A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome

Abstract

250-mg challenge dose produced a 41% improvement in UPDRS-III with dyskinesia (Supporting Information Table S1). However, she developed FOG on gait initiation, straight walking, doorways, and turning. FOG was associated with rising up onto the toes during straight walking and onto the toe of the outer rotating foot when turning, raising the possibility of a dystonic phenomenon (Video 2). She was diagnosed with on-state FOG. L-dopa was changed to immediate release and fractionated, amantadine 200 mg daily added, and she commenced gait rehabilitation without improvement. Intermittent subcutaneous apomorphine injections were initiated; however, after 6 months' therapy, FOG severity was increased ( Fig. 1), leading to~20 falls a day. Based on previous observations, 4,5 she commenced a 16-hour LCIG infusion. During week 1 of LCIG titration, FOG persisted despite rates that improved parkinsonism while causing dyskinesia, reaffirming on-state FOG. We then performed a rapid infusion titration with hourly increments in the continuous rate of 0.1 to 0.2 mL over 5 hours, starting from 2.1 mL/h, and discovered a higher rate of 3.0 mL/h that led to near-complete resolution of FOG. At 6 months, FOG remained much improved with ≤1 fall per week; however, she still reported FOG when using LCIG extra doses. At 7 months, she converted to 24-hour LCIG with a nocturnal rate of 1.4 mL/h for treatment of nocturnal left foot dystonia. Nocturnal oral L-dopa was no longer required. She reduced her daytime rate from 3.0 to 2.9 mL/h. At 9 months (Video 3), FOG was further reduced, averaging 1 fall every 4 weeks. Pre-LCIG, she had used a wheelchair intermittently for 6 months. She now always walks without aids and no longer avoids escalators or misses lift doors. She experiences two to three occurrences of start hesitation daily and mild, nondisabling dyskinesia of the right leg. Extra doses for mild, nondisabling off periods sometimes trigger transient start hesitation. Hand function is excellent and she recently resumed playing piano.We explored LCIG as treatment for on-state FOG 3 because plasma L-dopa levels with an LCIG infusion are more predictable than oral L-dopa dosing. We surprisingly discovered an interaction between L-dopa infusion rates and FOG behavior that suggested the existence of another FOG subtype (Fig. 1). We suggest the term "triphasic-on" FOG, to denote its presence in both "on" and "supra-on" states, but also the presence of a narrow "on" therapeutic window in the transition between these two states where FOG improves. It is plausible that "triphasic-on" FOG may have been present, but obscured, in at least some of the patients reported on by Espay and colleagues 3 because of the use of a single supra-on challenge dose and the unpredictable plasma L-dopa levels following oral L-dopa. In conclusion, our case suggests that some PD patients with on-state FOG might be able to be treated successfully and implies the existence of additional FOG subtypes.

A homozygous founder variant in PDE2A causes paroxysmal dyskinesia with intellectual disability

“…Consistently, Doummar et al, 2020 3 reported paroxysmal dyskinesia in patient 3 starting at 7 years, occurring 30–50 times per day with each attack lasting between 2–5 min. Of the 12 patients with biallelic PDE2A variants, only four display permanent choreodystonia (2/6 in this study and 2/6 in the previous patients), 3,7,8 reflecting that this is an inconsistent outcome of the disease. In line with the published data, 3,7,8 ID has been witnessed in all patients.…”

“…Biallelic variants in PDE2A are known to cause IDDPADS, an ultra‐rare disease for which only six patients have been reported so far 3,7,8 . WES revealed a novel homozygous missense variant in PDE2A : p.(Phe505Ser) as a potential causative variant that segregated with the disease in three Pakistani families presenting paroxysmal dyskinesia, developmental delay, cognitive abnormalities, speech impairment and seizures with onset as early as 3 months in Family C to 7 years in Family A.…”

“…In the same year, Haider et al, reported two patients of Iraqi descent with homozygous splice site change presenting seizures in both patients. However, only one had ataxia and none had dyskinesia or chorea 8 …”

Phosphodiesterase 2A inhibition corrects the aberrant behavioral traits observed in genetic and environmental preclinical models of Autism Spectrum Disorder

“…The modulation of cAMP and cGMP has been also reported to be key in learning and memory. Indeed, mutations of PDE2A have been found associated with intellectual disability [ 22 , 51 , 52 ] and PDE2A seems to have a prominent role in memory disorders [ 53 – 55 ]. Several studies have shown that Fmr1 -KO mice display cognitive impairments [ 56 – 59 ].…”

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…PDE2A is a dual-specific PDE that breaks down both cAMP and cGMP and is activated by cGMP. A homozygous splicing mutation in PDE2A was found in two patients with atypical Rett syndrome (RTT), displaying neurodevelopmental delay [ 34 ], while a homozygous loss-of-function mutation in PDE2A was associated with early-onset hereditary chorea-predominant movement disorder and intellectual disability (ID) [ 35 ]. Patients with bipolar disorder showed reduced PDE2A mRNA levels in the hippocampus, caudal entorhinal cortex, and striatum, while patients with SCZ, bipolar disorder, and major depressive disorder (MDD) showed reduced PDE2A mRNA levels in the amygdala.…”