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Intracranial calcifications in children and adults: Molecular and phenotypic characterization from a tertiary referral centre

C. Panteghini, M. Carecchio, D. Tonduti, C. Barzaghi, L. Magistrelli, A. Decio, L. Chiapparini, A. Pichiecchio, S. Esposito, C. Pantaleoni, D. Riva, I. Moroni, S. Orcesi, N. Nardocci, B. Garavaglia, Cerebral Calcification Study Group (Milan, Italy)

Meeting: 2016 International Congress

Abstract Number: 603

Keywords:

Session Information

Date: Tuesday, June 21, 2016

Session Title: Genetics (PD and Non-PD)

Session Time: 12:30pm-2:00pm

Objective: To analyze a series of pediatric and adult patients with idiopathic intracranial calcification by a dedicated gene panel through targeted re-sequencing TruSeq Custom Amplicon.

Background: Several genetic diseases characterized by cerebral calcification are known, such as idiopathic basal ganglia calcification, Aicardi-Goutières syndrome, Cockayne syndrome, Krabbe disease. They are a group of disabling neurological disorders with variable age at onset and heterogeneous clinical presentations including movement disorders.

Methods: 86 patients (50 pediatric onset, 36 adult onset) with intracranial calcification on CT scan, presenting with or without movement disorders were referred to our Neurogenetics Unit and recruited. Secondary causes (congenital infections, calcium/phosphates metabolism alterations) were ruled out. DNA samples were tested by targeted re-sequencing TruSeq Custom Amplicon (MiSeq Illumina platform). We used customized gene panels including 54 genes associated with known genetic diseases with cerebral calcification.

Results: 17/86 (19.8%) patients tested positive for pathogenic mutations in one of the genes analyzed. None had a positive family history. 10 pediatric patients (20%) carried mutations in one of the following genes: ERCC6, RNASEH2B gene (3), RNASET2, CYP2U1, IFIH1, COL4A1, SLC20A2, XPR1. 7 adult patients (19.4%) carried mutations in SLC20A2 (4), PDGFRB, TREM2 and IFIH1. Movement disorders were present in three adults, ranging from akinetic-rigid parkinsonism to chorea and paroxysmal dystonia. Pediatric patients displayed complex and hetereogenous phenotypes often including psychomotor retardation and pyramidal and extrapyramidal signs. Two cases aged 15 and 9 carried mutations in genes previously associated with adult IBGC; conversely, one subject aged 65 carried a mutation in IFIH1, not previously associated with adult disease.

Table 1: Clinical and molecular characterization of mutated subjects.
PATIENT SEX AGE OF ONSET CURRENT AGE CLINICAL FEATURES MUTATED GENE DNA VARIANT PROTEIN VARIANT
BDM659 M 53 65 Focal unilateral chorea SLC20A2 c.338C>G p.Ser113*
DYT1760 F 81 83 Dementia SLC20A2 c.1765G>A p.Gly589Arg
DYT1791 F 59 62 Memory impairment SLC20A2 c.1463A>G p.His488Arg
BDM716 F 3 15 Akinetic-rigid parkinsonism + Down Syndrome SLC20A2 c.1301C>G p.Ser434Trp
DYT1882 F 65 70 Akinetic-rigid parkinsonism SLC20A2 c.290-8A>G /
DYT1655 M 11 33 Paroxysmal dyskinesia PDGFRB c.676C>T p.Arg226Cys
DYT1977 M asymptomatic 67 Asymptomatic; bilateral pallidal calcification IFIH1 c.1879G>T p.Glu627*
HA460 F 27 31 Dementia, spastic paraplegia, seizures TREM2 c.257A>T p.Asp86Val
15-725 M 8 9 Generalized choreo-dystonic syndrome with acute onset. XPR1 c.1963C>T p.Arg655Cys
44/12 F first months 6 AGS-phenotype IFIH1 c.229C>T p.Arg77Trp
70309-219 M 4 months 10 AGS-phenotype RNASEH2B c.529G>A in omo p.Ala177Thr
DYT1934 M 4 months 3 AGS-phenotype (mild) RNASEH2B c.529G>A in omo p.Ala177Thr
MT6762 M 9 months 14 AGS-phenotype with atypical MRI RNASEH2B c.529G>A in omo p.Ala177Thr
MT6767 M 1 months 4 AGS-phenotype RNASET2 c.145G>T + c.397_399delAAG p.Glu49* + p.Lys133del
10-617 F first months 12 Cockayne Syndrome Phenotype ERCC6 c.1071delA + c.2203C>T p.Asp358Thrfs*2 + p.Arg735*
213/14 F 14 months 34 Spastic paraparesis, action dystonia superior limbs CYP2U1 c.1288+1G>A + c.1543_1546delTTAC / + p.Pro516Argfs*8
DYT2005 M prenatal 15 Severe mental retardation, spastic tetraplegia, drug-resistent epilepsy, congenital cataract, poroencephaly COL4A1 c.3041G>A p. Gly1014Asp
Table 1: Clinical and molecular characterization of mutated subjects.“

Conclusions: in our series, a molecular diagnosis was achieved in only 19.8% of cases, suggesting that several genes are still to be individuated. Even with extensive basal ganglia involvement, movement disorders are not the only clinical feature in early-onset cases and adults can be asymptomatic. NGS is a powerful instrument to widen the clinical spectrum of genes associated with cerebral calcifications.

To cite this abstract in AMA style:

C. Panteghini, M. Carecchio, D. Tonduti, C. Barzaghi, L. Magistrelli, A. Decio, L. Chiapparini, A. Pichiecchio, S. Esposito, C. Pantaleoni, D. Riva, I. Moroni, S. Orcesi, N. Nardocci, B. Garavaglia, Cerebral Calcification Study Group. Intracranial calcifications in children and adults: Molecular and phenotypic characterization from a tertiary referral centre [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/intracranial-calcifications-in-children-and-adults-molecular-and-phenotypic-characterization-from-a-tertiary-referral-centre/. Accessed July 1, 2025.

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