Susan Thompson

Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management of a well-characterized cohort of females with classical Rett syndrome. We aim to improve awareness and understanding of Rett syndrome amongst pediatricians, pediatric subspecialists and allied health professionals to enable early diagnosis and a streamlined enrolment approach for future clinical trials. Rett syndrome, a complex X-linked condition, affecting mainly females, is due to pathogenic variants of the MECP2 gene in most affected individuals. The Rett syndrome Multidisciplinary Management clinic at The Children’s Hospital at Westmead, Sydney, Australia, was established in 2000. This retrospective analysis of individuals who attended the clinic from 2000 to 2020 was performed to identify the incidence and predicted age of onset of Rett syndrome related comorbidities, disease progression and to review management principles. Data collected included age of Rett syndrome diagnosis, MECP2 genotype, clinical features and medical comorbidities, such as sleep disturbance, seizures, breathing irregularities, scoliosis, mobility, hand stereotypies, hand function, constipation, feeding ability, use of gastrostomy, communication skills, QTc prolongation, anthropometry, and bruxism. Analysis of 103 girls who fulfilled the clinical diagnostic criteria for classical Rett syndrome with a pathogenic variant of the MECP2 gene showed a median age of diagnosis of 3 years. The most frequent MECP2 variant was c.502 C>T.

3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL) deficiency can be a very severe disorder that typically presents with acute metabolic decompensation with features of hypoketotic hypoglycemia, hyperammonemia, and metabolic acidosis. A retrospective chart and literature review of Australian patients over their lifespan, incorporating acute and long-term dietary management, was performed. Data from 10 patients contributed to this study. The index case of this disorder was lost to follow-up, but there is 100% survival in the remainder of the cases despite several having experienced life-threatening episodes. In the acute setting, five of nine patients have used 900 mg/kg/day of sodium D,L 3-hydroxybutyrate in combination with intravenous dextrose-containing fluids (delivering glucose above estimated basal utilization requirements). All patients have been on long-term protein restriction, and those diagnosed more recently have had additional fat restriction. Most patients take L-carnitine. Three children and none of the adults take nocturnal uncooked cornstarch. Of the cohort, there were two patients that presented atypically—one with fulminant liver failure and the other with isolated developmental delay. Dietary management in patients with HMGCL deficiency is well tolerated, and rapid institution of acute supportive metabolic treatment is imperative to optimizing survival and improve outcomes in this disorder.