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Mutations in the key autophagy tethering factor EPG5 link neurodevelopmental and neurodegenerative disorders including early‐onset parkinsonism

Research Abstract

Objective

Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods

We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results

Through worldwide collaboration, we identified 211 patients, 97 of them previously unpublished, with recessive EPG5 variants. The phenotypic spectrum ranged from antenatally lethal presentations to milder isolated neurodevelopmental disorders. A novel Epg5 knock-in mouse model of a recurrent EPG5 missense variant featured motor impairments and defective autophagy in brain areas particularly relevant for the neurological disorders in milder presentations. Novel age-dependent neurodegenerative manifestations in our cohort included adolescent-onset parkinsonism and dystonia with cognitive decline, and myoclonus. Radiological features suggested an emerging continuum with brain iron accumulation disorders. Patient fibroblasts showed defects in PINK1-Parkin-dependent mitophagic clearance and α-synuclein overexpression, indicating a cellular basis for the observed neurodegenerative phenotypes. In Caenorhabditis elegans, EPG5 knockdown caused motor impairments, defective mitophagic clearance, and changes in mitochondrial respiration comparable to observations in C. elegans knockdown of parkinsonism-related genes.

Interpretation

Our findings illustrate a lifetime neurological disease continuum associated with pathogenic EPG5 variants, linking neurodevelopmental and neurodegenerative disorders through the common denominator of defective autophagy.

Research Authors
Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri,............, Nourelhoda A. Haridy,.............., Henry Houlden, Manolis Fanto, Heinz Jungbluth
Research Date
Research Journal
Annals of Neurology
Research Pages
932-950
Research Publisher
John Wiley & Sons, Inc.
Research Vol
Volume 98
Research Website
https://onlinelibrary.wiley.com/doi/full/10.1002/ana.78013
Research Year
2025

Nerve ultrasound as an adjunct to nerve conduction studies in Guillain–Barré syndrome diagnosis: a prospective Egyptian case–control study

Research Abstract

Background

Ongoing research aims to correlate ultrasound (US) findings with nerve conduction studies (NCS) results for the diagnosis of Guillain–Barré syndrome (GBS). NCS is currently the gold standard for confirming GBS diagnosis. This study aimed to compare nerve cross-sectional area (CSA) between GBS patients and controls and among different GBS subtypes, determine the correlation between CSA and NCS parameters, and identify a potential CSA cut-off value for early GBS screening. This study included 41 patients with GBS and 35 matched controls. Participants underwent comprehensive history taking, physical examination, NCS, and US measurement of CSA of peripheral nerves in upper and lower limbs. Receiver operating characteristic (ROC) analysis was performed to assess the ability of US CSA measurements to discriminate between GBS cases and controls.

Results

GBS patients had larger US nerve CSA than controls. No significant variations in CSA existed among different GBS electrophysiological subtypes. ROC curve analysis showed that median nerve CSAs at mid-forearm, pronator quadratus, and pronator teres were highly accurate for diagnosing GBS, with an area under the curve (AUC) of 1. Ulnar and posterior tibial nerve CSA were less precise. No substantial correlation existed between CSA and NCS parameters in the same nerve, although some association with clinical rating scales was present.

Conclusions

This study suggests nerve US may complement NCS in early GBS diagnosis, proposing CSA cut-off values for median, ulnar, and posterior tibial nerves. Further larger studies with standardized US protocols are needed to validate the reproducibility and diagnostic utility of these cut-offs.

Research Authors
Khalid O Mohamed, Hassan M Farweez, Shahera Sayed Ahmed Abd El Maged, Nourelhoda A Haridy
Research Date
Research Journal
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery
Research Publisher
Springer Berlin Heidelberg
Research Vol
Volume 61
Research Website
Khalid O Mohamed, Hassan M Farweez, Shahera Sayed Ahmed Abd El Maged, Nourelhoda A Haridy
Research Year
2025

Sleep disorders in a sample of Egyptian patients with Parkinson's disease: a case–control polysomnography study

Research Abstract

Background

Up to 96% of patients with Parkinson's disease (PD) experience sleep disturbances, which can emerge before motor symptoms. This study aims to determine the type of sleep disturbances in PD compared to controls using Parkinson's Disease Sleep Scale-2 (PDSS-2) and polysomnography (PSG). Twenty-four PD patients with sleep difficulties and 24 matched controls were included in this prospective case–control study. Sleep disturbances were diagnosed using screening questionnaires and PDSS-2. Patients were clinically assessed using Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). All participants were evaluated using Beck Depression Inventory (BDI), Montreal Cognitive Assessment (MoCA), and full-night video PSG.

