An 11-year-old male presented with progressive neurological decline, including spasticity, dystonia, and cognitive impairment, over the past 2 years. Initial symptoms included drooling, poor handwriting, gait disturbances, slurred speech, emotional changes, and frequent falls, which progressed to severe motor and cognitive deficits, rendering him bedridden and non-verbal. Two years ago, Wilson’s disease was diagnosed based on low serum ceruloplasmin, Kayser–Fleischer rings, magnetic resonance imaging findings showing basal ganglia hyperintensities, and an ATP7B gene mutation. Initial treatment with D-penicillamine, zinc, and pyridoxine was discontinued due to a hypersensitivity reaction, and the regimen was switched to trientine, zinc, and symptom management medications. Despite treatment, his condition worsened with increasing dystonia, spasticity, and choreoathetoid movements, leading to bilateral knee and elbow contractures and dislocation of the left hip joint requiring surgery.

Progressive neurodegeneration with the movement disorder can be challenging to diagnose. In this article, we present a 12-year-old female child with stroke and progressive neurocognitive decline that was followed by choreo-athetoid movements and worsening dystonia and epilepsy. There was diffuse cortical involvement with predominant frontal-parietal lobes involved, affecting speech and bladder bowel control. Despite no significant family history, the genetic evaluation helped us to diagnose the rare condition. We also discuss the various challenges faced while managing and diagnosing the patient and the role of surgical intervention for the management of difficult to control dystonias in such patients.

The iron regulatory protein IREB2 (Iron Responsive Element Binding Protein 2) plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism. Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia. However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated Ireb2 D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA. Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2 D826V/D826V mice. Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction. Mechanistically, Ireb2 D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function. This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2 D826V/D826V mice as a model for iron metabolism-driven neurodegeneration. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

Disclosure: S. Benjamin: None. K. Shams: None. M.H. Horani: None. A. Samuel: None.Background: Hemiballismus-hemichorea (HH) is a rare hyperkinetic movement disorder associated with nonketotic hyperglycemia. Although often self-limiting with glycemic control, prolonged and refractory symptoms are uncommon and rarely lead to rhabdomyolysis. Case Presentation: A 53-year-old female with type 2 diabetes mellitus presented with one week of choreoathetoid movements of the right upper extremity, with minor right lower extremity involvement. She had been off antidiabetic medications for over one year due to insurance limitations. Upon evaluation, head CT was unremarkable, labs showed glucose 409 mg/dL, bicarbonate 19 mmol/L, anion gap 20, BHB 8 mmol/L, C-peptide 0.8 ng/mL, and A1c >14%. Notably, creatinine was 1.48 mg/dL and CK elevated at 8,447 U/L. Imaging revealed basal ganglia hyperdensity, consistent with nonketotic hyperglycemia. MRI and MRA were limited by motion artifact and the patient declined repeat imaging with sedation. EEG showed no epileptiform activity. Despite insulin initiation and improving glycemic control, hemichorea persisted for several days, contributing to marked muscle overuse and resulting rhabdomyolysis. A combination of olanzapine and topiramate eventually led to significant motor symptom resolution. CK levels normalized with resolution of HH. Discussion: This case underscores the importance of recognizing rhabdomyolysis as a rare but potential complication of HH when symptoms are prolonged/refractory. While HH is usually reversible with glycemic control, sustained involuntary movements can result in metabolic complications including muscle breakdown. The patient’s elevated CK, renal dysfunction, and persistent chorea highlight this rare but serious complication. Conclusion: Refractory hemichorea secondary to nonketotic hyperglycemia can lead to rhabdomyolysis, a rare but clinically significant consequence. Multidisciplinary management and early recognition are key to avoiding systemic complications. This case also reinforces the importance of treatment access and adherence in chronic disease management.Presentation: Monday, July 14, 2025

Hemichorea represents a rare but clinically significant hyperkinetic movement disorder in diabetic patients, characterized by abrupt-onset, nonpatterned contractions involving both craniofacial and appendicular musculature. An 82-year-old Asian male who developed progressively worsening choreoathetoid movements with striking left-sided craniofacial predominance, accompanied by ipsilateral limb involvement. Comprehensive neurological assessment showed preserved sensorimotor function despite the dramatic movement disorder. Biochemical profiling revealed markedly elevated serum glucose (28.6mmol/L) and HbA1c (12.8%). Neuroimaging findings were pathognomonic, with T1-weighted MRI showing unilateral hyperintensity in the right lentiform nucleus, confirming diabetic striatopathy. The patient's clinical presentation was particularly notable for prominent oromandibular dyskinesias and episodic facial grimacing, highlighting the frequently overlooked craniofacial dimension of this condition. Hemichorea-hemiballismus syndrome as a time-sensitive neuroendocrine emergency requires immediate intervention. Movement disorders with craniofacial manifestations should prompt urgent evaluation for metabolic etiologies, as rapid glycemic correction can lead to complete neurological recovery.

