ABCD1 Research Articles

A case of X-Linked adrenoleukodystrophy caused by a novel mutation with singular clinical manifestation: unilateral lower limb weakness.

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues. It primarily affects the central nervous system white matter and the adrenal cortex. Clinical manifestations include myeloneuropathy, leukodystrophy, and adrenal insufficiency. Reliable methods for diagnosis include VLCFAs and genetic testing. We report the case of a 31-year-old male X-ALD patient who mainly presented with unilateral lower limb weakness. Adrenal insufficiency was not observed, and there was no evidence of peripheral nerve involvement in nerve conduction studies. MRI revealed only mild atrophy of thoracic spinal cord without other relevant abnormalities. Ultimately, Next-Generation Sequencing (NGS) and VLCFAs testing confirmed the diagnosis of X-ALD, and the NGS indicated a novel missense mutation.

Transient Ischaemic attack Emergency Referral (TIER): randomised feasibility trial results

BackgroundEarly assessment of patients with suspected transient ischaemic attack (TIA) is crucial to provision of effective care, including initiation of preventive therapies and identification of stroke mimics. Many patients with...

An in vitro and in vivo efficacy evaluation of gene therapy candidate SBT101 in mouse models of adrenomyeloneuropathy and in NHPs

Adrenomyeloneuropathy is a progressive neurodegenerative disease caused by pathogenic variants in the ABCD1 gene, resulting in very-long-chain fatty acid (VLCFA) accumulation that leads to dying-back axonopathy. Our candidate gene therapy, SBT101 (AAV9-human ABCD1 [hABCD1]), aims to ameliorate pathology by delivering functional copies of hABCD1 to the spinal cord. Transduced cells produce functional ABCD1 protein, thereby repairing the underlying biochemical defect. Invitro and invivo mouse studies were conducted to assess the biochemical and functional efficacy of SBT101 and show effective delivery to target tissues involved in the disease pathology: spinal cord and dorsal root ganglia. Administration of SBT101 to mixed glial cell cultures from Abcd1-Null mice, and to male Abcd1 knockout (Abcd1 -/y ) and double-knockout (Abcd1 -/y /Abcd2 -/- ) mice led to increased hABCD1 production and reduced VLCFA. Double-knockout mice also exhibited improved grip strength. Furthermore, we conducted biodistribution and safety assessments in nonhuman primates. Six-hour intrathecal lumbar infusions demonstrated effective transduction throughout target tissues,supporting the clinical feasibility of the procedure. SBT101 was well tolerated, with no observed SBT101-relatedmortality or clinical signs. These findings not only providepreclinical efficacy data for SBT101 but also inform clinically relevant SBT101 dose selection for patients with adrenomyeloneuropathy.

8536 Unusual Finding of Familial Adenomatous Polyposis in a Patient with X Linked Adrenoleukodystrophy

Abstract Disclosure: A. Deswal: None. A. Dwarakanathan: None. Introduction: X Linked Adrenal Leukodystrophy (X-ALD) is a rare hereditary genetic disorder of impaired peroxisomal metabolism due to a defective transmembrane protein, ADLP. Defective ADLP impairs transport of VLCFA-CoA esters across cytosol into peroxisomes leading to build-up of toxic VLCFA in the cells. X-ALD is caused by mutation in ABCD1 gene, located on X chromosome, which codes for ADLP. It has a broad clinical spectrum including Cerebral ALD, Adrenomyeloneuropathy and Adrenocortical insufficiency. X-ALD has a general prevalence of 1 in 17,000 newborns. Approximately 80% of males with X-ALD develop primary adrenal insufficiency in their lifetime. It can be diagnosed by measuring VLCFA levels in plasma , checking for ABCD1 gene mutation or by doing Brain MRI (depending upon phenotypical presentation ). Case presentation: We report a case of a 23 year old man who had primary adrenocortical insufficiency subtype of X-ALD. His mother was a carrier of ABCD1 gene mutation. He himself tested hemizygous for ABCD1 gene. He came to our office for a follow up visit after an episode of adrenal crisis for which he was hospitalized. He was started on replacement therapy with prednisone and fludrocortisone. Over the next couple of years, he was diagnosed with diabetes mellitus with initial HbA1C of 8.8%. GAD antibody test for type I DM came out negative. His diabetes was managed with metformin and pioglitazone( later discontinued) .By the age of 25,he was found to have polyposis of colon. He tested positive for APC gene mutation . He underwent a J pouch surgery . He also developed PICA aneurysm. Discussion: X-ALD is a hereditary progressive disease with no association between genetic and phenotypic presentations. Adrenal insufficiency type is usually the first to present. Cerebral ALD is typically diagnosed between the ages of 3-18 presenting as psychiatric illness. Myelopathy typically starts by middle age and involves the spinal cord, causing the affected individuals to develop gait disturbances , bladder and bowel dysfunction, with severe mobility dysfunction by 5th-6th decade of life. We present a unique case of a young man with adrenal insufficiency type of X-ALD who also developed gastrointestinal pathology. Per our literature review, X-ALD has not been seen associated with APC gene mutations or colon carcinomas . Pathology behind XLD revolves around ABCD1 gene mutaion causing VLCFA accumulation in plasma, fibroblasts, adrenal glands, oligodendrocytes , astrocytes etc. Whereas FAP involves APC gene mutation which affects the intestinal epithelial cells leading to their apoptosis and polyp formation. X-ALD and FAP are disorders of two different gene mutations with varied clinical presentations. But the question arises regarding finding of APC gene mutation in a patient with ABCD1 gene mutation that if it is a mere co-incidence or common mutation pathway linking these two disorders exists. Presentation: 6/2/2024