Results

The PD group had significantly higher BDI and lower MoCA scores than the controls. PD patients had significantly lower sleep efficiency (87.32% versus 95.48%) and longer sleep latency (29 versus 2.45 min), shorter REM latency (37.97 versus 78.94 min), higher N2 sleep percentage (65.32% versus 51.43%), and lower REM sleep percentage (15.89% versus 19.22%). PD patients also had a higher arousal index (11.35 ± 9.46/h versus 3.44 ± 2.93/h), more periodic leg movements (7 ± 6.64 versus 2.21 ± 2.39), and a higher apnea–hypopnea index (7.96 ± 4.91 versus 4.12 ± 3.71). Sleep latency showed a negative correlation with MoCA and a positive correlation with disease duration. REM sleep percentage was negatively correlated with BDI. Arousal index /hour was negatively correlated with age onset.

Conclusions

This study confirms significant sleep architecture differences between PD patients and controls, emphasising the importance of comprehensive sleep assessment and management in PD care.

Research Authors
Eman M Khedr, Jaidaa Mekky, Mohammad A Korayem, Gellan K Ahmed, Nourelhoda A Haridy
Research Date
Research Journal
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery
Research Publisher
Springer Berlin Heidelberg
Research Vol
Volume 61
Research Website
Volume 61
Research Year
2025

APOE genetic variability in an Egyptian cohort of PD

Research Abstract

Background: The apolipoprotein E (APOE) gene, encompassing three alleles (ε2, ε3, ε4), is a critical player in lipid metabolism and has been extensively studied for its role in neurodegenerative diseases. This study examines APOE genetic variability and its association with PD in an Egyptian cohort.

Methods: A total of 891 participants, including 422 PD patients and 469 healthy controls, were included in this study. APOE genotyping was performed using Kompetitive Allele Specific PCR (KASP) to detect the rs429358 and rs7412 SNPs, which define the APOE alleles. APOE alleles were categorized based on the genotypes into ε2, ε3, and ε4 groups. Clinical assessments of PD patients included age at onset, disease severity (MDS-UPDRS), and demographic factors. Statistical analyses compared APOE distributions between PD and control groups and examined associations with clinical variables.

Results: The ε3 allele was the most prevalent in the cohort (77.3%), aligning with global and African trends. The ε2 allele was observed in 11.4%, and the ε4 allele in 11.3%, with both frequencies being lower than reported African estimates. The ε3/ε3 genotype was predominant in both PD patients (72.51%) and controls (72.07%). The ε4/ε4 genotype was absent in PD cases and rare among controls (0.64%). No significant association was found between APOE genotypes and PD risk, age at onset, or disease severity.

Conclusion: Our findings do not support a significant role for APOE in PD susceptibility or severity in Egyptians.

Research Authors
Eman M Khedr, Martina B William, Aliaa El-Hosseiny, Ali Soliman Shalash, Gharib Fawi, Mohamed H Yousef, Shaimaa Ibrahim El-Jaafary, Hamin Lee, Alina Jama, Mohamed Koraym, Asmaa Helmy, Yara Salah, David Adel, Nourelhoda A Haridy, ......., Mohamed Salama
Research Date
Research Journal
Frontiers in Neuroscience
Research Publisher
Frontiers
Research Vol
Volume 19
Research Website
Frontiers
Research Year
2025

Frequency and risk factors of sleep problems in Egyptian patients with multiple sclerosis

Research Abstract

Background: Sleep problems impact over 65% of patients with multiple sclerosis (MS), a prevalence significantly greater than that observed in the general population. This study aimed to assess the frequency and risk-associated factors of sleep problems in a large MS cohort and evaluate their impact on quality of life (QoL).

Methods: The study included 103 participants with MS across different disease stages and 62 healthy controls. Assessment tools included the Expanded Disability Status Scale (EDSS), Pittsburgh Sleep Quality Index (PSQI), depression and fatigue scales, 9-Hole Peg Test, 25-foot walk test, cognitive function assessments, and QoL measures.

