Review of the spectrum of tuberous sclerosis complex: The Saudi Arabian Experience.

OBJECTIVES: To determine the prevalence of tuberous sclerosis complex (TSC) in the paediatric Saudi population and to characterise the range of clinical symptoms, neurocutaneous findings, neuroimaging results, and complications of the disease. METHODS: A total of 61 genetically confirmed TSC patients from the National Guard Health Affairs (NGHA) in Saudi Arabia were the subject of this retrospective descriptive analysis. The data were presented using descriptive measures. RESULTS: The mean age at diagnosis was found to be 4.9 years. Subependymal nodules (86.9%), numerous cortical tubers and/or radial migration lines (63.9%), and hypomelanotic macules (63.9%) were the 3 most common significant criteria. The vast majority (86.9%) of those diagnosed had epilepsy, of which 50% were considered medically intractable. Nearly half of our subjects underwent genetic testing, which revealed that TSC2 predominated over TSC1. Symptoms of Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders (TAND) were present in 66.7% of TSC1 patients and 73.9% of TSC2 patients. CONCLUSION: The findings of this study demonstrate that the clinical spectrum of TSC among Saudi children is consistent with the body of existing literature. The TSC2 was more prevalent than TSC1. The most frequent signs were cutaneous and neurological. Monitoring TSC patients regularly is crucial to identify any issues as soon as possible.

Epidemiology and Outcomes of Neurofibromatosis Type 1 (NF-1): Multicenter Tertiary Experience.

Purpose: The aim of this manuscript was to assess the epidemiology and clinical features of Neurofibromatosis type 1 (NF-1) based on the newly published revised NF-1 diagnostic criteria and to evaluate complications of NF-1 including neurodevelopmental disorders. Patients and methods: A retrospective cross-sectional observational study was conducted in the Ministry of National Guard Health Affairs (MNGHA) healthcare organization branches including four tertiary hospitals and 51 primary health care centers in different regions in Saudi Arabia. This study included all patients diagnosed with NF1 using the revised NIH diagnostic criteria published in 2021 that were registered at the electronic medical records (EMR) from 2015 to 2021. Results: A total of 184 patients fulfilled the diagnostic criteria and were included in this study. The median age at diagnosis was 11 years (IQR: 4.00-20.25). The most encountered diagnostic criteria in this study were Café-au-lait macules (85.3%), and (42.9%) were found to have two or more neurofibromas with plexiform neurofibroma being the most common subtype (23.36%), approximately (36.4%) of the patient with optic pathway glioma. Nearby (26.6%) of the patients displayed different type of tumors. Iris Lisch nodules were presented in 36.4% of patients at a median age of 12 years (IQR: 9.0-21.8). Cardiovascular abnormality was encountered in 9.8% of the patients. Around 27.7% of the patients reported headache and 11.4% of the patient suffered from different type of epilepsy. Besides, 10.5% of the patients had intellectual disability, 33.8% suffered from communication disorders, and 4.9% patients had ADHD. Conclusion: The results of this study will enable practitioners to adopt a more holistic approach and prioritize numerous attributes, which they can subsequently incorporate into their therapeutic methodologies. Furthermore, the identification of these attributes will facilitate an expeditious and accurate diagnosis. Hence, the implementation of intervention during its nascent phase may result in a more advantageous consequence.

Parkinsonism-dystonia-2: Case-series study from Saudi Arabia.

Parkinsonism-dystonia-2 PKDYS2 is an autosomal-recessive disorder, caused by pathogenic biallelic variants in SLC18A2 which encodes the vesicular monoamine transporter (VMAT2) protein. PKDYS2 is a treatable neurotransmitter disease, and the rate of diagnosis of this disorder has increased significantly with the advance of genomic technologies. Our report highlights a novel pathologic variant in one case and a novel finding on MRI Brain, consisting of a normal symmetrical signal intensity in the dorsal brainstem and pons, and it substantiates the significance of genetic testing in the evaluation of children with developmental delays, which influences clinical decisions to enhance patient outcomes.

Estimation of Vitamin D Levels Using a Chairside Diagnostic Test Kit in Patients with Gingivitis and Periodontitis: A Cross-Sectional Study.

