The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency
Julia-Palacios, Natalia Alexandra (Institut de Recerca Sant Joan de Déu)
Kuseyri Hübschmann, Oya (Heidelberg University)
Olivella, Mireia (Universitat de Vic)
Pons, Roser (University of Athens)
Horvath, Gabriella (University of British Columbia)
Lücke, Thomas (Ruhr-University Bochum (Alemanya))
Fung, Cheuk-Wing (The Hong Kong Children's Hospital)
Wong, Suet-Na (The Hong Kong Children's Hospital)
Cortès-Saladelafont, Elisenda (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Rovira-Remisa, M Mar (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Yıldız, Yilmaz (Hacettepe University (Ancara, Turquia))
Mercimek-Andrews, Saadet (University of Alberta (Canadà))
Assmann, Birgit (Heidelberg University)
Stevanović, Galina (University of Belgrade)
Manti, Filippo (Università degli Studi di Roma "La Sapienza")
Brennenstuhl, Heiko (Heidelberg University)
Jung-Klawitter, Sabine (Heidelberg University)
Jeltsch, Kathrin (Heidelberg University)
Sivri, H Serap (Hacettepe University (Ancara, Turquia))
Garbade, Sven F. (Heidelberg University)
García-Cazorla, Àngels (Institut de Recerca Sant Joan de Déu)
Opladen, Thomas (Heidelberg University)

Fecha:	2024
Resumen:	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.
Ayudas:	Instituto de Salud Carlos III P118/00111 Instituto de Salud Carlos III FI21/0073
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Evolving phenotype ; Genetic spectrum ; In silico analyses ; Long-term follow-up ; SSADH deficiency
Publicado en:	Journal of Inherited Metabolic Disease, Vol. 47 Núm. 3 (may 2024) , p. 447-462, ISSN 1573-2665

DOI: 10.1002/jimd.12723

16 p, 3.2 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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