VLDLR – Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium

Dysequilibrium syndrome is an autosomal recessive, non-progressive cerebellar ataxia with intellectual disability, truncal and peripheral ataxia, global developmental delay, and characteristic cerebellar hypoplasia on MRI ([PMID:19332571]). The causative gene, VLDLR, encodes the very low-density lipoprotein receptor, a key component of Reelin signaling guiding neuronal migration in cortex and cerebellum. Loss-of-function alleles in VLDLR have emerged as a pan-ethnic, clinically and molecularly well-defined cause of this dysequilibrium phenotype.

The first description identified six distinct VLDLR mutations in five unrelated families, including one nonsense and one missense allele, in individuals presenting with hypotonia, global developmental delay, and cerebellar hypoplasia ([PMID:19332571]). A consanguineous Turkish kindred was subsequently reported with a novel homozygous microdeletion in VLDLR segregating in two affected siblings with pachygyria and pontocerebellar atrophy ([PMID:20082205]).

In two unrelated Omani families, a homozygous missense founder variant, c.2117G>T (p.Cys706Phe), was identified on a shared haplotype in affected members with moderate intellectual disability, delayed ambulation, and truncal ataxia ([PMID:22973972]). An Italian patient homozygous for a novel p.Cys419Tyr substitution exhibited a very mild dysequilibrium phenotype, suggesting allelic heterogeneity influences severity ([PMID:27251579]).

Collectively, eleven probands across six unrelated families and multiple consanguineous pedigrees have confirmed biallelic VLDLR variants as the genetic basis of dysequilibrium syndrome. Segregation of homozygous or compound heterozygous mutations in affected siblings and families supports an autosomal recessive inheritance pattern.

Functional cellular assays of three missense mutations—p.Asp487Tyr, p.Asp521His, and p.Cys706Phe—demonstrate defective intracellular trafficking, ER retention, and failure to reach the plasma membrane for Reelin binding ([PMID:25173816]). Additional studies reveal prolonged ER retention, ubiquitination, and SEL1L-dependent proteasomal degradation of these VLDLR mutants, eliciting ER stress consistent with loss of receptor function ([PMID:29371607]).

Integration of genetic and experimental data yields a strong clinical validity for VLDLR in dysequilibrium syndrome. The concordance of AR segregation, diverse LoF alleles, and mechanistic cellular models underpins diagnostic testing and informs variant interpretation. Key take-home: Biallelic VLDLR mutations reliably cause autosomal recessive cerebellar hypoplasia with intellectual disability, guiding molecular diagnosis and genetic counseling.

References

• Journal of child neurology • 2009 • Mutations in VLDLR as a cause for autosomal recessive cerebellar ataxia with mental retardation (dysequilibrium syndrome). PMID:19332571
• Neurogenetics • 2010 • Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy. PMID:20082205
• BMC medical genetics • 2012 • A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion. PMID:22973972
• Neurogenetics • 2016 • Very mild features of dysequilibrium syndrome associated with a novel VLDLR missense mutation. PMID:27251579
• Biochimica et biophysica acta • 2014 • Impaired trafficking of the very low density lipoprotein receptor caused by missense mutations associated with dysequilibrium syndrome. PMID:25173816
• Scientific reports • 2018 • Degradation routes of trafficking-defective VLDLR mutants associated with Dysequilibrium syndrome. PMID:29371607

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