Aim: Periodontitis is an inflammatory condition of the periodontium that is instigated by microbial biofilms developed on the teeth. The purpose of the study was to ascertain the vitamin D status of gingivitis and periodontitis patients while maintaining a healthy group as the control using simple low-cost chairside pre-coated with 25-OH Vitamin D antigen rapid test kits. Materials and Methods: From outpatients visiting the college's periodontics clinics, a total of 101 patients were screened. The study sample includes 38 patients in the periodontitis group, 32 in the gingivitis group, and 31 in the healthy group. A middle-digit needle was used to collect blood samples, which were put into a test cassette with membrane that had been coated with 25-OH Vitamin D antigen on the test line area of the strip. Vitamin D Quick Test (Natejah) Semi-quantitatively detects 25-hydroxyvitamin D (25 (OH) D) in human finger-stick complete blood at a cutoff convergence of 30 ± 4 ng/mL. Vitamin D blood levels below 80 nmol/L are considered to have deficient vitamin 25(OH)D levels. Clinical parameters between healthy, gingivitis, and different stages of periodontitis subjects were compared using one-way ANOVA and Tukey's multiple comparison. Fisher's exact test was done to compare vitamin D levels in the three groups. Results: Fisher's exact test revealed that there was a statistically significant increase in the number of subjects with stages 4 and stage 3 periodontitis who lacked vitamin D levels (less than 80 nmol/L). Whereas least deficient in Vit D were noticed among Healthy and Gingivitis subjects. When compared to healthy individuals, gingivitis, and various stages of periodontitis had significantly higher mean PI values in a Tukey's multiple comparison. Vitamin D deficiency was found to be 27.5% in subjects with gingivitis and 71.5% in subjects with periodontitis. Conclusion: Periodontitis is associated with vitamin D deficiency, in contrast to gingivitis and healthy subjects. The severity of periodontitis was likewise linked to the amount of vitamin D in the individual's blood. When compared to expensive, time-consuming, and laborious laboratory methods, the findings of this study suggest that a simple inexpensive chairside pre-coated with 25-OH Vitamin D antigen rapid test kits can be considered a viable alternative for determining vitamin D levels.

Neonatal seizures: Etiologies, clinical characteristics, and radiological features: A cross-sectional study.

Seizures are a common clinical indication of central nervous system damage or abnormality in neonates. We aimed to identify the etiologies, clinical characteristics, and radiological features of neonatal seizures. This is a cross-sectional, retrospective, descriptive study using data obtained from the neonatal intensive care unit in King Abdulaziz Medical City (KAMC), a governmental, academic tertiary hospital in Riyadh, Saudi Arabia. The population of interest were neonates diagnosed with a neonatal seizure at KAMC between April 2015 and March 2019. A total of 61 patients with neonatal seizures were included in the study. The most common etiology was hypoxic-ischemic encephalopathy (43%). A total of 32 patients were full-term (52.5%). Around one-fifth of the study sample (21.3%) had a family history of neonatal seizures. Around 43.0% of the patients had epilepsy episodes. More than half of the patients (57.0%) were on one anti-seizure medication. Patients were followed up after 1 year, they had multiple comorbidities, including developmental delay, epilepsy, and cerebral palsy. Developmental delay was identified in 62.3% of the patients. A total of 19 patients have passed away (31%). Neonatal seizures are a common manifestation of neurologic disorders in neonates and are associated with high morbidity and mortality. Therefore, early identification of seizure etiology and proper management may help to improve the outcome.

