The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

Impact of COVID19 pandemic on patients with rare diseases in Spain, with a special focus on inherited metabolic diseases.

Introduction: The Covid-19 pandemic soon became an international health emergency raising concern about its impact not only on physical health but also on quality of life and mental health. Rare diseases are chronically debilitating conditions with challenging patient care needs. We aimed to assess the quality of life and mental health of patients with rare diseases in Spain, with a special focus on inherited metabolic disorders (IMD). Methods: A prospective case-control study was designed, comparing 459 patients suffering from a rare disease (including 53 patients with IMD) and 446 healthy controls. Quality of life (QoL) and mental health were assessed using validated scales according to age: KINDL-R and the Pediatric Symptom Checklist (PSC) for children and the WhoQoL-Bref questionnaire, GAD and PHQ-9 in adults. Results: First, children and adults (but not adolescents) with IMD showed greater psychological effects than controls (p = 0.022, p = 0.026 respectively). Second, when comparing QoL, only adult patients with IMD showed worse score than controls (66/100 vs 74,6/100 respectively, p = 0.017). Finally, IMD had better quality of life than other rare neurological and genetic diseases (p = 0.008) or other rare diseases (p < 0.001 respectively) but similar alteration of the mental status. Conclusions: Our data show that the pandemic had a negative impact on mental health that is more evident in the group of patients with IMD. Young age would behave as a protective factor on the perception of QoL. Furthermore, patients with IMD show a better QoL than other rare diseases.

The impact of COVID-19 pandemic on the diagnosis and management of inborn errors of metabolism: A global perspective.

Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.