Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Abstract

BackgroundWe present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses.MethodsWe collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification.ResultsWe collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two.ConclusionsGenetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review

“…At neuroimaging, three mild patients showed atypical brain CT scans with either no calcification in two cases (CT scan at 16 months, 7 months after onset in one patient; and at 15 months, 4 months after onset, and follow up at 4 years in the second), or diffuse microcalcifications in one. Additionally, the second patient with no calcifications [21] had deep and periventricular white matter changes at the first MRI that normalized at follow-up. Seven patients (P24-30) were compound heterozygous for the p.(Ala177Thr) mutation and the c.488C>T/p.…”

“…Variant c.1178A>T/p. (Asp393Val) was observed within exon 6 in only one patient (P43) and leads to the replacement of a negatively charged amino acid, the aspartic acid, with a valine (non-polar) at position 393 [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. Moreover, we identified in one patient (P44) the c.2471G>A/p.…”

“…All patients are descendants of parents and grandparents of Italian nationality and Italian patients with even one foreign parent were excluded. The patients were diagnosed in different centers, according to clinical suggestion guided by defined criteria [7,20,21]. Clinical data were obtained from medical records and through direct clinical contact while genetic data were acquired retrospectively except for 12 new diagnoses (Table 1).…”

“…The expression analysis of six interferon-stimulated genes was performed using the TaqMan Universal PCR Master Mix (Applied Biosystems, Paisley, UK), and cDNA derived from 40 ng total RNA. The relative abundance of target transcripts was measured using TaqMan probes for IFI27 (Hs01086370_m1), IFI44L (Hs00199115_m1), IFIT1 (Hs00356631_g1), ISG15 (Hs00192713_m1), RSAD2 (Hs01057264_m1), and SIGLEC1 (Hs00988063_m1), and normalized to the expression level of HPRT1 (Hs03929096_g1) and 18S (Hs999999001_s1) as described by Rice and collaborators [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. To perform this assay, the LightCycler 480 (Roche) was used.…”

Neuroimaging of Basal Ganglia in Neurometabolic Diseases in Children

“…However, it is the method of choice for calcium detection and the assessment of basal ganglia calcifications (BGC), which is the most common site of calcifications in the central nervous system. However, they can occur also in the gray and white matter junction, cerebellar parenchyma, the thalamus and dentate nucleus [ 55 , 56 ]. In general population, the prevalence of BGC is not well established and is estimated at 2–12.5% [ 55 , 56 ].…”