Effectiveness of intra-thecal methotrexate in refractory Anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND: Anti-N-methyl-d-aspartate "anti-NMDA" receptor encephalitis is one of the most common autoimmune encephalitis for which first- and second-line therapies have been recommended following international consensus. However, some refractory cases do not respond to the first- and second-line therapy and require further immune-modulatory therapies such as intra-thecal methotrexate. In this study, we reviewed six confirmed cases of refractory anti-NMDA receptor encephalitis from two tertiary centers in Saudi Arabia that required escalation of treatment and received a six-month course of intra-thecal methotrexate. The aim of this study was to evaluate the effectiveness of intra-thecal methotrexate as immunomodulatory therapy for refractory anti-NMDA receptor encephalitis. METHODS: We retrospectively evaluated six confirmed cases of refractory anti-NMDA receptor encephalitis who did not improve after first- and second-line therapy and received monthly intra-thecal methotrexate treatment course for six consecutive months. We reviewed patient demography, underlying etiologies, and compared their modified Rankin score prior to receiving intra-thecal methotrexate and six months after completing the treatment. RESULTS: Three of the six patients showed a marked response to intra-thecal methotrexate with a modified Rankin scale of 0-1 at 6-month follow-up. None of the patients experienced any side effects during or after intra-thecal methotrexate treatment, and no flareups were observed. CONCLUSION: Intra-thecal methotrexate may be a potentially effective and relatively safe escalation option for immunomodulatory therapy of refractory anti-NMDA receptor encephalitis. Future studies on intra-thecal methotrexate -specific treatment regimens may further support its utility, efficacy, and safety in treating refractory anti-NMDA receptor encephalitis.

Diagnostic Yield of Neuroimaging for Headache in a Pediatric Emergency Department: A Single Tertiary Centre Experience.

OBJECTIVES: This study aimed to examine headache neuroimaging findings among the pediatric population visiting the emergency department in Saudi Arabia. METHODS: This was a cross-sectional retrospective study of pediatric patients who presented to the emergency department with a headache as their primary complaint. Data were extracted from the electronic medical files of the patients at King Abdullah Specialized Children Hospital (KASCH) between 2015 and 2020. The diagnosis of headache was confirmed using a computerized tomography (CT) scan or magnetic resonance imaging (MRI) upon the patients' presentation. RESULTS: A total of 263 patients met the inclusion criteria, and their data were extracted. The CT scans were abnormal in 50% of the patients. The MRI showed abnormal findings for 26% of the patients. CT scans and MRI identified that abnormalities were predominantly among patients with the secondary type of headache. The most common abnormal findings on CT were sinusitis (16%), masses (7%), and hydrocephalus (7%). The most common abnormal findings on MRI were masses (8%), cysts (5%), and hydrocephalus (3%). Of all patients with headaches, 10% had a prior diagnosis of headache, and 12% had a family history of headache. A significantly higher percentage of patients with secondary headache were prescribed NSAID and required admission compared to patients with primary headache (p ≤ 0.05). There was no statistically significant differences in the proportion of patients diagnosed with primary and secondary headache in terms of their neurological examination and headache types (p = 0.43). CONCLUSIONS: Neuroimaging is essential for diagnosing headaches in children. Headaches were associated with sinusitis in children. The secondary type was more likely to have abnormal CT and MRI results. Primary type headaches were more common in those with a family history. CT scans and MRIs are needed when a headache is accompanied by an abnormal clinical evaluation. Neuroimaging and mild CT usage may be explored if there are clinical abnormalities or family history.

Orbital pseudotumor in pediatrics: A single tertiary center experience.

Orbital pseudotumor is a rare condition characterized by an idiopathic inflammatory process of the orbit with a polymorphous lymphoid infiltrate. It is misdiagnosed as orbital cellulitis or orbital mass with conjunctivitis in children.

Clinical Characteristics and Risk Factors of Neonatal Hypoxic-Ischaemic Encephalopathy and Its Associated Neurodevelopmental Outcomes During the First Two Years of Life: A Retrospective Study in Saudi Arabia.