Choreoathetoid Movements in a Type 2 Diabetic Patient Following Initiation of Oral Hypoglycemics: A Case Study

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control.

Post pump chorea (PPC) is characterized by choreoathetoid movements which sometimes appear in children following cardiopulmonary bypass surgery, usually within 2 weeks of surgery. Approximately 1% of children who have cardiac surgery develop this syndrome. The mean age of affected individuals is 8–34 months. Risk factors include deep hypothermia and circulatory arrest. This syndrome is often later associated with developmental delay and neurological deficits ranging from mild learning disabilities to progressive hypotonia with obtundation. Chorea can be transient or persistent. Neuroimaging usually reveals brain atrophy without focal abnormalities. The mechanism for this syndrome is not entirely clear, but the literature suggests it may be the result of microembolic phenomena of air, fat, shards of polyvinylchloride tubing, antifoaming agents, and/or platelet fibrin aggregates accumulated during surgery. Here we present a 16 years old boy who presented with choreoathetoid movements sixteen days following aortic balloon valvuloplasty due to congenital bicuspid aortic valve. He was successfully treated with deutetrabenazine and clonazepam for 3 months.

AimsThis study aimed to describe clinical features and outcomes of patients presenting to the emergency department with analytically confirmed methamphetamine intoxication, to determine the blood concentration of methamphetamine and to test its association with clinical findings.DesignThe Western Australian Illicit Substance Evaluation (WISE) study is a prospective observational cohort study.SettingRoyal Perth Hospital Emergency Department, Perth, Australia, between 2016 and 2018.ParticipantsPatients suspected to be intoxicated with a stimulant, hallucinogenic or cannabinoid substance and who required intravenous access or blood tests as part of standard care. Those predominantly alcohol intoxicated, behaviourally disturbed or opioid intoxicated were excluded. The 431 participants with detectable methamphetamine (> 0.001 mg/l) included in this analysis had a mean age of 33.2 (9.4) years and 286/431 (66.4%) were male.MeasurementsConcentration was reported for methamphetamine and other illicit drugs detected. Univariate associations of symptoms and signs, and physiological and laboratory parameters with methamphetamine concentration were determined and used to develop a multivariable model.FindingsThe median concentration of methamphetamine was 0.12 mg/L [Q1,Q3: 0.05, 0.27]. Psychotic symptoms were seen in 265/431 (61.5%) patients and intravenous or intramuscular sedation was required in 280/431 (65.0%). Mean heart rate was elevated at 105.9 (21.5) beats per minute, but other mean or median physiological parameters were within normal limits. A multivariable model showed that methamphetamine concentration was 27% lower in males (P = 0.026), 60% higher in those with palpitations (P = 0.013), 62% higher in those with choreoathetoid movements (P = 0.002) and increased by 1% for each unit (μg/L) increment in creatinine (P = 0.001).ConclusionsIn a cohort of emergency department patients with methamphetamine exposure, a multivariable model inferred a significant association between higher methamphetamine concentration and female sex, the presence of palpitations and choreoathetoid movements and creatinine concentration. The model showed no significant association with agitation, psychotic symptoms or other physiological or clinical parameters.

Abstract Osmotic demyelination syndrome (ODS) is characterized by noninflammatory demyelination within the central nervous system with symmetrical lesions in the pontine and extrapontine regions, such as the caudate, putamen, midbrain, thalamus, cerebellum, and corpus callosum. Clinical manifestations of ODS can be highly variable, including encephalopathy, bradykinesia, spastic quadriparesis, rigidity, dyskinesias, tremor, choreoathetoid movements, mutism, dysarthria, dysphagia, and ophthalmoparesis. Our study included 11 patients with ODS of whom 9 were male individuals (81.81%). The mean and median ages of the patients were 46 ± 19 years and 57 years, respectively. Most patients (90.9%) had hyponatremia, while one patient (9.1%) had hypernatremia. Magnetic resonance imaging findings were observed in 81.81% (n = 9) patients at presentation. Parkinsonism was the most common manifestation observed in 10 patients (90.9%), all of whom most commonly exhibited rigidity and bradykinesia. Postural tremor was observed in four patients (36.36%), masked facies in six patients (54.54%), dystonia in four patients (36.36%), perioral dyskinesias in three patients (27.27%), and choreoathetoid movements were observed in one patient (9.09%). ODS is typically associated with rapid correction of hyponatremia, especially in patients with predisposing factors. However, in this study, gradual hyponatremia correction was performed at a rate <8 mEq/L/24 hours in three patients who later developed ODS. Individuals with ODS may exhibit symptoms of both hypokinetic and hyperkinetic movement disorders due to changes in direct and indirect pathways. Extrapontine involvement can be attributed to either presynaptic striatal dopamine transporter depletion or a deficiency of postsynaptic dopamine receptors. In this study, both hypokinetic and hyperkinetic movement disorders can be observed in ODS; however, hypokinetic movement disorders in the form of parkinsonism were more common.

