Delineating the phenotype of autosomal‐recessive HPCA mutations: Not only isolated dystonia!

We read with interest the recent report of two further families with dystonia attributed to truncating HPCA mutations, confirming our identification of homozygous and heterozygous missense mutations in HPCA as the cause of autosomal-recessive, isolated dystonia in two unrelated families. The phenotype of these new cases described by Atasu and colleagues seemed to be more severe, encompassing learning difficulties and febrile seizures. We revisited our patients with HPCA mutations to provide videos and a detailed report of the motor and nonmotor phenotype and the clinical course, and reviewed the other reported cases to delineate the phenotypic spectrum of HPCArelated dystonia. Clinical details of our patients and the patients recently reported are summarized in Table 1. The emerging clinical spectrum thus encompasses childhood, adolescence, or early adulthood onset of either isolated dystonia or dystonia combined with infantile seizures, developmental delay, and cognitive underfunctioning. In our patients (see Videos 1–3), dystonia was generalized, mobile, and very jerky in one family (cases 1–3) and segmental with predominant hand affectation in case #4. Nonmotor features like depression, anxiety, and pain seemed to be quite prominent. Although the natural history of the classic genetically defined dystonias (e.g., attributed to TOR1A, THAP1, GNAL, and ANO3 mutations) is that of a gradual onset of dystonia which often spreads, but then follows a stable disease course once signs are established (typically over a few years), it is noteworthy that there was a clearly progressive course over 30 years in 1 patient and more subtle progression in three others. Similarly, the development of dysphagia (albeit mild) may be a clue, given that this is typically not a feature of the isolated dystonias. This clarification that HPCA mutations may cause not just isolated dystonia, but also combined dystonia has clinical implications. In this context, for example, two previous reports, focusing on isolated dystonia, failed to identify further cases of HPCA dystonia, suggesting that, overall, HPCA dystonia is rare. Thus, one implication of this delineation of the clinical phenotype would be that screening for HPCA mutations should be particularly considered in patients with dystonia combined with infantile seizures, mild cognitive underfunctioning, or in “seemingly isolated” dystonia with a progressive course including development of dysphagia. The protein encoded by HPCA, hippocalcin, is a neuronal calcium sensor protein exclusively expressed in the brain and at particularly high levels in the striatum. Preliminary data suggesting that it might have a role in regulating calcium signaling in striatal neurons would link hippocalcin dysfuntion with dystonia. In hippocampal neurons, hippocalcin has a critical role as a Ca sensor in long-term depression, and theoretically this might explain some cognitive underfunctioning (see Table 1). Moreover, hippocalcin interacts with KCNQ potassium channels, which, if mutated, are a recognized cause of benign familial infantile seizures. Thus, it seems conceivable that hippocalcin dysfunction itself may account for the infantile seizures present in half of the patients with HPCA dystonia. Identification of further cases will help in delineating the full clinical spectrum and, possibly, disease-specific management approaches for dystonia attributed toHPCAmutations.