INTRODUCTION/AIMS:Juvenile myasthenia gravis (JMG) patients report symptomatic improvement following thymectomy; however, there is a lack of published literature on biomarkers for interval improvement. This study aimed to investigate the utility of single-fiber electromyography to quantify changes post-thymectomy. METHODS:This was a retrospective medical record review of JMG patients who underwent thymectomy at Children's Healthcare of Atlanta between 2014 and 2024. Pre- and post-thymectomy orbicularis oculi jitter values and Myasthenia Gravis Activities of Daily Living (MG-ADL) scores were recorded. A two-sided paired t-test was used to compare results pre- and post-thymectomy and Pearson's correlations were calculated. RESULTS:Twelve JMG patients (6 female) with a mean age at diagnosis of 12.9 ± 4.5 (range 1.6-17.1) years, positive acetylcholine receptor antibodies, and normal thymus imaging underwent thoracoscopic thymectomy at 15.2 ± 3.3 (range 7.4-18.2) years. Post-thymectomy, there was a statistically significant decrease in mean jitter (interval 7.3 ± 7.4 months, mean difference -33.2 ± 32.6 μs, p = 0.04, n = 7) and MG-ADL scores (interval 2.5 ± 2.1 years, mean difference -2.2 ± 2.5, p = 0.02, n = 11). There were no significant correlations between timing of thymectomy after diagnosis and the change in mean jitter (r = 0.11, p = 0.8, n = 7) and MG-ADL (r = -0.19, p = 0.58, n = 11). No major post-surgical complications were observed. DISCUSSION:Thymectomy is well-tolerated and leads to both objective and subjective improvement in JMG patients.

INTRODUCTION/AIMS:Acute flaccid myelitis (AFM) is a poliomyelitis-like syndrome, characterized by severe flaccid weakness. Nerve conduction studies (NCS) and electromyography (EMG) may have a role in the diagnosis and prognostication of AFM, but have not been well studied. We aim to describe in detail electrodiagnostic studies in AFM and relate findings to outcome. METHODS:In this retrospective multi-center case series, we analyze electrodiagnostic data from patients with a probable or definite diagnosis of AFM. Patients were enrolled at 11 sites from four countries. A detailed description of NCS and EMG results is provided and findings are correlated to muscle strength and functional outcome. RESULTS:There were 85 patients included with definite or probable AFM based on AFM Working Group criteria. Patients were 54.1% male, median age 5.15 years (IQR 3.15-8.37), and median follow-up 833 days (range 40-3228). Electrodiagnostic abnormalities included decreased compound muscle action potential (CMAP) amplitude, reduced recruitment of motor unit action potentials (MUAPs), and fibrillation potentials in both affected and unaffected muscles, appearing as early as 6 days postonset and persisting beyond 7 years. CMAP amplitude and MUAP recruitment predicted muscle strength and functional status at last follow-up. Phrenic nerve studies correlated with respiratory outcomes in the small subset tested. Ten patients showed marked clinical improvement, accompanied by unexpectedly transient electrodiagnostic abnormalities. DISCUSSION:Electrodiagnostic studies in AFM reveal a distinctive pattern resembling poliomyelitis, with early-onset and persistent findings of denervation even in clinically normal muscles. The findings inform their use in diagnosis and prognostication.

BackgroundGlutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene variants are a known cause of congenital myasthenic syndrome (CMS), typically presenting with fatigable limb-girdle weakness and characteristic tubular aggregates on muscle biopsy, though recent reports have broadened the clinical spectrum.MethodsWe describe a 5-year-old boy presenting with hypotonia, progressive muscle weakness with head drop, cognitive delay, and visual impairment, found on neuromuscular genetic panel to have a novel homozygous missense variant in GFPT1 (c.1154G>A, p.Arg385Gln).ResultsFurther workup revealed white matter abnormalities with atrophy of corpus callosum and cerebellum on neuroimaging, myopathic motor unit potentials on electromyography, and non-specific changes on the left biceps muscle biopsy with absence of tubular aggregates. Stimulated jitter analysis of the right orbicularis oculi muscle showed increased jitter and blocking indicative of neuromuscular junction (NMJ) transmission defect. Trio whole-exome and trio whole-genome sequencing confirmed autosomal recessive GFPT1-related myasthenia.DiscussionThe muscle-eye-brain (MEB) phenotype of our case was like that of alpha-dystroglycanopathy, a glycosylation-related severe congenital muscular dystrophy. The presence of NMJ abnormalities expands the novel GFPT1 variant genotype-phenotype to include central nervous system features and muscle-eye-brain congenital myasthenic syndrome (MEB-CMS). This case study highlights the role of multiple specialists (neurologist, radiologist, ophthalmologist, pathologist, geneticist) and neurodiagnostic techniques (neuroimaging, electrodiagnostic, muscle pathology) to help deep phenotype symptomatic patients with novel gene variants found on next-generation sequencing.

