Benign Hereditary Chorea as a Manifestation of HPCA Mutation

Biallelic pathogenic variants in the HPCA gene encoding hippocalcin have been recently identified as causative of autosomal recessive (AR) isolated dystonia (MIM 224500). The first reported family consisted of three siblings presenting in the first decade of life with dystonia that progressively became generalized, with a more severe involvement of the upper limbs and craniocervical district. Pathogenic variants in HPCA were also identified in an unrelated subject affected by sporadic isolated dystonia. ¹ The pathogenic role of HPCA in causing AR dystonia was confirmed by the identification of truncating mutations in two unrelated individuals from two consanguineous Turkish families, displaying generalized dystonia with prominent bulbar involvement, febrile seizures, and neurodevelopmental delay. ² Yet, subsequent studies failed to identify additional pathogenic variants in patients with early onset isolated dystonia, suggesting HPCA variants are a rare cause of AR‐dystonia. ³ , ⁴ Recently, a novel HPCA missense variant was also found in a pediatric patient and two affected relatives with dystonia and intellectual disability. ⁵

HPCA encodes for a neuronal calcium sensor protein involved in sensing cytosolic calcium levels and regulating activity of voltage‐dependent calcium and potassium channels. ⁶ , ⁷ , ⁸ The gene is almost exclusively expressed in the brain with highest expression levels in the cortex, striatum, cerebellum, and hippocampus, ⁶ , ⁷ the latest implicated in memory formation. ¹ Hippocalcin has been intensely studied in relation to its role in dendritic maturation and synaptic plasticity of striatal neurons, where it is hypothesized to play a role in dystonia‐onset. Recent functional work suggests an overall loss‐of‐function mechanism for dystonia‐linked variants. ⁹

We report a case of an 8‐year‐old girl with a generalized chorea, homozygous for a novel HPCA variant.

Case Report

The patient is an 8‐year‐old girl, first‐born child from healthy consanguineous parents (first cousins) from Pakistan. Clinical and neurological examinations of her two siblings and parents were normal. Delivery and neonatal period were uneventful. Head and trunk control were reported on time, independent gait was at 26 months with later normal motor achievements. Parents reported mild language delay in mother tongue. She has learned Italian on admission in the nursery school, and now she can speak Urdu and Italian regularly from a lexical and syntactical point of view. On indication of preschool teachers, the child was referred to the Child Neurology and Psychiatry Unit of Spedali Civili of Brescia at the age of 6 years for “learning difficulties”; the neurological evaluation revealed nonrhythmic, unsustained, and non‐suppressible involuntary movements of upper and lower limbs and the orofacial district (Video 1). These movements were reported by parents as being present since age 2 starting from the face and increasing in intensity over time. They presented at rest, but were induced by intention and manifested as mild dysarthria, facial grimacing, and choreiform jerking of the trunk and limbs (Videos 2 and 3). Nevertheless, the girl's quality of life (QoL) did not seem to be affected by this movement disorder. She could write and draw well; she could also run and kick the ball without falling over and objects did not drop from her hands.

Video 1.

The child is filmed doing Mingazzini's arm test. Involuntary, irregularly timed, non‐repetitive and purposeless movements of the arms and face's muscles are evident. Recording videos demonstrate the poor pharmacological response to different treatment approaches: 1: no treatment; 2: pimozide 4 mg/die; 3: levodopa 75 mg/die; 4: carbamazepine 400 mg/die; 5: trihexyphenidyl 10 mg/die; 6: tetrabenazine 25 mg/die.

Video 2.

The child is filmed while walking. Gait is characterized by instability because of foot strike dysmetria and the presence of generalized chorea. Segments compare distinct treatment approaches: 7: pimozide 4 mg/die; 8: carbamazepine 400 mg/die; 9: Deltacortene (1 month trial); 10: trihexyphenidyl 10 mg/die; 11: tetrabenazine 25 mg/die.

Video 3.

The child is filmed while doing precision tasks with the upper limbs. 12: the child is writing. She can write slowly, but in a formally correct way. 13 and 14: the child performs an Archimedes spiral and another precision task with minimal instability of the graphic line.

To exclude secondary causes of chorea, a complete routine blood tests including antistreptolysin O titer (ASO), erythrocyte sedimentation rate (ESR), C‐reactive protein, iron metabolism, α‐fetoprotein, and prolactin level were performed with unremarkable results. Pharyngeal swab and a complete cardiological examination were normal. Additional investigations including ophthalmological and audiological examinations, electroencephalography, and brain magnetic resonance imaging (MRI) (conventional 1,5 Tesla) were found to be normal. Electromyographic (EMG) studies (polygraphy with EMG video recording) failed to identify a dystonic pattern. Neuro‐ophthalmological examination revealed mild oculomotor dyspraxia characterized by impaired smooth pursuit and hypometric saccadic gaze movements, sometimes associated with compensatory movements of the head or blinking.

