Dystonia in ATP2B3-associated X-linked Spinocerebellar Ataxia

X-linked transmission of ataxia (spinocerebellar ataxia, X-linked; SCAX) is relatively rare. A heterozygous (p.G1107D) mutation in isoform 3 of the plasma membrane calcium-transporting ATPase (ATP2B3) was previously reported to disrupt calcium export and lead to SCAX1 (OMIM #302500) in a boy and his uncle in a single family.¹ This protein is a member of the calmodulin-activated plasma membrane ATPase family, extruding excess calcium from the cell to maintain homeostasis. ATP2B3 is highly expressed within the presynaptic region of cerebellar granule cells.¹

The original article implicating ATP2B3 in SCAX1 predicted this point mutation would impair interactions with calmodulin. Confirmatory in vitro experiments demonstrated decreased calcium clearance from the cell in mutant constructs. Subsequently, a single patient with X-linked ataxia harboring both a hemizygous ATP2B3 (p.R482H) mutation and LAMA1 compound heterozygous mutations was reported.² Although a deleterious effect of the ATP2B3 (p.R482H) mutation was shown in vitro, incomplete penetrance for the ATP2B3 mutation was observed, and in the proband, a digenic effect of the ATP2B3 and LAMA1 mutations was postulated.

In the present family (Fig. 1A), a maternal grandfather exhibited ataxia and dysarthria as a child. No dementia was evident by MMSE. These symptoms were relatively stable for many years. This grandfather’s daughter was healthy and exhibited no signs of ataxia on examination. However, her 2 boys developed early childhood ataxia noted between their first and second birthdays. Over time, the boys exhibited increasingly prominent hypotonia, mild titubation, dysmetria, dysdiadochokinesis, and an ataxic gait. The pedigree thus suggested a nondegenerative, early-onset X-linked ataxia. Motion analysis laboratory evaluation indicated the presence of concurrent dystonia in the older boy (Supporting Information Video). His gait improved with levodopa administration, leading to a decrease in the number of falls sustained per week. Thus far, the boys’ course has been stable.

FIG. 1.

Familial cerebellar degeneration. A: Pedigree demonstrating X-linked inheritance of ataxia. B: MRI of brain demonstrates volume loss of the cerebellar hemispheres and vermis. [Color figure can be viewed at wileyonlinelibrary.com]

Family members were enrolled into our institutional review board–approved protocol, and whole exome sequencing of the affected individuals disclosed a hemizygous c.3321G>A (p.G1107D) mutation in ATP2B3. This was confirmed by Sanger sequencing. The unaffected mother was a heterozygous carrier for this mutation. ExAc Browser review (http://exac.broadinstitute.org; rs397514619) indicated a single heterozygous allele out of 28,066 alleles (allele frequency = 3.563e-05). No homozygous or hemizygous alleles were detected. A brain MRI disclosed isolated volume loss of the cerebellar vermis and hemispheres (Fig. 1B).

Thus we present a 3-generation pedigree also harboring the (p.G1107D) mutation originally reported by Zanni and colleagues.¹ Onset was in childhood in the hemizygous maternal grandfather and his 2 hemizygous grandsons, whereas a heterozygous daughter remained unaffected. This second unrelated family demonstrating X-linked recessive inheritance of an ATP2B3 mutation further validates the role of this calcium transporter as an important cause of X-linked ataxia and indicates that levodopa-responsive dystonia may also be a feature of this disease. Finally, in light of the recent identification of HPCA gene mutations in dystonia, ³ the identification of dystonia in ATP2B3 patients further implicates dysregulated calcium homeostasis in dystonia.