OBJECTIVE:To evaluate the utility of compound muscle action potential (CMAP) amplitudes as biomarkers of disease severity in newborn screening (NBS)-positive infants with spinal muscular atrophy (SMA). METHODS:We conducted a retrospective review of 21 infants identified through SMA NBS (11 with 2 SMN2 copies and 10 with 3 SMN2 copies). Baseline and serial right median, ulnar, and fibular motor nerve CMAP amplitudes (millivolts, mV) were obtained during the study. Functional outcomes were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). RESULTS:At baseline, infants with 2 SMN2 copies demonstrated significantly lower median, ulnar, and fibular CMAP amplitudes compared with infants with 3 SMN2 copies (p < 0.05). In contrast, baseline CHOP-INTEND scores did not differ significantly between the two groups. Prior to genetic confirmation, a right median CMAP amplitude ≥3.2 mV predicted ≥3 SMN2 copies. Following treatment, right median and fibular CMAP amplitudes demonstrated significant improvement over time, including in analyses accounting for SMN2 copies number. CONCLUSION:CMAP amplitudes obtained from multiple upper- and lower-extremity motor nerves provided objective electrophysiological measures that distinguished infants with two versus three SMN2 copies, despite similar baseline CHOP-INTEND scores. Furthermore, CMAP abnormalities were detectable in some cases before confirmatory genetic testing results became available. Serial CMAP measurements demonstrated significant longitudinal changes following treatment, whereas functional assessments approached ceiling values, supporting the potential value of electrophysiological monitoring in the era of disease-modifying therapies. SIGNIFICANCE:CMAP assessment is a useful adjunct in the evaluation of infants identified through SMA NBS.

Hereditary spastic paraplegia type 56 (HSP56) is a rare, autosomal recessive neurodegenerative disorder caused by pathogenic variants in the CYP2U1 gene which encodes a cytochrome P450 enzyme that is critical for fatty acid metabolism and mitochondrial function. Herein, we explore the diagnosis and management of three patients with novel variants in CYP2U1 and review the literature on phenotype-genotype correlations in CYP2U1-related disorders. Through whole-genome sequencing and targeted validation by Sanger sequencing, we identified novel causative CYP2U1 variants in three female patients from two families who presented with early-onset spastic paraplegia. Twin sisters of Middle Eastern descent were found to carry a novel, homozygous in-frame deletion, c.367_375del (p.Gly123_Tyr125del), that was predicted to disrupt CYP2U1 protein structure and enzymatic stability. A third patient of South Asian descent carried a homozygous missense variant in CYP2U1, c.1355 A > T (p.Asp452Val), also not previously reported in public databases. This patient also had axonal sensory motor polyneuropathy. Clinically, all the patients presented with progressive lower-limb spasticity and delayed motor milestones. Cognitive impairment and brain magnetic resonance imaging (MRI) findings of hypomyelination were observed in both twins, but not in the third patient. Comprehensive metabolic panels for all three patients showed no evidence of folate deficiency. A literature review revealed no genotype–phenotype correlation for CYP2U1, as both truncating and missense variants can present with clinical findings of variable severity and age of onset. These findings document the CYP2U1 genotypic and phenotypic spectrum and reinforce the need for early recognition and metabolic monitoring for patients with HSP56. Further studies are warranted to evaluate whether interventions targeting nutrition or mitochondrial function can improve outcomes in CYP2U1-related neurodegeneration.

