TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Dentate Gyrus Sharp Waves, a Local Field Potential Correlate of Learning in the Dentate Gyrus of Mice.

The hippocampus plays an essential role in learning. Each of the three major hippocampal subfields, dentate gyrus (DG), CA3, and CA1, has a unique function in memory formation and consolidation, and also exhibit distinct local field potential (LFP) signatures during memory consolidation processes in non-rapid eye movement (NREM) sleep. The classic LFP events of the CA1 region, sharp-wave ripples (SWRs), are induced by CA3 activity and considered to be an electrophysiological biomarker for episodic memory. In LFP recordings along the dorsal CA1-DG axis from sleeping male mice, we detected and classified two types of LFP events in the DG: high-amplitude dentate spikes (DSs), and a novel event type whose current source density (CSD) signature resembled that seen during CA1 SWR, but which, most often, occurred independently of them. Because we hypothesize that this event type is similarly induced by CA3 activity, we refer to it as dentate sharp wave (DSW). We show that both DSWs and DSs differentially modulate the electrophysiological properties of SWR and multiunit activity (MUA). Following two hippocampus-dependent memory tasks, DSW occurrence rates, ripple frequencies, and ripple and sharp wave (SW) amplitudes were increased in both, while SWR occurrence rates in dorsal CA1 increased only after the spatial task. Our results suggest that DSWs, like SWRs, are induced by CA3 activity and that DSWs complement SWRs as a hippocampal LFP biomarker of memory consolidation.SIGNIFICANCE STATEMENT Awake experience is consolidated into long-term memories during sleep. Memory consolidation crucially depends on sharp-wave ripples (SWRs), which are local field potential (LFP) patterns in hippocampal CA1 that increase after learning. The dentate gyrus (DG) plays a central role in the process of memory formation, prompting us to cluster sharp waves (SWs) in the DG [dentate SWs (DSWs)] during sleep. We show that both DSW coupling to CA1 SWRs, and their occurrence rates, robustly increase after learning trials. Our results suggest that the DG is directly affected by memory consolidation processes. DSWs may thus complement SWRs as a sensitive electrophysiological biomarker of memory consolidation in mice.

Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear.

Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression--and, thus, return of fear--is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy.

Bi-allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis-like disease.

Lysosomal storage diseases, including mucopolysaccharidoses, result from genetic defects that impair lysosomal catabolism. Here, we describe two patients from two independent families presenting with progressive psychomotor regression, delayed myelination, brain atrophy, neutropenia, skeletal abnormalities, and mucopolysaccharidosis-like dysmorphic features. Both patients were homozygous for the same intronic variant in VPS16, a gene encoding a subunit of the HOPS and CORVET complexes. The variant impaired normal mRNA splicing and led to an ~85% reduction in VPS16 protein levels in patient-derived fibroblasts. Levels of other HOPS/CORVET subunits, including VPS33A, were similarly reduced, but restored upon re-expression of VPS16. Patient-derived fibroblasts showed defects in the uptake and endosomal trafficking of transferrin as well as accumulation of autophagosomes and lysosomal compartments. Re-expression of VPS16 rescued the cellular phenotypes. Zebrafish with disrupted vps16 expression showed impaired development, reduced myelination, and a similar accumulation of lysosomes and autophagosomes in the brain, particularly in glia cells. This disorder resembles previously reported patients with mutations in VPS33A, thus expanding the family of mucopolysaccharidosis-like diseases that result from mutations in HOPS/CORVET subunits.