Clinical phenotype descriptions of the four index patients
| PURA phenotype | Patient 1 | Patient 2 | Patient 3 | Patient 4 | |
|---|---|---|---|---|---|
| Background | Mutation | c.726_727delGT (p.Phe243Tyrfs*50) | c.847delG (p. Glu283Arg fs*45) | c.616A>T (p.Ile206Phe) | c.697_699delTTC (p.Phe233del) |
| Inheritance | AD—de novo | AD—de novo | AD—de novo | AD—de novo | |
| Ethnicity | Caucasian | Caucasian | Caucasian | Caucasian | |
| Sex | F | F | F | F | |
| Family history of note | None | None | None | None | |
| Pregnancy | Natural, uneventful | Natural, uneventful | Natural, uneventful | ICSI, uneventful | |
| Delivery | NVD | NVD | NVD | Elective caesarian | |
| Gestational age (weeks) | 41 | 41 | 42 | 38 | |
| Birth weight | 3.74 kg (75th) | 3.50 kg (50th) | 3.73 kg (75th) | 3.012 kg (50th) | |
| OFC at birth | – | 34 cm (25th) | - | 35 cm (91st) | |
| Neonatal respiratory difficulty? | Single apnoeic/hyponoeic episode as a neonate | No | Supplementary oxygen required at birth | Central apnoea and hypothermia from day 2 of life | |
| Neonatal hypotonia? | Yes | No | Yes | Yes (severe from day 2 of life) | |
| Neonatal feeding difficulties? | Yes (required NG tube feeding) | No | Yes (required NG tube feeding) | Yes (required NG tube feeding) | |
| Age at last assessment | 4 years 7 months | 14 years 3 months | 12 years 10months | 6 years 9 months | |
| Developmental milestones | Sitting unsupported (age) | 2 years 6 months | 12 months | 13 months | Not reached |
| Walking independently (age) | Not reached | 24 months | 22 months | Not reached | |
| First words (age) | Not reached | 2 years 6 months | 3 years 6 months | 11 months | |
| Current developmental level | Gross motor | Unable to stand | Fully mobile, broad-based gait | Able to run; ataxic and broad-based gait | Non-ambulatory with central hypotonia, dystonia and dyskinesia |
| Fine motor | Pincer grip | Manages buttons and can use fork/spoon | Manages buttons | Pincer grip | |
| Language | No expressive language, appears to understand some words | Sentences; limited vocabulary | Short phrases, repetitive, difficult to understand, limited comprehension | Essentially non-verbal | |
| Behaviour | Startles easily | Anxiety, no sense of danger | Relatively easy child, some obsessional and attention-seeking behaviours, poor awareness of others | Startles easily, anxiety and behaviour consistent with global delay | |
| Growth parameters | Height | 111 cm (91st) | 145 cm (0.4th–2nd) | 154 cm (50th) | 123 cm (75%) |
| Weight | 19 kg (75th) | 33 kg (<0.4th) | 46.5 kg (50th) | 25 kg (75%) | |
| Head circumference | 50.6 cm (9th–25th) | 51 cm (<0.4th) | 56.0 cm (75th–91st) | 53 cm (75th) | |
| Facial features | Hypotonic facies, prominent forehead, epicanthic folds, mild telecanthus | Hypotonic facies, microcephaly, tall forehead, facial asymmetry (R<L), upslanting palpebral fissures, large central incisors | Slightly long face and full cheeks, high forehead, telecanthus | Hypotonic facies, mild frontal bossing, thin upper lip, some deciduous teeth possibly malformed | |
| Neurological | Limb posture | Feet held in plantar flexion, restricted movement at ankles | Normal | Normal | Hypotonic/dystonic |
| Tone | Hypotonic | Normal | Hypotonic | Hypotonic/dystonic | |
| Power | Mild generalised weakness | Normal | Mild generalised weakness | Mild generalised weakness | |
| DTRs/plantar responses | Diminished DTRs/normal plantar response | Normal | Difficult to elicit | Normal DTRs/normal plantar response | |
| Coordination | Poor | Poor | Poor | Poor | |
| Gait | Non-ambulatory | Broad-based | Broad-based | Non-ambulatory | |
| Cranial nerve anomalies? | Dysconjugate gaze | No | No | Dysconjugate gaze and intermittent ocular deviations | |
| Movement disorder? | No | No | No | Dystonic and choreoathetoid limb movements | |
| Seizures or ‘seizure-like’ episodes | ‘Seizure-like’ episodes (at 7 months) | No | ‘Seizure-like’ episodes (at 3years) | Epilepsy (onset at 14 months) with epileptic spasms | |
| Other neurological features/findings? | Normal CSF neurotransmitters | Nil | Nil | Early cortical visual impairment Elevated CSF di-hydro biopterin levels Sleep study—cyclical central apnoea | |
| Investigation results | MRI brain | Delayed myelination (at 3 years 5 months) | Normal (at 7 years 8 months) | Normal (at 10 years 3 months) | Multiple abnormalities (see figure 3) |
| EEG | Normal | Not performed | Abnormal | Abnormal | |
| Endocrine | Gonadotropin-dependent precocious puberty (early thelarche), on treatment with IM decapeptyl | Nil | Nil | Elevated prolactin level soon after birth Blunted cortisol response to stress Chronically low vitamin D levels despite treatment | |
AD, autosomal dominant; CSF, cerebrospinal fluid; DTR, deep tendon reflex; ICSI, intracytoplasmic sperm injection; IM, intramuscular; NVD, normal vaginal delivery; OFC, occipital-frontal circumference; NG, nasogastric.