Objective: To investigate neuropsychological and behavioural profile of PFBC patients.

Background: PFBC is a rare genetic neurodegenerative disorder characterized by abnormal calcium phosphate deposition basal ganglia, cerebellar dentate nuclei and subcortical white matter. To date, six causative genes have been identified (SCL20A2, XPR1, PDGFRB, PDGFB, MYORG, JAM2) [1,2,3]. Clinical manifestations are heterogeneous and no studies addressing the complexity of patients’ cognitive manifestations are available.

Method: Twenty PFBC patients were recruited at the Movement Disorders Unit of Padua University. A customized gene panel including all PFBC-related genes was used to analyze patients’ DNA. All patients underwent motor, behavioural, and complete neuropsychological evaluation allowing second level cognitive diagnosis [4]. Based on cognitive profile patients were categorized as follows: normal cognition (NC) (40%), mild cognitive impairment (MCI) (45%) and dementia (15%). Demented patients were excluded from further analyses.

Results: As a clinical variable, only severity of motor impairment distinguished between NC and MCI (UPDRS III, p<0.05). Clinically relevant cognitive differences (p<0.05) were found in visuo-spatial functions (VOSP, Benton), attention and set shifting (SDMT, TMTB-A, Alternate fluency), executive functions (Stroop time), verbal learning (WPAT).
Considering test’s failure percentages (below -1.5 SD), MCI showed significant worsening in processing speed (SDMT) and in verbal learning (WPAT) (p<0.05). Genetically, 4 patients carried MYORG mutations (20%), 2 SCL20A2 (10%), 1 PDGFRB (5%). MYORG gene mutations were associated with the highest rate of failures in neuropsychological multidomain tests (71%).

Conclusion: Global scales (MMSE, MoCA) showed no sensitivity to detect early cognitive alterations. Presence of MCI was characterized by visuo-spatial, executive/attentional and learning dysfunctions similarly to other basal ganglia pathologies [5]. Considering behavioral and neuropsychiatric traits, no difference was found. MYORG involvement in cognitive impairment is in line with previous findings [1]. Future studies in larger cohorts should aim at better defining cognitive pattern of alterations in PFBC.

References: 1. Grangeon, L., Wallon, D., Charbonnier, C., Quenez, O., Richard, A.-C., Rousseau, S., … Nicolas, G. (2019). Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype. Brain, 142(6), 1573–1586. 2. Nicolas, G., Pottier, C., Charbonnier, C., Guyant-Maréchal, L., Le Ber, I., Pariente, J., … & Martinaud, O. (2013). Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain, 136(11), 3395-3407. 3. Schottlaender, L. V., Abeti, R., Jaunmuktane, Z., Macmillan, C., Chelban, V., O’Callaghan, B., … & Houlden, H. (2020). Bi-allelic JAM2 variants lead to early-onset recessive primary familial brain calcification. The American Journal of Human Genetics, 106(3), 412-421. 4. Litvan, I. Goldman, J., G., Troster, A., I., Schmand, B., A., Weintraub, D., Peterson, R., C., et al. (2012). Diagnostic criteria to Mild Cognitive Impairment in Parkinson’s disease: Movement Disorder Society Task Force guidelines. Movement Disorders, 27(3), 349- 356. 5. Biundo R, Weis L, Pilleri M, Facchini S, Formento-Dojot P, Vallelunga A, Antonini A Diagnostic and screening power of neuropsychological testing in detecting mild cognitive impairment in Parkinson’s disease. J Neural Transm (Vienna). 2013 Apr;120(4):627-33

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cognitive-profiling-in-a-cohort-of-primary-familial-brain-calcification-pfbc-patients/