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Proc Natl Acad Sci U S A. Jun 10, 2008; 105(23): E32–E33.
PMCID: PMC2656353

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 quadrupedal 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 neural 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 “epiphenomenon” 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 hypoplasia 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 kindreds 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, homozygosity for any of >300 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 expected that quadrupedalism would be present only in the presence of one “specific mutation.”

The converse observation, of a correlation between genotype and phenotype, is also characteristic of inherited human disease. Different mutations in the same gene frequently lead to different clinical phenotypes. Contrary to the statement of Humphrey et al. (11), the Hutterite families in North America and families A and D in Turkey do not carry “the same homozygous mutation.” The Hutterite mutation is a complete genomic deletion of VLDLR; the mutations in Turkish families A and D are, respectively, a nonsense mutation and a single-base-pair deletion leading to a frame shift in VLDLR. It is not surprising, therefore, that features of the cerebellar hypoplasia syndrome, including presence or absence of quadrupedal walking, differ among families with different mutations in the gene.

Third, variable expression of a phenotype is frequently observed even among persons with the same mutation in a critical gene. Variable expression may be due to differences in genetic background of the individual, to differences in environmental exposures, or to chance. Among affected individuals in families A and D, none displays exclusively bipedal locomotion; two affected individuals can walk bipedally for short distances but prefer quadrupedal locomotion (1, 8).

Finally, the use of a walking frame to assist bipedalism in affected individuals (12) does not demonstrate that the cause of quadrupedalism was “local cultural environment.” Wearing eyeglasses assists persons with myopia. Should we then conclude that near-sightedness is caused by “local cultural environment”?

Some descriptions by the press of Turkish families with cerebellar hypoplasia and quadrupedal gait have portrayed the affected individuals as doomed to quadrupedal gait by the religious beliefs of their parents (13). We hope that future descriptions of these families will conform to standards reflected in recent genomic analyses of their disorder.

Footnotes

The authors declare no conflict of interest.

References

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13. Ahuja A. We're all made with quadrupedal walking ability. Times Online. 2007 Available at http://women.timesonline.co.uk/tol/life_and_style/women/the_way_we_live/article2671044.ece.

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