ABSTRACT Introduction/Aims Stimulated jitter analysis (stim‐JA) involves analyzing the variation in time intervals between stimulations and action potentials, expressed as the mean consecutive difference (MCD). The MCD upper limits are derived from adult populations and warrant a re‐evaluation in children to accurately diagnose neuromuscular junction (NMJ) defects. Methods A retrospective chart review was conducted which analyzed orbicularis oculi stim‐JA studies performed on children between January 2014 and December 2021. The clinical profile, acetylcholine receptor (AChR), and muscle‐specific kinase (MuSK) antibody status as well as stim‐JA study results were retrieved. Bootstrapping was applied to the stim‐JA studies to derive de novo MCD upper limits. Results Twenty‐seven stim‐JA studies were performed on patients aged 3–19 years with either definite myasthenia gravis presentations and NMJ defects ( n = 19, 17 AChR+, 2 MuSK+) or those with normal neurological examinations who were seronegative ( n = 8). Four hundred ninety‐nine apparent single fiber action potentials (ASFAPs) were analyzed with the individual and mean MCD significantly higher in children with autoimmune myasthenia ( p < 0.05). Bootstrapping analysis revealed that MCD upper limits of 39 μs for individual MCD and 24 μs for mean MCD significantly improved specificity ( p < 0.05) while maintaining sensitivity of the test in distinguishing definite MG NMJ defect from normal NMJ function. Discussion Stim‐JA using revised upper limits may help clinicians avoid the over‐diagnosis of NMJ disorders in children. Stim‐JA is a safe and well‐tolerated method to screen for definite MG in children over 2 years.

Background Complement inhibition (Ci) has revolutionized outcomes in disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), by improving prognosis and quality of life. However, Ci increases susceptibility to infection, despite use of immunization and prophylactic antibiotics. While infection risk with encapsulated bacteria is well documented, the true extent of this risk is not well characterized in children. Methods In this IRB-approved, retrospective study, we identified patients treated with Ci at Children's Healthcare of Atlanta from 2010 to 2025. Patients with solid organ transplant and hematopoietic stem cell transplant were excluded. Infections were identified via positive culture, and data were reviewed from 1st dose of Ci to 6 months following last dose. Infection rate was calculated as # infections/days at risk. Results Infection rates were assessed in 96 patients over 227 patient years. Median age at first Ci dose was 15 years (range 4 months to 20 years) and 52% were male. Ci indications included a cohort of children who were otherwise immune competent: aHUS (n=23), C3 glomerulopathy (n=6), Shiga-toxin producing Escherichia coli (STEC)-HUS (n=4), classic PNH (n= 9), and SARS-CoV-2 (n=1). The second cohort included patients who received additional immune suppression or had functional/surgical asplenia, including sickle cell disease (SCD) hyperhemolysis (n=29), autoimmune hemolytic anemia (AIHA) (n=4), PNH with bone marrow failure (BMF) (n= 12), refractory myasthenia gravis (MG) (n=3), thrombotic microangiopathy secondary to lupus (n=3), and other (n=2). All patients with infections were on antibiotic prophylaxis and up to date with meningococcal and pneumococcal vaccines. Among the immune competent cohort (n= 43), median duration of Ci treatment was 27.7 months (IQR 6.7, 80.0). Only 1 patient with STEC-HUS developed an infection, pseudomonas bacteremia, 8 days after first dose. Among the immunocompromised cohort (n= 53), median duration of Ci was 6.37 months (IQR 6, 17). There was no association of duration of Ci dosing (< 5 doses compared to ≥5 doses) and infection rate (p = 0.99). Nine immunocompromised patients developed significant infection(s), including bacteremia (n=5), candidemia (n= 1), invasive mold (n= 1), and pneumonia (n=2). Two children with SCD had bacteremia/fungemia; infections were identified within 1 day of first Ci dose and both patients died. In contrast, median time from first Ci dose in the remaining immunocompromised cohort to first infection was 122.5 days (IQR 61, 1068). Cumulative incidence of infection was significantly higher in the immunocompromised patients (1-yr estimate 12% vs 2%, p=0.008.) and they had significantly higher infection rate (p=0.016). There were ten deaths: 9 immunocompromised patients and 1 immune competent patient with a complex medical history. Two deaths were attributed to encapsulated bacterial infection. A patient with AIHA on several immunomodulators and splenectomy died from necrotizing pancreatitis and Klebsiella pneumoniae bacteremia 40 days after last Ci dose. A patient with SCD, on immunosuppression for a rare immune disorder, received one dose of eculizumab for hyperhemolysis 4 days prior to dying from Streptococcal pneumonia sepsis and meningitis; these infections were present prior to eculizumab administration. Conclusion This comprehensive institutional review demonstrates the favorable safety profile of Ci in pediatrics. Notably, no cases of meningitis were linked to Ci, duration of Ci was not associated with increased infection, and patients with aHUS and classic PNH had no significant infections. There were significantly more infections in the immunocompromised cohort, but there may be additional important confounding factors. Among those with SCD, given that all infections were identified within 1 day of first Ci, it is likely that these infections were drivers of hyperhemolysis (the Ci indication) and present prior to the drug. Thus, it's unlikely that Ci itself contributed to bacteremia. The underlying diagnosis in the remaining immunocompromised cohort, degree of immune suppression, and neutropenia are important infection risk factors; additional analyses accounting for degree of immune suppression and risk are pending. These data emphasize the importance of ongoing vigilance despite immunizations and antibiotics and education regarding infection risk and early symptom recognition.

Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder primarily affecting motor neurons, but immune dysfunction may contribute to disease progression and treatment response. While AAV9-delivered SMN1 gene therapy (e.g., Zolgensma) improves survival, long-term motor outcomes remain variable. This study integrates bulk and single-cell RNA sequencing (scRNA-seq) to define immune dysregulation in SMA. We analyzed peripheral blood from infants with SMA (n = 7 for bulk RNA-seq; n = 4 for scRNA-seq, <25 mo of age) along with age-matched healthy controls (n = 4 for bulk RNA-seq; n = 6 for scRNA-seq). We profiled differentially expressed genes, immune pathways, cell-cell interactions, and gene regulatory networks. SMA samples showed distinct transcriptomic signatures and elevated immune activation compared to controls. NECTIN1 was identified as a transcriptomic biomarker of disease progression, while HSPA7 was validated from prior reports. A 6- to 7-mo inflection point marked a transition from metabolic regulation to immune activation in SMA infants. NF-κB-related inflammatory gene expression was significantly elevated post-gene therapy relative to both pretreatment and healthy controls, with IL1B and RNF19B emerging as key transcriptomic mediators. scRNA-seq revealed early dysfunction and G1-phase arrest in CD4+ T-cells, along with a switch to RELB-mediated noncanonical NF-κB signaling. In symptomatic infants, CD8+ T-cells showed higher proliferation and exhaustion, with co-upregulation of TBX21 and EOMES, genes consistent with chronic stimulation and a trajectory toward terminal differentiation. Immune dysregulation is a central feature of SMA and may influence treatment response. These findings support future development of adjunct immunomodulatory strategies to enhance gene therapy efficacy and suggest that immune signatures may correlate with motor function outcomes.

INTRODUCTION:Krabbe disease, or globoid cell leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by deficient activity of the lysosomal enzyme galactosylceramidase (GALC). This deficiency leads to the toxic accumulation of psychosine, resulting in progressive demyelination and neuronal death. The clinical manifestations of Krabbe disease progress through different stages, starting with irritability, stiffness, and feeding difficulties, followed by myoclonic-like jerks in the upper and lower extremities, hypertonicity, and eventually severe hypotonia and lack of movement. METHODS:This case report features two newborn screening patients with (NBS)-positive Krabbe disease who underwent electrodiagnostic (EDX) testing and hematopoietic stem cell transplantation (HSCT) soon after birth. RESULTS:The EDX results indicated severe sensory-motor polyneuropathy of mixed demyelinating and axonal types. Biochemical analyses confirmed significantly reduced GALC enzyme activity and elevated psychosine levels in both cases. Genetic testing identified pathogenic variants, including compound heterozygous deletions and mutations within the GALC gene. At 6-month follow-up post-HSCT, one patient showed age-appropriate milestones and improvement in motor amplitudes on repeat nerve conduction studies. DISCUSSION:EDX testing is helpful in assessing NBS-positive Krabbe disease before confirmatory testing results become available. In conjunction with genetic confirmation and GALC enzyme levels, EDX test results were useful to counsel families that their seemingly normal newborn has severe disease and facilitated discussion toward timely treatment with HSCT. We suggest that EDX be included in the initial and follow-up evaluation of patients with Krabbe disease undergoing HSCT.