Results: Sleep problems were significantly more frequent in MS patients (68.9%) than in controls (30.6%). PSQI scores showed positive correlations with the number of MS relapses across the course of disease duration, walking impairment, fatigue and depression scores. Sleep problems were determined to adversely affect various domains of quality of life.

Conclusion: Our findings demonstrate that sleep problems are remarkably common among patients with MS. Patients experiencing poor sleep quality are typically associated with higher levels of fatigue, depression, greater difficulty with mobility, and more frequent disease relapses. These sleep problems significantly impaired the overall QoL in MS patients. A multidisciplinary approach is therefore essential for managing sleep disorders in MS.

Research Authors
Eman M Khedr, Gellan K Ahmed, Shady Safwat Hassan, Mohamed Nageh Foly, Motez Mahmoud Attia, Ahmed A Karim, Nourelhoda A Haridy
Research Date
Research Journal
Frontiers in Neurology
Research Publisher
Frontiers Media SA
Research Vol
Volume 16
Research Website
Volume 16
Research Year
2025

Frequency, Risk Factors, Sex Differences, and Predictors of Post-Stroke Depression: A Multicenter Upper Egypt Study

Research Abstract
Background
Post-stroke depression (PSD) is the most common neuropsychiatric complication following a stroke.
Objectives
This study investigated PSD frequency, associated risk factors, sex-specific differences, and predictors of PSD.
Methods
The study comprised a cohort of 370 individuals who were diagnosed with acute stroke. Patients underwent clinical evaluations, vascular risk factor analysis, stroke severity measurement (Scandinavian Stroke Scale), cognitive assessment (Mini-Mental State Examination), brain imaging, and depression screening (Hamilton Depression Rating Scale) at baseline and at six months. Functional outcomes were evaluated using the Barthel Index.
Results
PSD was observed in 28.7% of cases and was significantly associated with unmarried status, hypertension, diabetes, and obesity. PSD patients exhibited more severe neurological deficits and showed higher rates of Middle cerebral artery occlusions, small vessel disease, and bilateral lesions. Multivariate analysis identified hypertension, stroke recurrence, bilateral brain lesions, lower cognitive function, increased triglyceride levels, smoking, and specific neurological manifestations as independent risk factors for PSD. Gender differences were noted in sociodemographic factors but did not significantly affect outcomes.
Conclusion
PSD is prevalent, with potential key predictors including bilateral brain lesions, reduced cognitive function, and stroke recurrence. Findings emphasize the importance of early risk assessment and gender-sensitive approaches to PSD management.
Research Authors
Bastawy M Al Fawal, Gellan K Ahmed, Ahmed K Ibrahim, Mohamed A Abdelhamed, Nourelhoda A Haridy
Research Date
Research Journal
Aswan University Medical Journal
Research Pages
102-118
Research Publisher
Aswan University, Faculty of Medicine
Research Vol
Volume 147
Research Website
https://journals.ekb.eg/article_410432.html
Research Year
2025

In PD, Non-Invasive Trans-Spinal Magnetic Stimulation Enhances the Effect of Transcranial Magnetic Stimulation on Axial Motor Symptoms: A Double-Blind Randomized Clinical Trial

