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

内容摘要

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. 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. 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). 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.