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Background <p>Classic lissencephaly is a malformation of cortical development that includes agyria and pachygyria. The major clinical symptoms are developmental impairment, muscular hypotonia, and drug-resistant epilepsy. The severity of the clinical phenotype depends on the associated gene and mutation. This study aimed to systematically investigate the genotype-specific course of the disease including neurodevelopmental outcome, medical complications, use of non-pharmacological supportive therapies, and its impact on the quality of life of the affected families.</p> Methods <p>47 patients with genetically and radiologically confirmed lissencephaly were included with mutation in <i>LIS1/PAFAH1B1</i> (<i>n</i> = 38), <i>DCX</i> (<i>n</i> = 5 males), <i>DYNC1H1</i> (<i>n</i> = 2), <i>TUBA1A</i> (<i>n</i> = 1) and <i>TUBG1</i> (<i>n</i> = 1) genes. Standardized questionnaires were completed by families and treating pediatricians. Quality of life was assessed with the PedsQL™ Family Impact Module.</p> Results <p>Prenatal abnormalities, most commonly microcephaly, were observed in 14/37 (38%) of <i>LIS1/PAFAH1B1</i> patients and 2/5 (40%) of <i>DCX</i> patients. Early symptoms included microcephaly, developmental delay, muscular hypotonia, and epileptic seizures. The median age at suspected diagnosis was 5 months for <i>LIS1/PAFAH1B1</i> patients and 9 months for <i>DCX</i> patients. Compared to <i>LIS1/PAFAH1B1</i>, <i>DCX</i>-related lissencephaly patients showed significantly better neurodevelopmental outcome in reaching more advanced milestones such as walking unassisted (<i>z</i>=-2.23, <i>p</i> = 0.026) and speaking sentences (<i>z</i>=-2.53, <i>p</i> = 0.011). Frequent medical complications included recurrent respiratory infections (14/38 (37%) of <i>LIS1/PAFAH1B1</i> patients; 1/4 (25%) of <i>DCX</i> patients) and dysphagia/ vomiting (23/37 (62%); 2/4 (50%)), which may require tube feeding (15/38 (40%); 1/5 (20%)). A median of eight different supportive therapies was used per patient (range 1–17), with physiotherapy and respiratory therapy considered the most effective. The scores obtained for health-related quality of life (HRQL) were low (parental HRQL mean 61.23; SD 16.79).</p> Conclusions <p>Our study confirms the severely impaired developmental potential and frequent neurological and medical complications in lissencephaly patients from an early age. The psychomotor prognosis in <i>LIS1/PAFAH1B1</i>-related lissencephaly is significantly worse compared to <i>DCX</i>-related lissencephaly. Supportive therapies are used intensively and are considered to be very effective. The disease puts a high burden on caregivers and the entire family. This emphasizes the need for appropriate epilepsy treatment, personalized care for patients and professional support for their families.</p>

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Gene-specific long-term course, neurodevelopmental outcome and quality of life in patients with LIS1/PAFAH1B1-, DCX-, DYNC1H1-, TUBA1A- and TUBG1-related lissencephaly

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  • 发表日期：

    2026年5月23日

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  • Christiane R. Proepper,
  • Lisa-Maria Schwarz,
  • Sofia M. Schuetz,
  • Katja von Au,
  • Thomas Bast,
  • Nathalie Beaud,
  • Ingo Borggraefe,
  • Friedrich Bosch,
  • Melanie Busse,
  • Jena Chung,
  • Otfried Debus,
  • Katharina Diepold,
  • Thomas Fries,
  • Gero von Gersdorff,
  • Martin Haeussler,
  • Andreas Hahn,
  • Till Hartlieb,
  • Ralf Heiming,
  • Peter Herkenrath,
  • Gerhard Kluger,
  • Jonas H. Kreth,
  • Gerhard Kurlemann,
  • Peter Moeller,
  • Deborah J. Morris-Rosendahl,
  • Axel Panzer,
  • Heike Philippi,
  • Sophia Ruegner,
  • Carolina Toepfer,
  • Silvia Vieker,
  • Adelheid Wiemer-Kruel,
  • Anika Winter,
  • Gerhard Schuierer,
  • Ute Hehr,
  • Tobias Geis

摘要

Background

Classic lissencephaly is a malformation of cortical development that includes agyria and pachygyria. The major clinical symptoms are developmental impairment, muscular hypotonia, and drug-resistant epilepsy. The severity of the clinical phenotype depends on the associated gene and mutation. This study aimed to systematically investigate the genotype-specific course of the disease including neurodevelopmental outcome, medical complications, use of non-pharmacological supportive therapies, and its impact on the quality of life of the affected families.

Methods

47 patients with genetically and radiologically confirmed lissencephaly were included with mutation in LIS1/PAFAH1B1 (n = 38), DCX (n = 5 males), DYNC1H1 (n = 2), TUBA1A (n = 1) and TUBG1 (n = 1) genes. Standardized questionnaires were completed by families and treating pediatricians. Quality of life was assessed with the PedsQL™ Family Impact Module.

Results

Prenatal abnormalities, most commonly microcephaly, were observed in 14/37 (38%) of LIS1/PAFAH1B1 patients and 2/5 (40%) of DCX patients. Early symptoms included microcephaly, developmental delay, muscular hypotonia, and epileptic seizures. The median age at suspected diagnosis was 5 months for LIS1/PAFAH1B1 patients and 9 months for DCX patients. Compared to LIS1/PAFAH1B1, DCX-related lissencephaly patients showed significantly better neurodevelopmental outcome in reaching more advanced milestones such as walking unassisted (z=-2.23, p = 0.026) and speaking sentences (z=-2.53, p = 0.011). Frequent medical complications included recurrent respiratory infections (14/38 (37%) of LIS1/PAFAH1B1 patients; 1/4 (25%) of DCX patients) and dysphagia/ vomiting (23/37 (62%); 2/4 (50%)), which may require tube feeding (15/38 (40%); 1/5 (20%)). A median of eight different supportive therapies was used per patient (range 1–17), with physiotherapy and respiratory therapy considered the most effective. The scores obtained for health-related quality of life (HRQL) were low (parental HRQL mean 61.23; SD 16.79).

Conclusions

Our study confirms the severely impaired developmental potential and frequent neurological and medical complications in lissencephaly patients from an early age. The psychomotor prognosis in LIS1/PAFAH1B1-related lissencephaly is significantly worse compared to DCX-related lissencephaly. Supportive therapies are used intensively and are considered to be very effective. The disease puts a high burden on caregivers and the entire family. This emphasizes the need for appropriate epilepsy treatment, personalized care for patients and professional support for their families.