Specific Cognitive Changes due to Hippocalcin Alterations? A Novel Familial Homozygous Hippocalcin Variant Associated with Inherited Dystonia and Altered Cognition

Abstract

Background Recent research suggested an hippocalcin (HPCA)-related form of DYT2-like autosomal recessive dystonia. Two reports highlight a broad spectrum of the clinical phenotype. Here, we describe a novel HPCA gene variant in a pediatric patient and two affected relatives. Methods Whole exome sequencing was applied after a thorough clinical and neurological examination of the index patient and her family members. Results of neuropsychological testing were analyzed. Results Whole exome sequencing revealed a novel homozygous missense variant in the HPCA gene [c.182C>T p.(Ala61Val)] in our pediatric patient and the two affected family members. Clinically, the cases presented with dystonia, dysarthria, and jerky movements. We observed a particular cognitive profile with executive dysfunctions in our patient, which corresponds to the cognitive deficits that have been observed in the patients previously described. Conclusion We present a novel genetic variant of the HPCA gene associated with autosomal recessive dystonia in a child with childhood-onset dystonia supporting its clinical features. Furthermore, we propose specific HPCA-related cognitive changes in homozygous carriers, underlining the importance of undertaking a systematic assessment of cognition in HPCA-related dystonia.

Motor, epileptic, and developmental phenotypes in genetic disorders affecting G protein coupled receptors-cAMP signaling

“…Dystonia remains the core feature and is reported in seven out of nine described individuals, although other hyperkinetic MDs such as chorea and athetosis have been reported ( 53 ). Dystonia usually appears in childhood, mainly affecting the trunk, arms, and face.…”

“…Three de novo PDE10A mutations [c.898T>C (p.Phe300Leu), c.1000T>C (p.Phe334Leu), and c.1001T>G (p.F334C)] ( 9 , 51 – 53 ) have been associated with childhood-onset chorea (5 to 10 years of age) with normal cognitive development and no epilepsy.…”

“…This gene encodes for the neuron-specific calcium-binding protein HPCA. HPCA is widely expressed in the brain, particularly in the hippocampal pyramidal neurons and in medium spiny neurons of the striatum, where it is likely to modulate dopamine signaling, influencing the activity of potassium and calcium channels ( 2 , 53 ).…”

“…HPCA deficiency was initially associated to isolated dystonia ( 53 ), but subsequent reports expanded the clinical phenotype, describing patients presenting with variable combinations of seizures, developmental delay, intellectual disability, psychiatric symptoms, and dysphagia.…”

Childhood‐Onset Choreo‐Dystonia Due to a Recurrent Novel Homozygous Nonsense HPCA Variant: Case Series and Literature Review

“… 1 Thenceforth, despite large dystonia cohorts being screened, 2 , 3 only 10 cases from six pedigrees have been reported, with clinical features ranging from isolated dystonia to a syndrome featuring neurodevelopmental delay, generalized dystonia with bulbar involvement, and infantile seizures. 1 , 4 , 5 , 6 , 7 …”