Dystonic Cerebral Palsy-Like Presentation Caused by a Novel TCF20 Variant

Pankaj Prasun; Kylie Vermeire; Stephanie Ferimer

doi:10.14802/jmd.24007

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Letter to the editor Dystonic Cerebral Palsy-Like Presentation Caused by a Novel TCF20 Variant: Pankaj Prasun¹, Kylie Vermeire¹, Stephanie Ferimer²; Journal of Movement Disorders 2024;17(3):348-350.
DOI: https://doi.org/10.14802/jmd.24007
Published online: April 26, 2024

¹Department of Pediatrics, West Virginia University Medicine, Morgantown, WV, USA

²Departments of Orthopedics, Physical Medicine and Rehabilitation, West Virginia University Medicine, Morgantown, WV, USA

Corresponding author: Pankaj Prasun, MD Department of Pediatrics, West Virginia University Medicine, One Medical Center Drive, Morgantown, WV 26506, USA / Tel: +1-304-598-4000 / Fax: +1-304-974-3257 / E-mail: Pankaj.prasun@hsc.wvu.edu

• Received: January 5, 2024 • Revised: March 20, 2024 • Accepted: April 25, 2024

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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REFERENCES

Dear Editor,

Cerebral palsy (CP) is a group of nonprogressive disorders of posture and motor impairment resulting from injury to the developing brain [1]. Dystonic CP is characterized by sustained, repetitive, and patterned movements such as twisting of the trunk or the extremities. Often, there is a sudden increase in tone associated with movements or emotions. The differential diagnosis of dystonic CP is broad and includes movement disorders and neurodegenerative, neuromuscular, and neurometabolic conditions. Many inherited conditions, such as Leigh syndrome, pyruvate dehydrogenase deficiency, glutaric aciduria type 1, dopa-responsive dystonia, and Rett syndrome, can be misdiagnosed as dystonic CP. With the availability of next-generation sequencing and frequent utilization of genetic tests, many individuals with a previous diagnosis of dystonic CP will be diagnosed with an inherited, slowly progressive neurodegenerative disorder or a neurodevelopmental disorder (NDD). We found a novel de novo TCF20 variant in an 18-year-old girl with learning disability, dysarthria, ataxia, spasticity, and fluctuating dystonia. She was previously diagnosed with dystonic CP.

The patient was born to a 33-year-old primigravida mother. There were no pregnancy complications. She was born at 42 weeks gestation by spontaneous vaginal delivery. She weighed 3,232 g (15th centile) and was 53 cm (70th centile) in length. There were no complications during delivery. She had mild jaundice that required phototherapy. Otherwise, the neonatal period was unremarkable. The patient attained her early developmental milestones mostly on time. However, she had mild speech delay and slurring of speech. As a toddler, her parents noticed that she had trouble getting up from a sitting position and had an abnormal gait compared to her peers. She was enrolled in early intervention services and received physical, speech, and occupational therapies. The patient went to a regular school. She was diagnosed with learning disabilities and had an individualized education plan. She graduated from high school with special assistance and plans to attend a technical school. During her teenage years, she started to develop spasticity and dystonia of her lower limbs. Her dystonia was more noticeable after exertion. She was referred to neurology for an evaluation of dystonia. Magnetic resonance imaging of the brain and spine was unremarkable. A diagnosis of dystonic CP was made. The patient was then referred to the physical medicine and rehabilitation department. She was given botulinum toxin injections for spasticity. Due to the fluctuating nature of her dystonia, a genetic cause was suspected, leading to a genetic referral at 18 years of age. At her genetic evaluation, dysarthria and gait imbalance due to spasticity and dystonia of the lower limbs were noted (Figure 1). Because of the patient’s history of learning disability and speech delays, genetic conditions such as chromosomal structural defects or monogenic NDDs were suspected. Whole-genome sequencing revealed a novel de novo variant, c.792C>A (p.Tyr264Ter), in TCF20. This variant introduces a premature termination codon in exon 2 of the TCF20 gene and is expected to result in loss of function, which is a known disease-causing mechanism underlying TCF20-related NDD. This variant is pathogenic based on American College of Medical Genetics variant classification guidelines, as it is a nonsense variant in a gene where loss of function is a disease-causing mechanism (PVS1) and is de novo in this patient with no family history of disease (PS2) [2]. In addition, this variant is absent from the gnomAD database version 4.0 (PM2) [3]. The minimum on-target average read depth reported by the performing laboratory was 30X.

TCF20 encodes a chromatin-binding protein that regulates gene expression. TCF20 was first associated with autism spectrum disorder [4]. However, it was later found to be associated with NDDs of varying severity [5]. The core findings related to TCF20-related NDD are developmental delays, variable intellectual disability, hypotonia, structural brain abnormalities, and neurobehavioral abnormalities. Subtle but nonspecific dysmorphic facial features have been described.5,6 In addition, movement disorders such as gait abnormalities, paroxysmal dyskinesia, tremors, and ataxia are reported in some individuals [5,6]. Most of the patients were diagnosed in childhood. However, a few patients have been adults at the time of diagnosis [6]. Two individuals with dystonia as the presenting clinical feature were diagnosed in adulthood [7]. One patient was 43 years old at diagnosis. He had a history of speech delay and learning disability as a child, similar to our patient. The other individual was 21 years old at diagnosis. She had gait abnormalities beginning in early childhood in addition to spasticity and dystonia that worsened with stress, which is very similar to our patient.

TCF20 was found to be essential for neurogenesis in the developing mouse brain [8]. A recent study showed that the Rett syndrome protein MeCP2 interacts with TCF20 [9]. MeCP2 and TCF20 are highly coexpressed in neurons and regulate many neuronal genes. Movement disorders are also prevalent in Rett syndrome patients. The MeCP2-TCF20 interaction might explain the similarity of clinical features between patients with Rett syndrome and patients with TCF20-related NDD.

Although TCF20-related NDD is known to be associated with movement abnormalities, we have described here an individual with a novel TCF20 variant who was initially diagnosed with dystonic CP. The findings in our patient suggest that TCF20-related NDD can primarily present with tone abnormalities and may be misdiagnosed as dystonic CP.

Notes

Ethics Statement

This report is a retrospective clinical observation that does not require ethics committee approval at this institution. A written informed consent for publication in medical journal has been obtained from the patient’s legal guardian.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author contributions

Conceptualization: Pankaj Prasun. Investigation: Pankaj Prasun, Stephanie Ferimer. Formal analysis: Pankaj Prasun, Kylie Vermeire. Writing—original draft: Pankaj Prasun. Writing—review & editing: all authors.

Acknowledgments

The authors would like to acknowledge Jessica Pugh, Carla Swanson, Paige Snyder, and Nicole Matthews from the Division of Genetics at West Virginia University Medicine for their continuous support to the patient.

Figure 1.

Flexion of the right ankle (A) and toes of the left foot (B) during episodes of dystonic posturing.

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