Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.

The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases.

PURPOSE: This report describes the National Institutes of Health Undiagnosed Diseases Program, details the Program's application of genomic technology to establish diagnoses, and details the Program's success rate during its first 2 years. METHODS: Each accepted study participant was extensively phenotyped. A subset of participants and selected family members (29 patients and 78 unaffected family members) was subjected to an integrated set of genomic analyses including high-density single-nucleotide polymorphism arrays and whole exome or genome analysis. RESULTS: Of 1,191 medical records reviewed, 326 patients were accepted and 160 were admitted directly to the National Institutes of Health Clinical Center on the Undiagnosed Diseases Program service. Of those, 47% were children, 55% were females, and 53% had neurologic disorders. Diagnoses were reached on 39 participants (24%) on clinical, biochemical, pathologic, or molecular grounds; 21 diagnoses involved rare or ultra-rare diseases. Three disorders were diagnosed based on single-nucleotide polymorphism array analysis and three others using whole exome sequencing and filtering of variants. Two new disorders were discovered. Analysis of the single-nucleotide polymorphism array study cohort revealed that large stretches of homozygosity were more common in affected participants relative to controls. CONCLUSION: The National Institutes of Health Undiagnosed Diseases Program addresses an unmet need, i.e., the diagnosis of patients with complex, multisystem disorders. It may serve as a model for the clinical application of emerging genomic technologies and is providing insights into the characteristics of diseases that remain undiagnosed after extensive clinical workup.

Comparing multislice electrocardiogram-gated spiral computerized tomography and transesophageal echocardiography in evaluating aortic atheroma in patients with acute ischemic stroke.

OBJECTIVE: The aim of this study was to compare transesophageal echocardiography (TEE) and cardiac-gated computerized tomography (CGCT) in detecting aortic atherosclerosis (AA). BACKGROUND: There is evidence that AA can be a source of embolic material causing ischemic stroke. TEE is a well-established tool for detecting cardiac sources of emboli in patients with stroke, but it has distinct limitations in the detection of AA. METHOD: This was a prospective study of patients admitted with the diagnosis of ischemic stroke between February and November of 2000. Among this cohort are patients who underwent both TEE and CGCT for the evaluation of stroke cause. The CGCT studies were retrieved and interpreted by a radiologist with special expertise in chest tomography, and TEE studies were read by an echocardiographer with special expertise in reading and performing TEE. The interpreters were unaware of the results obtained by the other. The AA was estimated by measuring atheroma thickness in millimeters. The relations between the two tests were analyzed graphically using Bland-Altman, and Pollock plots. Results from Pearson (r), Spearman (r(s)), and intraclass correlation tests were also estimated. RESULTS: The aortic atheroma thickness in millimeters was compared between CGCT and TEE in 32 patients, who underwent both studies. The intraclass correlation was 0.93, with high correlation (r = 082, r(s) = 0.83). CGCT detected smaller AA more often, and provided more information about the shape of atheromatous plaques. CONCLUSION: CGCT is similar to TEE in detecting AA. CGCT may detect smaller atheromas and be better in defining atheroma morphology.

Interobserver and intraobserver reliabilities of multislice electrocardiogram-gated spiral computerized tomography in evaluating aortic atheroma in patients with acute ischemic stroke.

OBJECTIVE: The objective of this study was to demonstrate the reliability of cardiac-gated computerized tomography (CGCT) in diagnosing aortic atheroma in patients with ischemic stroke. MATERIALS AND METHODS: Two radiologists each read 32 CGCT studies and estimated aortic atheroma and interreliability/intrareliability measures. RESULTS: The intraobserver intraclass correlation coefficients (ICCs) were 0.95 and 0.87 for the diagnosis of aortic atheroma with CGCT. The interrater ICC was 0.93. CONCLUSION: This prospective study demonstrated that CGCT is a reliable imaging modality with good interreader and intrareader reproducibilities.

Intra-arterial thrombolytic therapy in peri-coronary angiography ischemic stroke.

BACKGROUND: Intra-arterial thrombolysis (IAT) for peri-coronary angiography (CA) stroke may be safe and efficacious. However, IAT may increase the risk of intracranial hemorrhage (ICH). METHODS: A retrospective study was performed involving 3 university hospitals. All peri-CA IAT-treated cases were identified. Patient demographics, stroke severity, angiographic findings, thrombolytic use, modified Rankin Scale (mRS), ICH, and mortality were determined. RESULTS: A total of 21 patients with post-left CA stroke were treated with IAT (mean age 71.8+/-12.3 years). Arterial occlusion was found in 14 (66.7%) and 7 (33.3%) of the anterior and posterior circulation, respectively. Mean time-to-therapy was 36+/-12 minutes from the time the neurological deficit was noted. mRS < or =2 occurred in 10 of 21 (48%) patients. Patients with younger age and shorter time-to-IAT had more complete arterial recanalization and clinical recovery. Symptomatic ICH occurred in 3 (14%) cases, and 4 (19%) patients died. CONCLUSIONS: Peri-CA IAT appears to be feasible and safe without increased risk of symptomatic ICH and death when compared with the previously reported IAT literature.

