Rare POLR2A Variant Linked to Developmental Regression Shows Response to Low-Dose Dopamine Therapy

A single case report from China describes a girl with a rare genetic neurodevelopmental disorder caused by a de novo variant in the POLR2A gene, whose condition included a feature not previously documented in confirmed cases: marked neurodevelopmental regression. The report, published in Frontiers in Neuroscience, also describes a striking response to low-dose levodopa-benserazide hydrochloride, a dopamine agent, after long-term rehabilitation had produced only modest benefits.

According to the authors, fewer than 40 patients have been reported worldwide, a figure they interpret as suggesting frequent misdiagnosis and underdiagnosis. The disorder typically presents in infancy with hypotonia, developmental delay, and multisystem manifestations, and no standardized therapeutic regimens have been established for clinical management.

The patient in this report presented with neonatal hypotonia and developmental delay. At 2 years and 4 months of age, she developed sleep-associated dystonia-like nodding and limb tremors that were initially suspected to represent epileptic seizures. By 3 years of age, she had exhibited marked neurodevelopmental regression, losing the ability to walk and sit independently, together with deterioration of language function.

The diagnostic turning point came from whole-exome sequencing, which identified a de novo heterozygous POLR2A variant, c.3379C>T, resulting in a p.L1127F substitution in the protein. The identification of this variant confirmed the diagnosis of NEDHIB, placing the girl’s constellation of symptoms within the known genetic framework of the disorder while adding regression and dystonia-like episodes to its observed presentation.

Treatment began conventionally, with long-term rehabilitation training, but this yielded only modest clinical benefits. The authors report marked improvements in the girl’s motor and cognitive performance, accompanied by the complete resolution of the nodding episodes that had initially mimicked seizures. With dose titration during follow-up, her clinical status remained stable without symptom relapse.

The authors themselves frame the result as highlighting the potential benefit of low-dose dopamine therapy, not as proof of efficacy across the disorder.

The report’s second major contribution is the documentation of neurodevelopmental regression. According to the authors, regression has not previously been documented in confirmed NEDHIB cases, meaning this case expands the phenotypic spectrum associated with POLR2A-related disease. The authors suggest the finding offers novel insights into the clinical diagnosis and differential diagnosis of NEDHIB.

As with all single-patient reports, the conclusions carry inherent limitations. A response observed in one child cannot establish that levodopa-benserazide will benefit other patients with NEDHIB, and the natural variability of the disorder means the clinical stability during follow-up cannot be definitively attributed to the medication without controlled comparison.

Subject of Research: A rare POLR2A genetic neurodevelopmental disorder presenting with regression and responding to dopamine therapy

Article Title: De novo POLR2A p.(L1127F) variant presenting with neurodevelopmental regression and dystonia, with favorable response to low-dose dopamine therapy: a case report and literature review

Article References: Cao, Z., Shen, Q., Tangzhu, C., Guo, X., Huang, Q., Ge, X., Zhao, Q., & Shi, X. (2026). De novo POLR2A p.(L1127F) variant presenting with neurodevelopmental regression and dystonia, with favorable response to low-dose dopamine therapy: a case report and literature review. Frontiers in Neuroscience, 20, Article 1997676. https://doi.org/10.3389/fnins.2026.1997676

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1997676

Keywords: POLR2A, NEDHIB, neurodevelopmental regression, dystonia, dopamine therapy, levodopa, whole-exome sequencing, hypotonia, genetics, case report, novo, L1127F