Objective: This study aimed to determine the clinical characteristics and factors associated with neonatal hypoxic-ischaemic encephalopathy (HIE) and its neurodevelopmental outcomes. Methods: We conducted retrospective case-control research to investigate the clinical and labour-related risk factors for HIE. In addition, a single-centre cohort study was conducted on infants with HIE to describe their neurodevelopment from birth to 24 months. For this investigation, cases with a diagnosis of HIE who were born at King Abdullah Children's Specialist Hospital (KASCH), Riyadh, Saudi Arabia, between 2015 and 2019 were identified and matched with controls from the same facility (1:4). Each case's clinical information was extracted using electronic medical records. In addition, 24-month follow-up HIE cases were included in a cohort study to describe their neurodevelopmental outcomes. Results: The sample includes 60 infants diagnosed with HIE and 234 infants serving as controls, with a mean gestational age of 38.8 weeks (SD 1.6) and a predominance of males (56.4%). Around one-third of the HIE cases (36.6%) had moderate HIE (stage 2), whereas 35.1% of infants had severe HIE (stage 3), according to Sarnat staging. Compared to the control group, children with HIE were twice as likely to be born to mothers with maternal comorbidities and more likely to have prepartum and intrapartum complications. A 24-month follow-up of neurodevelopmental outcomes for HIE babies revealed that approximately 24% exhibited delays in gross motor skill development, 22% in fine motor skill development, 33% in language skill development, and 22% in social skill development. Conclusion: In the HIE group, maternal comorbidities and prepartum or intrapartum complications were more common. The severity grade of HIE can be used to predict neurodevelopmental consequences. Enhancing patient care and rehabilitation requires a minimum of 24 months of neurodevelopmental follow-up.

Milder presentation of autosomal dominant fatty acyl CoA reductase 1-related syndrome: Report of the first Middle Eastern patient and review of the literature.

The FAR1-related phenotypes caused by the FAR1 gene encodes the peroxisomal protein fatty acyl-CoA reductase 1 (FAR1), which is required to reduce fatty acids to fatty alcohols used to form ether-linked alkyl bonds. Biallelic loss-of-function variants have been associated with severe psychomotor developmental delay, seizures, cataracts, growth retardation with microcephaly, and spasticity. However, heterozygous variants in FAR1 have been recently linked to a rare genetic disorder called cataracts, spastic paraparesis, and speech delay (CSPSD). Here, we present the first Middle Eastern patient with a de novo pathogenic heterozygous variant in FAR1 identified by exome sequencing (ES) analysis and a detailed overview of the reported clinical phenotypes and genotypes. Our patient represents the milder end of the clinical spectrum, with medication-free seizures by the first year of life, proper speech and fine motor development, as well as an absence of other previously reported features such as learning difficulties, axial hypotonia, and joint contracture. In addition, she had developmental dysplasia of the hip (DDH) that failed medical management, as well as faltering growth. Our patient adds to the small number of patients recognized to date and expands the clinical spectrum to provide better clinical delineation, improve diagnosis, and develop precision medicine approaches for this disorder.

Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome.

BACKGROUND: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40 mg daily of elamipretide in patients with BTHS. METHODS: This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments). RESULTS: For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7 m (P = 0.0004) at week 64 and 91.0 m (P = 0.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64 weeks (P = 0.0002) and 56.7 Newtons at 76 weeks (P = 0.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs. CONCLUSIONS: Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs. HIGHLIGHTS: A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS.

Quality of life in Barth syndrome.

Introduction: Barth syndrome (BTHS) is a rare X-linked disorder characterized by cardiomyopathy, neutropenia, growth abnormalities, and skeletal myopathy. There have been few studies investigating health-related quality of life (HRQoL) in this population. This study investigated the impact of BTHS on HRQoL and select physiologic measures in affected boys and men. Methods: In this study, we characterize HRQoL in boys and men with BTHS through cross-sectional analysis of a variety of outcome measures including the Pediatric Quality of Life Inventory (PedsQLTM) Version 4.0 Generic Core Scales, PedsQLTM Multidimensional Fatigue Scale, Barth Syndrome Symptom Assessment, the PROMISTM Fatigue Short Form, the EuroQol Group EQ-5DTM, the Patient Global Impression of Symptoms (PGIS), and the Caregiver Global Impression of Symptoms (CaGIS). For a specific subset of participants, physiologic data were available in addition to HRQoL data. Results: For the PedsQLTM questionnaires, 18 unique child and parent reports were analyzed for children aged 5-18 years, and nine unique parent reports were analyzed for children aged 2-4 years. For the other HRQoL outcome measures and physiologic measurements, the data from 12 subjects (age range 12-35 years) were analyzed. Based on parent and child reports, HRQoL is significantly impaired in boys and men with BTHS, especially in school functioning and physical functioning. Parent and child reports of more severe fatigue are significantly correlated with more impaired HRQoL. When exploring the potential relationship between physiology and HRQoL, the CaGIS as a whole for pediatric subjects and individual questionnaire items from the PGIS and CaGIS for pediatric subjects assessing tiredness, muscle weakness, and muscle pain showed the strongest correlations. Conclusion: This study provides a unique characterization of the HRQoL in boys and men with BTHS using a variety of outcome measures, and it highlights the negative impact of fatigue and muscle weakness on HRQoL in BTHS. Trial registry name: A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects with Barth Syndrome (TAZPOWER). https://clinicaltrials.gov/ct2/show/NCT03098797.Registration Number: NCT03098797.

