Progressive Neurological Decline Research Articles

Multiple Synchronous Spinal Dural Arteriovenous Fistulas: A Systematic Literature Review.

Spinal dural arteriovenous fistulas (SDAVFs) lead to progressive neurological decline with symptoms such as paraparesis, bowel and bladder dysfunction, and sensory disturbances because of impaired spinal cord venous drainage. This study aimed to systematically review the literature on multiple synchronous SDAVFs and present 2 cases from our institution. A comprehensive search was performed to identify all published cases of multiple synchronous SDAVFs. Overall, 23 patients with multiple synchronous SDAVFs were identified, including 21 from 19 articles and 2 from this study. The clinical presentation, lesion location, radiographic features, surgical treatment, and outcomes were analyzed in each patient. All patients in this study were male, and the duration from symptom onset to diagnosis in many of these patients was longer than that previously reported. Previous studies suggested that multiple SDAVFs typically occurred within 3 or fewer vertebral levels. However, >50% of the examined patients had remote lesions separated by more than 3 vertebral levels. Patients with remote lesions had a significantly worse outcome (1/7 vs 8/11, 95% CI 0.001-0.998; P = .049). Accurately locating fistulas before spinal angiography is critical for managing multiple remote SDAVFs. Considering the possibility of multiple remote SDAVFs, careful interpretation of imaging findings is essential for an accurate diagnosis and appropriate treatment planning.

Fanconi anemia neuroinflammatory syndrome: brain lesions and neurologic injury in Fanconi anemia

AbstractFanconi anemia (FA) is a complex inherited bone marrow failure syndrome characterized by chromosomal instability and defective DNA repair, causing sensitivity to DNA interstrand crosslinking agents. Our understanding of the full adult phenotype of the disease continues to evolve, because most patients with FA died of marrow failure in the first decade of life before more recent advances in allogeneic hematopoietic cell transplantation. Herein, we report a previously undescribed, clinically concerning, progressive neurologic syndrome in patients with FA. Nine nonimmunosuppressed pediatric patients and young adults with FA presented with acute and chronic neurological signs and symptoms associated with distinct neuroradiological findings. Symptoms included, but were not limited to, limb weakness, papilledema, gait abnormalities, headaches, dysphagia, visual changes, and seizures. Brain imaging demonstrated a characteristic radiographic appearance of numerous cerebral and cerebellar lesions with associated calcifications and often a dominant ring-enhancing lesion. Tissue from the dominant brain lesions in 4 patients showed nonspecific atypical glial proliferation, and a small number of polyomavirus-infected microglial cells were identified by immunohistochemistry in 2 patients. Numerous interventions were pursued across this cohort, in general with no improvement. Overall, these patients demonstrated significant progressive neurologic decline. This cohort highlights the importance of recognizing FA neuroinflammatory syndrome, which is distinct from malignancy, and warrants careful ongoing evaluation by clinicians.

Treatment of an anterior cervicothoracic myelomeningocele together with spine deformity correction in a child: illustrative case.

Anterior cervicothoracic myelomeningoceles are a rare pathology. In reported cases, treatment has included shunting, isolated resection and repair without deformity correction, or isolated deformity correction without meningocele repair. The authors describe a pediatric patient with an anterior cervicothoracic myelomeningocele presenting with progressive neurological decline, who underwent simultaneous treatment of the myelomeningocele to detether the spinal cord and achieve major correction of the scoliotic deformity. A 15-year-old girl was born with C7-T1-T2 hemivertebrae and anterior cervical myelomeningocele at C7-T1. She developed progressive cervical thoracic scoliosis, left hemiparesis initially, and additional right hemiparesis eventually. She underwent surgical repair via C7, T1, and T2 corpectomies with intradural detethering of the spinal cord. The scoliosis was treated with C7-T2 Ponte osteotomies and C2-T5 posterior fixation, followed by anterior reconstruction with a titanium cage and anterior plate from C6 to T3. The myelomeningocele was adequately treated with good correction of the patient's deformity. The patient had postoperative improvement in her strength and solid arthrodesis on postoperative imaging. The authors describe the successful treatment of an anterior cervicothoracic myelomeningocele and associated scoliosis in a child. This is a unique report of a combined strategy to achieve both deformity correction and detethering of the spinal cord.

Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model.

Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults. We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts. The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes. We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.

Patient-Reported Outcomes and Medical Provider Satisfaction Among Adult and Pediatric Ataxia-Telangiectasia Patients.