Neuropsychological assessment (Table 1) showed a profile of global intellectual functioning ¹⁰ and adaptive functioning ¹¹ within the normal range (only speed of execution was found to be weak) associated with difficulties in visual‐constructive and visual attentive tasks. ¹² , ¹³ , ¹⁴ Verbal and visual memory ¹⁵ assessment did not detect any impairment. As concerned academic skills, ¹⁶ , ¹⁷ a mild reading and writing disorder was found. Formal language skills ¹⁸ (lexical and syntactic comprehension/production) were in the normal range. A moderate deficit in speech ¹⁹ also appeared in rapid naming, reading tasks, or repeating sentences.

TABLE 1.

Neuropsychological profile

Neuropsychological assessment		Clinical range
Intelligence indexes
Verbal comprehension 10
Visual perceptual reasoning 10	115 a	Normal
Working memory 10	94 a	Normal
Processing speed 10	59 a	Deficit
General ability 10	115 a	normal
Academic skills
Reading speed 16	−1.39 b	Borderline
Reading accuracy 16	0.18 b	Normal
Writing accuracy 17	−1.45 b	Borderline
Language skills
Viking speech scale 19	Level II	Mild deficit
Lexical production 18	−1–0 b	Normal
Lexical comprehension 18	0–1 b	Normal
Syntactic production 18	−2 b	Deficit
Syntactic comprehension 18	−1–0 b	Normal
Memory skills
Verbal recall 15	9 c	Borderline
Delayed verbal record 15	50 c	Normal
Visual spatial record 15	16 c	Normal
Delayed visual spatial record 15	25 c	Normal
Executive functions
Selective visual attention 14	−1.57 b	Borderline
Sustained visual attention 14	−1.87 b	Borderline
Verbal working memory 24	−1.52 b	Borderline
Shifting 24	−1.13 b	Borderline
Visual spatial and visual motor skills
Visual integration skills 12	6 c	Borderline
Movement ABC2 13	0.1 c	Deficit
Adaptive functions
Vineland adaptive behavior scales 11
Communication	79 a	Borderline
Socialization	104 a	Normal
Daily living	98 a	Normal

^a Performance expressed in standard scores (mean, 100; SD, 15; normal range, 85 and higher; borderline range, 84–71; pathological range, 70 and lower).

^b Performance expressed in z scores (mean, 0; sd 1; normal range, −0.99 and higher; borderline range, −1.0–1.99; pathological range, −2 and lower).

^c Performance expressed in centiles (normal range, 16 and higher; borderline range, 5–15; pathological range, 5 and lower). II level at Viking speech scale: speech is imprecise, but usually understandable to unfamiliar listeners.

After obtaining informed consent, whole‐exome sequencing (WES) was performed on genomic DNA and relevant variants were validated by Sanger sequencing. WES analysis revealed a novel homozygous missense variant (c.248G>A, p. Arg83Gln) in the HPCA gene, classified as likely pathogenic based on current American College of Medical Genetics and Genomics guidelines. Both parents were heterozygous carriers of the variant. The variant has never been reported before and is not present in the gnomAD population database; it affects a highly conserved amino acid and is consistently predicted as damaging by several bioinformatic tools.

Therapeutic attempts with pimozide, levodopa, carbamazepine, corticosteroid, and trihexyphenidyl failed to reduce her movement disorder. Parents reported slight improvements (such as a better accuracy in precision tasks, eg, use of the knife) only with tetrabenazine 25 mg/day, which is still ongoing. After 2 years of follow up, the clinical course is stable.

Video segments were extracted from the regular neurological examination. Segments are organized in three sections (1, 2, and 3). We present videos of the child performing specific tasks during the neurological examination to illustrate the evolution of the movement disorder and to document the treatment's efficacy.

Discussion

Pathogenic variants of hippocalcin have been reported to date only in few patients with childhood‐onset generalized dystonia and adolescence‐onset segmental dystonia. ¹ , ² , ⁵ To the best of our knowledge, this is the first clinical report proving a choreiform phenotype in association to HPCA gene mutations.