Research Abstract
Background:
Axial symptoms in Parkinson’s disease (PD) often respond poorly to pharmacological treatment. We evaluated whether combining repetitive transcranial magnetic stimulation (rTMS) and repetitive spinal magnetic stimulation (rSMS) is more effective than rTMS alone in improving axial and other motor disabilities in PD.
Methods:
A total of 42 PD patients with axial symptoms were randomly allocated to 2 experimental intervention groups: Group I received active rTMS + active rSMS (2000 pulses; 20 Hz; 80% resting motor threshold for each motor area “M1” + 1500 pulses rSMS 10 Hz, at 50% of maximal stimulator output). Group II received active rTMS + sham rSMS with the same number of pulses. Both groups received 10 sessions (5 consecutive days/week for 2 weeks). Assessments using Freezing of Gait Questionnaire, walking speed, Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) parts II and III, and Parkinson’s Disease Questionaire-39 (PDQ-39) were performed at baseline (T0), end of sessions (T1), and 1 month later (T2).
Results:
At T0, Group II showed higher walking speed. At T1 and T2, Group I demonstrated significantly greater improvements in MDS-UPDRS parts II, III, and sub-items of part III. Group I showed stronger improvement in TUG-T and average fast velocity immediately post-intervention, but this effect diminished after 1 month. PDQ-39 scores for leisure activity and walking problems were significantly higher in group I.
Conclusions:
These findings indicate that combining rTMS and rSMS for 10 sessions is more effective than rTMS alone in managing PD’s motor and axial symptoms. The effect size of the outcome is large enough to be of significance in clinical practice.
Research Authors
Eman M Khedr, Nourelhoda A Haridy, Mohammad A Korayem, Ahmed Mamdouh Tawfik, Ahmed A Hamed
Research Date
Research Journal
Neurorehabilitation and Neural Repair
Research Pages
126-137
Research Publisher
SAGE Publications
Research Vol
Volume 39
Research Website
https://journals.sagepub.com/doi/abs/10.1177/15459683241300547
Research Year
2024

Outcomes and safety of mechanical thrombectomy, alteplase, and conventional medical care in the treatment of acute M2 segment middle cerebral artery occlusion: a comparative study

Research Abstract

Background

Data on mechanical thrombectomy (MT) to treat M2 occlusions of the middle cerebral artery (MCA) are sparse. We report the outcome and safety of MT versus intravenous recombinant tissue plasminogen activator (IV rTPA) versus conventional medical treatment (CMT) of acute ischemic stroke (AIS) due to occlusion of the M2 segment of the MCA. This prospective longitudinal intervention study compared the outcomes and safety of MT, rTPA, and CMT in M2 occlusion AIS patients. National Institutes of Health Stroke Scale (NIHSS), modified Rankin scale (mRS), and recanalization rate assessed outcomes.

Results

74 AIS patients were recruited (23 MT, 23 rTPA, 28CMT). MT group had significantly higher admission NIHSS (p = 0.018) and mRS (p = 0.023) than rTPA. At 24 h, NIHSS improved more with MT and rTPA than CMT (p < 0.0001). At 3 months, mRS were better with MT and rTPA versus CMT (p < 0.0001). Successful recanalization occurred in 73.9% of the MT group. 69% of the MT group required stent retrieval plus aspiration thrombectomy, and 60.9% required ≥ 3 trials, but outcomes did not differ by technique or number of trials. A good outcome (mRS 0–2) at 3 months was achieved in 69.6% MT versus 65.2% rTPA versus 7.1% CMT (p < 0.0001). Symptomatic intracranial hemorrhage (sICH) rates were slightly, but insignificantly, higher with CMT. Mortality did not significantly differ between groups.

Conclusions

For M2 occlusions, MT and rTPA achieved better early and 3-month outcomes than CMT; however, MT was not superior to rTPA. MT of M2 is feasible and effective, with a lower hemorrhage rate than rTPA and CMT.

Research Authors
Eman M Khedr, Ahmed Elbassiouny, Mahmoud Nageeb, Ahmed Aly, Khalid O Mohamed, Nourelhoda A Haridy
Research Date
Research Journal
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery
Research Publisher
Springer Berlin Heidelberg
Research Vol
Volume 61
Research Website
https://link.springer.com/article/10.1186/s41983-025-00935-y
Research Year
2025

Effects of transcranial magnetic stimulation on sleep quality in fibromyalgia: A double-blind randomized clinical trial

Research Abstract

Objectives

The aim of the current study was to assess the therapeutic impact of repeated low frequency repetitive transcranial magnetic stimulation (rTMS) over the right dorsolateral prefrontal cortex (rDLPFC) on sleep problems in patients with fibromyalgia.

Methods

Forty two patients with fibromyalgia who had sleep difficulties were randomly assigned to receive either real or sham rTMS treatment. Patients received 20 treatment sessions (5 sessions per week) in which 1200 rTMS pulses were applied over the rDLPFC using a frequency of 1 Hz and an intensity of 120 % of the resting motor threshold. All participants were evaluated at baseline, and then 1 month and 3 months after treatment using the Fibromyalgia Impact Questionnaire (FIQ), Pittsburgh Sleep Quality Index (PSQI), Medical Outcomes Study Sleep Scale (MOS-SS) and polysomnography (PSG).

