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Background <p>Epilepsy is a frequent feature of genetic neurodevelopmental disorders and is increasingly recognized as a disorder of disrupted neuronal networks rather than isolated focal pathology. <i>DYNC1H1</i>, encoding the heavy chain of cytoplasmic dynein 1, is implicated in a broad spectrum of neuromuscular and central nervous system disorders, including intellectual disability, malformations of cortical development (MCDs), and epilepsy.</p> Case presentation <p>We report a female patient with drug-resistant epilepsy beginning at 9 years of age, normal brain MRI and multiple seizure types, including focal motor, tonic–clonic, epileptic spasms, and atypical absence seizures. She also presented with lower limb hypotrophy, <i>pes cavus</i>, and axonal neuropathy. Genetic testing revealed a heterozygous NM_001376.5(DYNC1H1):c.752G &gt; A(p.Arg251His) variant in the N-terminal tail domain, inherited from her father and shared by two siblings with cognitive and gait difficulties. Motor disability progressed over time, and current therapy reduced but did not eliminate seizures.</p> Conclusions <p>This case expands the phenotypic spectrum of DYNC1H1-related disorders, demonstrating that tail-domain variants can cause late-childhood epilepsy even in the absence of cortical malformations. The coexistence of central and peripheral involvement highlights widespread dynein-mediated network disruption, while intrafamilial variability underscores the heterogeneity of these conditions.</p>

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Enlarging the phenotypical spectrum of DYNC1H1-related epilepsy

  • 期刊论文

  • 发表日期：

    2026年4月27日

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  • Giada Vega,
  • Diletta Camussi,
  • Guja Astrea,
  • Emanuele Bartolini

摘要

Background

Epilepsy is a frequent feature of genetic neurodevelopmental disorders and is increasingly recognized as a disorder of disrupted neuronal networks rather than isolated focal pathology. DYNC1H1, encoding the heavy chain of cytoplasmic dynein 1, is implicated in a broad spectrum of neuromuscular and central nervous system disorders, including intellectual disability, malformations of cortical development (MCDs), and epilepsy.

Case presentation

We report a female patient with drug-resistant epilepsy beginning at 9 years of age, normal brain MRI and multiple seizure types, including focal motor, tonic–clonic, epileptic spasms, and atypical absence seizures. She also presented with lower limb hypotrophy, pes cavus, and axonal neuropathy. Genetic testing revealed a heterozygous NM_001376.5(DYNC1H1):c.752G > A(p.Arg251His) variant in the N-terminal tail domain, inherited from her father and shared by two siblings with cognitive and gait difficulties. Motor disability progressed over time, and current therapy reduced but did not eliminate seizures.

Conclusions

This case expands the phenotypic spectrum of DYNC1H1-related disorders, demonstrating that tail-domain variants can cause late-childhood epilepsy even in the absence of cortical malformations. The coexistence of central and peripheral involvement highlights widespread dynein-mediated network disruption, while intrafamilial variability underscores the heterogeneity of these conditions.