Preventability of ischemic stroke/transient ischemic attack in a tertiary care center in Argentina

IntroductionCardiovascular disease remains a leading cause of morbidity and mortality worldwide, with many individuals presenting with acute ischemic stroke or transient ischemic attack (AIS/TIA) due to underlying vascular risk factors (VRF). While these patients typically undergo routine evaluations for acute treatment, the prevention of these conditions is often underestimated. This study reports the prevalence of non-optimized VRF and estimates their degree of avoidability in a cohort of patients treated in a tertiary care center following AIS/TIA. MethodsThis retrospective study enrolled patients older than 18 years who experienced AIS/TIA over a two-year period. Preventability was defined as the degree to which an acute cerebrovascular event could have been prevented if the VRF had been appropriately treated. Using the variables determined at the onset of AIS or TIA, we developed a 10-point scale to classify the degree of preventability (not preventable [score of 0], low preventability [score of 1–3], and high preventability [score of 4 or higher]). We further defined sub-scores based on the effectiveness of treatment of high blood pressure [HBP] (0-2 points), dyslipidemia [DLP] (0-2 points), atrial fibrillation [AF] (1 point), active smoking [AS] (1 point), obesity (1 point), previous coronary heart disease [CHD] (1 point), and previous AIS/TIA (2 points). Demographic factors, etiologies, and imaging findings were evaluated, tabulated independently, and subsequently correlated with clinical findings extracted from the available patient records. ResultsOf the 395 patients (334 with AIS and 61 with TIA), 376 (95.19 %) exhibited some degree of preventability, whereas 19 (4.81 %) presented with a nonpreventable event. In total, 296 (74.94 %) presented a low preventable event, and 80 (20.25 %) presented a high preventable event. Applying the Chi-square test of independence to stroke etiology highlighted cardio-aortic embolism and large artery atherosclerosis as groups with a significantly higher burden of risk factors necessitating intervention, while patients with stroke of other etiologies had more adequate control of VRF. In terms of stroke severity, as determined by the National Institutes of Health Stroke Scale (NIHSS), patients with NIHSS scores >5 were more likely to experience preventable events. According to the ABCD2 score, higher risk scores were significantly associated with a higher preventive factor burden; however, age, sex, vascular territory, and Canadian TIA scores were not related to the prevention of AIS/TIA. ConclusionsThe high percentage of preventable events reflects the need to study other factors that may contribute to unhealthy lifestyles in this population. Potential reasons for poor health include high levels of stress, sleep deprivation, working conditions and an unhealthy diet. Further studies are required to better understand these phenomena.