Quality of Life in Barth Syndrome Barth syndrome is a rare disorder characterized by heart issues, muscle weakness, tiredness, exercise intolerance, and growth delays. The study was done to determine the effect of Barth syndrome on health-related quality of life of the boys and men affected. We analyzed health-related quality of life questionnaires completed by subjects and/or their parents from the following: • Interdisciplinary Barth Syndrome Clinic at Kennedy Krieger Institute. There were 24 subjects in total from this clinic. • Baseline data from a clinical drug trial for Barth Syndrome that included both health-related quality of life data and physical function data. There were data from 12 subjects in total from the trial. We discovered that health-related quality of life is significantly impaired in boys and men with Barth syndrome, especially in school and physical function. Parent and child reports of more severe tiredness are significantly linked with impaired health-related quality of life. There are strong relationships between some health-related quality of life reports and physical function measurements. Tiredness and muscle weakness negatively impact health-related quality of life. We are hopeful that the results of this study will be used in the treatment of boys and men with Barth syndrome to result in improved health-related quality of life.

Pediatrics COVID-19 and neurological manifestations: Single tertiary centre experience.

IMPORTANCE: Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome that is caused by a novel coronavirus 2 (SARS-CoV-2). It originated in China late December 2019 and was declared a global pandemic on March 12, 2020. Most reports of COVID-19 cases either presented with neurological manifestations or complications involve adults. Only few cases were reported in pediatric patients. OBJECTIVE: To report COVID-19 pediatric cases with neurological manifestations and identify the wide spectrum of its manifestations. DESIGN SETTING AND PARTICIPANTS: This was a retrospective, observational case series. Data of pediatric patients infected by SARS-CoV-2 presenting with neurological manifestations at King Abdullah Specialized Children Hospital in King Abdulaziz Medical City in Riyadh were collected from May 23 to June 30, 2020. RESULTS: We encountered 5 COVID-19 cases with neurological manifestations. Three patients who were previously healthy had new-onset neurological symptoms. Symptoms and signs included encephalopathy, ataxia, headache, seizure, papilledema, ophthalmoplegia, hyporeflexia, and different clinical spectra, such as Miller Fisher syndrome, meningoencephalitis, and idiopathic intracranial hypertension. Other patients attending our center were incidentally found to be SARS-CoV-2-positive, which caused a delay in the investigations required to reach diagnosis. CONCLUSIONS AND RELEVANCE: Our cases highlight the wide clinical spectrum of neurological manifestations in COVID-19 patients. Given the paucity of information about pediatric COVID-19 cases with neurological symptoms, we here reported these cases to shed light on the association between SARS-CoV-2 and neurological presentation. Moreover, our study indicates that many investigations are being delayed and could affect diagnosis and treatment.

The Leukodystrophy Spectrum in Saudi Arabia: Epidemiological, Clinical, Radiological, and Genetic Data.

