Gabriella Horvath

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.

Psychiatric manifestations in patients with tetrahydrobiopterin (BH4) defects are common, and may occur even with treatment of the underlying disorder. The neurobiological background of these conditions has been linked to abnormalities of neurotransmitters, such as dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid. Here, we review the psychiatric profile of all patients with BH4 defects followed in the pediatric and adult metabolic clinics at our center. Three patients with autosomal recessive (AR) guanosine triphosphate cyclohydrolase (GTPCH) deficiency and three patients with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency were reviewed. All patients had behavioral disturbances and two had significant psychiatric comorbidities. These included attention deficit/hyperactivity disorder, anxiety, depression, aggression, or oppositional defiant disorder. One patient with PTPS deficiency had a severe psychiatric presentation, requiring inpatient admission and temporary placement into foster care for intensive behavioral therapy. Another with AR GTPCH deficiency was diagnosed with aggressive behavioral dysregulation requiring intensive psychiatric treatment. Management of the psychiatric manifestations of BH4 defects can be challenging, due to lack of information and studies of interactions between psychiatric medications on the deficient neurotransmitters and their receptors in these conditions. Further studies are needed to establish safety and efficacy of these treatments.