Background
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal movements, postures, or both [
1] and can result from lesions or perturbed function in motor networks involving the basal ganglia, cerebellum, thalamus, and sensorimotor cortex [
2]. Childhood- or adolescent-onset dystonia is often caused by acquired or genetic disorders [
3], which may affect the motor networks by biochemical deficits, metabolic derangement with or without neuronal degeneration, or perturbed structural development.
Dystonia-deafness syndrome (DDS) is a well-known clinical entity, with sensorineural deafness typically manifesting earlier than dystonia. The underlying etiology varies and is often difficult to pinpoint. In a recent series of 20 patients, the cause was genetic in five, acquired in two, and unknown in 13 [
4].
We present a female who in childhood received cochlear implants for infant-onset sensorineural deafness, exhibited mild dysmorphic facial features, finger contractures, constipation, and stagnation of psychosocial skills. During adolescence, she developed generalized dystonia, which at age 19 had become life-threatening and was treated with deep brain stimulation (DBS) of the internal pallidum bilaterally. At age 22, whole exome sequencing identified
ACTB p.Arg183Trp heterozygosity, first described in twin brothers with DDS [
5,
6]. Four similar patients were recently reported [
7‐
9], and the variant associated with the Baraitser-Winter cerebrofronto-facial syndrome (BWCFF type 1 (BRWS1, OMIM#243310) [
10].
The main aim of this case report is to present 4-year follow-up indicating the marked, life-improving benefits of pallidal stimulation, and brain imaging findings that strongly indicate loss of normal function of striatal neurons, including those harboring dopamine type 2 receptors, as the cause of the dystonia. We also propose a hypothesis for the pleiotropic manifestations of this form of dystonia-deafness syndrome based on diverse developmental functions of beta-actin with different temporal susceptibility and compensation by other forms of actin.
Discussion
We have presented a now 23-year-old woman with dystonia-deafness syndrome and mild developmental defects compatible with a BWCFF syndrome, caused by the
ACTB p.Arg183Trp variant. This specific variant has been reported in only six previous patients, who all had similar phenotypes, with childhood-onset sensorineural deafness and adolescent-onset dystonia [
5‐
9]. In our patient, adolescent-onset action dystonia in the extremities progressed axially over a few years to a severe generalized and life-threatening dystonia. Deep brain stimulation of the internal pallidum bilaterally at age 19 was feasible despite previous bilateral cochlear implants and had an immediate beneficial effect that is largely sustained after 4-year follow-up.
Brain imaging data show that in the striatum, and particularly in the putamen, there is both reduced dopamine type 2 (D2)-receptor binding and reduced glucose uptake, indicating reduced function or degeneration of striatal/putaminal neurons, including those that harbor D2-receptors. Also, there is indication of a mild loss of dopaminergic terminals. These unprecedented imaging data corroborate in vivo the post-mortem neuropathological findings of the originally reported monozygotic twin brothers in whom the
ACTB p.Arg183Trp variant was discovered [
5,
6]. Both twins died in their early twenties of aspiration pneumonia secondary to adolescent-onset, severe generalized dystonia. Abundant eosinophilic spherical structures in the striatum, consistent with degenerating neurons and processes, were strongly actin- and actin-depolymerizing factor (ADF)/cofilin-positive, suggesting a defect in actin turnover [
5]. Additional actin- and ADF/cofilin-immunoreactivity was noted in the globus pallidus and substantia nigra. Through a systematic search for sequence variants in
ACTB and
ACTG1, the p.Arg183Trp variant was found, and lymphoblast cell line studies suggested altered actin cytoskeletal architecture and function, possibly by reducing depolymerization dynamics [
6]. In vitro study of p.Arg183Trp ACTB demonstrated a gain-of-function effect: slower actin filament growth, higher ATP-hydrolysis, and faster depolymerization with impaired formation of long, stable filaments [
15].
The identical variant was recently described in a mother and daughter [
7] with early-onset sensorineural deafness and hand dystonia in late adolescence. Progression to generalized dystonia was rapid in the daughter and slow in the mother. Both responded well to pallidal DBS (at ages 21 and 42, follow-up 12 and 4 months, respectively). The fifth patient was a boy with infant-onset sensorineural hearing loss, mild intellectual disability, and adolescent-onset dystonia with rapid generalization [
8]. Left motor cortex stimulation had limited benefit, a status dystonicus ensued, and he died despite medically induced coma. Finally, the same variant was recently identified by WES in a 39-year-old man with severe hearing loss diagnosed at age 3 and reported onset of dystonia at age 24 with retro-torticollis, progressing to generalized dystonia [
9], treated from age 29 with good benefit from pallidal DBS [
16].
