Reply to Herz et al. and Humphrey et al.: Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion.

Reply to Herz et al. and Humphrey et al.: Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion Mutations in the very low-density lipoprotein receptor VLDLR are responsible for cerebellar hypoplasia with qua-drupedal gait (1). The most likely mechanism leading to this phenotype is that VLDLR deficiency in the brain at a key stage of development precludes the normal formation of neu-ral structures critical for gait. Quadrupedal gait is an integral part of VLDLR-associated cerebellar hypoplasia syndrome in these families (1, 2). It is not necessary to invoke an ''epiphe-nomenon'' or ''unfavorable environmental conditions'' to explain the phenotype (3), but rather simply considering clinical heterogeneity in the context of genomic understanding of complex traits is sufficient. Disequilibrium syndrome was first described by the Swedish neuropediatrician Bengt Hagberg and colleagues (4) as a form of cerebral palsy characterized by a variety of congenital abnormalities. Subsequently, Schurig et al. (5) described, in the North American Hutterite population, inherited cerebellar disorder with mental retardation, the genetic basis of which proved to be homozygous deletion of the VLDLR gene and the adjacent noncoding LOC401491 sequence (6). Based on the phenotypic similarities of the Swedish and Hutterite patients , the acronym DES-H [disequilibrium syndrome-Hutterites, Online Mendelian Inheritance in Man (OMIM) accession no. 224050] was adopted for this syndrome (6). Our results (1) and those of others (7) extend these findings to different VLDLR mutations leading to cerebellar hyp-oplasia and related disequilibrium features, including in some families bipedal gait (5, 6), in other families quadrupedal gait (1, 8), and in another family ''gait ataxia'' (7). Additional kin-dreds with disequilibrium syndrome and quadrupedal gait have been described in Brazil (9) and Iraq (10). It will be interesting to know whether mutations responsible for the phenotype in these families lie in the VLDLR gene or in one of the other loci linked to this genetically heterogeneous phenotype (1). The comments of Humphrey et al. (11) address three fundamental features of genomic analysis of human traits: allelic heterogeneity, genotype–phenotype correlations, and variable expression. Allelic heterogeneity—the expression of the same phenotype due to different mutations in a gene—is characteristic of virtually all human genetic disease. For example, homozygos-ity for any of Ͼ300 different mutations in the LDL receptor leads to hypercholesterolemia. It was to be expected, therefore , that in different families different mutations in VLDLR would lead to a phenotype comprising cerebellar hypoplasia with quadrupedal gait. It would not be …