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. ANN NEUROL 2025;98:932-950.

INTRODUCTION/AIMS:Identifying sensitive response measures is crucial for evaluating treatment efficacy in SMA patients. Current electrodiagnostic (EDX) measures include compound muscle action potential (CMAP), motor unit number index (MUNIX), and motor unit size index (MUSIX). Functional measures include Hammersmith functional motor scale extended (HFMSE), Children's Hospital of Philadelphia infant test of neuromuscular disorders (CHOP-INTEND), and the revised upper limb module (RULM). Here, we compared EDX to traditional functional measures for monitoring treatment response in pediatric SMA. METHODS:A retrospective chart review of 16 non-ambulatory, late-onset (> 6 months of age) SMA children seen between January 2017 and June 2024 was performed. Motor nerve conduction study (NCS) recordings from the right median-abductor pollicis brevis (APB) and ulnar-abductor digiti minimi (ADM) nerve muscle pairs and functional scores were compared using Spearman correlation and a generalized linear mixed model (GLMM). RESULTS:EDX measures were significantly reduced in SMA children compared to healthy, age-matched controls (p < 0.05). Median abductor pollicis brevis (APB) CMAP amplitudes demonstrated moderate to strong correlations with CHOP-INTEND (r = 0.64, p < 0.05) and RULM (r = 0.77, p < 0.05) scores, and the GLMM revealed that APB CMAP significantly decreased over time (Beta = -0.02, p < 0.05) in the non-treatment compared to the treatment group. HMFSE showed a declining trend in patients who received only risdiplam. DISCUSSION:Median-APB CMAP amplitude demonstrated sensitivity in capturing treatment response. A prospective study comparing nusinersen and risdiplam in a larger, clinically diverse cohort with a longer follow-up period is needed.

Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics. Zolgensma® is the first effective and approved gene therapy for SMA caused by biallelic mutation in the SMN1 gene. In three children with SMA treated with Zolgensma®, neuronal, glial, inflammation, and vascular markers in the plasma exhibited a quicker response, emphasizing their potential as valuable biomarkers of treatment efficacy in clinical trials. We chose the novel Nucleic acid Linked Immuno-Sandwich Assay, to investigate a predefined panel of neuroinflammatory markers in plasma samples collected from SMA patients at baseline and six months after Zolgensma® treatment. We identified a set of novel targets whose levels differed between pre and post Zolgensma® treatment group and that were responsive to treatment. Even though our results warrant validation in larger SMA cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in SMA clinical trials.

Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.

Background:Neurogenetic disorders caused by pathogenic variants in four genes encoding non-erythrocytic spectrins ( SPTAN1, SPTBN1, SPTBN2, SPTBN4) range from peripheral and central nervous system involvement to complex syndromic presentations. Heterozygous pathogenic variants in SPTAN1 are exemplary for this diversity with phenotypes spanning almost the entire spectrum. Methods:Through international collaboration we identified 14 families with genetically unsolved distal weakness and unreported heterozygous SPTAN1 loss-of-function variants including frameshift, nonsense and splice-acceptor variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two patients. Results:All 20 patients presented with early childhood onset distal weakness. The severity varied both within families and between different families. Foot abnormalities ranged from hammer toes and pes cavus to distal arthrogryposis. Electrophysiology showed mixed myogenic and neurogenic features. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes with mild dystrophic and chronic neurogenic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in tissues derived from two patients. Conclusions:We provide evidence for the association of SPTAN1 loss-of-function variants with childhood onset distal myopathy in 14 families. This finding extends the phenotypic spectrum of SPTAN1 loss-of-function variants ranging from intellectual disability to distal weakness with a predominant myogenic cause. KEY MESSAGES:SPTAN1 loss-of-function variants, including frameshift, nonsense and splice site variants cause a novel childhood onset distal weakness syndrome with primarily skeletal muscle involvement. Hereditary motor neuropathies and distal myopathic disorders present a well-known diagnostic challenge as they demonstrate substantial clinical and genetic overlap. The emergence of SPTAN1 loss-of-function variants serves as a noteworthy example, highlighting a growing convergence in the spectrum of genotypes linked to both hereditary motor neuropathies and distal myopathies.

