Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome

PurposeTo investigate walking ability in Japanese patients with Rett syndrome (RTT).MethodsWalking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database.ResultsUnivariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X.ConclusionsMeaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.     

Novel compound heterozygous ACO2 mutations in an infant with progressive encephalopathy: A newly identified neurometabolic syndrome

BackgroundThe ACO2 gene encodes mitochondrial aconitase, the enzyme involved in the second step of the tricarboxylic acid cycle, catalyzing the interconversion of citrate into isocitrate. To date, fewer than 20 families harboring ACO2 mutations have been identified since the first report of a neurodegenerative disorder such as infantile cerebellar retinal degeneration in 2012. Subsequently, various phenotypes, from isolated optic atrophy to spastic paraplegia, have been recognized. Here, we report a case of a newly identified neurometabolic syndrome resulting from novel ACO2 mutations, which expands the genetic spectrum and increases clinical awareness in real-world clinical practice.Case reportA 2-month-old boy presented with hypotonia, cyanosis, and abnormal eye movements. He had severe psychomotor retardation and intractable seizures manifesting with cyanotic episodes. Diffuse cerebral atrophy and bilateral optic atrophy were noted without cerebellar atrophy. With unremarkable results on comprehensive diagnostic work-up and targeted genetic tests, whole exome sequencing revealed novel compound heterozygous variants in ACO2 (p.Met393Ile and p.Cys448Ser), which were confirmed by Sanger sequencing. Although no definitive signs suggestive of metabolic disturbances or mitochondrial dysfunction have been noted in patients with ACO2 mutations to date, elevated plasma glutamate levels were noted in our case.ConclusionA high index of clinical suspicion and awareness of this disease may aid in the diagnosis of cases with unknown neurodegenerative diseases, facilitated by deep sequencing.     

D2 autoreceptor switches CB2 receptor effects on [3H]-dopamine release in the striatum

CB₂ receptors (CB₂R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB₂R, we performed experiments of [³H]-dopamine release in dorsal striatal slices. We found a paradoxical increase in K⁺-induced [³H]-dopamine release by CB₂R activation with GW 833972A and JWH 133 two selective agonist. To understand the mechanism involved, we tested for a role of the D₂ autoreceptor in this effect; because in pallidal structures, the inhibitory effect of CB₁ receptors (CB₁R) on GABA release is switched to a stimulatory effect by D₂ receptors (D₂R). We found that the blockade of D₂ autoreceptors with sulpiride prevented the stimulatory effect of CB₂R activation; in fact, under this condition, CB₂R decreased dopamine release, indicating the role of the D₂ autoreceptor in the paradoxical increase. We also found that the effect occurs in nigrostriatal terminals, since lesions with 6-OH dopamine in the middle forebrain bundle prevented CB₂R effects on release. In addition, D₂–CB₂R interaction promoted cAMP accumulation, and the increase in [³H]-dopamine release was prevented by PKA blockade. D₂–CB₂R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB₂R agonist induced contralateral turning in amphetamine-treated rats, which was prevented by sulpiride, indicating the role of the interaction in motor behavior. Thus, these data indicate that the D₂ autoreceptor switches, from inhibitory to stimulatory, the CB₂R effects on dopamine release, involving the cAMP → PKA pathway in nigrostriatal terminals.     

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [¹¹C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [¹¹C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [¹¹C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [¹¹C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [¹¹C]UCB-J in PET studies. In addition, observation of low binding for [¹¹C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [¹¹C]UCB-J PET data.