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Lesions within the skull base are the most challenging targets for percutaneous biopsy due to the likelihood of encountering a critical structure along any needle trajectory. Due to ICA proximity, the petrous apex is considered unsafe. We describe a novel percutaneous CT-guided approach for biopsying a petrous apex lesion via a contralateral mandibular condylar notch (subzygomatic approach). To our best knowledge, this approach has not been reported and can be safely employed with thorough planning.
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Osso Petroso , Tomografia Computadorizada por Raios X , Humanos , Osso Petroso/diagnóstico por imagem , Osso Petroso/patologia , BiópsiaRESUMO
PURPOSE: Spinal extradural arachnoid cysts (SEDACs) are thought to arise from leakage of CSF through a spinal dural defect. This study investigates the demographics and imaging spectrum of SEDACs at our academic institution and compares them with those reported in the literature. METHODS: Fifty cases with documented MRI diagnosis of SEDAC, Nabors criteria type I meningeal cyst (MC), were identified from retrospective review of imaging records between 1999 and 2020. Patient demographics, presenting symptoms, cyst characteristics, and management outcomes were studied. Statistical analysis was performed to determine associations between maximum cyst size and presenting symptoms along with other imaging findings. RESULTS: In all 50 subjects, SEDACs were solitary (single) and sporadic (non-familial). The majority were incidental (62%), located posteriorly (92%) and laterally (80%) in the thoracic and thoracolumbar regions (34%, 30%). They were associated with mild mass effect upon the thecal sac (50%) and bone remodeling (92%). Among symptomatic SEDACs, back pain and radiculopathy were the most reported (68%). Larger cysts were located caudally in the spinal canal, and were associated with greater thecal mass effect, bone remodeling, and septations. Four out of six subjects who underwent surgical management had complete or partial remission. One had cyst recurrence. CONCLUSION: In this largest series of SEDACs, most were discovered incidentally, stable over time, and located in the thoracic spine dorsal to the thecal sac. When symptomatic, back pain and radiculopathy were the most common presenting symptoms. Treatment with complete surgical excision may yield the best results for symptomatic lesions.
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Cistos Aracnóideos , Radiculopatia , Doenças da Medula Espinal , Humanos , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/cirurgia , Cistos Aracnóideos/complicações , Estudos Retrospectivos , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/cirurgia , Dor nas Costas , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: The oculomotor nerve (OMN) innervates the pupil, ciliary body, upper eyelid, and extraocular muscles through two divisions: a superior division that innervates the levator palpebrae superioris (LPS) and superior rectus (SR), and an inferior division that supplies the medial rectus (MR), inferior rectus (IR), inferior oblique (IO), and parasympathetic fibers to the pupil and ciliary body. We present a case of complete splitting of the cisternal segment of bilateral OMNs that was discovered incidentally on magnetic resonance imaging (MRI) in a patient who had no ocular complaints. CASE REPORT: A 69-year-old patient was found to have bilateral splitting of the cisternal segments of OMNs during an MRI for trigeminal neuralgia workup. Both nerves sprang from the midbrain as distinct roots. They were symmetric on the right and minimally asymmetric on the left. On both sides, the medial root was slightly inferiorly situated. The patient had no visual problems and continued to function normally. A review of the literature for similar cases identified no such variants; however, it did identify eight examples of OMN fenestrations produced by aneurysms (AN), six of which had no OMN palsy symptoms. CONCLUSION: An anatomic variant of split bilateral OMN cisternal segments is described. The superior and inferior divisions may have different brainstem origins. Although this variant is an anatomic curiosity, it may have clinical significance and explain the various presentation of compressive OMN palsies.