Toxicity of antiviral Remdesivir on human liver’s ATP binding cassette subfamily D member 3 transporters

Background and objective: The World Health Organization advises against the use of the antiviral drug Remdesivir to treat severe COVID-19 infections due to potential toxicity. The molecular mechanism of this toxicity is not well established. ATP-binding cassette (ABC) transporters play an essential role in the transport of various drugs in many illnesses. Objective: This study examines the possible role of ATP-binding cassette, subfamily D, member 3 (ABCD3) in Remdesivir toxicity. Methods: Real-time PCR and MTT assays were used to demonstrate the toxicity of Remdesivir on ABCD3 gene expression in the HepG2 cell line. Enzyme-linked immunosorbent assay was used to detect serum ABCD3 levels, Prestige24i was used to detect C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST) in the serum. Nano-Checker710 was used to detect D-dimer in the serum of the patients. Results: Remdesivir exhibits dose-dependent toxicity to the HepG2 cell line. The drug toxicity is significantly increased at three doses of 5, 10, and 20 µg/ml in virus-free hepatic cell lines. It suppressed ABCD3 gene expression in both the HepG2 cell line and COVID-19 patients’ sera. COVID-19 virus increases serum levels of CRP, ALT, AST and D-dimer. The drug lowers serum CRP, transiently lowers D-dimer, and increases ALT and AST levels. Conclusion: Remdesivir suppressed ABCD3 gene expression and increased levels of inflammatory markers. Remdesivir contributes to hepatocyte damage independently of the COVID-19 virus.

Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion

A nine-year boy with adrenoleukodystrophy due to an ABCD1 whole gene deletion was diagnosed with the active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient’s MRI showed gadolinium resolution; whole blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant showing reactivity to peroxisomes, suggesting an immune response, however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient’s whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Easily misdiagnosed X-linked adrenoleukodystrophy

BackgroundAddison’s disease and X-linked adrenoleukodystrophy (X-ALD) (Addison’s-only) are two diseases that need to be identified. Addison’s disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison’s-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison’s disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD.MethodsWe retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics.ResultsTwo patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison’s disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394–2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison’s-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum.ConclusionsPatients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison’s disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison’s-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

A Clinical-Radiomics Nomogram for Predicting Early Ischemic Stroke Risk in Patients with Transient Ischemic Attack

To develop and validate a clinical-radiomics nomogram for predicting early ischemic stroke risk in patients who sustain a transient ischemic attack (TIA). A retrospective training dataset (n= 76) and a prospective validation dataset (n= 34) of patients with TIA were studied. Image processing was performed using ITK-snap and Artificial Intelligent Kit. Radiomics features were selected in R. A nomogram predicting recurrent TIA/stroke in 90 days as a recurrent ischemic event was established. Model performance was assessed by computing the receiver operating characteristic curve and decision curve analysis (DCA). We found a higher proportion of diabetes and hypertension in the patients with recurrent TIA compared with the stable patients in both the training and validation datasets (P < 0.05). Recurrent patients had significantly higher ABCD2 scores and plaque scores compared to stable patients. ABCD2 score and necrotic/lipid core area were independent risk factors for recurrent ischemic events (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.47-6.40; and OR, 1.20; 95% CI, 1.07-1.41, respectively). The radiomics model had area under the curve values of 0.737 (95% CI, 0.715-0.878) in the training dataset and 0.899 (95% CI, 0.706-0.936) in the validation dataset, which was superior to the ABCD2 score and plaque model for predicting stroke recurrence (P < 0.05). The nomogram predicting recurrent ischemic events was 0.923 (95% CI, 0.895-0.978) in the training dataset and 0.935 (95% CI, 0.830-0.959) in the validation dataset. DCA confirmed the clinical value of this nomogram. The nomogram, based on clinical ABCD2 score, carotid plaque components and radiomics score, shows good performance in predicting the risk of recurrent ischemic events in patients with TIA.

Newborn Screening for X-Linked Adrenoleukodystrophy (X-ALD): Biochemical, Molecular, and Clinical Characteristics of Other Genetic Conditions.

