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

Background Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) is a rare autosomal-dominant condition caused by pathogenic POLR2A variants. It typically presents in infancy with hypotonia, developmental delay, and multisystem manifestations. Fewer than 40 patients have been reported worldwide, suggesting frequent misdiagnosis and underdiagnosis. To our knowledge, neurodevelopmental regression has not been documented in confirmed NEDHIB cases, and no standardized therapeutic regimens are established for clinical management. Case description The patient presented with neonatal hypotonia and developmental delay. At 2 years and 4 months, she developed sleep-associated dystonia-like nodding and limb tremors that were initially suspected to represent epileptic seizures. By 3 years of age, she exhibited marked neurodevelopmental regression: loss of the ability to walk and sit independently, together with deterioration of language function. Electroencephalography (EEG) demonstrated background slowing accompanied by epileptiform discharges. Whole-exome sequencing identified a de novo heterozygous POLR2A variant c.3379C > T (p. L1127F), which confirmed the diagnosis of NEDHIB. Results Long-term rehabilitation training yielded only modest clinical benefits. After initiation of the dopamine agent levodopa-benserazide hydrochloride, marked improvements in motor and cognitive performance were observed, accompanied by the complete resolution of nodding episodes. With dose titration during follow-up, her clinical status remained stable without symptom relapse. Conclusion This case expands the phenotypic spectrum associated with POLR2A -related NEDHIB and suggests that neurodevelopmental regression may occur within the phenotypic spectrum of this disorder. Our findings also highlight the potential benefit of low-dose dopamine therapy, offering novel insights into the clinical diagnosis, differential diagnosis, and therapeutic management of NEDHIB.