Previously, “choreatic movements” have been described only in the proband's father of Siegert et al ⁵ when he was a child. The proband described here showed a hyperkinetic movement disorder with subtle onset in the first years of life, which progressively evolved into generalized writhing movements more prevalent in the orofacial and upper limb districts, and absent during sleep. However, this movement disorder had a low functional impact on daily life activities, and the patient only came to our attention at age of 6 years old. Additional neurological features were mild neurodevelopmental delay, moderately dysarthria, mild oculomotor dyspraxia, and some learning difficulties, with a minor impact on QoL and academic success.

From a movement disorder perspective, hyperkinetic movements in children are associated with dysfunction of the basal ganglia, cerebral cortex, cerebellum, and other motor pathways because of static or progressive injury. ²⁰ Such movements are commonly seen in the dyskinetic form of cerebral palsy, the main differential diagnosis to rule out, but they also are important features of congenital, acquired, and degenerative diseases ²⁰ (such as ataxia telangiectasia, Sydenham's chorea, neurotransmitter disorders, and Wilson's disease).

As previously reported, ²¹ some phenotype–genotype correlations emerged for HPCA, with truncating variants being associated to a more severe degree of cognitive dysfunction. ²¹ The present patient would confirm this observation, because the milder cognitive phenotype might correlate with the presence of a missense variant. Regarding the distribution of the movement disorder, an orofacial involvement seems to be a common feature in all forms of HPCA mutation. ²¹

Based on studies in knockout mice models, hippocalcin has been also implicated in hippocampus' synaptic plasticity where it is hypothesized to play a role in memory formation. ²² However, memory impairments were not reported by any of the individuals with identified HPCA mutation. ¹ , ²

Neuropsychological assessment in our patient showed mild learning difficulties and low performance in some neuropsychological tests involving visual‐constructive and visual attentive tasks, possibly influenced by the neuro‐ophthalmological impairment exhibited by our patient. Difficulties in encoding verbal and visual information were previously reported in two members of an index family by Charlesworth et al ¹ and in one member of Atasu et al. ² More studies are needed to explain if oculomotor dyspraxia is a mutation‐related sign or an incidental finding.

In conclusion, we expand the spectrum of movement disorders associated to HPCA dysfunction to include a spectrum of extrapyramidal movement disorders including chorea. These usually present generalized distribution, with a more marked upper limb and craniocervical involvement and with a relatively benign clinical course. From a neuropsychological point of view, a low performance in verbal fluency and visuospatial abilities seems to be a common feature of HPCA‐related conditions. Based on these considerations, this case adds another genetic cause to the syndrome of benign hereditary chorea (BHC) (OMIM 118700), which is defined as “onset of chorea in infancy or early youth, relatively poor clinical progression, and absence of other major neurological deficits, particularly prominent cognitive decline”. ²³ HPCA should not be included only in dystonia gene panels, but sequencing of the gene should be recommended in patients with early onset hyperkinetic movement disorders, especially when combined with cognitive or neuropsychological under functioning.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

S.B.: 1A, 1B, 1C, 2C, 3A, 3B

S.M.: 1A, 1C, 2A, 2B, 2C, 3B

P.I.: 2B, 2C, 3B

E.M.V.: 2B, 2C, 3B

E.F.: 1A, 2C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent was obtained by the child's parents. Informed consent was also obtained to publish identifying images in an online open‐access publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This work was supported by funds from the Italian Ministry of Health (Ricerca Corrente 2022 to IRCCS Fondazione Mondino). The authors declare that there are no conflicts of interest relevant to this work. Research was undertaken with the understanding and written consent of each participant and according to the journal principles.

Financial Disclosures for the Previous 12 Months: E.M.V. is the Associate Editor for Journal of Medical Genetics; Genetics Section Editor for Pediatric Research; Genetics Section Editor for The Cerebellum; and Genetics Section Editor for Neurological Sciences. E.M.V. is a member of the Editorial Board of Movement Disorders Clinical Practice and member of the Steering Committee of ASAP GP2 (Global Parkinson Genetic Program). E.M.V. receives research support from the Italian Ministry of Health, CARIPLO Foundation, Telethon Foundation Italy, Pierfranco and Luisa Mariani Foundation, and European Community (Eranet Neuron). E.F. is the President of SINPIA (Italian Society of Childhood and Adolescence Neuropsychiatry); Past President of the board of SENP (Société Européenne de Neurologie Pédiatrique). She is the Associate Editor of Minerva Pediatrics (formerly Minerva Medica) and the Scientific Director of International Aicardi‐Goutières Syndrome Association (IAGSA). E.F. receives research support from the National Institute of Health (NIH), Italian Ministry of Health, Cariplo Foundation, and Regione Lombardia. She is a consultant for GW Pharmaceuticals and Fidia Farmaceutici S.p.A.