69-Year-Old Female with Progressive Supranuclear Palsy, Frontotemporal Dementia, Focal Hyperkinesia and one variant in the GCH1 gene and in the CSF1R gene

Special Article: Movement Disorders

Austin Alzheimers J Parkinsons Dis. 2023; 6(1): 1038.

69-Year-Old Female with Progressive Supranuclear Palsy, Frontotemporal Dementia, Focal Hyperkinesia and one variant in the GCH1 gene and in the CSF1R gene

Panteleimon Oikonomou¹*; Sabine Hellwig²; Thomas Wehrum²; Horst Urbach³; Wolfgang H Jost¹

¹Center for Movement Disorders, Parkinson-Klinik Ortenau, Wolfach, Germany

²Department of Psychiatry and Psychotherapy Medical Center - University of Freiburg, Germany

³Department of Neuroradiology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Germany

*Corresponding author: Panteleimon Oikonomou Center for Movement Disorders, Parkinson-Klinik Ortenau, Wolfach, Germany. Email: p.oikonomou@parkinson-klinik.de

Received: March 20, 2023 Accepted: April 28, 2023 Published: May 05, 2023

Abstract

How insignificant is the detection of gene variants in a novel clinical presentation of an atypical Parkinson’s syndrome with positive family history? We present the case of a 69-year-old woman with Progressive Vertical Supranuclear Palsy (PSP), focal hyperkinesia, non-L-dopa-responsive asymmetrical Parkinsonism, postural instability as well as apraxia, cognitive, speech and frontal disorder, with a positive family history, MRI evidence of mesial temporal atrophy and tau-PET evidence of tau pathology as well as identification of one variant in the GCH1 gene and one variant in the CSF1R gene. The fact that the clinical presentation and radiological finding of our patients are not compatible with a known and well described genetic disorder caused by pathogenic mutations of these genes, supports the notion that the detected gene variants have an uncertain significance in the pathogenesis of our patient’s disease.

Nevertheless, the novel description of the phenotype of our case of PSP with frontal lobe features, focal hyperkinesia and a positive family history, points to an in-vivo tauopathy, in which a genetic burden may play a role. The follow-up of the patient und her family may offer further insights into the pathophysiology of complex neurodegenerative diseases in the spectrum of tauopathies, offering possible new therapeutic targets.

Abbrevations: PSP: Progressive Supranuclear Palsy; FTD: Frontotemporal Dementia; CBS: Corticobasal Syndrome; GCH1: Guanosine 50-Triphosphate Cyclohydrolase I; GTPCH1: GTP Cyclohydrolase 1; LRD: L-Dopa-Responsive Dystonia. PD: Parkinson Disease; HDLS: Hereditary Diffuse Leukoencephalopathy with Spheroids; I-123-FP-CIT; SPECT: N-(3-Fluoropropyl)-2β-Carbomethoxy-3β-(4-[123I]iodophenyl) Nortropane Single-Photon Emission Computed Tomography. FDG-PET: Fluorodeoxyglucose-Positronemission Tomography; CSF: Cerebrospinal Fluid; NGS (Next-Generation Sequencing).

Introduction

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder, with prominent 4R-tau neuropathology, a variety of clinical presentations due to an effect on four clinical domains (ocular motor dysfunction, postural instability, akinesia, cognitive impairment) [1], and a spectrum of overlapping phenotypic subtypes from the Richardson-syndrome to variants such as PSP with parkinsonism, speech disorder, Frontotemporal Dementia (FTD) and Corticobasal Syndrome (CBS) [2]. Though PSP is generally regarded as a sporadic disorder, there is increasing evidence suggesting that a series of common and rare genetic variants have an impact on sporadic and familial forms of PSP [3]. A PSP-like phenotype with focal hyperkinesia, not associated with PSP-CBS and drug-induced hyperkinetic disorder has not been described before to our knowledge.

Guanosine 50-triphosphate cyclohydrolase I (GCH1) is located on chromosome 14 (14q22) and encodes the enzyme GTP cyclohydrolase 1 (GTPCH1) [4]. Loss-of-function mutations in GCH1 gene have been shown to cause autosomal recessive GCH-deficient hyperphenylalaninemia and autosomal dominant L-Dopa-Responsive Dystonia (LRD) [5]. Although LRD is a rare neurometabolic disease, characterized with dystonia that begins in childhood and responds dramatically and permanently to Low-Dose Llevodopa (L-dopa), an association with Parkinsonism in old age has been reported [4]. Furthermore, patients with sporadic Parkinson Disease (PD) have an increased frequency of pathogenic GCH1 mutations, which have previously been reported to cause LRD [5]. Thus, rare GCH1 coding variants are considered as a risk factor for PD [6].

Colony stimulating factor 1 receptor (CSF1R) gene is located on chromosome 5 (5q32) and encodes a cell-surface receptor primarily for the cytokine CSF-1, which controls the production, differentiation, and function of macrophages [7]. Mutations affecting the tyrosine kinase domain of CSF1R cause Hereditary Diffuse Leukoencephalopathy with spheroids (HDLS) [8,9]. Possible roles of CSF1R in neurodegenerative diseases including PD have been proposed [7].

Case Description

A 69-year-old female patient presented in our clinic with a history of slowly progressive symptoms since approximately one year including initial visual disturbances i.e. diplopia, and later an inability to make vertical eye movements combined with dizziness and headaches, involuntary movements of the left arm, an unsteady shuffling gait with falls, and amnestic aphasia. According to her husband, the patient's personality und behaviour showed alterations including irritability and emotional instability. In addition, cognitive changes such as concentration and memory impairment, as well as dysfunction of rational thinking and executive functions were also present. Everyday life activities were hence restricted with a heavy dependency on her husband.

A positive family-history was reported. The patient´s brother had "brain damage", unknown diagnoses and died at the age of 60. No neurological issues were identified in the children and the parents of the patient.

A detailed neurological examination revealed vertical supranuclear palsy viewing up, involuntary exploratory stereotypic choreiform movements of the distal upper left extremity with dystonic component, hypo- and bradykinesia mainly left-sided, pronounced postural instability, applause sign, non-fluent aphasia, idiomotoric apraxia, as well as executive (abnormal Luria-test) and behavioral dysfunction with affective lability.

Diagnostic Assessment

The diagnostic assesments were performed in the University Medical Center Freiburg. The Magnetic Resonance Imaging (MRI) of the head showed mesiotemporal atrophy including entorhinal atrophy and minor atrophy seen in the superior vermis more pronounced on the right side (Figure 1). N-(3-Fluoropropyl)-2β-carbomethoxy-3β-(4-[123I]iodophenyl) nortropane single-photon emission computed tomography (I-123-FP-CIT SPECT) revealed a slightly reduced availability of dopamine transporters in the right striatum (Figure 2).