Ataxia-telangiectasia (A-T) is a rare genetic condition with malfunctioning DNA repair processes resulting in significant clinical findings, including progressive neurologic decline, elevated malignancy risk, immunodeficiency, oculocutaneous telangiectasias, and severe pulmonary disease. Research has been limited into the quality of life of such patients and yet to be completed are studies quantitatively analyzing psychosocial, physical, and cognitive patient-reported outcomes (PROs) within the A-T population. PRO evaluations of 90 international adult and pediatric A-T patients and their caregivers were completed via secure online administration of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms evaluating anger, cognition, mood, social health, fatigue, pain, anxiety, and upper extremity function. The impact of age, gender, race/ethnicity, prior malignancy diagnosis, and current supportive treatment interventions on such PROs was additionally assessed. Finally, given the importance of medical providers in the care of A-T patients and the impact of patient satisfaction on healthcare outcomes, we further analyzed, via a novel survey, how patients and caregivers perceived their primary A-T healthcare provider's A-T expertise, trustworthiness, accessibility, and level of compassion. It was found that a diagnosis of A-T complexly impacts patient PROs, but such data offers the potential for preventative and therapeutic interventions to improve the care of such patients. While most A-T patients and their caregivers feel their primary A-T medical provider has expertise and compassion in addition to being accessible and trustworthy, a significant percentage of study subjects did not agree that their provider was an expert in A-T or overall trustworthy.

NCOG-30. ENVIRONMENTAL ENRICHMENT AND HEALTH OUTCOMES AFTER RADIATION

Abstract Individuals treated with brain radiation (RT) are at a disproportionately increased risk of accelerated aging and symptom burden. The aim of this abstract is to describe the health outcomes experienced by brain tumor (BT) survivors who received Photon (XRT) and Proton-Beam (PBRT) in relation to levels of environmental enrichment (EE). The study employed a cross-sectional cohort design among persons with glioma (WHO Grade 2 and 3) treated with RT approximately 5 years following diagnosis. EE consists of social network/engagement, physical activity, and employment status/financial stability measured by the Berkman-Syme Social Network Index, International Physical Activity Questionnaire, Vocational Index Scale, and two Socioeconomic Questions, respectively. EE level is classified into low, moderate, or high tertile. Montreal Cognitive Assessment measured cognitive function. Cortical atrophy is measured using temporal brain MRI images from the time of diagnosis, 3 years after, and at the time of enrollment. Images were processed using FreeSurfer. MD Anderson Symptom Inventory – BT module was used to measure functional status. Two-Way ANOVA described the health outcomes among individuals who received XRT and PBRT. Thirty-nine participants, 18 with astrocytoma and 19 with oligodendroglioma, completed the study protocol. Eighteen individuals received XRT (5 were categorized into Low EE, 10 to Moderate EE and 3 had High levels of EE) and 21 received PBRT (8 were categorized into Low EE, 7 had Moderate EE and 6 had High EE). Individuals who received XRT and had High levels of EE had higher scores in MoCA, lower cortical atrophy rate, and lower symptom burden than individuals who had Moderate and Low EE. BT survivors are at an increased risk of accelerated aging and progressive neurological decline. Providing an enriched environment may serve to reduce symptom burden, promote healthy brain aging, and improve cognitive and functional status in BT survivors receiving radiation.

Progressive neurological decline associated with intracranial calcification in Down syndrome; Fahr disease mimic?

Progressive neurological decline associated with intracranial calcification in Down syndrome; Fahr disease mimic?

Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy

Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin's E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.

Knowing Your Target: Altered Mental Status From an Unsuspected Source

Daratumumab is a human monoclonal antibody targeting CD38 that is used in the treatment of multiple myeloma. In addition to being a target for cancer-related treatment, CD38 also plays a significant role in the immune response to infection. CD38 deficiency can increase susceptibility to several bacterial infections. This article discusses the case of a 52-year-old female with a history of IgG multiple myeloma status post autologous stem cell transplant with relapse who was receiving therapy with daratumumab, lenalidomide, and dexamethasone. She presented to the emergency department with a history of 3 to 4 days of generalized weakness, poor appetite, nausea, vomiting, watery stools, and fevers. Her symptoms did not improve with initial fluid resuscitation and broad-spectrum antimicrobials; instead, she experienced progressive neurological decline. This case illustrates how utilizing targets for cancer-directed treatments can also affect immune function, which may leave patients susceptible to unique infections that may not otherwise be commonly encountered. Therefore, advanced practitioners must understand the functional role of these targets and the sequelae that could occur when expression is altered by pharmacological therapies to allow for expeditious recognition and management.