Introduction Neuronal ceroid lipofuscinosis-type 1 (NCL-1) is a neurodegenerative lysosomal storage disorder. Vitamin D-dependent rickets type 1 (VDDR-1) is a rare cause of refractory rickets. Here, we report an unusual association of NCL-1 with VDDR-1. Case A 3-year-old boy presented with a history of seizures from 45 days of life, delayed development, and loss of attained milestones at 20 months of age, along with progressive vision impairment since 1 year. Examination showed a failure to thrive, microcephaly, rachitic rosary, checkerboard and phylloid type of pigmentary mosaicism, fundus showed disc pallor with generalized narrowing of arterioles, bilateral retinitis pigmentosa, spasticity and dystonia, brisk reflexes, extensor plantar, and left choreoathetoid movements. Investigations showed hypocalcemia (7.8 mg/dL), normal phosphorus (3.9 mg/dL), elevated alkaline phosphatase (508.8 U/L), elevated parathyroid hormone (513.35 pg/mL), low 1,25-dihydroxy-vitamin D (9.93 pg/mL), and normal renal function. The child had metabolic acidosis, elevated ammonia (403.9 micromol/L), lactate (95 mg/dL, normal range 4.5-19.8 mg/dL), and creatine phosphokinase (432 U/L) level, and normal tandem mass spectroscopy. X-ray wrist showed healing vitamin deficiency rickets. Abnormal electroencephalogram was suggestive of low voltage activity. Magnetic resonance imaging brain showed gross cerebral and cerebellar atrophy. A muscle biopsy showed scattered atrophic fibers and several ultrastructural granular osmiophilic deposits and some mitochondrial aggregates of varying size were observed. Mitochondrial respiratory chain enzyme assay exhibited complex-1 deficiency (activity < 30%). Genetic analysis showed two pathogenic mutations: homozygous nonsynonymous variation c.674T > C in exon 7 of the PPT1 gene and a homozygous frameshift variation c.1178_1179delAA in exon 7 of CYP27B1 confirming the diagnosis of NCL-1 with VDDR-1. The child was treated with a low protein diet, levetiracetam, clonazepam, trihexyphenidyl, haloperidol, calcium supplement, calcitriol, and sodium benzoate; some improvement in clinical and biochemical parameters was noted on follow-up. Conclusion This is a novel association of NCL-1 with VDDR-1 associated with complex-1 mitochondrial deficiency which has previously not been reported in the literature.

Background and Aim: The classic definition of acute encephalitis consists of altered consciousness associated with fever, seizures or focal neurological alterations on neuroimaging or electroencephalography. However, there are particularities that may provide a glimpse of the probably autoimmune versus infectious etiology of the same neurological picture. Case presentation: A 19-month-old male starts with motor clumsiness and refusal to ambulation and leg claudication in the context of febrile pharyngotonsillitis. Simultaneously, first episode of forced gaze’s lateralization and cephalic deviation with right tonic movements and sucking. On examination: intense irritability with no contact, denial-type stereotypies, hemiparetic gait, pronation and adduction of the right arm and foot with frequent stumbling. Results: Neuroimaging tests, electroencephalogram, laboratory tests and antistreptolysin-O were normal, no pathological clinical exome and detection of antibodies in cerebrospinal fluid paired with serum. Such as diagnosis: acute autoimmune encephalitis due to anti-NMDA-R (N-methyl-D-aspartate Receptor) antibodies and movement disorder (choreoathetosis, hemidystonia). We initiate treatment with intramuscular penicillin and oral clobazam with erratic response. Fortunately, high doses of intravenous (iv) corticosteroids and immunoglobulins, oral corticotherapy and iv rituximab on our patient were used. Months later, clear improvement with autonomous ambulation without assistance, adequate manual opening and entire disappearance of dystonic-myoclonic movements. Conclusions: Choreoathetoid movements accompanied by irritability in an infectious context should lead us to think of Sydenham's chorea. However, new developments in the analysis of biological samples and a high index of suspicion may lead us to autoimmune pathology and the consequent early use of immunotherapy with optimal results.