The state of California (CA) added X-linked adrenoleukodystrophy (X-ALD) to newborn screening (NBS) in 2016 via the measurement of C26:0-lysophosphatidylcholine (C26:0-LPC) in a two-tier fashion, followed by sequencing of the ABCD1 gene. This has resulted in the identification of individuals with genetic conditions beyond X-ALD that can also result in elevated C26:0-LPC by NBS. We describe the biochemical, molecular, and clinical characteristics of nine patients from two metabolic centers in California who screened positive by NBS for elevated C26:0-LPC between 2016 and 2022 and were ultimately diagnosed with a genetic condition other than X-ALD. Seven individuals were diagnosed with Zellweger spectrum disorder (ZSD) due to biallelic variants in PEX genes. One male was diagnosed with Klinefelter syndrome and one female was found to have an X chromosome contiguous gene deletion syndrome after the identification of a heterozygous VUS and hemizygous VUS variant in ABCD1, respectively. Patients with ZSD had significantly higher first- and second-tier C26:0-LPC levels compared to the two non-ZSD cases. Identification of children with ZSD and atypical patterns of ABCD1 variants is a secondary benefit of NBS for X-ALD, leading to earlier diagnosis, prompt therapeutic initiation, and more accurate genetic counseling. As screening for X-ALD continues via the measurement of C26:0-LPC, our knowledge of additional genetic conditions associated with elevated C26:0-LPC will continue to advance, allowing for increased recognition of other genetic disorders for which early intervention is warranted.

Beyond RCTs: Short-term dual antiplatelet therapy in secondary prevention of ischemic stroke and transient ischemic attack.

Randomized controlled trials (RCTs) proved the efficacy of short-term dual antiplatelet therapy (DAPT) in secondary prevention of minor ischemic stroke or high-risk transient ischemic attack (TIA). We aimed at evaluating effectiveness and safety of short-term DAPT in real-world, where treatment use is broader than in RCTs. READAPT (REAl-life study on short-term Dual Antiplatelet treatment in Patients with ischemic stroke or Transient ischemic attack) (NCT05476081) was an observational multicenter real-world study with a 90-day follow-up. We included patients aged 18+ receiving short-term DAPT soon after ischemic stroke or TIA. No stringent NIHSS and ABCD2 score cut-offs were applied but adherence to guidelines was recommended. Primary effectiveness outcome was stroke (ischemic or hemorrhagic) or death due to vascular causes, primary safety outcome was moderate-to-severe bleeding. Secondary outcomes were the type of ischemic and hemorrhagic events, disability, cause of death, and compliance to treatment. We included 1920 patients; 69.9% started DAPT after an ischemic stroke; only 8.9% strictly followed entry criteria or procedures of RCTs. Primary effectiveness outcome occurred in 3.9% and primary safety outcome in 0.6% of cases. In total, 3.3% cerebrovascular ischemic recurrences occurred, 0.2% intracerebral hemorrhages, and 2.7% bleedings; 0.2% of patients died due to vascular causes. Patients with NIHSS score ⩽5 and those without acute lesions at neuroimaging had significantly higher primary effectiveness outcomes than their counterparts. Additionally, DAPT start >24 h after symptom onset was associated with a lower likelihood of bleeding. In real-world, most of the patients who receive DAPT after an ischemic stroke or a TIA do not follow RCTs entry criteria and procedures. Nevertheless, short-term DAPT remains effective and safe in this population. No safety concerns are raised in patients with low-risk TIA, more severe stroke, and delayed treatment start.

Adult-onset clinical presentation of ABCD1 gene mutations and X-Linked adrenoleukodystrophy: a case report and review of the literature

Adult-onset clinical presentation of ABCD1 gene mutations and X-Linked adrenoleukodystrophy: a case report and review of the literature

ABCD2-I Score Predicts Unplanned Emergency Department Revisits within 72 Hours Due to Recurrent Acute Ischemic Stroke.

the ABCD2 score is valuable for predicting early stroke recurrence after a transient ischemic attack (TIA), and Doppler ultrasound can aid in expediting stroke triage. The study aimed to investigate whether combining the ABCD2 score with carotid duplex results can enhance the identification of early acute ischemic stroke after TIA. we employed a retrospective cohort design for this study, enrolling patients diagnosed with TIA who were discharged from the emergency department (ED). The modified ABCD2-I (c50) score, which incorporates a Doppler ultrasound assessment of internal carotid artery stenosis > 50%, was used to evaluate the risk of acute ischemic stroke within 72 h. Patients were categorized into three risk groups: low risk (with ABCD2 and ABCD2-I scores = 0-4), moderate risk (ABCD2 score = 4-5 and ABCD2-I score = 5-7), and high risk (ABCD2 score = 6-7 and ABCD2-I score = 8-9). between 1 January 2014, and 31 December 2019, 1124 patients with new neurological deficits were screened, with 151 TIA patients discharged from the ED and included in the analysis. Cox proportional hazards analysis showed that patients in the high-risk group, as per the ABCD2-I (c50) score, were significantly associated with revisiting the ED within 72 h due to acute ischemic stroke (HR: 3.12, 95% CI: 1.31-7.41, p = 0.0102), while the ABCD2 alone did not show significant association (HR: 1.12, 95% CI: 0.57-2.22, p = 0.7427). ABCD2-I (c50) scores effectively predict early acute ischemic stroke presentations to the ED within 72 h after TIA.

