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HOME > J Mov Disord > Volume 16(3); 2023 > Article
Letter to the editor
A Novel Variant of GCH1 in Dopa-Responsive Dystonia With Oculogyric Crises and Intrafamilial Phenotypic Heterogeneity
Taewoo Kim1orcid, Su Hyeon Ha1orcid, Dallah Yoo1corresp_iconorcid, Kyung Sun Park2orcid, Tae-Beom Ahn1orcid
Journal of Movement Disorders 2023;16(3):339-342.
DOI: https://doi.org/10.14802/jmd.23085
Published online: July 24, 2023

1Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea

2Department of Laboratory Medicine, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea

Corresponding author: Dallah Yoo, MD, PhD Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea / Tel: +82-2-958-8437 / Fax: +82-2-958-8490 / E-mail: youdalla@gmail.com
• Received: April 28, 2023   • Revised: June 26, 2023   • Accepted: July 24, 2023

Copyright © 2023 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
Dopa-responsive dystonia (DRD) is a rare, treatable disorder caused by the dysfunction of enzymes involved in the biosynthesis of dopamine, leading to dopamine deficiency [1]. The most common form of DRD, also known as Segawa disease, is an autosomal dominant heterozygous variant in the guanosine triphosphate cyclohydrolase-1 (GCH1) gene, resulting in a deficiency of tetrahydrobiopterin (BH4), an essential cofactor for tyrosine hydroxylase (TH), which catalyzes the rate-limiting step of dopamine synthesis. The typical presentation of Segawa disease is childhood-onset lower limb dystonia and diurnal fluctuation worsening toward the evening, with an excellent response to low doses of levodopa. However, phenotypic and genetic heterogeneity and sex-specific differences in penetrance frequently lead to misdiagnosis, which delays levodopa treatment and results in permanent orthopedic deformities requiring unnecessary surgical procedures [2].
Oculogyric crises (OGCs) are rare dystonic movement disorders characterized by paroxysmal, conjugate, tonic, and typically upward deviation of the eyes, lasting minutes to hours without crowding of consciousness [3]. The underlying pathophysiology of OGC remains unknown, but it mostly occurs in hypodopaminergic states, including acute complications of dopamine receptor-blocking agents or neurometabolic disorders affecting dopamine metabolism, such as DRD [3]. OGC has rarely been reported in patients with autosomal-dominant GCH1-DRD [4], although it is a common feature of DRD caused by sepiapterin reductase (SPR) deficiency, another disorder of BH4 synthesis [1].
Here, we report two cases in a family with a novel heterozygous likely pathogenic variant in GCH1, NM_000161.3:c.605T>G, p.(Val202Gly), highlighting OGC as an atypical feature of autosomal-dominant GCH1-DRD with intrafamilial phenotypic variation.
A 75-year-old woman presented to the clinic with her daughter complaining of recurrent episodes of loss of facial expression, heavy eyelids, speech disturbances, drooling, and resting tremors in the limbs over 10 years. Episodes occurred once or twice a year during the transitional period between seasons, lasted for one month, and spontaneously improved. Precipitation factors, including diurnal fluctuations, were not evident. A neurological examination during an episode revealed hypomimia, bradykinesia, rigidity, and resting tremors in both arms, which were slightly more affected on the right side (Supplementary Video 1 in the online-only Data Supplement, segment 1). She walked slowly with short steps and reduced swings of both arms and showed dystonic gait on the right leg with inversion of the ankle.
Her 50-year-old daughter showed remarkable resting tremors in both legs and gait disability. Upon careful review of her medical history, the onset of her symptoms occurred as a toddler, and she recalled repeated falls. She had undergone several spine and hip surgeries for Legg-Carve-Perthes disease since the age of 7 years. From the age of 24, she began to experience recurrent episodes of severe generalized tremors once every two years, which were alleviated in the morning and aggravated in the evening. At 38 years of age, the tremor was accompanied by a sustained involuntary upward deviation of both eyes, which occurred once every two years, lasted for 3 to 5 days, and then spontaneously regressed. Episodic tremor and upward ocular deviations with diurnal fluctuation were objectively documented by nurses and physicians, but OGC was not suspected at that time. No culprit drugs for OGC were found. She was misdiagnosed with essential tremors, and only propranolol and clonazepam were repeatedly prescribed, with no response. Her OGCs manifested for approximately 10 years and spontaneously disappeared. To refine her diagnosis, she underwent neurological examination, which showed mild bradykinesia and large amplitudes of resting tremors in all limbs, with the left side being more affected (Supplementary Video 1 in the online-only Data Supplement, segment 3). Both arms showed reemergent tremors when stretched forward. During walking, abnormal posturing, including inversion, tiptoeing, and toe flexion, was observed.
Other family members did not have any known neurological disorders (Figure 1A). Dopamine transporter imaging was performed, and the presynaptic terminals were preserved in both patients (Figure 1B). A small dose of levodopa (200 mg/day) was used for diagnosis, which markedly improved motor symptoms in the proband and her daughter (Supplementary Video 1 in the online-only Data Supplement, segments 2 and 4, respectively). Considering familial parkinsonism with leg dystonia, normal dopamine transporter uptake, an excellent response to levodopa, and a history of OGC in the daughter, DRD was suspected. Genetic analysis of the GCH1 gene, the most common cause of DRD, was performed. A novel heterozygous variant, NM_000161.3:c.605T>G, p.(Val202Gly), in exon 5 of GCH1 was detected in both the proband and her daughter (Figure 1C). This variant meets the criteria to be classified as likely pathogenic based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) Interpreting Sequence Variant Guidelines and ClinGen recommendations (https://clinicalgenome.org/): PP3_Strong (BayesDel_noAF score: 0.595906) [5], PS4_Supporting (this variant was identified in one family), and PM2_Supporting (this variant is not found in either gnomAD (https://gnomad.broadinstitute.org/) or KOVA (https://www.kobic.re.kr/kova/). The novel variant is located in the GTP cyclohydrolase 1 domain (https://www.ebi.ac.uk/interpro/) and is highly conserved among 100 vertebrate genomes (PhyloP100way score: 9.313).
We highlighted the intrafamilial phenotypic variations and atypical features of DRD with a heterozygous likely pathogenic variant in GCH1. The mother presented with late-onset parkinsonism and leg dystonia without diurnal fluctuations, and her parkinsonism did not progress for 10 years. The daughter had a long medical history of toddler-onset gait difficulty, adult-onset generalized tremor, and transient OGCs in her 30 s and 40 s with typical diurnal fluctuations. A small dose of levodopa dramatically improved motor symptoms in both patients; the mother had residual symptoms, while her daughter completely escaped lifelong disability, except for complications of orthopedic deformities. Although most patients with GCH1-DRD become symptom-free after levodopa replacement, residual signs could occur with an incomplete response to levodopa and are more frequent in patients who are older at diagnosis, as in this study [6].
Recognizing and correctly diagnosing OGC is essential to avoid missing treatable inherited rare movement disorders [3]. DRD is one of the most common cause of OGC, following the use of dopamine receptor-blocking agents. Among DRDs, the percentages of OGC reported are 62% in SPR, 34% in TH, and 12% in autosomal-recessive GCH1 pathogenic variants [1]. Except for this case, OGC in autosomal-dominant GCH1-DRD has only been reported in one patient [4].
Seasonal fluctuations or lifelong variations in symptoms in autosomal-dominant GCH1-DRD have not been reported previously. This is because patients with treatable DRD are difficult to follow-up over a long period without treatment after diagnosis. A similar case of DRD caused by TH deficiency, a 24-year-old man who manifested unusually prolonged dystonic episodes with relative interictal normalcy and not diurnal fluctuations, showed temporal variations over the years before diagnosis [7]. As in the case of the current patient’s daughter, lifelong variation in symptoms resulted in misdiagnosis as a somatization disorder for 22 years.
DRD is frequently diagnosed late, with a mean diagnostic delay of 13.5±13.3 years [2]. This is because DRD is a rare disease with an approximate incidence of 0.5–1 per million, and its clinical and genetic heterogeneity is extremely high [1]. In addition, sex-specific factors include female predominance of the autosomal dominant form of GCH1-DRD, accompanied by a younger age of onset and more dystonia phenotypes in females than in males. To avoid missing a rare treatable movement disorder, atypical features and red flags of DRD could help identify the diagnosis and facilitate the initiation of replacement therapy.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.23085.