Eti - Anatomico - Clinical Correlation of Dejerine - Roussy Syndrome with Choreoathetoid Movement and Ataxic - Hemiparesis in Localization of Stroke - A Case Report

Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders

SummaryThe homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

This is a case report of a 26 year old girl who presented with choreiform movements of the upper and lower limbs and generalised tonic clonic seizures who had an entity called clinically isolated syndrome of multiple sclerosis on investigation. The pooled incidence rate in 75 reporting countries was 2.1 per 100,000 persons/year, with 32 years of age being the mean age of diagnosis. But multiple sclerosis is a white matter disease and choreiform movements are due to involvement of the grey matter of the brain. There have only been a few case reports of patients with multiple sclerosis having choreoathetoid movements reported.

Neurologic problems are frequently described in infants with nutritional vitamin B12 (cobalamin) deficiency.Major neurologic consequences of infantile cobalamin deficiency include delays or regression in neurodevelopment and the occurrence of involuntary movements METHODS: We reviewed the medical records of infants with cobalamin deficiency and divided infants with involuntary movements into two groups as those, who developed involuntary movements during vitamin B12 supplementation (Group I) and those, who developed involuntary movements prior to supplementation therapy (Group II). We evaluated a total of 32 infants with the diagnosis of cobalamin deficiency. Involuntary movements were observed in 12 out of 32 infants. Group I and Group II consisted of 6 infants each. Of the infants with involuntary movements, five were exclusively breastfed until the time of diagnosis. The majority of infants in Group II had choreoathetoid movements; twitching and myoclonus in the face, tongue, and lips, and tremor in the upper extremities. These involuntary movements disappeared in one to three weeks after clonazepam therapy. In Group I; shaking movements, myoclonus, tremor, and twitching or protrusion were observed in patients' hands, feet, tongue, and lips on the 3rd-5th day of cobalamin supplementation. These involuntary movements disappeared within 5-12 days of clonazepam therapy. Recognition of nutritional cobalamin deficiency is important to perform a differential diagnosis of the condition from seizures or other causes of involuntary movements and avoid aggressive therapy and over treatment.

Abstract Introduction Paroxysmal hypnogenic dyskinesia (PHD) is a rare subset of paroxysmal dyskinesias characterized by recurring involuntary dystonic or choreoathetoid movements that occur during sleep or immediately after an arousal from sleep. These episodes often occur without loss of consciousness or trigger and lack association with epileptiform electroencephalography (EEG) activity. Report of case(s) A 61-year-old male with obstructive sleep apnea compliant with PAP was referred for abnormal nighttime movements for the past 9 years. The episodes were characterized by stereotyped involuntary dystonic posturing involving his upper extremities or his entire body lasting up to 15 seconds. The onset of the events occurred invariable during nighttime sleep and resulted in awakenings from sleep. He denied dream enactment as well as other symptoms suggestive of sleep-related movement disorders or parasomnias. Sleep deprived EEG demonstrated left temporal slowing during wakefulness and drowsiness and captured a typical event that occurred during NREM stage II sleep and had no ictal correlate. An MRI of the brain was unremarkable. During overnight polysomnogram, his current PAP settings were found to be effective, and three episodes of body stiffening consistent with his typical events were captured. These episodes were found to occur after awakening from REM sleep and lasted less than 10 seconds each. There was no EEG correlate, and REM atonia was preserved throughout. The patient was started on oxcarbazepine for the nocturnal movements, which reduced the frequency of events from 12 to 4 events per night. Oxcarbazepine was tapered and discontinued due to side effects and incomplete control of the events. Genetic testing for epilepsy syndromes is pending. Conclusion PHD is a rare syndrome of involuntary movements which begin during sleep or cause awakenings from sleep and can be misdiagnosed as a sleep disorder. It is crucial for the sleep physician to be aware of possible neurological causes of sleep-related movement disorders. Furthermore, our patient’s partial response to oxcarbazepine may further support that PHD may have an epileptic origin although not well characterized. Support (if any) Advancing Innovation in Residency Education (AIRE) Pilot Program Training Grant

