Chorea is a symptom of numerous pathophysiologically and clinically heterogeneous genetic conditions. A number of developments have been made in this field over the last years linked to improved genomic testing, large cohort collaborations and improved understanding of the molecular mechanisms. This review aims to provide an update on the new genetic conditions and phenotypes linked to chorea disorders, their modification factors and pathophysiological background. Several novel genetic conditions have been linked to chorea over the last 3 years, including mutations in FTH1, NAA60, ACBD6 or TOR1AIP2. Also, novel phenotypes have been established and linked to chorea, such as Adult-onset Neurodegeneration in Nucleotide Excision Repair Disorder (NERD-ND). Major advances have been made in understanding of the pathophysiological role of somatic instability in HD. Striatal pallidal neurons (SPNs) with 150–500 + CAG repeats seem to lose positive and then negative features of neuronal identity, de-repress senescence/apoptosis genes, ultimately leading to cell death. Improved recognition of the genetic background of chorea leads to more effective diagnostic processes, better prognostication and improved personalized treatment. The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful. This has potential major therapeutic implications not only in HD but also in other neurological repeat expansion disorders.
M. Ostrožovičová, M. Škorvánek· Current Neurology and Neuros...· 0 citations
Heterozygous pathogenic variants in the
KCNQ2
gene underlie a broad phenotypic spectrum ranging from self-limited (familial) neonatal epilepsy (SeLNE) to developmental and epileptic encephalopathy or isolated intellectual disability. The
KCNQ2
gene encodes subunits of a voltage-gated potassium channel involved in neuronal excitability, and its mutations are known to have both loss-of-function (LoF) and gain-of-function (GoF) effects, resulting in distinct neurological syndromes. The recurrent missense LoF variant
KCNQ2
p.(Arg214Trp) has been previously reported in a single family with a presumed SeLNE phenotype, without detailed adult follow-up and with additional database-reported evidence suggesting a broader phenotype associated with this recurrent variant.
Here, we report a family with two adult carriers of the heterozygous
KCNQ2
p.(Arg214Trp) variant identified through whole-exome sequencing, including long-term follow-up into late adulthood. In addition, a literature review of previously reported cases carrying the same recurrent variant was performed.
Both individuals presented with early-onset focal epilepsy with a relapsing course, characterized by prolonged seizure-free periods followed by recurrence in adulthood. The proband demonstrated transient motor regression, developmental delay, moderate intellectual disability, ataxia and fine motor impairment. The father exhibited milder cognitive impairment and additional comorbidities in later life.
These findings challenge the concept of
KCNQ2
p.(Arg214Trp) as a self-limited epilepsy-associated variant and indicate a broader phenotypic spectrum, with persistence of epilepsy and associated neurological and non-neurological comorbidities into adulthood. Our report provides new insights into adult outcomes, aiding in genetic counseling and the long-term management of affected individuals. More extensive studies with larger cohorts carrying this variant are necessary to better define the full phenotypic spectrum and to distinguish comorbidities associated with different etiological factors, including perinatal factors.
P. Christova, M. Ostrožovičová, J. Neupauerová et al.· BMC Neurology· 0 citations