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Doenças do Nervo Oculomotor , Nervo Oculomotor , Humanos , Idoso , Nervo Oculomotor/diagnóstico por imagem , Achados Incidentais , Doenças do Nervo Oculomotor/diagnóstico por imagem , Doenças do Nervo Oculomotor/etiologia , Músculos Oculomotores/diagnóstico por imagem , Músculos Oculomotores/inervação , Imageamento por Ressonância Magnética/métodosRESUMO
Transient global amnesia (TGA) is a neurological condition characterized by temporary memory loss and classically associated with a reversible unilateral punctate focus of restricted diffusion in the cornu ammonis 1 (CA1) region of the hippocampus. Historically, the lesions were considered to be transient in nature with no long-term imaging abnormality. However, more recent studies have challenged the concept that there are no long-term neurological sequelae. In line with this evidence, we explore the role of ultra-high-resolution imaging using 7 Tesla MRI to evaluate for long-term imaging abnormalities in a 63-year-old woman with a typical clinical course and acute TGA imaging findings. The 7 Tesla MRI revealed a residual lesion on susceptibility-weighted imaging (SWI) with evidence of gliosis and volume loss at the site of the acute lesion in CA1 eight months after the acute episode. This case challenges the traditional mantra of TGA as a fully reversible condition with no long-term imaging findings, suggesting the need for further research using ultra-high-field MRI to determine TGA's potential long-term imaging sequelae and any association with neurocognitive sequelae.
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Amnésia Global Transitória , Feminino , Humanos , Pessoa de Meia-Idade , Amnésia Global Transitória/diagnóstico por imagem , Amnésia Global Transitória/etiologia , Amnésia Global Transitória/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética , Progressão da Doença , Hipocampo/diagnóstico por imagemRESUMO
The 5-year relative survival rate for pancreatic cancer is currently the lowest among all cancer types with a dismal 13%. A Kirsten rat sarcoma virus (KRAS) gene mutation is present in approximately 90% of patients with pancreatic cancer; however, KRAS-specific drugs are not yet widely used in clinical practice for pancreatic cancer, specifically the KRASG12D variant. Advances in genomic testing revealed an opportunity to detect genetic alterations in a subset of patients with no KRAS mutation termed KRAS wild-type. Patients with KRAS wild-type tumors have a propensity to express driver alterations, hence paving the way for utilizing a targeted therapy approach either via clinical trials or standard-of-care drugs. These alterations include fusions, amplifications, translocations, rearrangements and microsatellite instability-high tumors and can be as high as 11% in some studies. Here, we discuss some of the most notable alterations in KRAS wild-type and highlight promising clinical trials.
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BACKGROUND: Interns experience challenges in their transition from medical school to residency. Orientation is traditionally delivered by faculty and administrators and often does not address practical skills needed by interns during the transition. OBJECTIVES: The objective is to address traditional orientation gaps and improve incoming interns' transition experience. Methods: We identified opportunities with our intern orientation using a quality improvement methodology. Plan Do Study Act (PDSA) cycle 1 consisted of a pilot boot camp. PDSA cycle 2 was conducted over two weeks, June 9-23, 2021, at the Detroit Medical Center, Detroit, MI. Participation was voluntary. Residents were assigned incoming interns on a 1:1 basis. Five virtual sessions were conducted addressing: daily workflow, documentation, presentation skills, and utilization of the Electronic Health Record (EHR). All participants received pre- and post-program surveys. Results: Twenty-two rising second- and third-year residents (26%) and 22 incoming interns (58%) participated. There was a significant improvement in the understanding of daily workflow (mean improvement 0.957, p=0.003), and most tasks associated with EHR including comfort with the sign-out process (mean improvement 1.21; p=0.002), accessing specific team lists (mean improvement 1.75, p=0.001), writing orders (mean improvement 1.41; p=0.002), composing documentation (mean improvement 1.23; p=0.001). Writing notes improved significantly (mean improved by 0.52; p=0.04). Nearly all (93.2%) stated the program achieved its overall goals and believed (92.9%) the program should be continued for incoming intern classes. CONCLUSION: A targeted orientation bootcamp led by near-peers positively impacted the intern experience improving understanding of day-to-day responsibilities and comfort utilizing the electronic health record.