Enhancing stroke risk prediction in patients with transient ischemic attack: insights from a prospective cohort study implementing fast-track care.

Fast-track care have been proved to reduce the short-term risk of stroke after transient ischemic attack (TIA). We aimed to investigate stroke risk and to characterize short- and long-term stroke predictors in a large cohort of TIA patients undergoing fast-track management. Prospective study, enrolling consecutive TIA patients admitted to a Northern Italy emergency department from August 2010 to December 2017. All patients underwent fast-track care within 24 h of admission. The primary outcome was defined as the first stroke recurrence at 90 days, 12 and 60 months after TIA. Stroke incidence with 95% confidence interval (CI) at each timepoint was calculated using Poisson regression. Predictors of stroke recurrence were evaluated with Cox regression analysis. The number needed to treat (NNT) of fast-track care in preventing 90-day stroke recurrence in respect to the estimates based on baseline ABCD2 score was also calculated. We enrolled 1,035 patients (54.2% males). Stroke incidence was low throughout the follow-up with rates of 2.2% [95% CI 1.4-3.3%] at 90 days, 2.9% [95% CI 1.9-4.2%] at 12 months and 7.1% [95% CI 5.4-9.0%] at 60 months. Multiple TIA, speech disturbances and presence of ischemic lesion at neuroimaging predicted stroke recurrence at each timepoint. Male sex and increasing age predicted 90-day and 60-month stroke risk, respectively. Hypertension was associated with higher 12-month and 60-month stroke risk. No specific TIA etiology predicted higher stroke risk throughout the follow-up. The NNT for fast-track care in preventing 90-day stroke was 14.5 [95% CI 11.3-20.4] in the overall cohort and 6.8 [95% CI 4.6-13.5] in patients with baseline ABCD2 of 6 to 7. Our findings support the effectiveness of fast-track care in preventing both short- and long-term stroke recurrence after TIA. Particular effort should be made to identify and monitor patients with baseline predictors of higher stroke risk, which may vary according to follow-up duration.

Four-dimensional lipidomics profiling in X-linked adrenoleukodystrophy using trapped ion mobility mass spectrometry

Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility spectrometry and MS has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions—retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra—providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFAs) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0 and C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.

Molecular analysis of ABCD1 gene in moroccan patients with X-linked adrenoleukodystrophy

Molecular analysis of ABCD1 gene in moroccan patients with X-linked adrenoleukodystrophy

Rate of atrial fibrillation by Holter-Stroke Risk Analysis in undetermined TIA/rapidly improving stroke symptoms patients.

Holter-SRA (Stroke Risk Analysis) is an automated analysis of ECG monitoring for Atrial Fibrillation (AF) detection. The aim of this study was to evaluate the rate of AF in undetermined TIA/Rapidly improving stroke symptoms (RISS) patients. Prospective study of undetermined TIA/RISS patients who presented to the emergency department. Early vascular studies (angio CT, transthoracic echocardiography and ECG) were performed in emergency department. The Holter-SRA device was placed for 2 h and the patients were classified into: confirmed AF, high risk of AF or low risk of AF. Prolonged ambulatory monitoring (7 days) was carried out every month for patients with a high-risk pattern. The results were evaluated until definitive detection of AF or low-risk pattern. The endpoints were rate of AF and vascular recurrence at 90 days. Over a period of 24 months, 83 undetermined TIA/RISS patients were enrolled. The mean age was 70 ± 10 years and 61% were men. The median ABCD2 score was 4 points (1-7). After 2 h of monitoring in the emergency department, AF was detected in one patient (1.2%), 51 patients with a low-risk pattern and 31 patients (37.3%) showed a high-risk pattern of AF. During the ambulatory monitoring, of the 31 patients high risk pattern patients, AF was diagnosed to 17 cases and of the 51 patients with a low-risk pattern, one case experienced a recurrent vascular due to undetected AF (1.9% false negative). Three patients (3.6%) suffered a vascular recurrence within the first 90 days, before AF diagnosis. In our study, AF was detected in 22.9% of the 83 patients with indeterminate TIA/RISS. Holter-SRA has allowed us to increase the detection of AF, especially those patients with a high-risk pattern in the first 3 months.

