Spinal muscular atrophy type 0 is the most severe phenotype of the disease, with patients presenting with contractures, weakness, and respiratory failure at birth, and is typically fatal within weeks. We describe the case of a patient with spinal muscular atrophy type 0 who was treated with both nusinersen and onasemnogene abeparvovec. She has made modest motor improvements since treatment initiation with a 30-point improvement in CHOP-INTEND score, and continues to make motor gains at age 13 months without regression of function, although she remains profoundly weak. Although she has had motor improvements, she has also had continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash. This case highlights the challenges in treating those with more severe disease phenotypes and raises questions of how some systemic complications may respond to current SMN replacement therapies.

BackgroundAge‐related changes in sleep may directly contribute to cognitive dysfunction and underlying pathological progression contributing to Alzheimer’s Disease or related dementias (AD/ADRDs). While acetylcholinesterase inhibitors (AChEIs) are FDA‐approved for the treatment of AD‐related cognitive impairments, these drugs also disrupt sleep. Positive allosteric modulators (PAMs) targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) have produced cognitive and arousal enhancing as well as sleep‐modifying effects in aged and/or AD rodents models. The present study provided the first comparison of baseline sleep measures in young and old monkeys, then examined the effects of novel M1 mAChR PAMs VU0486846 and VU0453595, compared with the AChEI, Donepezil on sleep in aged monkeys.MethodEight young adult (4 male/4 female, 6‐8 years old) and 10 aged cynomolgus macaques (6 males/4 females, 19‐25 years old) were implanted with subcranial electrodes and a wireless transmitter (L04, DSI) for undisturbed telemetric recording of electroencephalography (EEG) from their home cage. After baseline sleep assessments, aged monkeys were tested once weekly with donepezil (3.0‐10 mg/kg, PO), VU0486846 (3.0‐30 mg/kg, PO), or VU0453595 (1.0‐10 mg/kg, PO), administered 2 hours prior to lights out (0600:1800 light:dark schedule). EEG was recorded and sleep stages including total sleep time (TST), % TST in rapid eye movement sleep (REM), N1, N2, and N3 non‐REM sleep were determined and summed across the 12 hour dark period.ResultAged monkeys showed significantly less % TST in N3 and REM sleep and increased N1 sleep compared to young monkeys. Donepezil dose‐dependently reduced TST, increased % REM and trended toward a decrease in N2 and N3 stage sleep. In contrast, M1 PAMs, within dose ranges known to be physiologically active in monkeys, did not alter sleep parameters.ConclusionAged‐related and donepezil‐mediated sleep disruptions in aged monkeys are consistent with the clinical literature. Lack of effects by M1 mAChR PAMs in aged monkeys when dosed prior to lights out may suggest fewer disruptive effects compared to AChEIs or that there is insufficient cholinergic tone for an M1 PAM to alter sleep. Future studies will assess the arousal enhancing effects of M1 PAMs when dosed during waking periods in aged monkeys.Funding: AG054622, DA017763

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