SPCR-05 ENVIRONMENTAL ENRICHMENT AMONG BRAINTUMOR SURVIVORS

Abstract Individuals from underserved communities who received photon radiation are at a disproportionately increased risk of accelerated aging and symptom burden that significantly impacts independence and overall functioning. There is limited knowledge of environmental factors that mitigate these long-term sequelae. The aim of the study is to explore if higher levels of environmental enrichment (EE) are neuroprotective against accelerated brain aging experienced by brain tumor (BT) survivors who received radiation. METHODS: The study employed a retrospective cohort design among persons with low-grade glioma treated with radiation approximately 5 years from the original diagnosis (N=39). EE consists of social network/engagement, physical activity, and employment status/financial stability measured by the Berkman-Syme Social Network Index, International Physical Activity Questionnaire, Vocational Index Scale, and Socioeconomic Questionnaires, respectively. EE at enrollment is classified into high, moderate, or low levels. Montreal Cognitive Assessment and Symbol Digit Modality Test at enrollment measure cognitive function. Karnofsky Performance Status Scale and the MD Anderson Symptom Inventory – BT module at enrollment are used to measure functional status. Cortical volume is measured using temporal brain MRI images from the time of diagnosis, 3 and 5 years after diagnosis. Images are processed using FreeSurfer segmentation software. Linear mixed models will estimate mean cerebral atrophy and explore the association to cognitive and functional data across time adjusted for covariates. RESULTS: Research analysis in progress. Thirty-nine participants have been enrolled in the study. The median age is 44, 22 are male, and 27 are female. There are 18 Individuals diagnosed with Astrocytoma and 19 with Oligodendroglioma. Thirty-three percent of individuals have low EE, 43.5% have moderate EE, and 23% have high EE. CONCLUSION: BT survivors are at an increased risk of accelerated aging and progressive neurological decline. EE may serve as a positive stimulation that improves neuroplasticity and reduces accelerated aging after brain radiation.

The natural history study of preclinical genetic Creutzfeldt-Jakob Disease (CJD): a prospective longitudinal study protocol

BackgroundCreutzfeldt-Jakob Disease (CJD) is the most common prion disease in humans causing a rapidly progressive neurological decline and dementia and is invariably fatal. The familial forms (genetic CJD, gCJD) are caused by mutations in the PRNP gene encoding for the prion protein (PrP). In Israel, there is a large cluster of gCJD cases, carriers of an E200K mutation in the PRNP gene, and therefore the largest population of at-risk individuals in the world. The mutation is not necessarily sufficient for the formation and accumulation of the pathological prion protein (PrPsc), suggesting that other, genetic and non-genetic factors affect the age at symptoms onset. Here we present the protocol of a cross-sectional and longitudinal natural history study of gCJD patients and first-degree relatives of gCJD patients, aiming to identify biological markers of preclinical CJD and risk factors for phenoconversion.MethodsThe study has two groups: Patients diagnosed with gCJD, and first-degree healthy relatives (HR) (both carriers and non-carriers of the E200K mutation in the PRNP gene) of patients diagnosed with gCJD. At baseline, and at the end of every year, healthy participants are invited for an “in-depth” visit, which includes a clinical evaluation, blood and urine collection, gait assessment, brain MRI, lumbar puncture (LP), and Polysomnography (PSG). At 6 months from baseline, and then halfway through each year, participants are invited for a “brief” visit, which includes a clinical evaluation, short cognitive assessment, and blood and urine collection. gCJD patients will be invited for one “in-depth” visit, similar to the baseline visit of healthy relatives.DiscussionThis continuous follow-up of the participants and the frequent assessments will allow early identification and diagnosis in case of conversion into disease. The knowledge generated from this study is likely to advance the understanding of the underlying clinicopathological processes that occur at the very beginning of CJD, as well as potential genetic and environmental risk factors for the development of the disease, therefore advancing the development of safe and efficient interventions.Trial registrationThe study is an observational study. It has registered retrospectively in https://clinicaltrials.gov/ and has been assigned an identification number NCT05746715.