Central precocious puberty in a boy with X-linked adrenoleukodystrophy caused by a novel ABCD1 mutation

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder caused by pathogenic variants in the ABCD1 gene. The symptoms include primary adrenal insufficiency (PAI), progressive spinal cord disease, inflammatory demyelinating cerebral disease, and primary hypogonadism. It is exceptionally rare that pediatric PAI is accompanied by central precocious puberty (CPP). The purpose of this study was to better understand the diversity of clinical manifestations of X-ALD and to identify the ABCD1 gene mutation in a case of a boy with X-ALD accompanied by CPP. We collected clinical, laboratory and imaging data, and used whole-exome sequencing (WES) analysis to evaluate the pathogenicity of the variant. We also predicted the potential deleterious effects of the novel mutation using Mutation Taster and generated three-dimensional protein structures using Swiss-Model and PyMOL Viewer software. The patient presented with PAI accompanied by CPP. Adrenal gland CT revealed adrenal hypoplasia. Gonadotropin-releasing hormone stimulation tests revealed CPP. WES revealed a novel variant (c.1376dup) in the ABCD1 gene, which resulted in a reading frameshift and a premature termination codon (p.Leu461ProfsTer95). Sanger sequencing confirmed that the variant was inherited from his heterozygous mother. Mutation Taster predicted that the variant could be harmful. The overall three-dimensional structures of the mutant wild-type proteins were visually distinct. Our results shed light on additional aspects of X-ALD. The premature activation of the hypothalamic-pituitary-gonadal axis may possibly be related to the pathogenic ABCD1 gene mutation.

Application of bedside HINTS, ABCD2 score and truncal ataxia to differentiate cerebellar–brainstem stroke from vestibular neuritis in the emergency room

Background and purposeAcute vestibular syndrome (AVS) typically manifests as isolated dizziness or vertigo with no apparent neurological impairments. However, distinguishing life-threatening stroke from innocuous peripheral vestibular lesions in the emergency...

Intrathecal administration of mesenchymal stem cells in patients with adrenomyeloneuropathy.

X-linked adrenomyeloneuropathy (AMN) is an inherited neurodegenerative disorder associated with mutations in the ABCD1 gene and the accumulation of very long-chain fatty acids (VLFCAs) in plasma and tissues. Currently, there is no effective treatment for AMN. We have aimed to evaluate the therapeutic effects of mesenchymal stem cell (MSC) transplantation in patients with AMN. This is a small cohort open-label study with patients with AMN diagnosed and treated at the University Hospital in Olsztyn, Poland. All patients met clinical, biochemical, MRI, and neuropsychological criteria for AMN. MSCs derived from Wharton jelly, 20 × 106 cells, were administered intrathecally three times every 2 months, and patients were followed up for an additional 3 months. The primary outcome measures included a blinded assessment of lower limb muscle strength with the Medical Research Council Manual Muscle Testing scale at baseline and on every month visits until the end of the study. Additional outcomes included measurements of the timed 25-feet walk (T25FW) and VLFCA serum ratio. Three male patients with AMN with an age range of 26-37 years participated in this study. All patients experienced increased muscle strength in the lower limbs at the end of the study versus baseline. The power grade increased by 25-43% at the baseline. In addition, all patients showed an improvement trend in walking speed measured with the T25FW test. Treatment with MSCs in patients with AMN appeared to be safe and well tolerated. The results of this study demonstrated that intrathecal administration of WJ-MSC improves motor symptoms in patients with AMN. The current findings lend support to the safety and feasibility of MSC therapy as a potentially viable treatment option for patients with AMN.