<h3>Objective:</h3> To discuss a rare case of chorea presenting as the initial manifestation of autoimmune disease. <h3>Background:</h3> Autoimmune chorea, including paraneoplastic, post-infectious, and idiopathic etiologies, is one of the leading causes of adult-onset chorea behind Huntington’s and vascular diseases.¹ In particular, in primary antiphospholipid syndrome (APS) and systemic lupus erythematosus, chorea is the initial manifestation of disease in 0.9 to 2% of cases.^1,2 <h3>Design/Methods:</h3> Verbal and written consent were obtained from the patient. <h3>Results:</h3> 73-year-old female with PMH of ITP, left MCA ischemic stroke, SDH, and DVT on anticoagulation who presented initially to ED with choreoathetoid movements starting 3 days prior to admission. History was unremarkable for triggering factor. Head imaging was unremarkable for acute intracranial process. B12, folate, TSH, electrolytes, RPR, serum copper, ANA, anti-dsDNA, SS-A, SS-B, Smith, and RNP antibodies negative. Lupus anticoagulant, β2 glycoprotein, and anti-cardiolipin antibodies positive. EEG unremarkable. Pelvic ultrasound negative. Genetic testing for Huntington’s negative. LP normal with exception of positive Coxsackie B1–B6 and A24 antibodies. After five-day course of IVIg, movements improved and she was discharged on no immunosuppression. Five weeks later, patient returned to ED with worsening of choreoathetoid movements. Repeat head CT again negative for acute pathology. Repeated spinal was unremarkable. Patient received Solumedrol 1g for four days with significant improvement in symptoms, and discharged on Prednisone 60 mg daily with recommendation to follow-up with rheumatology and neurology. On follow-up several months later, patient maintained on Prednisone 5 mg daily with no recurrence of choreoathetoid movements. <h3>Conclusions:</h3> While chorea is not the most commonly reported movement disorder in the context of autoimmune disease, it is often a delayed diagnosis, resulting in recurrent admissions and healthcare costs. Laboratory testing for autoimmune disorders should be included in the initial work-up of new-onset chorea to establish the diagnosis and properly treat as to prevent development of fulminant disease. <b>Disclosure:</b> Ms. Alayon has nothing to disclose. Mrs. Goodis has nothing to disclose. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Catalyst. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for eisai. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Argenx. Dr. Feinberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Feinberg has stock in Amarin. Stuart N. Kieran, MD has nothing to disclose. Dr. Wirkowski has nothing to disclose.

<h3>Objective:</h3> To report on further 8 affected individuals from 7 independent families with one missense and three ultra-rare or novel predicted loss-of-function (LOF) biallelic <i>NDUFA13</i> variants and provide follow-up clinical-radiological details from the previously reported families. <h3>Background:</h3> Biallelic variants in NADH-ubiquinone oxidoreductase 1 alpha subcomplex 13 (<i>NDUFA13</i>) have been associated with mitochondrial Complex I (CI) deficiency, nuclear type 28 in three affected individuals from two families. Currently, with only two families reported, the clinical and molecular spectrum of <i>NDUFA13</i>-related CI deficiency remains poorly characterized. <h3>Design/Methods:</h3> Using the Gene Matcher platform and extensive international data sharing, 7 families reported here were identified. Proband only or trio exome sequencing (ES), variant filtering, and Sanger segregation analysis in 7 families were carried out in 4 different centers following the protocols described previously. Skin biopsies were obtained and cultured fibroblasts were prepared for whole-cell lysates and subsequent SDS-PAGE/western blot analysis was performed. <h3>Results:</h3> There were 6 females and 5 males, 10 of whom are currently alive with a mean age of 8.9 ±5.4 years. The disease was mostly of infantile onset and progressed slowly in 64%. Moderate-to-severe developmental delay/intellectual disability (64%), microcephaly (27%), encephalopathy (54%), epileptic seizures (54%), optic atrophy (54%), oculomotor abnormalities (91%), and neuromuscular phenotype including dysarthria (54%), hypotonia (73%), and spasticity (70%) were among the frequent features. Choreoathetoid movements (60%), dyskinesia (70%), bradykinesia (55%), and truncal ataxia (60%) were frequently displayed movement abnormalities. Bilateral symmetric T2 hyperintense lesions in the substantia nigra (72.7%), basal ganglia lesions (27.2%), periaqueductal gray matter and/or dentate nuclei signal alterations (54.5%), mild cerebellar atrophy (45.4%), and supratentorial white matter volume loss (27.2%) were frequent neuroimaging features. Complex I activity was decreased and complex IV activity was increased in the patient-derived skin fibroblasts, whereas NDUFA13 protein levels were undetectable. <h3>Conclusions:</h3> This study provides a cumulative phenotypic characterization of <i>NDUFA13-</i>related disease. <b>Disclosure:</b> Dr. Kaiyrzhanov has nothing to disclose. Dr. Kaiyrzhanov has nothing to disclose.