Video 1.

Marked improvements following a small dose of levodopa (200 mg/day) in patients with dopa-responsive dystonia caused by a novel heterozygous GCH1 gene variant (NM_000161.3:c.605T>G, p.(Val202Gly)). Segment 1: A 75-year-old woman (mother) with seasonally fluctuating parkinsonism before levodopa treatment. Segment 2: After levodopa treatment, the mother’s parkinsonism improved, but residual motor signs persisted. Segment 3: A 50-yearold woman (daughter) with a prolonged history of tremor-dominant parkinsonism and leg dystonia before levodopa treatment. Segment 4: After levodopa treatment, the daughter showed a remarkable response, and symptoms were almost fully resolved.

Ethics Statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Kyung Hee University Hospital (IRB No. 2022-12-072) and with the 2013 Helsinki declaration and its later amendments. Informed consent was obtained from the patient included in the study.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author contributions

Conceptualization: Dallah Yoo. Data curation: Taewoo Kim, Dallah Yoo. Formal analysis: all authors. Investigation: all authors. Methodology: all authors. Supervision: Dallah Yoo, Kyung Sun Park, Tae-Beom Ahn. Validation: all authors. Visualization: Taewoo Kim, Dallah Yoo. Writing—original draft: Taewoo Kim. Writing—review & editing: all authors.

We are grateful to the patients and their families for willingly permitting and actively cooperating with the study to prevent delay in the diagnosis of dopa-responsive dystonia in anyone else.
Figure 1.
Pedigree, dopamine transporter imaging, and Sanger sequencing in cases of dopa-responsive dystonia. A: A pedigree chart shows the proband (a red arrow) and her daughter. Age is indicated below the symbol, and the age at symptom onset is also indicated for the two affected individuals. In the case of the daughter patient, tremor started at the age of 24, but gait disturbance was suspected from the age of 4. B: Dopamine transporter uptake in 18F-FP-CIT PET scans was preserved in both individuals. C: Sanger sequencing identified a novel likely pathogenic variant in GCH1 (NM_000161.3:c.605T>G, p.(Val202Gly)) in the proband and her daughter (bottom) compared to the wild-type sequence (top). The arrow indicates the position of compound heterozygous variants. yo, years old; PET, positron emission tomography.
jmd-23085f1.jpg
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