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Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes.

Authors :
Novelli, Maria
Tolve, Manuela
Quiroz, Vicente
Carducci, Claudia
Bove, Rossella
Ricciardi, Giacomina
Yang, Kathryn
Manti, Filippo
Pisani, Francesco
Ebrahimi‐Fakhari, Darius
Galosi, Serena
Leuzzi, Vincenzo
Source :
Movement Disorders Clinical Practice. Jul2024, p1. 13p. 3 Illustrations.
Publication Year :
2024

Abstract

Background Objectives Methods Results Conclusions The GCH1 gene encodes the enzyme guanosine triphosphate cyclohydrolase I (GTPCH), which catalyzes the rate‐limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters. Autosomal dominant GTPCH (adGTPCH) deficiency is the most common cause of dopa‐responsive dystonia (DRD), whereas the recessive form (arGTPCH) is an ultrarare and poorly characterized disorder with earlier and more complex presentation that may disrupt neurodevelopmental processes. Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome.The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature.Clinical, biochemical, and genetic data and treatment response of 45 patients are presented.Three phenotypes were outlined: (1) early‐infantile encephalopathic phenotype with profound disability (24 of 45 patients), (2) dystonia‐parkinsonism phenotype with infantile/early‐childhood onset of developmental stagnation/regression preceding the emergence of movement disorder (7 of 45), and (3) late‐onset DRD phenotype (14 of 45). All 3 phenotypes were responsive to pharmacological treatment, which for the first 2 must be initiated early to prevent disabling neurodevelopmental outcomes. A gradient of BH4 defect and genetic variant severity characterizes the 3 clinical subgroups. Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher likelihood of intellectual disability.The clinical spectrum of arGTPCH deficiency is a continuum from early‐onset encephalopathies to classical DRD. Genotype and biochemical alterations may allow early diagnosis and predict clinical severity. Early treatment remains critical, especially for the most severe patients. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
23301619
Database :
Academic Search Index
Journal :
Movement Disorders Clinical Practice
Publication Type :
Academic Journal
Accession number :
178379218
Full Text :
https://doi.org/10.1002/mdc3.14157