) Lamotrigine (4.5 mg/kg/day) (1.25 mg/kg/day) | PLP (40 mg/kg/day) Phenobarbital (9 mg/kg/day) |
| Breakthrough seizures with fever | + | + | + (seizure relapse on viral infections or sleep deprivation) | Not applicable | Not applicable | + | – | + | – | + | + | – |
| Motor neurological exam | Unremarkable | Unremarkable | Hypertonia, stereotypies | NA | NA | Mild axial hypotonia, stereotypies | Unremarkable | Unremarkable | Hyperreflexia of all limbs | Hypotonia, mild dysmetria, wide based gait | Hypotonia, mild dysmetria, wide based and ataxic gait | Mild hypotonia |
| Developmental delay | +, with ASD | – | + | Not applicable | Not applicable | +, with ASD | – | – | – | + | + | – |
| Speech delay | + | – | + | Not applicable | Not applicable | + | – | – | NA | + | + | Not applicable |
| School performance or IQ | NA | Average school performance | NA | Not applicable | Not applicable | DQ = 70, 2nd percentile (Bayley-III Cognitive Composite score) | NA | Excellent school performance | NA | NA | NA | Not applicable |
| Minor dysmorphic features | – | – | + g | – | – | – | + h | – | – | + i | – | – |
| Neuro-imaging (age)j | MRI (6 w): mild WM changes MRI (9 mo): mild hydrocephalus. MRI (3.5 y): normal | Not performed | MRI (Day 10): WM changes, large paraventricular (pseudo)-cysts, thin posterior CC, PLIC is not myelinated. | MRI (Day 1): WM changes, large paraventricular (pseudo)-cysts, thin posterior CC, PLIC is not myelinated. | MRI (Day 6): cystic leukencephalopathy | MRI (8 mo): normal. | MRI (2 mo): normal | MRI (4 wks): normal | MRI (10 mo): normal | MRI (2 days): underdeveloped frontal gyri. Subsequent MRI (age NA): thin posterior CC. | Initial MRI (age NA): normal. Subsequent MRI (age NA): slight asymmetry in height of the hippocampi, WM changes. | 2 MRI’s (2 days and 3 w): WM changes, mild dilatation of the lateral and third ventricles, PLIC is not myelinated. |
aElevated lactate but normal pH; bFirst measured after B6 treatment; cTreatment response is graded as follows: no response, partial (= mild or only short-term reduction), good (= marked long-term reduction), seizure free; dWhen combined with AEDs; eRefers to initial seizures; fThis patient has a movement disorder and lacks true epileptic seizures; gStrabismus, slight upslant of eyes and a slightly prominent forehead; hBilateral syndactyly of the third and fourth fingers; iJoint laxity; jShowing only main findings here, detailed MRI features are described in Supplementary Table 1.
AEDs = anti-epileptic drugs; ASD = autism spectrum disorder; CC = corpus callous; C-section = Caesarean section; DCDA = dichorionic diamniotic twin pregnancy; DQ = developmental quotient; HC = head circumference; mo = month(s); NA = not available; PLIC = posterior limb of the internal capsule; PN = pyridoxine; PLP = pyridoxal 5’-phosphate; VUS = variant of uncertain significance; w = weeks; WM = white matter; y = years.