Females with JNCL experienced a later onset but more rapidly progressive disease course than did males. On average, females experienced JNCL symptom onset one year later and death one year earlier. Females also experienced earlier loss of independence in ability to perform ADLs and a tendency to earlier loss of independent gait and intelligible speech. The ability to perform ADLs is influenced by multiple domains affected in JNCL children, including cognition, physical ability, and vision. Thus, independence in ADLs is a good general indicator of overall disease severity. In addition, parents reported a poorer physical QoL in female children. Other QoL domains were not different between males and females, suggesting that physical factors contribute more greatly to loss of independence than do cognitive or behavioral factors. However, our results show that sex differences are not limited to physical impairment but include age at onset of vision loss and behavioral symptoms.
A biological basis for the more severe disease course in females is not obvious. JNCL is an autosomal recessive disease that affects males and females at a similar rate. In adult-onset neurodegenerative disease, female sex is often associated with a milder course. In tests of fine motor control and speech articulation in subjects with Parkinson’s disease (PD), women outperform men (Gillies and McArthur 2010
). The protective effect of female sex may be due to hormonal factors. Indeed, decreasing levels of endogenous estradiol in women is associated with symptom worsening in PD (Gillies and McArthur 2010
). Estrogen may also have a protective role in neurodegenerative diseases (Brann et al 2007
; McEwen and Alves 1999
). Despite this proposed protective benefit of estrogen, JNCL females demonstrated earlier loss of independent function during post-pubertal years, when estrogen levels should be elevated. It is possible that, rather than being neuroprotective, estrogen plays a role in the more rapid course in JNCL females. Additionally, the second X-chromosome in females may contribute to sex differences in JNCL. For example, due to imprinting, females may have deleterious effects from a paternally inherited X-chromosome gene. Alternatively, there may be some protective gene on the Y-chromosome.
One explanation for the sex-based differences in JNCL may relate to the proposed autoimmune component to its pathogenesis. Multiple autoantibodies have been detected in the CNS of both animal models and human JNCL (Chattopadhyay et al 2002
; Lim et al 2006
). Suppressing the immune system reduces these autoantibodies and slows disease progression in animal models (Seehafer et al 2011
). Females have a higher incidence of autoimmune diseases in general, but sex-based differences in the clinical phenotypes of these diseases vary (McCombe et al 2009
). Differences in incidence and clinical course may be partially attributed to the sexual dimorphism observed in the human immune system. Females have a more robust antibody response to vaccines regardless of menstrual status, and estrogen itself has been shown to increase antibody production. Diseases with a predominant autoantibody immune process, such as Systemic Lupus Erythematosus (SLE), are more likely to worsen with higher estrogen levels (Grimaldi 2006
). Therefore, while estrogen may be neuroprotective, it may also increase autoantibody production in JNCL and thus accelerate disease progression.
Another potential contributor to earlier age at loss of independent function may be a lower baseline muscle mass in females. In the general population, males have a higher percentage of lean body mass even before the onset of puberty (Rowland 2005
). It is possible that, because males start with greater muscle mass, the degenerative effects on physical function are seen later in JNCL boys. However, it is not clear if loss of functional independence is related to muscle mass or to other aspects of motor control including cognitive planning. Thus, while muscle mass may contribute to preserved physical function in males, it is unlikely to account entirely for these differences.
The discrepancy in independent function may also be due to social constructs of gender expectations. Parents demonstrate a gender bias in physical expectations for children starting at a young age. Although infants do not have sex-based differences in motor development, mothers of female infants have lower expectations for their children’s ability to perform motor tasks (Mondschein et al 2000
). After infancy, parents allow boys more independence with less supervision during risky behaviors. In physical tasks that both girls and boys are able to complete, parents are still more likely to assist their daughters while encouraging independence from their sons (Morrongiello and Dawber 1999
). Translating these results to JNCL, it is possible that parents of daughters set lower expectations for physical ability. They may be more likely to assist with ambulation and ADLs and less likely to encourage independent function. It is also possible that gender bias contributes to the reported later age at onset of vision loss in females. Thus, the observed differences in function and age at onset may result in part from differences in parental expectations and behavior.
There are several potential limitations to our study. We relied on parent recall of symptom onset, which created a potential recall bias. There is some variability from year to year in reported age at onset, which could also reflect differences in the way that questions were asked. In an effort to minimize these limitations, we only analyzed the data obtained at the most recent assessment. Another limitation is that the age at death analysis included subjects who did not have genetic confirmation data available. Thus, it is possible that some subjects did not have mutations in CLN3. We attempted to eliminate incorrectly diagnosed subjects by excluding those with an age at death uncharacteristically late for classic JNCL disease (greater than 30 years of age). This age criterion was based on our extensive clinical experience with JNCL disease. However, if all subjects were included, regardless of age at death, comparable results were obtained.
Despite these potential limitations, the data indicating later age at onset and more rapid progression in females are compelling. Furthermore, we have no reason to think that the study design introduced a systematic bias for sex-based differences. It is possible that a combination of several factors, including autoimmunity, muscle mass differences, parental expectations, or others result in a more rapid disease progression in females. The biological mechanism underlying neurodegeneration in JNCL remains unknown. It is possible that identification of the primary mechanism will provide an explanation for some of these differences. Additional work on specific sex-based differences in JNCL may provide a better understanding of the molecular underpinnings of the disease process and point the way to future therapeutics.