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Mutations in VLDLR as a Cause for Autosomal Recessive Cerebellar Ataxia With Mental Retardation (Dysequilibrium Syndrome)

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada,

Carsten Bonnemann, MD

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia

Joachim Herz, MD

University of Texas Southwestern Medical Center, Dallas, Texas

Stephanie Neuert, MSc

Department of Medical Genetics, University of Calgary, Calgary, Canada

Chandree Beaulieu, BSc

Department of Medical Genetics, University of Calgary, Calgary, Canada

James N. Scott, MD

Department of Radiology, Foothills Hospital, Calgary, Canada

Anuradha Venkatasubramanian, MD

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia

Jillian S. Parboosingh, PhD

Department of Medical Genetics, University of Calgary, Calgary, Canada

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.

Key Words: VLDLR • cerebellar hypoplasia • dysequilibrium syndrome

This version was published on October 1, 2009

Journal of Child Neurology, Vol. 24, No. 10, 1310-1315 (2009)
DOI: 10.1177/0883073809332696


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