Table 1.
Summary of clinical findings of individuals with biallelic PRUNE1 mutations
| Patient 1 (SZ51-1) | Patient 2 (SZ51-2) | Karaca et al. (2015) | Zollo et al. (2017) | Costain et al. (2017) | Karakaya et al. (2017) | Iacomino et al. (2018) | Alfadhel et al. (2018) | Alhaddad et al. (2018) | Papuc (2019) | Fujii (2019) | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age at evaluation | 4 yo | 20 mo | 1.5−5.5 yo | 0.3−21.0 yo | 2.2 yo | 3 yo | 9 mo | 12 mo; 30 mo | 0 m−12 yo | 1.2 yo | 12 mo |
| Sex | F | M | 1 F, 2 M | 9 F; 4 M | M | M | M | 2 F | 10 F; 2 M | M | F |
| Ethnicity | European | European | 1 Saudi; 2 Turkish | Omani, Iranian, Italian and Indian | Ojibwe-Cree | Turkish | European (Italian) | Saudi | Lebanese; Turkish; European; North African | Sri Lankan | Japanese |
| Variant Zygosity | Comp Het | Comp Het | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Homozygous | Comp Het |
| Variants | c.383G > A; p.Arg128Gln |c.520G > T; p.Gly174* | c.383G > A; p.Arg128Gln |c.520G > T; p.Gly174* | c.88G > A; p.Asp30Asn, c.316G > A; p.Asp106Asn | c.88G > A; p.Asp30Asn, c.160C > A; p.Pro54Thr, c.316G > A; p.Asp106Asn, c.889C > T; p.Arg297Trp | c.521-2A > G | c.874_875insA; p.H292Qfs*3 | c.316G > A; p.Asp106Asn | c.383G > A; p.Arg128Gln | c.316G > A; p.Asp106Asn, c.515 T > C; p.Leu172Pro, g.150984457-151016662del; delExons 2-8 | c.316G > A; p.Asp106Asn | c.316G > A; p.Asp106Asn |c.540 T > A; p.Cys180* |
| Consanguinity | No | No | Yes | Yes | No | Yes | No | Yes | Yes | Yes | No |
| DD | +; profound | +; profound | +; profound (3/3) | +; (13/13) | +; profound | +; regression | + | +; profound (2/2) | + (10/12); 2 NA | + | + |
| ID | + | + | +; (3/3) | +; (13/13) | + | + | NA | +; (1/2) | + (11/12); 1 NA | +; severe | + |
| Brain abnormalities | + | + | +; (3/3) | +; (10/13) | + | + | + | +; (2/2) | + (10/12); 2 NA | + | + |
| Microcephaly | + | + | +; (3/3) | +; (13/13) | − | +; secondary | − | +; (2/2) | + (2/12); 5 Normal; 5 NA | + | − |
| Language delay | +; absent language | +; absent language | +; (3/3) | +; (13/13) | +; absent language | NA | NA | +; (1/2) | + (10/12); 2 NA | + | NA |
| Scoliosis/Kyphosis | + | + | NA | NA | NA | + | NA | − | +; (3/12) | NA | NA |
| Vision problems | +; optic atrophy, esotropia | +; congenital mild intermittent esotropia | NA | +; (5/13) | +; cortical blindness | +; optic atrophy | NA | +, bilateral rudimentary iris strands, congenital cataracts (1/2) | +; cortical blindness (2/12); saccadic eye movements (2/12); nystagmus (2/12) | NA | − |
| Muscle tone abnormalities | +; axial hypotonia, distal limb hypertonia/spasticity | +; increased limb tone, brisk tendon reflexes | +; central hypotonia, spastic quadriparesis, hyperreflexia (2/3) | +; (13/13) | +; neonatal generalized hypotonia, infantile spasms | +; neonatal generalized hypotonia, lower extremity spasticity and clonus | +; profound/severe global hypotonia, diffusely reduced tendon reflexes | +; central/axial hypotonia, spasticity, hyperreflexia (2/2) | +; hypotonia (5/12), spasticity (12/12), absent DTRs (5/12) | +; hypotonia, spastic tetraparesis | +; hypotonia, spastic quadriparesis, hyperreflexia |
| GERD/Dysphagia | +; severe GERD | + | NA | NA | NA | NA | NA | +; (1/2) | +; Dysphagia (11/12) | NA | NA |
| Seizures | + | + | NA | +; (6/13) | + | + | + | − | +; (11/12) | + | + |
| Seizure type and onset | Onset at 6mo; Gelastic, complex partial myoclonic seizures, infantile spasms | Onset at 6 mo; Infantile spasms | NA | NA | NA | Onset at 2 mo; focal motor seizures and flexor spasms | Onset at 6 mo; upper/lower limbs epileptic spasms | − | Onset 1 mo-8 mo; Clonic/myoclonic seizures (4/12) | Onset at. 6 mo; epileptic spasms | Onset at. 8 mo; epileptic spasms |
| Abnormal EEG findings | Background slowing, infrequent temporal spike waves | Modified hypsarrythmia, multifocal epileptiform discharges | NA | NA | Hypsarrhythmia | NA | Slowed background, multifocal epileptic abnormalities | Normal EEG (2/2) | Focal spasms (2/12); Slow multifocal spikes (2/12) | Focal tonic, myoclonic seizures | Hypsarrythmia |
