The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240)

Abstract

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.

On Spinocerebellar Ataxia 21 as a Mimicker of Cerebral Palsy

“…e1 None of our patients experienced dystonia, chorea, myoclonus, or behavioral abnormalities, as previously reported (eTable 1, links.lww.com/NXG/A526). 2-4,6,7,e1,e2 Both our patients exhibited mild parkinsonian features, which is in line with previous reports of parkinsonism in patients with SCA21. 2,3 Our findings add support to the notion that SCA21 is a neurodevelopmental syndrome and a mimicker of ataxic CP.…”

“… 2 , 3 Our findings add support to the notion that SCA21 is a neurodevelopmental syndrome and a mimicker of ataxic CP. Congenital presentation in some cases 7 ,e1 and absence of a family history of ataxia were reasonable arguments to consider ataxic CP. Furthermore, transient improvement in a previous reported case makes an evaluation challenging.…”

“…6 However, slow progression and lack of convincing perinatal incidents should alert neurologists about SCA21 even when neuroimaging is normal, as reported in this work and previously. 7 In most SCA21 cases, cerebellar atrophy has been described. [3][4][5][6] Finally, other mimickers of ataxic CP have been reported with de novo variants in SPTBN2, associated with spinocerebellar ataxia 5 e3 and with variants in KCNC3 and ITPR1.…”

“…Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant disease associated with pathogenic variants in the transmembrane protein 240 ( TMEM240 ) gene. 1-7,e1,e2 In this report, we present 2 patients with sporadic SCA21, one of them diagnosed with ataxic CP.…”

Quantitative measures of motor development in Angelman syndrome

“…Clinically relevant outcome measures are necessary to evaluate the utility of ASOs and additional personalized therapies such as gene replacement therapy, which are on the horizon. In addition, clinical data from other NDDs, such as spinocerebellar ataxia, Noonan syndrome, Phelan‐McDermid Syndrome, and Dup15q Syndrome show a strong relationship between degree of motor impairment and other behavioral domains such as cognition, suggesting quantitative motor measures offer an objective primary outcome and a surrogate marker of clinically meaningful change in other domains of interest in clinical trials (Ackerly et al, 2003; Burdekin et al, 2020; Costales & Kolevzon, 2015; Dhamne et al, 2017; Pierpont et al, 2009; Soorya et al, 2018; Wilson et al, 2020; Zwanenburg et al, 2016). This is conceivably the case for pwAS, in whom we know motor planning and coordination plays a role in deficits such as apraxia impacting expressive language delays.…”