Chromatic Pupillometry in Isolated Rapid Eye Movement Sleep Behavior Disorder

Background: Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. Objectives: To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. Methods: iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. Results: We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. Conclusion: The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Retinal vascular impairment in Wolfram syndrome: an optical coherence tomography angiography study

To evaluate differences in macular and optic disc circulation in patients affected by Wolfram Syndrome (WS) employing optical coherence tomography-angiography (OCTA) imaging. In this retrospective study, 18 eyes from 10 WS patients, 16 eyes of 8 patients affected by type I diabetes and 17 eyes from 17 healthy controls were enrolled. All patients were imaged through OCT and OCTA and vascular parameters, as perfusion density (PD) and vessel length density (VLD) were measured. OCTA showed reduced PD in WS patients at the macular superficial capillary plexus (SCP, 27.8 ± 5.3%), deep vascular complex (DVC, 33.2 ± 1.9%) and optic nerve head (ONH, 21.2 ± 9.1%) compared to both diabetic patients (SCP 33.9 ± 1.9%, P < 0.0001; DVC 33.2 ± 0.7%, P = 1.0; ONH 33.9 ± 1.3, P < 0.0001) and healthy controls (SCP 31.6 ± 2.5, P = 0.002; DVC 34.0 ± 0.7%, P = 0.089; ONH 34.6 ± 0.8%, P < 0.0001). Similarly, VLD was lower in WS patients at the SCP (10.9 ± 2.7%) and ONH levels (7.5 ± 4.1%) compared to diabetic patients (SCP 13.8 ± 1.2%, P = 0.001; DVC 13.8 ± 0.2%, P < 0.0001; ONH 13.0 ± 0.7%, P = < 0.0001), but higher in DVC (15.7 ± 1.2%, P < 0.0001). Furthermore, VLD was lower in WS patients in all the vascular parameters compared to controls (SCP 13.8 ± 1.5%, P < 0.0001; DVC 17.3 ± 0.6%, P < 0.0001; ONH 15.7 ± 0.5%, P < 0.0001). A significant microvasculature impairment in the macular SCP and ONH microvasculature was demonstrated in eyes affected by WS. Microvascular impairment may be considered a fundamental component of the neurodegenerative changes in WS

Capturing the Pattern of Transition From Carrier to Affected in Leber Hereditary Optic Neuropathy

center dot PURPOSE: To capture the key features patterning the transition from unaffected mutation carriers to clinically affected Leber hereditary optic neuropathy (LHON), as investigated by optical coherence tomography. center dot DESIGN: Observational case series. center dot METHODS: Four unaffected eyes of 4 patients with LHON with the first eye affected were followed across conversion to affected, from 60 days before to 170 days after conversion. The primary outcome measures were multiple timepoints measurements of peripapillary retinal nerve fiber layer (RNFL) thickness for temporal emiside of the optic nerve (6 sectors from 6-11, clockwise for the right eye and counterclockwise for the left eye) in all patients and nasal emi-macular RNFL and ganglion cell layer (GCL) thickness in 2 patients. center dot RESULTS: While the presymptomatic stage was characterized by a dynamic thickening of sector 8, the beginning of the conversion coincided with an increase in the thickness of the sectors bordering the papillo-acular bundle (6 and 7 for the inferior sectors, 10 and 11 for the superior sectors) synchronous with the thinning of sectors 8 and then 9. Conversely, the GCL did not undergo significant changes until the onset of visual loss when a significant reduction of thickness became evident. center dot CONCLUSION: In this study we demonstrated that the thinning of sector 8 can be considered the structural hallmark of the conversion from the presymptomatic to the affected state in LHON. It is preceded by its own progressive thickening extending from th

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts. Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively. Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes

Electrognathography: diagnostic adjunct in the treatment of closed-lock joint [Elettrognatografia: ausilio diagnostico nel trattamento del closed-lock.]

[No abstract available

An Alternating Minimization Method for Sparse Channel Estimation

ISBN 978-3-642-15994-7, SoftcoverInternational audienceThe problem of estimating a sparse channel, i.e. a channel with a few non-zero taps, appears in many fields of communication including acoustic underwater or wireless transmissions. In this paper, we have developed an algorithm based on Iterative Alternating Minimization technique which iteratively detects the location and the value of the channel taps. In fact, at each iteration we use an approximate Maximum A posteriori Probability (MAP) scheme for detection of the taps, while a least square method is used for estimating the values of the taps at each iteration. For approximate MAP detection, we have proposed three different methods leading to three variants for our algorithm. Finally, we experimentally compared the new algorithms to the Cramer-Rao lower bound of the estimation based on knowing the locations of the taps. We experimentally show that by selecting appropriate preliminaries for our algorithm, one of its variants almost reaches the Cramer-Rao bound for high SNR, while the others always achieve good performance