Expanding the phenotype in argininosuccinic aciduria: need for new therapies

• DOI: 10.1007/s10545-017-0022-x
• Publication Date: 2017-03-01T13:38:44Z
• Authors: Julien Baruteau; Elisabeth Jameson; Andrew A. Morris; Anupam Chakrapani; Saikat Santra; Suresh Vijay; Huriye Kocadag; Clare E. Beesley; Stephanie Grunewald; Elaine Murphy; Maureen Cleary; Helen Mundy; Lara Abulhoul; Alexander Broomfield; Robin Lachmann; Yusof Rahman; Peter H. Robinson; Lesley MacPherson; Katharine Foster; W. Kling Chong; Deborah A. Ridout; Kirsten McKay Bou...; Simon N. Waddington; Philippa B. Mills; Paul Gissen; James E. Davison
• Keywords: Ventriculomegaly; Natural history study

Abstract Objectives This UK‐wide study defines the natural history of argininosuccinic aciduria and compares long‐term neurological outcomes in patients presenting clinically or treated prospectively from birth with ammonia‐lowering drugs. Methods Retrospective analysis medical records prior to March 2013, then prospective until December 2015. Blinded review brain MRIs. ASL genotyping. Results Fifty‐six were defined as early‐onset ( n = 23) if symptomatic < 28 days age, late‐onset later, selectively screened perinatally due a familial proband 10). The median follow‐up was 12.4 years (range 0–53). Long‐term all groups showed similar phenotype including developmental delay (48/52), epilepsy (24/52), ataxia (9/52), myopathy‐like symptoms (6/52) abnormal neuroimaging (12/21). Neuroimaging findings included parenchymal infarcts (4/21), focal white matter hyperintensity cortical cerebral atrophy nodular heterotopia (2/21) reduced creatine levels (4/4). 4/21 adult went mainstream school without need additional educational support 1/21 lives independently. Early‐onset had more severe involvement visceral organs liver, kidney gut. All half presented hyperammonaemia. Screened normal ammonia at received treatment preventing sequenced 19) 20 mutations found. Plasma argininosuccinate higher compared patients. Conclusions Our further genotype–phenotype correlations. does not correlate severity hyperammonaemia plasma acid levels. disturbance nitric oxide synthesis may be contributor disease. Clinical trials providing merit consideration.