Thus, of the seven patients reported, only the four who received pallidal stimulation have survived. The p.Arg183Trp carriers published were all symptomatic
. Except for the Dutch family [
7], the variant seems to have occurred de novo
, also in our patient, since both parents are healthy.
The beta-actin protein (ACTB) is an important component of the cytoskeleton and is expressed by all cells in the body along with several other forms of actin [
17,
18]. The range of affected organs and symptoms underscores the pleiotropy of
ACTB disease-causing variants. Midline facial dysmorphogenesis is typical, manifests from a very early age and is likely to be congenital, potentially related to migratory disturbances in cranial neural crest cells that establish facial skeletal structures. Indeed, mouse fibroblasts lacking beta-actin exhibit severe migratory deficiency in vitro and neural crest cells exhibit migratory arrest and subsequent cell death in beta-actin knockout mice [
19,
20]. Interestingly, lack of beta-actin in mouse fibroblasts, embryonic stem cells, and embryos leads to compensatory upregulation of gamma- and alpha-actin expression [
20]. Such cross-isoform compensation, together with the heterozygosity of the
ACTB p.Arg183Trp variant, could contribute to the mildness of the cerebrofronto-facial phenotype.
One of the most penetrant phenotypes is early-onset deafness [
10]. Although the underlying cause of deafness in
ACTB patients is unclear, animal studies have demonstrated a critical role of beta-actin in the maintenance of hair cell stereocilia function, with progressive hearing loss starting at 6 weeks of age in
ACTB knockout mice [
21].
Several sequence variants of
ACTB, as well as of
ACTG1, severely perturb brain development [
10]. By contrast, the
ACTB p.Arg183Trp variant of our patient (and the six other patients reported to date) is associated with a milder neurodevelopmental deficit, with preserved macroscopic brain structure and only slight delay of initial psychomotor development, indicating no catastrophic or debilitating defects in the main prenatal and early postnatal phases of neurogenesis, axon outgrowth or synaptogenesis.
Intriguingly, overt striatal symptoms including dystonia appear to arise first around puberty in both females and males. Puberty marks a period of substantial changes in striatal volume, synaptogenesis and dopaminergic function, related among other things to adolescent-specific behavioral features related to risk-taking and reward perception [
22‐
27]. Beta-actin is a pivotal molecule in a variety of pre- and postsynaptic processes, and its dysfunction (unless compensated for by other forms of actin) would be expected to impact on synaptic signaling, plasticity, and functions such as neurotrophin uptake [
28]. All such effects could compromise striatal function. It is not unlikely that increasing demands placed on striatal connections by pubertal modulation could predispose to deleterious sequelae, including synapse regression, and cell death, when
ACTB is mutated.
Thus, we propose that the dystonia-deafness syndrome caused by ACTB p.Arg183Trp heterozygosity can be explained by specific functions of beta-actin that are compromised in different cell types and cellular functions at different developmental stages. In sequence, these would be neural crest migration and proliferation (facial dysmorphogenesis), hair cell stereocilia function (infant-onset deafness), and synaptic maintenance in the face of pubertal changes in striatal function (adolescent-onset dystonia). Moreover, we propose that partial compensation by the upregulation of other forms of actin, in particular gamma-actin, modulates the degree of severity and the temporal pattern of susceptibility exhibited by the different phenotypic characters. For example, neural crest function is only mildly affected, the striatum is resistant to dystonic pathology until impacted by puberty-related activity and synaptic changes, whereas hair cells are totally incapacitated. It will be interesting to assess the expression patterns of different actin forms in cellular models derived from patients with this particular ACTB variant.
In conclusion, this is the seventh patient reported to date with DDS caused by the ACTB p.Arg183Trp variant and is one of four patients who have survived the associated severe, generalized dystonia, due to substantial improvement from pallidal stimulation. Brain imaging of dopaminergic transmission in our patient strongly indicates dysfunction and/or loss of striatal neurons, including those harboring dopamine type 2-receptors. We hypothesize that this particular ACTB gain-of-function variant renders striatal neurons vulnerable to cell death as a consequence of changing demands on striatal neurons and connections occurring during adolescence and thereby causes dystonia. ACTB sequencing should be included in the work-up of dystonia-deafness syndrome. Deep brain stimulation of the internal pallidum bilaterally should be strongly considered to treat generalized dystonia in ACTB p.Arg183Trp carriers.