Results

There were significant time (pre, 1month, and 3 months)X group (real versus sham group) interactions in all 3 clinical rating scales; FIQ (Df = 1.425, F = 237.645, P = 0.001), PSQI (Df = 2, F = 64.005, P = 0.001), MOS-SS (Df = 2, F = 28.938, P = 0.001) due to the fact that the real group improved significantly more over time than the sham group. Similarly, the real group improved more on the PSG parameters than the sham group. The effect sizes were large both in the rating scales and PSG, indicating a substantial clinical improvement. Correlation as an exploratory analysis between the changes (pre - post 3 months) in MOS-SS and PLMs index (/h) showed significant negative correlation (r = −0.643, P = 0.002).

Conclusions

20 sessions of LF-rTMS over rDLPFC can improve sleep quality in both subjective (PSQI and MOSS) as well as objective (PSG) rating scales.
Research Authors
Marwa Y Badr, Reham A Amer, Hend M Aref, Rehab M Salem, Heba A Elmokadem, Nourelhoda A Haridy, Eman M Khedr
Research Date
Research Journal
Sleep Medicine
Research Pages
354-361
Research Publisher
Elsevier
Research Vol
Volume 124
Research Website
https://www.sciencedirect.com/science/article/abs/pii/S1389945724004647
Research Year
2024

The impact of sex differences on stroke risk factors and 3-month outcomes in patients receiving thrombolytic therapy for acute ischemic stroke

Research Abstract

Background

Acute ischemic stroke (AIS) is a major public health issue, and women have a disproportionate share of stroke-related disability and mortality, which is poorly understood. This study aimed to determine the effect of sex differences on AIS treated by thrombolysis using recombinant tissue plasminogen activator (rTPA). The study included 134 AIS patients eligible for rTPA. Risk factors, clinical presentation, thrombolysis response, complications, and outcomes were recorded. The outcomes were measured using the National Institute of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) 3 months after stroke. The incidence of intracranial haemorrhage was also determined.

Results

Among 134 AIS patients treated with rTPA (59% male, 41% female), females had higher rates of hypertension (67.3% versus 49.4%, p = 0.040) and atrial fibrillation (AF) (12.7% versus 2.5%, p = 0.020), while smoking was more prevalent in males (31.6% versus 0%, p < 0.0001). Cardioembolism was more frequent in females than in males (23.6% versus 6.3%, p = 0.004). Females also had shorter onset-to-door (110.7 ± 63 versus 131.1 ± 50.2 min, p = 0.035) and onset-to-needle times (151.6 ± 66.5 versus 173.7 ± 50.6 min, p = 0.046). Both sexes showed significant improvements in NIHSS (males: 11.58 ± 3.7 to 6.05 ± 5.6; females: 11.64 ± 4.7 to 6.9 ± 5.9; p < 0.0001) and mRS scores (males: 3.34 ± 1.05 to 2.03 ± 2; females: 3.53 ± 1 to 2.02 ± 2; p < 0.0001) over 3 months, with no significant differences between sexes. Predictors of poor outcome (mRS 3–6) differed: diabetes mellitus (DM) (OR 7.79, p = 0.002) and longer door-to-needle time (OR 1.04, p = 0.008) for males, and hemorrhage (OR 9.41, p = 0.048) for females. Hemorrhage predicted mortality in males (OR 27.08, p < 0.0001), while AF was associated with increased mortality in females (OR 8.06, p = 0.024).

Conclusions

This study revealed sex-specific differences in AIS risk factors, aetiology, and rTPA treatment timelines, although post-treatment improvements were comparable between sexes. Notably, outcome predictors and mortality factors differed by sex. These findings emphasize the need for sex-specific considerations in AIS management and risk assessment.

Research Authors
Eman M Khedr, Noha Abo-Elfetoh, Asmaa M Hasan, Ahmed Nasreldein, Nourelhoda A Haridy
Research Date
Research Journal
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery
Research Publisher
Springer Berlin Heidelberg
Research Vol
Volume 60
Research Website
https://link.springer.com/article/10.1186/s41983-024-00900-1
Research Year
2024
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