Background: Leukodystrophies (LDs) are inherited heterogeneous conditions that affect the central nervous system with or without peripheral nerve involvement. They are individually rare, but collectively, they are common. Thirty disorders were included by the Global Leukodystrophy Initiative Consortium (GLIA) as LDs. Methods: We conducted a retrospective chart review of a consecutive series of patients diagnosed with different types of LD from four large tertiary referral centers in Riyadh, Saudi Arabia. Only those 30 disorders defined by GLIA as LDs were included. Results: In total, 83 children from 61 families were identified and recruited for this study. The male-to-female ratio was 1.5:1, and a consanguinity rate of 58.5% was observed. An estimated prevalence of 1:48,780 or 2.05/100,000 was observed based on the clinical cohort, whereas a minimum of 1:32,857 or 3.04/100,000 was observed based on the local genetic database. The central region of the country exhibited the highest prevalence of LDs (48.5%). The most common LD was metachromatic leukodystrophy (MLD), and it accounted for 25.3%. The most common disorder based on carrier frequency was AGS. Novel variants were discovered in 51% of the cases, but 49% possessed previously reported variants. Missense variants were high in number and accounted for 73% of all cases. Compared with other disorders, MLD due to saposin b deficiency was more common than expected, Pelizaeus-Merzbacher-like disease was more prevalent than Pelizaeus-Merzbacher disease, and X-linked adrenoleukodystrophy was less common than expected. The mortality rate among our patients with LD was 24%. Conclusion: To the best of our knowledge, this is the largest cohort of patients with LD from Saudi Arabia. We present epidemiological, clinical, radiological, and genetic data. Furthermore, we report 18 variants that have not been reported previously. These findings are of great clinical and molecular utility for diagnosing and managing patients with LD.

The re-occurrence of cardiomyopathy in propionic acidemia after liver transplantation.

Cardiomyopathy is a frequent complication of propionic acidemia (PA). It is often fatal, and its occurrence is largely independent of classic metabolic treatment modalities. Liver transplantation (LT) is a treatment option for severe PA as the liver plays a vital role in metabolism of the precursors that accumulate in patients with PA. LT in PA is now considered to be a long-lasting and valid treatment to prevent cardiac disease. The subject of this report had severe cardiomyopathy that largely disappeared prior to undergoing a LT. Three years following the transplant, there was recurrence of cardiomyopathy following a surgery that was complicated with a postoperative aspiration pneumonia. On his last hospital admission, he was presented with pulmonary edema and heart failure. He continued with episodes of intractable hypotension, despite maximum inotropic and diuretic support. He died following redirection of care. We conclude that lethal cardiomyopathy may develop several years after successful LT in patients with PA.

PARS2-associated mitochondrial disease: A case report of a patient with prolonged survival and literature review.

Biallelic pathogenic variants in mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) PARS2 are associated with mitochondrial cytopathy. Here, we report the tenth case of an individual with biallelic PARS2 pathogenic variants, detected by exome sequencing (ES), and a literature review of ten cases of PARS2 mutations. Our patient displayed symptoms and clinical and laboratory findings similar to those reported previously with normal lactate levels. These symptoms included seizure disorder (which was managed with antiepileptics), developmental delay, and progressive cardiomyopathy which manifested at 19 years of age. The patient received a vitamin regimen including antioxidants as part of his treatment regimen. While further studies are required to conclusively establish the beneficial role of vitamin and cofactor administration on the mitochondria in PARS2-associated mitochondrial disease, these factors may have delayed the onset of cardiomyopathy.

High-dose hydroxocobalamin achieves biochemical correction and improvement of neuropsychiatric deficits in adults with late onset cobalamin C deficiency.

Cobalamin C (cblC) deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in MMACHC and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late-onset cblC may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late-onset cblC disease, and their biochemical and clinical responses to high-dose hydroxocobalamin. The 28-year-old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high-dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high-dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high-dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late-onset cblC disease.

Metabolic Strokes in Propionic Acidemia: Transient Hemiplegic Events Without Encephalopathy.

Metabolic strokes are a notable feature associated with acute catabolic crises in patients with propionic acidemia. Despite their importance, these events are not well characterized. Here, we present the clinical history of a patient with propionic acidemia who developed 5 episodes of acute hemiparesis between 3 and 11 years of age. The clinical finding of hemiparesis associated with 4 of these 5 events were shorted lived (2-5 days). Neuroimaging showed signal changes in the basal ganglia manifesting many years following the initial episode. Two of the episodes were accompanied by definite seizures. Based on these factors, the hemiparetic events were most consistent with metabolic strokes, though what is distinctive is that most of the events occurred without evidence of metabolic decompensation; brain magnetic resonance imaging findings were not suggestive in the acute setting. We present a framework for evaluating suspected metabolic stroke in propionic acidemia, in light of the sometimes perplexing clinical heterogeneity underlining these events.