Females experience a more severe disease course in Batten disease

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.

Figure 1. Disease onset was one year later in girls

Mean age at onset was 6.2 +/− 1.4 years in females (N=30) and 5.2 +/− 1.0 years in males (N=30), t(60)=3.08 (p=0.003). □ = mean. Box=mean +/− SD. Whiskers= mean +/− 1.96*SD.

Figure 2. Females had a later age at onset of vision loss and behavior problems

Histogram of the distribution of age at onset in females (A) and males (B) for vision loss, cognitive decline, seizures, behavior problems, and motor impairment.

Figure 2. Females had a later age at onset of vision loss and behavior problems

Histogram of the distribution of age at onset in females (A) and males (B) for vision loss, cognitive decline, seizures, behavior problems, and motor impairment.

Figure 3. At all ages, females had a lower average Functional Capability score

Median UBDRS Functional Capability scores were determined from subjects’ most recent assessments (Female N=37, Male N=40). Lower scores reflect lower capability. Females ( ) had overall lower scores than did males ( ) but there was no difference in rate of decline. Female linear fit: y = −1.2x + 31. Male linear fit: y=−1.2 +32.

Figure 4. Females lost independent ADLs earlier in the disease course

Kaplan-Meier survival curve of female (solid line) and male (dotted line) loss of independent ADLs, p=0.005. Females = --------- Males = ‑ ‑ ‑ ‑

Figure 5. Females had significantly lower physical QoL

Mean physical QoL was 28.09 +/− 28.46 in females (N=22) and 49.37 +/− 31.25 in males (N=27), t(47)= −2.47 (p=0.02). □ = mean. Box=mean +/− SD. Whiskers= mean +/− 1.96*SD.

Figure 6. Females had an earlier age at death

Mean age at death was 20.95 +/− 4.46 years in females (N=128) and 22.21 +/− 4.20 years in males (N=98), t(224) = −2.17 (p-0.03). □ = mean. Box=mean +/− SD. Whiskers= mean +/− 1.96*SD.