Alternative titles; symbolsLEUDEN SYNDROME▼ DescriptionLeukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) is characte...
Alternative titles; symbols
Leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome (LEUDEN) is characterized by global developmental delay apparent in early childhood, followed by episodic neurologic regression or decompensation associated with systemic stress, such as febrile infection. Affected individuals have hypotonia, gait difficulties or ataxia, poor or absent speech with dysarthria, and variable motor abnormalities, including spasticity, dystonia, extrapyramidal signs, and tremor. Many patients have seizures. Brain imaging shows diffuse white matter abnormalities, poor myelination, thin corpus callosum, and generalized cerebral atrophy with enlarged ventricles. The clinical features of the disorder and the abnormal brain imaging findings are progressive (summary by Mao et al., 2020).
▼ Clinical Features
Mao et al. (2020) reported 8 unrelated children, between 18 months and 13 years of age, with LEUDEN syndrome. The patients presented in infancy with global developmental delay, often associated with additional neurologic signs, including nystagmus, seizures, and hypotonia. Most had poor overall growth, mildly delayed walking by 2 years of age, and delayed speech with dysarthria, although patient 9 was nonambulatory and nonverbal at age 4 years. The patients showed progressive loss of developmental milestones associated with fever and illnesses, suggesting neurologic decompensation during stress. The disorder was progressive, and the regression often occurred abruptly, including loss of speech, poor eye contact, postural instability, and a decline in motor skills. Common persistent features included dystonia, truncal or gait ataxia, hypotonia, hypertonia with spasticity and hyperreflexia, tremor, bradykinesia, and parkinsonism. All patients had cognitive impairment, although the older ones were able to attend special schools. One patient had severe involuntary motor abnormalities, including myoclonus, hemiballismus, and choreoathetosis. Four patients had seizures, including focal complex and generalized, and a few had progressive microcephaly (down to -3 SD). A few had nonspecific dysmorphic features, including short philtrum, retrognathia, hypotelorism, fifth finger or toe clinodactyly, esotropia, astigmatism, strabismus, and progressive contractures. Brain imaging in all patients showed T2-weighted hyperintensities in the subcortical white matter, periventricular white matter, and sometimes in the brainstem or spinal cord, consistent with diffuse leukoencephalopathy. Other brain imaging findings included diffuse hypomyelination, thin corpus callosum, cerebellar atrophy, and generalized cerebral atrophy with enlarged ventricles. One patient had polymicrogyria.
The heterozygous mutations in EIF2AK2 gene that were identified in patients with LEUDEN syndrome by Mao et al. (2020) occurred de novo.
▼ Molecular Genetics
In 8 unrelated children with LEUDEN syndrome, Mao et al. (2020) identified de novo heterozygous missense mutations in the EIF2AK2 gene (see, e.g., 176871.0001-176871.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The mutations were spread throughout the gene, but most occurred in the kinase or double-stranded RNA-binding motif (DSRM) domains. Studies of fibroblasts derived from 3 patients showed that the mutant proteins were stably expressed, but had decreased kinase activity toward EIF2S1 (603907) compared to wildtype. Patient cells also showed decreased levels of the downstream regulator ATF4 (604064), and 2 of the cell lines showed impaired response to stress induced by poly(I:C) treatment. Mao et al. (2020) concluded that reduced EIF2S1 phosphorylation would interfere with downstream molecular pathways critical for responding to cellular stressors, which may lead to neurologic decompensation and damage. These downstream effects may impact the EIF2B protein complex, which activates the stress response: biallelic mutations in related EIF2B genes, including EIF2B1 (606686) and EIF2B2 (606454), are associated with an overlapping phenotype (see VWM, 603896). Given that EIF2AK2 requires dimerization for the kinase to function, the authors postulated a dominant-negative effect as the pathogenetic mechanism, rather than haploinsufficiency or a gain-of-function effect.