Genetic Dystonia‐ataxia Syndromes: Clinical Spectrum, Diagnostic Approach, and Treatment Options

Abstract

Background Dystonia and ataxia are manifestations of numerous disorders, and indeed, an ever‐expanding spectrum of genes causing diseases that encompass dystonia and ataxia are discovered with the advances of genetic techniques. In recent years, a pathophysiological link between both clinical features and the role of the cerebellum in the genesis of dystonia, in some cases, has been proposed. In clinical practice, the genetic diagnosis of dystonia‐ataxia syndromes is a major issue for genetic counseling, prognosis and, occasionally, specific treatment. Methods For this pragmatic and educational review, we conducted a comprehensive and structured literature search in Pubmed, OMIM, and GeneReviews using the key words “dystonia” and “ataxia” to identify those genetic diseases that may combine dystonia with ataxia. Results There are a plethora of genetic diseases causing dystonia and ataxia. We propose a series of clinico‐radiological algorithms to guide their differential diagnosis depending on the age of onset, additional neurological or systemic features, and imaging findings. We suggest a sequential diagnostic approach to dystonia‐ataxia syndromes. We briefly highlight the pathophysiological links between dystonia and ataxia and conclude with a review of specific treatment implications. Conclusions The clinical approach presented in this review is intended to improve the diagnostic success of clinicians when faced with patients with dystonia‐ataxia syndromes.

Extending the Phenotypic Spectrum Associated with STUB1 Mutations: A Case of Dystonia

“…Recent genetic studies suggested the molecular pathways of dystonia and ataxia being closely intertwined. With more than 100 genetic conditions associated with a phenotypic spectrum encompassing both entities, there has been emerging data suggesting that dystonia is a network disorder involving both the cerebellum and basal ganglia—2 closely interconnected structures rather than the disorder related solely to the abnormalities in the basal ganglia. This concept has been supported by clinical studies (cerebellar abnormalities reported in patients with cervical dystonia), by a number of neuroimaging studies including diffusor tensor imaging, tractography, and [18F]‐fluorodeoxyglucose–positron‐emission tomography, and animal studies .…”

“…When family history is suggestive of an autosomal‐recessive pattern of inheritance, Friederich's ataxia (ATX‐FXN), ataxia‐telangiectasia (ATX‐ARL13B, ATX‐ATM), and AOA1 (ATX‐APTX) and 2 (ATX‐SETX) are the top differential diagnoses . It is prudent to remember the reversible causes of ataxia such as vitamin E deficiency (ATX‐TTPA; clues include proprioception loss, pyramidal signs, retinopathy), Refsum's disease (ATX‐PHY; anosmia, retinitis pigmentosa, hearing loss, ichthyosis), or biotin‐thiamine‐responsive basal ganglia disease (mutations in the SLC19A3 gene) . Dystonia may be associated with metabolic disorders such as, for example, Willson's disease (DYT/ATX‐ATP7B; Kayser‐Fleischer ring, liver disease, parkinsonism, myoclonus), neurodegeneration with brain iron accumulation (NBIA; NBIA/DYT/PARK‐CP, NBIA/DYT‐PANK2, NBIA/DYT/PARK‐PLA2G6), lysosomal storage disorders (eg, Pelizaeus Merzbacher disease [ATX/HSP‐GJC2], Niemann‐Pick type C), mitochondrial disorders, and parkinsonian disorders …”

“…1 It is prudent to remember the reversible causes of ataxia such as vitamin E deficiency (ATX-TTPA; clues include proprioception loss, pyramidal signs, retinopathy), 17 Refsum's disease (ATX-PHY; anosmia, retinitis pigmentosa, hearing loss, ichthyosis), or biotin-thiamine-responsive basal ganglia disease (mutations in the SLC19A3 gene). 1,17 Dystonia may be associated with metabolic disorders such as, for example, Willson's disease (DYT/ATX-ATP7B; Kayser-Fleischer ring, liver disease, parkinsonism, myoclonus), 17 neurodegeneration with brain iron accumulation (NBIA; NBIA/DYT/PARK-CP, NBIA/ DYT-PANK2, NBIA/DYT/PARK-PLA2G6), lysosomal storage disorders (eg, Pelizaeus Merzbacher disease [ATX/HSP-GJC2], Niemann-Pick type C), mitochondrial disorders, and parkinsonian disorders. 1,17 If the family history was suggestive of an autosomaldominant inheritance, the combination of ataxia and dystonia would prompt further analysis for the SCA spectrum disorders, including SCA1 (pyramidal signs, muscular atrophy, decreased deep tendon reflexes, loss of proprioception, bulbar dysfunction), SCA2 (pyramidal signs, peripheral neuropathy, fasciculations, muscle atrophy, parkinsonism, autonomic dysfunction), SCA3 (nystagmus, pyramidal signs, peripheral neuropathy, muscle atrophy), SCA6 (diplopia, dizziness, peripheral neuropathy), and SCA17 (chorea, cognitive impairment, parkinsonism, behavioral changes).…”

“…1,17 If the family history was suggestive of an autosomaldominant inheritance, the combination of ataxia and dystonia would prompt further analysis for the SCA spectrum disorders, including SCA1 (pyramidal signs, muscular atrophy, decreased deep tendon reflexes, loss of proprioception, bulbar dysfunction), SCA2 (pyramidal signs, peripheral neuropathy, fasciculations, muscle atrophy, parkinsonism, autonomic dysfunction), SCA3 (nystagmus, pyramidal signs, peripheral neuropathy, muscle atrophy), SCA6 (diplopia, dizziness, peripheral neuropathy), and SCA17 (chorea, cognitive impairment, parkinsonism, behavioral changes). 1,17 Dystonia may also be paroxysmal or episodic such as seen in paroxysmal kinesigenic dyskinesia (associated with mutation in the PRRT2 gene), and episodic ataxia type 2. 17 Following initial negative genetic testing including trinucleotide disorders, the whole-exome sequencing result in our patient was suggestive of autosomal-recessive SCA16 (ATX-STUB1).…”

“…1,17 Dystonia may also be paroxysmal or episodic such as seen in paroxysmal kinesigenic dyskinesia (associated with mutation in the PRRT2 gene), and episodic ataxia type 2. 17 Following initial negative genetic testing including trinucleotide disorders, the whole-exome sequencing result in our patient was suggestive of autosomal-recessive SCA16 (ATX-STUB1).…”