Reproducibility of transesophageal echocardiography in evaluating aortic atheroma in stroke patients.

Although transesophageal echocardiography (TEE) is a well-established tool in delineating the cardiac and aortic sources of emboli in stroke patients, its reproducibility in detecting aortic atherosclerosis (AA) that may lead to stroke is not well documented. The aim of this study is to demonstrate the inter- and intra-observer agreement in diagnosing AA based on the TEE study. During the study period, 2 echocardiographers read 32 TEE studies performed on a group of stroke patients. The AA was estimated by measuring the largest atheroma thickness in millimeters (mm). The intra-observers and intraclass correlation coefficients (ICC) were 0.97 and 0.85, respectively, for the 2 TEE observers. The inter-rater ICC coefficient between TEE readers was 0.91. In conclusion, TEE detected AA and defined high proportions of the morphological characteristics of atheroma with good reproducibility among inter and intra-observers.

Thrombolytic therapy of acute ischemic stroke: correlation of angiographic recanalization with clinical outcome.

BACKGROUND AND PURPOSE: The effect of vessel patency, following recombinant tissue plasminogen activator (rtPA) administration, on clinical outcome in acute ischemic stroke (AIS) has been controversial. We studied the effect of recanalization following intraarterial (IA) and intravenous/IA (IV/IA) rtPA on clinical outcome in AIS. METHODS: Recanalization was classified angiographically as complete (as compared with unoccluded vessel, thrombolysis in myocardial infarction classification [TIMI] 3), none (with no change from prethrombolysis, TIMI 0), and partial (when a change in the flow from baseline was noted, TIMI 1-2). Outcomes were symptomatic intracranial hemorrhage (sICH), 90-day modified Rankin scale (< or = 2 as a good outcome), and 3-month mortality. RESULTS: Ninety-six patients had either combined IV/IA (41) or IA (55) rtPA for AIS during a 7-year period. Any recanalization occurred in 69%; 55% of those had a good outcome versus 23% in the rest (Odds ratio = 3.9; 95% confidence interval [CI] = 1.4-11.2; P = .007). Only 24% had complete recanalization; 74% had a good outcome versus 36% in the nonrecanalization group (OR = 5.1; 95% CI = 1.6-16.8; P = .002). When adjusted to time to therapy and vessel occluded, these results lessened but remained significant. The sICH rate with any recanalization was 7.6% versus 13.3% in patients with persistent clot (relative risk (RR) = 0.6; 95% CI = 0.2-2.0; P = .45). Death occurred in 19.7% of those whose vessels recanalized versus 33.3% in the rest (RR = 0.56; 95% = 0.26-1.19; P = .2). CONCLUSION: A total of 24% and 69% of patients had complete and any recanalization, respectively, following endovascular rtPA therapy of AIS. The degree of recanalization was directly related to time to therapy and associated with good clinical outcome without an increase in the rate of adverse effect.

Predictors of hyperacute clinical worsening in ischemic stroke patients receiving thrombolytic therapy.

BACKGROUND AND PURPOSE: Although long-term outcome determinants in acute ischemic stroke (AIS) patients have been defined, less is known about those predicting hyperacute worsening after thrombolytic therapy (TT). We investigated predictors of short-term clinical worsening (National Institutes of Health Stroke Scale [NIHSS] change > or =4 within 24 hours of admission). METHODS: We studied 201 AIS patients who received TT within 6 hours of symptom onset. We determined baseline demographics, comorbidities, NIHSS at baseline and at 24 hours after TT, head computed tomography scan before and within 24 hours after TT, and angiographic recanalization in patients treated with intra-arterial (IA) thrombolysis. Significance of relationships was evaluated by t test or Wilcoxon signed rank sum test. Logistic regression model (LRM) was fitted to determine independence of significant variables. RESULTS: Of 201 patients, 13% worsened, 39% improved, and 48% remained unchanged 24 hours after TT. Most patients (72%) received IA thrombolysis. Patients who deteriorated, compared with those who improved, were more likely to have complicating intracranial hemorrhage (ICH; P<0.001), absent recanalization (P=0.026), and higher blood glucose (BG; P=0.049). Hyperglycemia (>150 mg/dL) was greater in patients who worsened even in presence of recanalization (P=0.004, odds ratio [OR] 6.47). LRM showed that adjusted OR for increased risk of bad outcome and mortality for an increase of BG by 50 mg/dL is 1.56 and 1.38, respectively. CONCLUSIONS: Hyperglycemia and ICH are independent predictors of hyperacute worsening in AIS patients receiving TT. Although recanalization is the purpose of IA thrombolysis, its impact on clinical improvement may not be apparent without strict BG control.

Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion.

BACKGROUND AND PURPOSE: The objective of this study was to determine the clinical features, angiographic findings, and response to treatment with thrombolytic therapy in patients with ischemic stroke caused by acute occlusion of the distal internal carotid artery. METHODS: This is a retrospective case series from a prospectively collected stroke database for patients with acute internal carotid occlusion presenting within 6 hours of stroke onset to evaluate safety, feasibility, and response to thrombolytic therapy. The University Hospital-based brain attack database was reviewed over a 5-year period. Demographics, clinical features, stroke mechanisms, severity, imaging findings, type of thrombolysis, treatment responses, mortality, and long-term outcome using modified Rankin Scale and Barthel Index were determined. The short-term outcome was assessed using the National Institutes of Health Stroke Scale (NIHSS). Acute thrombolytic therapy was administered using recombinant tissue plasminogen activator or urokinase given intra-arterially or in combination with intravenous (IV) routes. RESULTS: Two hundred seven patients treated with thrombolysis between 1995 and 2000 were reviewed, and of these, 101 were studied with cerebral angiography. Eighteen patients were identified with acute ischemic stroke and ipsilateral occlusion of the distal internal carotid artery. Time to treatment was the most powerful predictor of response to thrombolytic therapy (P<0.001). The response to therapy also correlated well with the severity of the initial clinical deficit as judged by the NIHSS (P<0.001). There was no difference in recanalization rate, symptomatic hemorrhage, and NIHSS for IV/intra-arterial (IA) versus IA alone (P=NS). Complete angiographic recanalization was accomplished in 80% of those who received combined IV/IA thrombolysis and in 62% of those who received IA therapy (P=NS). Those with distal occlusions extending to the middle and anterior cerebral arteries were the least likely to respond to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 20% of the patients receiving IV/IA therapy, and in 15% of the IA only (P=NS). At 24 hours, the NIHSS dropped by 3 points in the IA group and 4 points in the IV/IA group (P=NS). Mild disability with independence was found in 77% of the survivors at 3-month follow-up. The mortality rate was 50% in this group despite thrombolysis. CONCLUSIONS: Thrombolytic therapy using a combination of IV and IA routes and using the IA-only route may be effective in improving outcome for the patients suffering from occlusion of the distal internal carotid artery. Shorter intervals between onset and treatment seem to be correlated with higher rate of recanalization and improved outcome.

Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes.

OBJECTIVE: To determine the feasibility of combined intravenous and intra-arterial thrombolytic therapy for acute ischemic strokes and to evaluate its associated risks, using magnetic resonance imaging as a triage tool. Intravenous treatment followed by intra-arterial infusion may increase the rate of recanalization and lead to better clinical results, with reduced frequency of intracranial hemorrhage. METHODS: Our Brain Attack Team evaluated patients who presented within 3 hours after symptom onset. Patients who did not demonstrate improvement and exhibited no evidence of intracranial hemorrhage on head computed tomographic scans were treated with intravenously administered recombinant tissue plasminogen activator (0.6 mg/kg) and underwent emergency magnetic resonance imaging of the head. T2-weighted turbo-gradient and spin echo and echo-planar diffusion- and perfusion-weighted imaging scans were obtained. Patients with evidence of imaging abnormalities indicating acute cortical infarction underwent cerebral angiography. After determination of vessel occlusion, intra-arterially administered urokinase (up to 750,000 units) or intra-arterially administered recombinant tissue plasminogen activator (maximal dose, 0.3 mg/kg) was used to achieve recanalization. RESULTS: We treated 45 patients with this protocol. The mean age was 67 +/- 13 years, and 58% of the patients were women. There was a significant improvement in National Institutes of Health Stroke Scale scores after treatment. There was good correlation between abnormal perfusion-weighted imaging findings and cerebral angiographic findings (complete vessel occlusion). The incidence of symptomatic intracranial hemorrhage was 4.4% in this cohort. Seven patients died in the hospital, and the majority of survivors (77%) experienced good outcomes (Barthel index of >or=95) 3 months after treatment. CONCLUSION: Our data demonstrate that this protocol is feasible and that combined intravenous and intra-arterial thrombolysis to treat acute ischemic strokes is sufficiently safe to warrant further evaluation.