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BACKGROUND: Direct common carotid artery puncture (DCP) is conventionally used as a bailout technique in stroke patients. However, little is known about the relevant anatomy. OBJECTIVE: Examine the relationship of the common carotid artery (CCA) to surrounding structures based on different DCP trajectories passing through the artery's center. METHODS: Fifty randomly selected head/neck CTAs were analyzed. The trajectory of DCP and relationship to the internal jugular vein (IJV) and thyroid were analyzed at 1 cm intervals above the clavicle on 7 axial sections. Using the trans-carotid sagittal plane (TCSP) as the 0° trajectory, we plotted 3 additional trajectories at 30° intervals and the relationship with the IJV and thyroid proximity was graded as following: 0 = absent, 1 = adjacent, and 2 = crossing. The CCA tortuosity index (TI) was also analyzed for each vessel. RESULTS: Analysis of 2800 trajectories across 100 CCAs showed that the IJV and thyroid were least encountered on the axial sections 2 cm above the clavicle, at 0° on the right (9 thyroids and 6 IJV), and at 90° on the left (0 Thyroids and 14 IJVs). The TI of the CCA was significantly lower above the clavicle than its entire length (p<0.001). CONCLUSION: DCP performed 2 cm above the clavicle at 0° on the right, and 90° on the left appears to minimize encounters with the IJV and thyroid gland, reducing potential complications. However, despite these findings, ultrasound guidance remains vital for DCP safety. Further focus on endovascular device safety in DCP is needed.
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Recurrent hepatocellular carcinoma (HCC) poses a significant challenge after liver transplantation, affecting approximately 10-23% of patients with a median onset of 13 months post-transplantation. Extrahepatic involvement, such as lung, bone, adrenal glands, peritoneum, lymph nodes, and central nervous system (CNS), is commonly observed among transplant recipients with HCC recurrence. Notably, vascular invasion (VI), including microvascular invasion (MiVI) and macrovascular invasion (MVI), substantially increase the risk of recurrence by 2.42- and 7.82-fold, respectively. This article presents a unique case of a 72-year-old male patient with a history of HCV-related cirrhosis and HCC who underwent orthotopic liver transplantation (OLT). Six years later, he presented to the emergency department following a fall, which led to the discovery of a pathologic fracture of T7 and an incidental intracranial mass during imaging. Subsequent biopsy confirmed metastatic HCC in the T7 lesion, while magnetic resonance imaging revealed two enhancing brain masses. One mass measured 4.8 cm in the left occipitotemporal lobe, and the other measured 1.7 cm in the right frontal gyrus. Notably, the patient had exhibited MiVI and a mildly elevated alpha-fetoprotein level (AFP) of 7.6 ng/mL at the time of his OLT. This case underscores the predictive value of MiVI in HCC recurrence post-OLT. Accordingly, extended post-transplantation surveillance is crucial for patients with HCC and MiVI. Moreover, this report highlights the uncommon occurrence of delayed brain metastasis following OLT in a patient with HCC.
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Neoplasias Encefálicas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Masculino , Humanos , Idoso , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Cirrose Hepática/complicações , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
The role of circulating tumor DNA (ctDNA) is expanding in oncology practices, and it is increasingly being used for targeted therapies and disease monitoring. It is minimally invasive and provides data from both primary and secondary sites of disease. Herein, we report a unique case of a patient with microsatellite instability-high (MSI-H) pancreatic adenocarcinoma (PDAC) treated with neoadjuvant chemotherapy and pembrolizumab who achieved a pathologically confirmed complete resolution of the tumor. A 75-year-old female was diagnosed with pancreatic adenocarcinoma (PDAC) in the uncinate process with aortocaval and retrocrural adenopathy. Next-generation sequencing was obtained via ctDNA testing, and the patient was initiated on cytotoxic chemotherapy while awaiting results. ctDNA revealed MSI-H status, and pembrolizumab was added to the cytotoxic chemotherapy regimen. At follow-up after five cycles of treatment, excellent treatment response was noted on magnetic resonance imaging (MRI) of the abdomen, demonstrating the resolution of the pancreatic mass and adenopathy. Six months of neoadjuvant treatment was given in total, after which the patient underwent resection with curative intent and achieved a complete pathological response with no evidence of disease. The role of ctDNA testing in directing treatment and influencing follow-up has already demonstrated great value. In our case, ctDNA adequately replaced conventional tissue biopsy, alleviating the burden of invasive testing on the patient. This is of great value, especially for patients with non-resectable tumors as well as in several other clinical scenarios. Our case also contributes to the growing body of literature demonstrating the role of immune-directed therapy for MSI-H PDAC.
