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Case Reports
. 2009 Oct;24(10):1310-5.
doi: 10.1177/0883073809332696. Epub 2009 Mar 30.

Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome)

Kym M Boycott  1 , Carsten Bonnemann, Joachim Herz, Stephanie Neuert, Chandree Beaulieu, James N Scott, Anuradha Venkatasubramanian, Jillian S Parboosingh
Affiliations
Case Reports

Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome)

Kym M Boycott et al. J Child Neurol. 2009 Oct.

Abstract

Dysequilibrium syndrome is a genetically heterogeneous condition that combines autosomal recessive, nonprogressive cerebellar ataxia with mental retardation. Here, we report the first patient heterozygous for 2 novel mutations in VLDLR. An 18-month-old girl presented with significant hypotonia, global developmental delay, and truncal and peripheral ataxia. Magnetic resonance imaging of the brain demonstrated hypoplasia of the inferior cerebellar vermis and hemispheres, small pons, and a simplified cortical sulcation pattern. Sequence analysis of the VLDLR gene identified a nonsense and missense mutation. Six mutations in VLDLR have now been identified in 5 families with a phenotype characterized by moderate-to-profound mental retardation, delayed ambulation, truncal and peripheral ataxia, and occasional seizures. Neuroanatomically, the loss-of-function effect of the different mutations is indistinguishable. VLDLR-associated cerebellar hypoplasia is emerging as a panethnic, clinically, and molecularly well-defined genetic syndrome.

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Figures

Figure 1
Figure 1
MRI of the brain demonstrating typical neuroimaging findings of VLDLR-associated cerebellar hypoplasia in this patient. (A) Sagittal T1W and (B) Coronal T2W images demonstrating hypoplasia of the inferior vermis and cerebellar hemispheres (A and B) and a small pons (A). (C) Axial T1W image demonstrating mild simplification of the sulcation pattern, a slightly thickened cerebral cortex and lack of clear anteroposterior gradient. (D) Coronal T1W demonstrating horizontal hippocampi with no evidence of malrotation.
Figure 2
Figure 2
Identification and characterization of the mutations causing VLDLR-associated cerebellar hypoplasia in this patient. (A) Comparison of the normal and mutant sequences obtained for the patient and a control. The patient is a compound heterozygote for the p.D521H and p.Y571LfsX7 mutations. (B) Sequence alignment of homologous YWTD domains in members of the low density lipoprotein receptor (LDLR) family. The highlighted (red) aspartic acid, p.D521, in the VLDLR protein, mutated in this patient, is invariant amongst family members. Abbreviations: APOER2, apolipoprotein E receptor 2; LDLR, low density lipoprotein receptor; LRP, low density lipoprotein related protein. (C) Localization of mutations known to cause VLDLR-associated cerebellar hypoplasia relative to exon position and functional domains. Mutations leading to a premature stop codon are in black; the missense mutation is in blue. The VLDLR deletion present in the Hutterite patients in not shown. Abbreviations: EGFR, epidermal growth factor repeat motif; OLSD, O-linked sugar domain; TM, transmembrane domain; CD, cytoplasmic domain.
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