Objective: To describe the clinical phenotype of autosomal recessive GTP cyclohydrolase deficiency (ARGTPCHD), its genetic and metabolic correlates, and their possible predictive value through a systematic review of the literature and the presentation of 4 new cases.

Background: The GCH1 gene encodes the enzyme GTP cyclohydrolase I (GTPCH), which catalyzes the limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters.

Autosomal dominant GTPCH deficiency (ADGTPCHD) is the most common genetic cause of dopa-responsive dystonia (DRD), whereas the recessive form is an ultra-rare and poorly known disorder with an earlier and more complex presentation that may disrupt ongoing neurodevelopmental processes.

Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome.

Method: We reported 4 new cases of ARGTPCHD and systematically reviewed data from 41 patients published since the first description of the disease. Clinical features, biochemical and genetic data, and treatment response of 45 patients were collected and analyzed.

Results: Three phenotypes were outlined: an early-infantile encephalopathic phenotype leading to profound disability (24/45 patients); a neurodevelopmental dystonia-parkinsonism phenotype with infantile/early-childhood onset developmental stagnation/regression preceding the emergence of MD (7/45); a late onset DRD-phenotype (14/45). All three phenotypes are responsive to the pharmacological treatment, which needs to be timely for the first two to prevent disabling neurological outcomes. 

A gradient of BH4 defect and genetic variant severity characterize the three clinical subgroups.  Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher probability of intellectual disability.

A few reported variants were associated with ADGTPCHD and ARGTPCHD, suggesting a minor impact on the enzymatic activity of the variants associated with the recessive form.

Conclusion: The clinical spectrum of ARGTPCHD can be classified into three phenotypes covering a continuum from early-onset encephalopathies to classical DRD. Genotype and specific biochemical features may allow early diagnosis and possibly predict clinical severity. Early treatment remains critical, especially for patients with the most severe presentations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-recessive-gtpch-deficiency-redefining-the-phenotypic-spectrum-and-outcome/