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BACKGROUND: The Diamondback 360® Coronary Orbital Atherectomy System (Cardiovascular Systems Inc., St. Paul, MN) is the first and only orbital atherectomy system approved by the US FDA for the treatment of severely calcified lesions. While the device has proven to be safe in clinical trials, real-world data are minimal. METHODS: The Manufacturer and User Facility Device Experience (MAUDE) database was queried for reports on the Diamondback 360® Coronary from January 2019 to January 2022. RESULTS: A total of 566 events were reported during the study period. After the exclusion of duplicate reports, the final cohort included 547 reports. The most common mode of failure was break or separation of a device part (40.4%, n = 221) mainly due to breaking in the tip of the ViperWire (66.1%), driveshaft (22.7%), or crown (12.2%). The most common vessel associated with events was the left anterior descending artery (31.4%), followed by the right coronary artery (26.9%), left circumflex (21.6%), and left main coronary artery (6.4%). The most common clinical adverse outcome was perforation (33.0%, n = 181) with 23.7% resulting in cardiac tamponade. Most perforation cases were treated by covered stent (44.2%), surgery (30.5%), stent (98%), and balloon angioplasty (9%). There were 89 (16.3%) events of death with 67% due to perforation (p < 0.001). CONCLUSION: Our study provided a glimpse of real-world adverse outcomes and common modes of failure due to orbital atherectomy. The most common mode of failure was the break or separation of a device part and the most common complication was perforation according to the MAUDE database. It will help physicians to anticipate complications and escalate care appropriately.
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Objective: To investigate the performance of a commercially available artificial intelligence (AI) algorithm for the detection of pulmonary embolism (PE) on contrast-enhanced computed tomography (CT) scans in patients hospitalized for coronavirus disease 2019 (COVID-19). Patients and Methods: Retrospective analysis was performed of all contrast-enhanced chest CT scans of patients admitted for COVID-19 between March 1, 2020 and December 31, 2021. Based on the original radiology reports, all PE-positive examinations were included (n=527). Using a reversed-flow single-gate diagnostic accuracy case-control model, a randomly selected cohort of PE-negative examinations (n=977) was included. Pulmonary parenchymal disease severity was assessed for all the included studies using a semiquantitative system, the total severity score. All included CT scans were sent for interpretation by the commercially available AI algorithm, Aidoc. Discrepancies between AI and original radiology reports were resolved by 3 blinded radiologists, who rendered a final determination of indeterminate, positive, or negative. Results: A total of 78 studies were found to be discrepant, of which 13 (16.6%) were deemed indeterminate by readers and were excluded. The sensitivity and specificity of AI were 93.2% (95% CI, 90.6%-95.2%) and 99.6% (95% CI, 98.9%-99.9%), respectively. The accuracy of AI for all total severity score groups (mild, moderate, and severe) was high (98.4%, 96.7%, and 97.2%, respectively). Artificial intelligence was more accurate in PE detection on CT pulmonary angiography scans than on contrast-enhanced CT scans (P<.001), with an optimal Hounsfield unit of 362 (P=.048). Conclusion: The AI algorithm demonstrated high sensitivity, specificity, and accuracy for PE on contrast-enhanced CT scans in patients with COVID-19 regardless of parenchymal disease. Accuracy was significantly affected by the mean attenuation of the pulmonary vasculature. How this affects the legitimacy of the binary outcomes reported by AI is not yet known.
