Table 1

Clinical phenotype descriptions of the four index patients

PURA phenotypePatient 1Patient 2Patient 3Patient 4
BackgroundMutationc.726_727delGT (p.Phe243Tyrfs*50)c.847delG (p. Glu283Arg fs*45)c.616A>T (p.Ile206Phe)c.697_699delTTC (p.Phe233del)
InheritanceAD—de novoAD—de novoAD—de novoAD—de novo
Family history of noteNoneNoneNoneNone
PregnancyNatural, uneventfulNatural, uneventfulNatural, uneventfulICSI, uneventful
DeliveryNVDNVDNVDElective caesarian
Gestational age (weeks)41414238
Birth weight3.74 kg (75th)3.50 kg (50th)3.73 kg (75th)3.012 kg (50th)
OFC at birth34 cm (25th)-35 cm (91st)
Neonatal respiratory
Single apnoeic/hyponoeic episode as a neonateNoSupplementary oxygen required at birthCentral apnoea and hypothermia from day 2 of life
Neonatal hypotonia?YesNoYesYes (severe from day 2 of life)
Neonatal feeding difficulties? Yes (required NG tube feeding)NoYes (required NG tube feeding)Yes (required NG tube feeding)
Age at last assessment4 years 7 months14 years 3 months12 years 10months6 years 9 months
Developmental milestonesSitting unsupported (age)2 years 6 months12 months13 monthsNot reached
Walking independently (age)Not reached24 months22 monthsNot reached
First words (age)Not reached2 years 6 months3 years 6 months11 months
Current developmental levelGross motorUnable to standFully mobile, broad-based gaitAble to run; ataxic and broad-based gaitNon-ambulatory with central hypotonia, dystonia and dyskinesia
Fine motorPincer gripManages buttons and can use fork/spoonManages buttonsPincer grip
LanguageNo expressive language, appears to understand some wordsSentences; limited vocabularyShort phrases, repetitive, difficult to understand, limited comprehensionEssentially non-verbal
BehaviourStartles easilyAnxiety, no sense of dangerRelatively easy child, some obsessional and attention-seeking behaviours, poor awareness of othersStartles easily, anxiety and behaviour consistent with global delay

Growth parametersHeight111 cm (91st)145 cm (0.4th–2nd)154 cm (50th)123 cm (75%)
Weight19 kg (75th)33 kg (<0.4th)46.5 kg (50th)25 kg (75%)
Head circumference50.6 cm (9th–25th)51 cm (<0.4th)56.0 cm (75th–91st)53 cm (75th)
Facial featuresHypotonic facies, prominent forehead, epicanthic folds, mild telecanthusHypotonic facies, microcephaly, tall forehead, facial asymmetry (R<L), upslanting palpebral fissures, large central incisorsSlightly long face and full cheeks, high forehead, telecanthusHypotonic facies, mild frontal bossing, thin upper lip, some deciduous teeth possibly malformed
NeurologicalLimb postureFeet held in plantar flexion, restricted movement at anklesNormalNormalHypotonic/dystonic
PowerMild generalised weaknessNormalMild generalised weaknessMild generalised weakness
DTRs/plantar responsesDiminished DTRs/normal plantar responseNormalDifficult to elicitNormal DTRs/normal plantar response
Cranial nerve anomalies?Dysconjugate gazeNoNoDysconjugate gaze and intermittent ocular deviations
Movement disorder?NoNoNoDystonic 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 neurotransmittersNilNilEarly cortical visual impairment
Elevated CSF di-hydro biopterin levels
Sleep study—cyclical central apnoea
Investigation resultsMRI brainDelayed myelination (at 3 years 5 months)Normal (at 7 years 8 months)Normal (at 10 years 3 months)Multiple abnormalities (see figure 3)
EEGNormalNot performedAbnormalAbnormal
EndocrineGonadotropin-dependent precocious puberty (early thelarche), on treatment with IM decapeptylNilNilElevated 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.