Síndrome meníngeo crónico. Afectación meníngea de etiología no infecciosa

Noninfectious chronic meningitis (NICM) is defined as meningeal inflammation unrelated to an infectious process that progresses with signs and symptoms which persist for more than four weeks. The most common clinical manifestation is headache in varying combinations with altered mental status, focal neurological signs, fever, nuchal rigidity, myelopathy, cranial neuropathies, or polyradiculopathies. The approach to NICM begins with a medical history, full physical examination, and additional tests (serological tests, brain imaging tests, lumbar puncture, and biopsy of skin lesions and lymph nodes). Cerebral and meningeal biopsy can be considered in cases that progress with progressive neurological decline and an inconclusive systemic or CSF study. Systemic diseases with meningeal involvement tend to progress with a combination of chronic or relapsing chronic meningitis and uveitis (uveo-meningeal syndromes). For the initial treatment, high doses of corticosteroids and, in refractory cases, immunosuppressants are required. Neoplastic meningitis presents with both solid tumors and with malignant cerebral and hematological neoplasms; its treatment depends on the type of neoplasm. The drugs most commonly associated with NICM are intravenous non-steroidal anti-inflammatory drugs, sulfamides, penicillins, and immunoglobulins. The prognosis is good, with improvement after withdrawal of the drug implicated.

Intradural Extramedullary Pyogenic Abscess: Incidence, Management, and Clinical Outcomes in 45 Patients With a Mean Follow Up of 2 Years.

Retrospective review. Spinal intradural extramedullary abscess (SIEA) is a rare disease with an unknown incidence. In this study, we systematically described the clinical course of SIEA in a large cohort with acute onset of neurological illness, assessed the morbidity and mortality rates, and determined the potential risk factors for mortality. Electronic medical records of patients diagnosed with SIEA at a single institution for the period between September 2005 and December 2020 were retrieved. Over a period of 15years, 881 patients with spinal infections were treated either conservatively or surgically at our center, of whom 45 patients (45/881, 5.1%) had SIEA. The overall mean age was 69.6 ± 5.6years of patients diagnosed with SIEA and all of them underwent posterior decompression via laminectomy. The mean Charlson Comorbidity Index (CCI) was 6.9 ± 2.5, indicating a poor baseline reserve. Progressive neurological decline was observed in all patients (mean motor score, 88.6 ± 9.7). The in-hospital rate and 90-day mortality were 4.4% and 10%, respectively. Mortality was not surgery related. Most importantly, the patients' motor deficits and blood infection parameters significantly improved after surgery. Risk factors for mortality were increased age, comorbidities as measured by CCI, and preoperative motor weakness (MS). Immediate surgical decompression via laminectomy, with antiseptic irrigation and drainage of the subdural space, followed by antibiotic therapy, appears to be the key to ensuring beneficial clinical outcomes to treatment of rare diseases such as SIEA.

Emergency surgical decompression for spontaneous spinal epidural hematoma in octogenarians: risk factors, clinical outcomes, and complications

PurposeSpontaneous spinal epidural hematoma (SSEH) is a rare but disabling disease. Although several cases have been reported in the literature, their treatment remains unclear, especially in patients with advanced age. We, therefore, aimed to describe the clinical outcomes of cervical SSEH in octogenarians with an acute onset of neurological illness undergoing laminectomy.MethodsElectronic medical records from a single institution between September 2005 and December 2020 were retrieved. Data on patient demographics, neurological conditions, functional status, surgical characteristics, complications, hospital course, and 90-day mortality were also collected.ResultsTwenty-two patients aged ≥ 80 years with SSEH undergoing laminectomy were enrolled in this study. The mean Charlson comorbidity index was 9.1 ± 2.0, indicating a poor baseline reserve. Ten individuals (45.5%) were taking anticoagulant agents with a pathologic partial thromboplastin time (PTT) of 46.5 ± 3.4 s. Progressive neurological decline, as defined by the motor score (MS), was observed on admission (63.8 ± 14.0). The in-hospital and 90-day mortality were 4.5% and 9.1%, respectively. Notably, the MS (93.6 ± 8.3) improved significantly after surgery (p < 0.05). Revision surgery was necessary in 5 cases due to recurrent hematoma. Anticoagulant agents and pathological PTT are significant risk factors for its occurrence. Motor weakness and comorbidities were unique risk factors for loss of ambulation.ConclusionsLaminectomy and evacuation of the hematoma in octogenarians with progressive neurological decline induce clinical benefits. Emergent surgery seems to be the “state of the art” treatment for SSEH. However, potential complications associated with adverse prognostic factors, such as the use of anticoagulants, should be considered.

