Prospective cohort study of neurodevelopmental outcomes following extreme neonatal hyperbilirubinaemia in Australia.

AIM: This study aimed to establish the incidence and nature of neurodevelopmental outcomes following extreme neonatal hyperbilirubinaemia in an Australian cohort. METHODS: A prospective cohort study of neurodevelopmental outcomes up to 3 years of age of infants born between 2010 and 2013 at ≥34 weeks gestation, with total serum bilirubin ≥450 µmol/L and/or clinical signs of acute bilirubin encephalopathy. Outcome measures comprised neurological examination, Bayley Scales of Infant and Toddler Development, 3rd edition and Ages and Stages Questionnaire, 3rd edition. RESULTS: The Australian estimated incidence of kernicterus is 0.35 per 100 000 live births. Within the follow-up cohort of 26, three children have clinical neurodevelopmental impairment: one has gross motor function classification system level 4 cerebral palsy, audiological deficiency and visual impairment; the second has gross motor function classification system level 1 cerebral palsy and the third has global developmental delay with autism spectrum disorder. Mean Bayley Scales of Infant and Toddler Development, 3rd edition scores were: cognition 10.3 (SD 1.5), receptive communication 9.4 (SD 1.8), expressive communication 9.2 (SD 2.4), fine motor 10.4 (SD 2.6) and gross motor 9.2 (SD 2.3). CONCLUSION: The Australian national rate of kernicterus compares favourably with global estimates. Future preventative strategies in this context include universal neonatal hyperbilirubinaemia assessment and mandated adverse outcome reporting and investigation.

Diaphragmatic Eventration in Sisters with Asparagine Synthetase Deficiency: A Novel Homozygous ASNS Mutation and Expanded Phenotype.

BACKGROUND: Asparagine Synthetase Deficiency (ASNSD; OMIM #615574) is a newly described rare autosomal recessive neurometabolic disorder, characterised by congenital microcephaly, severe psychomotor delay, encephalopathy and progressive cerebral atrophy. To date, seven families and seven missense mutations in the ASNSD disease causing gene, ASNS, have been published. METHODS: We report two further affected infant sisters from a consanguineous Indian family, who in addition to the previously described features had diaphragmatic eventration. Both girls died within the first 6 months of life. Whole exome sequencing (WES) was performed for both sisters to identify the pathogenic mutation. The clinical and biochemical parameters of our patient are compared to previous reports. RESULTS: WES demonstrated a homozygous novel missense ASNS mutation, c.1019G > A, resulting in substitution of the highly conserved arginine residue by histidine (R340H). CONCLUSION: This report expands the phenotypic and mutation spectrum of ASNSD, which should be considered in neonates with congenital microcephaly, seizures and profound neurodevelopmental delay. The presence of diaphragmatic eventration suggests extracranial involvement of the central nervous system in a disorder that was previously thought to exclusively affect the brain. Like all previously reported patients, these cases were diagnosed with WES, highlighting the clinical utility of next generation sequencing in the diagnosis of rare, difficult to recognise disorders.