Table 1.
Clinical and genetic details of all affected individuals with causative variants in PPFIBP1
| Ind. | Agea(sex) | Variant (GenBank:NM_003622.4) | Development | Seizure types (age of onset) | MRI (age) | ICCsb | Neurological findings | Microcephaly | Growth | CHD | Ophthalmologic features |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ind. 1 | 19 years (M) | c.1146+1G>A (p.?), homozygous | moderate ID, delayed speech, normal motor development | focal impaired awareness (4 years) | normal (18 years) | not done | none | yes | SGA | no | normal |
| Ind. 2 | 6 yearsc (6 years) (F) | c.2654del (p.Tyr885Leufs∗4), homozygous | profound DD, no speech, unable to sit | focal, generalized tonic clonic (2 months) | paucity of the WM, VM, hypoplastic CC, Blakes's pouch cyst (5 years) | yes | spastic tetraplegia, nystagmus | yes | short stature, low weight | no | bilateral papillary pallor, no eye contact |
| Ind. 3-1 | 11 years (M) | c.1368_1369del (p.Glu456Aspfs∗3), homozygous | profound DD, no speech, unable to sit | epileptic spasms, focal, tonic clonic, tonic (7 months) | periventricular leukomalacia, metopic synostosis | yes | spastic tetraplegia | yes | SGA, low weight | yes | poor fixation |
| Ind. 3-2 | 7 years (M) | c.1368_1369del (p.Glu456Aspfs∗3), homozygous | profound DD, no speech, unable to sit | epileptic spasms, LGS (2 months) | moderate hyperintensity of periventricular white matter, mild VM (2 years) | yes | spastic tetraplegia | yes | SGA, low weight | yes | normal |
| Ind. 3-3 | 5 years (M) | c.1368_1369del (p.Glu456Aspfs∗3), homozygous | profound DD, no speech, unable to sit | epileptic spasms, focal, multifocal (1 day) | VM, abnormal signal intensity of the WM, bilateral temporal and left occipital pachygyria (3 days) | yes | spastic tetraplegia | yes | SGA, low weight | yes | normal |
| Ind. 4 | 11 months (M) | c.1368_1369del (p.Glu456Aspfs∗3), homozygous | profound DD no speech, unable to sit | epileptic spasms, focal, generalized tonic, status epilepticus (5 months) | VM, paucity of the WM, bilateral parietal and occipital pachygyria (5 months) | yes | spastic diplegia, hyperreflexia | yes | SGA, short stature | yes | haemorrhagic retinitis, chronic retinal detachment, right eye exotropia w/ slow pupillary reaction |
| Ind. 5-1 | 8 yearsc (8 years) (F) | c.2413C>T (p.Arg805∗), homozygous | profound DD, no speech, unable to sit | focal, myoclonic (2 months) | not done | yes | spastic tetraplegia | yes | SGA, short stature, low weight | no | N/A |
| Ind. 5-2 | 2 yearsc (4 years) (F) | c.2413C>T (p.Arg805∗), homozygous | profound DD, no speech, unable to sit | focal, myoclonic, tonic (1 months) | not done, VM on CT | yes | hypertonia of the limbs, dystonia | yes | short stature | no | normal |
| Ind. 6-1 | 6 years (M) | c.1468C>T (p.Gln490∗), homozygous | profound DD, no speech, sat independently at 6 years | generalized tonic clonic, myoclonic (4 months) | VM, cortical atrophy, demyelination of periventricular WM, thin CC, cerebellar vermian hypoplasia | not done | hypertonia of the limbs | yes | short stature, low weight | no | optic atrophy, followed light |
| Ind. 6-2 | 2 years (M) | c.1468C>T (p.Gln490∗), homozygous | profound DD, no speech, no head support | generalized tonic clonic, myoclonic, excessive smacking movements (2 months) | asymmetrical VM, cortical atrophy, demyelination of periventricular WM, thin CC, cerebellar vermian hypoplasia | yes | spasticity, rigidity, dystonic movement | yes | short stature, low weight | yes | optic atrophy, couldn't follow light |
| Ind. 7 | 4 years (F) | c.403C>T (p.Arg135∗), homozygous | severe DD, no speech, motor delay but can stand and walk | epileptic spasms, focal with apnoea, myoclonic (4 months) | normal at 4 months; thin CC, periventricular dysmyelination, possibly reduction of the WM at 1.5 years | not done | hypotonia | yes | normal | no | normal |
| Ind. 8 | N/A (F) | c.1417_1427del (p.Ala473Lysfs∗20), homozygous | profound DD, no speech, unable to sit | generalized tonic clonic (6 months) | bilateral parietal pachygyria, periventricular heterotopia, VM, hyperintensity and paucity of the WM | N/A | hypotonia, nystagmus | no, but low OFC | SGA | yes | normal, but poor fixation |
| Ind. 9 | 2 years 6 monthsc (3 years 9 months) (M) |
c.1300C>T (p.Gln434∗), homozygous | severe DD, no speech, can sit but not walk | epileptic spasms and gaze (2 months) | abnormal | N/A | spastic tetraplegia, no sphincter control | yes | SGA | no | blindness |
| Ind. 10 | 1 years 2 month (M) | c.2629C>T (p.Arg877∗), homozygous | severe DD, no speech yet, motor delay | focal myoclonic, epileptic spasms (1 week) | abnormal myelination of the periventricular WM and at corona radiata and centrum semiovale, hypoplastic CC, mild VM | N/A | hypotonia, nystagmus | yes | N/A | no | right ptosis, left iris coloboma, diffuse chorioretinal degeneration |
| Ind. 11 | 5 months (M) | c.1468C>T (p.Gln490∗), homozygous | severe DD, no speech yet, no head support | focal, myoclonic (2 weeks) | cortical atrophy, deep Sylvian fissures, mild VM, prominent basal ganglia, hypoplastic CC, retrocerebellar and bitemporal arachnoid cysts | yes | hypotonia, dystonia, brisk reflexes, nystagmus | yes | SGA | yes | optic atrophy |
| Ind. 12 | 5 years 11 months (F) | c.2654del (p.Tyr885Leufs∗4), homozygous | profound DD, no speech, unable to sit | focal, generalized (6 months) | VM, leukoencephalopathy, paucity of the WM, suspected periventricular microcalcifications, frontal polymicrogyria, temporoparietal thickening of the cortex (5 years) | not done | hypotonia, dyskinesia, stereotypic movements | yes | short stature, low weight | N/A | abnormalities of VEPs |
| Fetus (ind. 13) | 25th GW | c.2177G>T (p.Gly726Val), homozygous | developmental age estimated around 22nd GW | – | – | yesd | – | yes | IUGR | – | – |
Abbreviations: CC, corpus callosum; CHD, congenital heart defect; DD, developmental delay; F, female; IUGR, intrauterine growth restriction; GDD, global developmental delay; GW, gestational week; ICCs, intracranial calcifications; ID, intellectual disability; LGS, Lennox-Gastaut syndrome; M, male; N/A, not available; OFC, occipitofrontal circumference; SGA, small for gestational age; VEPs, visually evoked potentials; VM, ventriculomegaly; WM, white matter.
Further clinical details are provided in Table S4.
a
Age at last assessment.
b
On CT scan.
c
Deceased (age at death).
d
ICCs seen on X-ray babygram.