Autophagy is a fundamental and evolutionary conserved biological pathway with vital roles in intracellular quality control and homeostasis. The process of autophagy involves the engulfment of intracellular targets by autophagosomes and their delivery to the lysosome for digestion and recycling. We have previously reported recessive variants in EPG5, encoding for the ectopic P-granules 5 autophagy protein with a crucial role in autophagosome-lysosome fusion, as the cause of Vici syndrome (VS), a severe multisystem neurodevelopmental disorder defined by a combination of distinct clinical features including callosal agenesis, cataracts, cardiomyopathy, immunodeficiency, and hypopigmentation. Here, we present extensive novel genetic, clinical, neuroradiological and pathological features from the largest cohort of EPG5-related disorders reported to date, complemented by experimental findings from patient cells and models of EPG5 defects in Caenorhabditis elegans and Mus musculus. We identified 200 patients with recessive EPG5 variants, 86 of them previously unpublished. The associated phenotypic spectrum ranged from antenatally lethal presentations and the classic VS phenotype (n=60) to much milder neurodevelopmental disorders with less specific manifestations (n=140). Myopathic features and epilepsy with variable progression were frequently observed. Novel manifestations included early-onset parkinsonism and dystonia with cognitive decline during adolescence, hereditary spastic paraplegia (HSPP), and myoclonus. Radiological findings included previously recognized EPG5-related features with callosal abnormalities and pontocerebellar hypoplasia, and a range of novel features suggesting an emerging continuum with disorders of brain iron accumulation or copper metabolism as well as HSPPs. Genotype-phenotype studies suggested a correlation between predicted residual EPG5 expression and clinical severity, especially regarding disease progression and survival. The Epg5 p.Gln331Arg knock-in mouse, a model of milder EPG5-related disorders, showed an age-related motor phenotype and impaired autophagic clearance in several brain regions mirroring those also affected in humans. In Caenorhabditis elegans, epg-5 knockdown gave rise to neurodevelopmental features and motor impairment comparable to defects in parkinsonism-related genes, abnormal mitochondrial respiration, and impaired mitophagic clearance early in life. Cellular assays revealed impaired PINK1-Parkin dependent mitophagic clearance in patient fibroblasts. Our findings expand the phenotypic spectrum of EPG5-related disorders and indicate a life time continuum of disease that overlaps with other disorders of defective autophagy and intracellular trafficking. Our observations also suggest close links between early-onset neurodevelopmental and neurodegenerative conditions of later onset due to EPG5 defects, in particular dystonia and parkinsonism, highlighting the fundamental importance of dysfunctional autophagy in the pathophysiology of common neurodegenerative disorders.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis work was supported by grants from the European Union Horizon 2020 Programme (765912 DRIVE H2020-MSCA-ITN-2017) to CD, MF and HJ, Action Medical Research (2446) to HJ and MF, and Action Medical Research (GN2959) to KS and MRD. HSD was supported by the Koeln Fortune Program/Faculty of Medicine, University of Cologne (371/2021 and 243/2022), as well as the Cologne Clinician Scientist Program/Medical Faculty/University of Cologne and German Research Foundation (CCSP, DFG project No. 413543196). AA was supported by the Max Planck Gesellschaft. TSB was supported by the Netherlands Organisation for Scientific Research (ZonMw Vidi, grant 09150172110002), and acknowledges ongoing support from EpilepsieNL and CURE Epilepsy. KO is supported by Estonian Research Council grant PRG2040. Funding bodies did not have any influence on study design, results, and data interpretation or final manuscript.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:IRB of Medical Faculty, University of Cologne gave ethical approval for this work.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.