Intravitreal gene therapy preserves retinal function in a canine model of CLN2 neuronal ceroid lipofuscinosis

CLN2 neuronal ceroid lipofuscinosis is a rare hereditary neurodegenerative disorder characterized by deleterious sequence variants in TPP1 that result in reduced or abolished function of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Children with this disorder experience progressive neurological decline and vision loss starting around 2–4 years of age. Ocular disease is characterized by progressive retinal degeneration and impaired retinal function culminating in total loss of vision. Similar retinal pathology occurs in a canine model of CLN2 disease with a null variant in TPP1. A study using the dog model was performed to evaluate the efficacy of ocular gene therapy to provide a continuous, long-term source of human TPP1 (hTPP1) to the retina, inhibit retinal degeneration and preserve retinal function. TPP1−/− dogs received an intravitreal injection of 1 x 1012 viral genomes of AAV2.CAG.hTPP1 in one eye and AAV2.CAG.GFP in the contralateral eye at 4 months of age. Ophthalmic exams, in vivo ocular imaging and electroretinography were repeated monthly to assess retinal structure and function. Retinal morphology, hTPP1 and GFP expression in the retina, optic nerve and lateral geniculate nucleus, and hTPP1 concentrations in the vitreous were evaluated after the dogs were euthanized at end stage neurological disease at approximately 10 months of age. Intravitreal administration of AAV2.CAG.hTPP1 resulted in stable, widespread expression of hTPP1 throughout the inner retina, prevented disease-related declines in retinal function and inhibited disease-related cell loss and storage body accumulation in the retina for at least 6 months. Uveitis occurred in eyes treated with the hTPP1 vector, but this did not prevent therapeutic efficacy. The severity of the uveitis was ameliorated with anti-inflammatory treatments. These results indicate that a single intravitreal injection of AAV2.CAG.hTPP1 is an effective treatment to inhibit ocular disease progression in canine CLN2 disease.

Spinal Meningioma Surgery in Octogenarians: Functional Outcomes and Complications over a 2-Year Follow-Up Period.

Background and Objectives: Population aging in industrial nations has led to an increased prevalence of benign spinal tumors, such as spinal meningiomas (SMs), in the elderly. The leading symptom of SM is local pain, and the diagnosis is confirmed after acute neurological decline. However, little is known about the optimal treatment for this frail patient group. Therefore, this study sought to assess the clinical outcome, morbidity, and mortality of octogenarians with SMs and progressive neurological decline undergoing surgery and to determine potential risk factors for complications. Materials and Methods: Electronic medical records dated between September 2005 and December 2020 from a single institution were retrieved. Data on patient demographics, neurological conditions, functional status, degree of disability, surgical characteristics, complications, hospital course, and 90-day mortality were collected. Results: Thirty patients aged ≥80 years who were diagnosed with SMs underwent posterior decompression via laminectomy and microsurgical tumor resection. The patients presented with a poor baseline history (mean CCI 8.9 ± 1.6 points). Almost all SMs were located in the thoracic spine (n = 25; 83.3%). Progressive preoperative neurological decline was observed in 21/30 (n = 21; 70%) patients with McCormick Scores (mMCS) ≥3, and their mean motor score (MS) was 85.9 ± 12.3. in the in-hospital and 90-day mortality rates were 6.7% and 10.0%, respectively. The MS (93.6 ± 8.3) and mMCS (1.8 ± 0.9) improved significantly postoperatively (p < 0.05). The unique risk factor for complications was the severity of comorbidities. Conclusions: Decompressive laminectomy and tumor removal in octogenarians with progressive neurological decline improved patient functional outcomes at discharge. Surgery seems to be the “state of the art” treatment for symptomatic SMs in elderly patients, even those with poor preoperative clinical and neurologic conditions, whenever there is an acceptable risk from an anesthesiological point of view.

AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range

BackgroundHereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan. MethodsWe performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing. ResultsWe describe 7 patients (4 males, 2–31 years of age) with developmental delay and spasticity.Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly. ConclusionIn this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.

