Anesthesia outcomes in lysosomal disorders: CLN3 and GM1 gangliosidosis.

Natural history studies of pediatric rare neurometabolic diseases are important to understand disease pathophysiology and to inform clinical trial outcome measures. Some data collections require sedation given participants' age and neurocognitive impairment. To evaluate the safety of sedation for research procedures, we reviewed medical records between April 2017 and October 2019 from a natural history study for CLN3 (NCT03307304) and one for GM1 gangliosidosis (NCT00029965). Twenty-two CLN3 individuals underwent 28 anesthetic events (age median 11.0, IQR 8.4-15.3 years). Fifteen GM1 individuals had 19 anesthetic events (9.8, 7.1-14.7). All participants had the American Society of Anesthesiology classification of II (8/47) or III (39/47). Mean sedation durations were 186 (SD = 54; CLN3) and 291 (SD = 33; GM1) min. Individuals with GM1 (6/19, 31%) were more frequently prospectively intubated for sedation (CLN3 3/28, 11%). Minor adverse events associated with sedation occurred in 8/28 (28%, CLN3) and 6/19 (32%, GM1) individuals, frequencies within previously reported ranges. No major adverse clinical outcomes occurred in 47 anesthetic events in pediatric participants with either CLN3 or GM1 gangliosidosis undergoing research procedures. Sedation of pediatric individuals with rare neurometabolic diseases for research procedures is safe and allows for the collection of data integral to furthering their understanding and treatment.

Characterizing upper limb function in the context of activities of daily living in CLN3 disease.

In CLN3 disease, impairments in motor function are frequently reported to have later onset compared to visual and cognitive decline, but upper limb motor function has yet to be explored in this population. In a cohort of 22 individuals with CLN3, we used a novel application of multiple measures to (1) characterize motor function, particularly of the upper limbs, in activities of daily living (ADLs), and (2) explore associations between motor function and age as well as visual ability, disease severity, and cognitive function, as evaluated by the Unified Batten Disease Rating Scale (UBDRS), a validated CLN3 disease measure. ADLs that required coordination, speed, and fine motor control were particularly challenging for children with CLN3 based on item-level performance across direct assessments (Jebsen-Taylor Hand Function Test [JTHFT] and MyoSet Tools) and caregiver reports (Pediatric Evaluation of Disability Inventory-Computer Adaptive Testing [PEDI-CAT] and Patient-Reported Outcomes Measurement Information System [PROMIS] Pediatric Upper Extremity). Poorer visual ability, disease severity, and cognitive function were associated with worse performance on these measures, whereas age had limited impact. These findings support the need for children with CLN3 to receive skilled clinical evaluation and treatment tailored to their individual needs, particularly in the context of ADLs, as their symptom profile progresses.

Evaluation of age of death in Niemann-Pick disease, type C: Utility of disease support group websites to understand natural history.

Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disease affecting the visceral organs and the central nervous system. The age of initial presentation varies from fetal to adult onset, although childhood onset is most common. The life expectancy for the full spectrum of NPC patients is not well defined, and it is unknown if current supportive care impacts the natural history. In order to assess age of death for a large cohort of NPC patients, we "crowd-sourced" age and year of death from information posted on disease support group website memorial walls. We analyzed data from 338 individuals who died between 1968 and 2018. In addition to age of death, gender can be inferred from given names and photographs. The median age of death was 13 years with a range from 0.1-69 years. Although sex significantly affects survival of NPC1 mutant mice, we did not observe a gender dependent survival difference in NPC patients. Median age of survival across time increased between the earliest patients and the most recently deceased patient; however, we found no significant change in survival over the last 20 years. These data suggest that supportive medical care has not impacted survival in the recent past and provides support for the use of historic controls in evaluating therapeutic interventions.