Childhood‐onset progressive dystonia associated with pathogenic truncating variants in CHD8

Abstract

Originally described as a risk factor for autism, CHD8 loss-of-function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8-related phenotype with the description of two unrelated patients who presented with childhood-onset progressive dystonia. Whole-exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild-to-moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder-associated genes whose mutations can also result in dystoniadominant phenotypes.

CHD8-related disorders redefined: an expanding spectrum of dystonic phenotypes

“…However, very few well-characterized instances have so far been described, limiting our understanding of the actual relevance of such manifestations in the overall clinical presentation and management of CHD8 -NDD patients. The case series presented in this work validates the observation, made by Doummar et al in 2021, that CHD8 heterozygous loss-of-function variants can be associated with phenotypes prominently characterized by young-onset dystonia, with mild-to-moderate, in some cases even barely detectable signs of neurocognitive disorders [ 10 ]. Despite the limited number of cases, a heterogeneous spectrum of dystonic manifestations has already been recorded, ranging from focal to generalized, from paroxysmal or action-induced to permanent, from apparently isolated to complex with spasticity and cerebral palsy-like pictures.…”

“…This consideration is especially relevant regarding genes involved in regulatory processes or showing a higher expression in the central nervous system even in postnatal life [ 18 ]. The pathophysiological bases of motor system involvement in CHD8 -related disorders are still unclear; however, the characterization of important CHD8 targets relevant to movement disorders such as beta-catenin and SCN2A [ 19 ], the recurrent identification of cerebellar structural abnormalities in probands [ 8 , 10 ], and recent animal experiments highlighting a crucial role for CHD8 in extrapyramidal nervous structures’ development [ 20 ], represent promising research prospects for investigating the etiological plausibility of this connection.…”

“…However, the growing implementation of non-targeted high-throughput genomic profiling assays, in the forms of whole-exome and whole-genome sequencing analyses, for the diagnosis of patients not primarily referred for neurodevelopmental abnormalities, has been adding new layers to the complexity of CHD8 -related phenotypes. In 2021, our group described two probands with pathogenic CHD8 truncating variants and childhood-onset progressive dystonia, suggesting that the spectrum of CHD8 -related disorders may include a dystonic component, whose characteristics of progressive intensification and generalization are capable of exerting a major impact on the quality of life of affected individuals [ 10 ].…”

Quantification of Behavioral Deficits in Developing Mice With Dystonic Behaviors

“…This difference in behavioral onset could indicate a neurodevelopmental period during which network dysfunction leads to dystonia, coinciding with a critical developmental window that also appears relevant to other neurodevelopmental disorders including autism spectrum disorders (14). In accordance with this hypothesis, a number of the recently identified dystonia-associated mutations involve genes that are also known for their role in neurodevelopment, including the autism-associated gene, CDH8 (15)(16)(17)(18)(19)(20). In addition, dystonia is also a frequent comorbidity in infants with other genetic, neurodevelopmental disorders including Rett syndrome (MECP2 mutations) (21,22), Partington syndrome (ARX mutations) (23), and as mentioned before, in an array of patients with autism spectrum disorders (24,25).…”