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BACKGROUND AND PURPOSE: CSF-venous fistulas (CVFs) associated with spontaneous intracranial hypotension (SIH) may have a transient appearance, relative to contrast arrival, which may influence the diagnostic performance of lateral decubitus CT myelography (CTM). We developed a dynamic CTM protocol using real-time bolus-tracking (dCTM-BT) to improve the temporal resolution and standardize the timing of CTM acquisitions post-intrathecal contrast administration. The purpose of our study was to evaluate the feasibility of the dCTM-BT technique and evaluate its diagnostic yield for CVF detection, stratified by brain MRI SIH findings. MATERIALS AND METHODS: Patients with suspected SIH without extradural fluid collection on spine MRI who underwent dCTM-BT were retrospectively reviewed. CT bolus monitoring was performed at the upper thoracic level. Following the visualization of dense intrathecal contrast, at least 3 CTM acquisitions of the spine were obtained and reviewed by 2 neuroradiologists. The Bern SIH score was calculated on the brain MRI. The diagnostic yield for CVF detection was evaluated, stratified by Bern score categories and a receiver operating characteristic (ROC) analysis. RESULTS: Out of 48 patients, 23 (48%) had a CVF on dCTM-BT, located at T1-5 (n = 4), T6-12 (n = 18), L1 (n = 1), with 70% on the right. CVF was identified in 22/22 (100%) of patients who had a high Bern score, 1/7 (14%) of those who had an intermediate score, and 0/19 (0%) of those who had a low score. The area under the ROC curve was 0.99 (95% CI, 0.98-1.00). The optimal cutoff was a Bern score of ≥5 (96% sensitivity, 100% specificity). CONCLUSIONS: dCTM-BT is feasible and has excellent diagnostic performance for CVF identification/localization. The Bern score is strongly associated with CVF detection and may help inform who will benefit from dCTM-BT.
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Fístula , Hipotensão Intracraniana , Humanos , Vazamento de Líquido Cefalorraquidiano/complicações , Estudos Retrospectivos , Mielografia/métodos , Hipotensão Intracraniana/diagnóstico , Tomografia Computadorizada por Raios X/métodos , Imageamento por Ressonância Magnética/métodos , Neuroimagem , Fístula/complicaçõesRESUMO
Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.
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The subventricular zone (SVZ) of the lateral ventricles represents a main region where neural stem cells (NSCs) of the mature central nervous system (CNS) reside. Bone Morphogenetic Proteins (BMPs) are the largest subclass of the transforming growth factor-ß (TGF-ß) superfamily of ligands. BMP4 is one such member and plays important roles in adult NSC differentiation. However, the exact effects of BMP4 on SVZ adult NSCs in CNS ischemia are still unknown. Using oxygen and glucose deprivation (OGD) as an in vitro model of ischemia, we examined the behavior of adult NSCs. We observed that anoxia resulted in reduced viability of adult NSCs, and that BMP4 treatment clearly rescued apoptotic cell death following anoxia. Furthermore, BMP4 treatment exhibited a strong inhibitory effect on cellular proliferation of the adult NSCs in normoxic conditions. Moreover, such inhibitory effects of BMP4 treatment were also found in OGD conditions, despite the enhanced cellular proliferation of the adult NSCs that was observed under such ischemic conditions. Increased neuronal and astroglial commitment of adult NSCs were found in the OGD conditions, whereas a reduction in differentiated neurons and an increase in differentiated astrocytes were observed following BMP4 treatment. The present data indicate that BMP4 modulates proliferation and differentiation of SVZ-derived adult NSCs and promotes cell survival in the in vitro model of ischemic stroke.
