Autosomal dominant GCH1 mutations causing spastic paraplegia at disease onset

Highlights

• Autosomal dominant GCH1 mutations can present with spastic paraplegia.

• In these patients, basal ganglia signs can develop only decades later.

• Patients with GCH1 mutations are levodopa responsive.

• GCH1 should be included in gene panels for hereditary spastic paraplegia.

Abstract

Background

Autosomal dominant GCH1 mutations are known to cause dopa-responsive dystonia (DRD). In this case series, we confirm a variant phenotype, characterized by predominant spastic paraplegia at disease onset with development of dystonia and/or parkinsonism only decades later.

Methods

Clinical trajectories of four patients from three families with pathogenic variants in GCH1 are described, illustrated by videos of the motor phenotype before and during treatment with levodopa. An extensive literature review was performed on previous reports of spasticity in patients with autosomal dominant GCH1 mutations.

Results

All patients presented during childhood or early adolescence with gait and leg spasticity. Three patients developed basal ganglia signs only in the fifth decade; the youngest patient has not yet developed dystonia, bradykinesia or hypokinesia. All patients responded to levodopa/carbidopa with improvement of gait and of dystonia, hypokinesia and/or rigidity. In all patients, spasticity decreased but did not disappear. Spasticity has been described previously in DRD, but in most cases co-existent basal ganglia signs were identified early in the disease course.

Conclusion

GCH1 mutations may cause a phenotype initially resembling hereditary spastic paraplegia (HSP) rather than DRD, with basal ganglia signs developing only after decades. In order not to miss this treatable condition, GCH1 should be included in HSP gene panels and its testing is pivotal in patients with spastic paraplegia, especially if there are concomitant basal ganglia signs and/or diurnal fluctuation.

Introduction

Autosomal dominant GTP Cyclohydrolase I (GCH1) gene mutations cause dopa-responsive dystonia (DRD), typically presenting with childhood-onset lower limb dystonia with diurnal fluctuations and an excellent response to levodopa [1]. More recently, adult-onset parkinsonism due to nigral degeneration, thus resembling Parkinson's disease [2] has been added to the clinical spectrum of GCH1 mutations.

DRD is part of the differential diagnosis of hereditary spastic paraplegias (HSP), the main reason being that lower limb dystonia can be confused with spastic paraparesis [3]. Furthermore, patients with GCH1 mutations can be misdiagnosed for having spastic diplegic cerebral palsy [4]. Interestingly, GCH1 mutations have also been found in patients with phenotypes that are in fact compatible with hereditary spastic paraplegia (HSP) [5,6]. This is surprising and warrants confirmation, as it is difficult to link the neurobiological consequence of GCH1 mutations (dopamine and serotonin deficiency) to spasticity.

We here describe a series of patients with GCH1 mutations and initial HSP-like phenotypes, in whom basal ganglia signs developed only after decades. We also provide a literature overview of earlier reports on spasticity in DRD.