| Abnormal MRI findings | Moderate/severe progressive global brain atrophy; cerebral and cerebellar atrophy | Mildly prominent lateral ventricles and sulci, thinner splenium and corpus callosum | Brain atrophy (3/3); Cortical atrophy, cerebral and cerebellar atrophy, thin corpus callosum, delayed myelination | Delayed myelination (5/13), wide spread white matter hypodensity or abnormalities (4/13), Cerebral/cerebellar atrophy (3/13), thin corpus callosum (2/13) | Cortical atrophy, small cerebellum; bilateral cerebral white matter loss with thinning of corpus callosum | Cerebral and cerebellar atrophy with delayed myelination, inferior vermis hypoplasia | Diffuse cortical atrophy, severe thinning of white matter, signal changes in periventricular white matter and pons, thin corpus callosum | Abnormal corpus callosum and mild cerebral atrophy (2/2); delayed mielination (1/2); prominent CSF spaces (1/2) | Cerebral atrophy (7/12), Cerebellar atrophy (6/12); Hyperintense brain lesions (4/12) | Immature cortex differentiation, punctate cerebellar hemorrhages, discrete signs of hypoxia | Diffuse cerebral and cerebellar atrophy, thin corpus callosum. Midbrain and pontine tegmentum atrophy. White matter damage, nut not delayed myelination |
| NCV/EMG findings | NA | NA | NA | NA | NA | Neurogenic findings | Neurogenic findings | NA | Slowed NCVs (5/12) | NA | NA |
| Measurements at evaluation | OFC: 41.5 cm (−5.3 s.d.); Weight: 15.1 kg (24th %ile); Length: 94 cm (−2.0 s.d.) | OFC: 41.0 cm (−5.3 s.d.); Weight: 12.8 kg (70th %ile); Length: 86 cm (77th %ile) | NA | NA | OFC: 49.5 cm (50th %ile); Weight: 16.5 kg (95th %ile); Length: 90 cm (90th %ile) | OFC:48 cm (−2 s.d.) | NA | OFC: −2.1 and −2.3 s.d.; Weight: −2.0 and −2.5 s.d.; Length: −2.1 and − 2.5 s.d. | OFC: −2.96 to +2 s.d.; Weight: −1.08 to +2.63 s.d. | OFC < 3rd %ile | OFC: 43.5 cm (−0.82 s.d.); Weight: 8.4 kg (−0.31 s.d.); Length: 73.8 cm (−0.26 s.d.) |
| Dysmorphic features | NA | NA | +; (2/3) | +; Phlagiocephaly (13/13) | +; tall forehead, bitempral narrowing, low set ears, flat nasal bridge, narrow high arched palate | +; Brachycephaly, large ears | +; Epicanthus, frontal plagiocephaly, brachydactyly, detached and hypoplastic nipples | +; (1/2) Plagiocephaly, epicanthal folds, hypertelorism, flat nasal bridge, abnormal dentition w/widely spaced teeth, micrognathia, low-set ears, hirsutism | +; (1/12): Micrognathia | Retrognathia | Phlagiocephaly |
| Other findings | Exaggerated startle and aversion to various sensory stimuli; Left hip dysplasia | Exaggerated startle; bilateral Babinski signs and sustained ankle clonus | NA | NA | Bilateral talipes equinovarus. Bilateral absent median nerve response. Central hypoventilation and sleep apnea. Bulbar palsy with absent swallow, gastrostomy | Regression. Knee contractures, hip dislocation; respiratory insufficiency (8 mo). Tracheostomy, nasogastric tube dependent | Distal joint arthrogryposis; respiratory distress. Babinksi sign observed. Bilatral talipes equinovarus, bell shaped thorax. Spinal motor neuron involvement | NA | Slow NCVs (5/12); Arthrogryposis/contractures (2/12); Hypertrophic cardiomyopathy (2/12); Pectus excavatum (1/12); Clubfoot (1/12); Death (8/12) | Bilateral deviation of 3rd toe over 4th toe | MR spectroscopy showed decreased concentration of N-acetyl aspartate and choline, and increased concentration of myoinositol |
| Previous Testing | Normal mitochondral respiratory chain activity testing | NA | NA | NA | Normal CMA, Beckwith–Wiedemann, Prader–Willi, SMARD1, DM1, and CCHS testing. Normal metabolic and biochemical testing | NA | Metabolic testing normal. Targeted molecular testing for SMN1, EXOSC3, EXOSC8 | Normal biochemical, metabolic, urine organic acids, and CMA testing (1/2) | Normal metabolic testing (6/12) | Normal CMA testing | NA |
MR: magnetic resonance