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AVC Isquêmico , Células-Tronco Neurais , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Diferenciação Celular/fisiologia , Proliferação de Células , Células Cultivadas , Glucose/farmacologia , Humanos , Hipóxia/metabolismoRESUMO
Background: The Turnpike catheters (Teleflex, Wayne, PA, USA) is a microcatheter that was approved by the Food and Drug Administration in November 2014 to be used to access discrete regions of the coronary and peripheral vasculature. Methods: The Manufacturer and User Facility Device Experience (MAUDE) database was queried for reports of the Turnpike catheters from March 2015 through August 2021. Results: A total of 216 reports were found during the study period. After excluding duplicate reports (n = 21), our final cohort included 195 reports. The most common failure mode was catheter tip break or detachment (83%, n = 165) which was significantly associated with over-torquing (p-value = 0.025). The most common clinical consequence was the entrapment of the catheter (33%, n = 65), followed by vessel injury (7.8% n = 15) and vessel occlusion (3.6%, n = 7). Most patients had no consequences (47.0%, n = 93) or recovered (11%, n = 22). A total of 4 deaths were reported. 35.8% of reports (n = 69) specified the presence of severe calcification in the target vessel. Over torquing by interventionists was reported in 33.2% of events (n = 64). Conclusion: Despite clinical trials demonstrating the safety of the Turnpike catheters, complications can still occur. These data serve to inform operators about potentional risks and complications associated with the use of the device. Physicians should avoid over-torqueing which seems to be the most common mechanism for device complications.
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This protocol entails a simple method for isolation, culturing, and in vitro differentiation of adult neural stem cells from the dentate gyrus in the hippocampus and the subventricular zone of adult mice. Cultured adult neural stem cells are an important in vitro model to investigate stem cell properties such as proliferation and differentiation and to expand the understanding of plasticity in the adult brain. For complete details on the use and execution of this protocol, please refer to Isaksen et al. (2020).
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Técnicas de Cultura de Células/métodos , Separação Celular/métodos , Células-Tronco Neurais/citologia , Animais , Encéfalo/citologia , Células Cultivadas , Dissecação , CamundongosRESUMO
Small bowel obstruction (SBO) secondary to pelvic inflammatory disease (PID) is a rare complication only reported on a few occasions. We presented a 38-year-old female with an acute abdomen secondary to PID diagnosed via CT and MRI abdomen. The patient was treated in a conservative manner and recovered with no further complications. In our case, the learning point is the consideration of such an etiology in women with no previous surgical history presenting with an acute abdomen.
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Pseudolipoma, also known as pseudolipoma of the Glisson's capsule, is an encapsulated lesion that contains degenerated fat and is enveloped by the liver capsule. In this report, we discuss a 37-year-old male presenting with dysuria and microscopic hematuria who revealed an incidental finding of a pseudolipoma on a CT scan of the abdomen.
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Introduction: Hereditary spastic paraplegia is a clinically and genetically heterogeneous neurological entity that includes more than 80 disorders which share lower limb spasticity as a common feature. Abnormalities in multiple cellular processes are implicated in their pathogenesis, including lipid metabolism; but still 40% of the patients are undiagnosed. Our goal was to identify the disease-causing variants in Sudanese families excluded for known genetic causes and describe a novel clinico-genetic entity. Methods: We studied four patients from two unrelated consanguineous Sudanese families who manifested a neurological phenotype characterized by spasticity, psychomotor developmental delay and/or regression, and intellectual impairment. We applied next-generation sequencing, bioinformatics analysis, and Sanger sequencing to identify the genetic culprit. We then explored the consequences of the identified variants in patients-derived fibroblasts using targeted-lipidomics strategies. Results and Discussion: Two homozygous variants in ABHD16A segregated with the disease in the two studied families. ABHD16A encodes the main brain phosphatidylserine hydrolase. In vitro, we confirmed that ABHD16A loss of function reduces the levels of certain long-chain lysophosphatidylserine species while increases the levels of multiple phosphatidylserine species in patient's fibroblasts. Conclusion: ABHD16A loss of function is implicated in the pathogenesis of a novel form of complex hereditary spastic paraplegia.
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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.