Abstract 15 Safety of DUOC-01, Intrathecal Cord Blood-Derived Cellular Therapy, as an Adjunct to Allogeneic Cord Blood Transplantation in Children with Inherited Metabolic Diseases

IntroductionUnrelated donor umbilical cord blood transplantation (CBT) improves function and extends life in children with certain inherited metabolic diseases (IMDs); however, progressive neurologic decline often occurs during the few months post-CBT prior to donor engraftment in the brain, causing residual, irreversible impairments. We previously described donor engraftment in the brain after CBT and developed DUOC-01, a monocyte-derived CB cell product, to attempt to accelerate donor cell delivery to the brain.ObjectiveThe objective of this study was to determine manufacturing feasibility and safety of intrathecal DUOC-01 in a phase I study in children with IMDs undergoing CBT after myeloablative cytoreduction (busulfan/cyclophosphamide/anti-thymocyte globulin).MethodsDUOC-01 was manufactured in adherent cell culture in a GMP lab over 21 days with a target dose of ≤100 × 105 cells. When cell dose permitted, 80% of the CB unit was used for transplant and 20% of the same unit was used to manufacture DUOC-01. Otherwise, DUOC-01 was manufactured from a unique CB unit. On day ≥+28 post-CBT, if there was evidence of hematopoietic engraftment without severe graft versus host disease or morbidity, DUOC-01 cells were harvested and administered intrathecally. Safety was monitored via neurologic exams, neuroimaging, and CSF studies.ResultsForty patients (aged 0-15 years) underwent CBT, 37 engrafted with donor cells. Median infused total nucleated cell count was 6.5 × 107/kg (range 2.9-33.1 × 107/kg); median time to neutrophil engraftment was 20 days (range 13-46 days). Ten patients did not receive DUOC-01 cells for the following reasons: engraftment failure (3), transplant-related morbidity (4), and low manufacturing yield (3). Thirty patients received 0.2-100 × 105 DUOC-01 cells intrathecally for a median of 31 days (range 27-77 days) post-CBT (19 with the same CB donor and 11 with a unique CB donor). Two patients developed transient fever and hypotension hours after unique-donor DUOC-01, consistent with an inflammatory response. Hydrocortisone (HC) was added to the final formulation, and post-validation, seven additional patients received unique-donor DUOC-01+HC without incident. No other DUOC-01-related serious adverse events occurred.DiscussionDUOC-01 is a CB-derived product intended to accelerate donor cell delivery to the brain of children with IMDs undergoing CBT. Intrathecal DUOC-01 administration is well-tolerated post-CBT from the same donor and, with the addition of HC, also from a unique donor. Escalating DUOC doses are being tested for safety and exploration of potential efficacy in a phase Ia trial of adults with multiple sclerosis.

Potassium channel Kir 4.1 regulates oligodendrocyte differentiation via intracellular pH regulation.

In humans, loss-of-function mutations of Kcnj10 in SeSAME/EAST syndrome, which encodes the inwardly rectifying K+ channel 4.1 (Kir 4.1), causes progressive neurological decline. Despite its rich expression in oligodendrocyte (OL) lineage cells and an emerging link with demyelinating disease, the function of Kir 4.1 in OLs is unclear. Here we show a novel role of Kir 4.1 in OL development. Kir 4.1 expression is markedly greater in OLs than in OL precursor cells (OPCs), and the down-regulation of Kir 4.1 impairs OL maturation by affecting OPC differentiation. Interestingly, Kir 4.1 regulates the intracellular pH of OPCs and OLs via the Na+ /H+ exchanger, which underlies impeded OPC differentiation by Kir 4.1 inhibition. Furthermore, Kir 4.1 regulates GSK3β and SOX10, two molecules critical to OPC development. Collectively, our work opens a new avenue to understanding the functions of Kir 4.1 and intracellular pH in OLs.

Intermittent lipid nanoparticle mRNA administration prevents cortical dysmyelination associated with arginase deficiency

Arginase deficiency is associated with prominent neuromotor features, including spastic diplegia, clonus, and hyperreflexia; intellectual disability and progressive neurological decline are other signs. In a constitutive murine model, we recently described leukodystrophy as a significant component of the central nervous system features of arginase deficiency. In the present studies, we sought to examine if the administration of a lipid nanoparticle carrying human ARG1 mRNA to constitutive knockout mice could prevent abnormalities in myelination associated with arginase deficiency. Imaging of the cingulum, striatum, and cervical segments of the corticospinal tract revealed a drastic reduction of myelinated axons; signs of degenerating axons were also present with thin myelin layers. Lipid nanoparticle/ARG1 mRNA administration resulted in both light and electron microscopic evidence of a dramatic recovery of myelin density compared with age-matched controls; oligodendrocytes were seen to be extending processes to wrap many axons. Abnormally thin myelin layers, when myelination was present, were resolved with intermittent mRNA administration, indicative of not only a greater density of myelinated axons but also an increase in the thickness of the myelin sheath. In conclusion, lipid nanoparticle/ARG1 mRNA administration in arginase deficiency prevents the associated leukodystrophy and restores normal oligodendrocyte function.