Penetrance of PD in Glucocerebrosidase Gene Mutation Carriers

In their study, Anheim et al.¹ attempt to estimate the penetrance of Parkinson disease (PD) among GBA mutation carriers by studying familial PD. They determined that the PD penetrance in GBA carriers was approximately 30% at age 80 under a dominant model, and concluded that families could be counseled that GBA can be considered a dominant causal gene with reduced penetrance. We are troubled by this conclusion.

While GBA is an important risk factor for parkinsonism,² the majority of patients with Gaucher disease and GBA mutation carriers never develop PD.³ Data from a large Gaucher Registry demonstrated that among patients homozygous for GBA mutations, the probability of developing PD before age 70 was 5%–7%, and 9%–12% before age 80.⁴ In the study by Anheim et al., ascertainment bias could be inflating the penetrance assessment. But our concern actually runs deeper, and relates to attaching labels to modes of inheritance in such instances.

It is becoming increasingly clear that the boundaries between what were once considered “simple” Mendelian disorders and complex disorders are often quite blurred. In a 2000 editorial, Drs. Dipple and McCabe⁵ stated: “There is no obvious clear distinction between simple Mendelian and complex traits: genetic diseases represent a continuum with diminishing influence from a single primary gene influenced by modifier genes, to increasingly shared influence by multiple genes.” Thus, categorizing GBA-associated parkinsonism as a Mendelian trait may be unnecessary and confusing.

We fear that a health care provider might communicate a dominant mode of inheritance without fully understanding the complexity of the situation. This may prompt unnecessary anxiety in a patient population already at risk for a recessive disorder.

• Copyright © 2012 by AAN Enterprises, Inc.