RELN and VLDLR mutations underlie two distinguishable clinico‐radiological phenotypes

Abstract

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

“…Individuals with RELN mutations often exhibit cortical abnormalities and neonatal seizures whereas persons with VLDLR mutations presented with non-progressive congenital cerebellar ataxia. 13 Here, we report three consanguineous families with an autosomal-recessive form of ID and global developmental delay associated with homozygous truncating mutations in TBC1D23. Interestingly, all subjects for whom brain MRI was performed have PCH in common.…”

Genetics and mechanisms leading to human cortical malformations

“…The rare mutations in RELN or its receptor VLDLR (Very Low Density Lipoprotein Receptor) lead to frontal predominant mild lissencephaly (diffuse pachygyria) with severe hippocampal and cerebellar hypoplasia [150,155]. In rare cases, patients with RELN or VLDLR mutations may show pontocerebellar hypoplasia (PCH), a neurodegenerative disorder with prenatal onset mainly affecting infratentorial structures, leading to combined pontocerebellar hypoplasia and atrophy at birth [156,157].…”

“…Patients with severe congenital microcephaly and PMG have for example, shown mutations in WDR62 (WD repeat-containing protein 62), NDE1, RTNN and RAB3GAP1/2 and RAB18 [240][241][242]. PMG with microcephaly or normal brain size, corpus callosum dysgenesis and cerebellar hypoplasia may also be related to tubulin and MT-motor gene mutations such as KIF1B binding protein, TUBA1A, TUBB, TUBB2B, TUBB3, and DYNC1H1 (see Tables 1 and 2) [156,199,237].…”

Ataxia in children: early recognition and clinical evaluation

“…These conditions encompasses a constellation of genetic conditions with involvement of several genes and distinctive clinic-radiological phenotypes [35]. …”