VLDLR-associated Pontocerebellar Hypoplasia with Nonprogressive Congenital Ataxia and a Diagnostic Neuroimaging Pattern

Mutations of the very low density lipoprotein receptor (VLDLR) cause severe cerebellar hypoplasia, pontine hypoplasia, and pachygyria (OMIM #224050).[1] Clinically, it leads to nonprogressive congenital ataxia, cognitive impairment, and markedly delayed or absent ambulation. Additional features include pes planus, hyperreflexia, seizures, and short stature.[2] [3] This disorder is inherited in an autosomal recessive fashion.

A 2-year-old boy, second child of consanguineous Iraqi parents, was presented with truncal ataxia and hypotonia; he was unable to stand unaided. He had cognitive and speech delay (spoke only single words) and congenital esotropia ([Video 1]). Formal developmental testing was not performed; the estimated developmental age was less than 18 months. Overall he made developmental progress. Cranial magnetic resonance imaging (MRI; [Fig. 1A–D]) showed pontine hypoplasia, severe cerebellar hypoplasia, lack of vermis foliation, and frontotemporal pachygyria, a constellation unique to VLDLR-associated disorder. Multigene panel analysis confirmed a homozygous c1553T > C variant of VLDLR. This specific variant is not described in literature before. Nevertheless, in view of the overall context a pathogenic effect is most likely.

Video 1

3 years old patient crawling, getting up to stand by holding on examination table and grabbing a doll. Movement pattern shows truncal ataxia and global hypotonia. Patient has a congenital esotropia.

Fig. 1 (A) Sagittal T1 magnetic resonance image (MRI) of the patient at the age of 2 years 7 months revealing reduced pontine dimension (prominence and cranio-caudal length) and marked hypoplasia of the vermis without foliation. (B) Sagittal T1 MRI of a 3-year-old neurologically normal child for comparison: normal proportion of pontine prominence and normal size of vermis with foliation is evident. (C) Coronal T2 MRI showing marked hypoplasia of cerebellar vermis and hemispheres. (D) Axial T2 MRI demonstrating lack of gyration of both temporal lobes.

This observation underlines the importance of clinical examination, MRI pattern recognition, and targeted genetic analysis to confirm a rare form of congenital ataxia.

• References

• 1 Boycott KM, Flavelle S, Bureau A. , et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet 2005; 77 (03) 477-483
• 2 Sonmez FM, Gleeson JG, Celep F, Kul S. The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients. J Child Neurol 2013; 28 (03) 379-383
• 3 Micalizzi A, Moroni I, Ginevrino M. , et al. Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation. Neurogenetics 2016; 17 (03) 191-195