Faculty Bibliography

BACKGROUND AND PURPOSE: Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. METHODS: We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed. RESULTS: A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage (P=0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P=0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P=0.047). CONCLUSIONS: Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

GM1-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal beta-galactosidase. We have identified seven American black bears (Ursus americanus) found in the Northeast United States suffering from GM1-gangliosidosis. This report describes the clinical features, brain MRI, and morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of a GM1-mouse. The bears presented at ages 10-14months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T2-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of the brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid beta-galactosidase activity in cultured skin fibroblasts was only 1-2% of control values. In the brain, ganglioside-bound sialic acid was increased more than 2-fold with GM1-ganglioside predominating. GA1 content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in the GM1-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the GM1 mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T(1042) to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several black bears with GM1-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.

BACKGROUND: Translating knowledge derived from medical research into the clinical setting is dependent on the representativeness of included patients. Therefore we compared baseline data of patients included in a recent large study addressing young stroke in comparison to a large representative stroke registry. METHODS: We analysed baseline data of 5023 patients (age 18-55 years) with an acute cerebrovascular event included in the sifap1 (Stroke in Young Fabry Patients) study. For comparison 17007 stroke patients (age 18-55 years) documented (2004-2010) in a statutory stroke registry of the Institute of Quality Assurance Hesse of the Federal State of Hesse (GQH), Germany. RESULTS: Among 17007 juvenile (18-55 years) patients identified in the GQH registry 15997 had an ischaemic stroke or TIA (91%) or an intracranial haemorrhage (9%). In sifap1 5023 subjects were included. Sex distribution was comparable (men: 59% sifap1 versus 60.5% GQH) whereas age differed between the groups: median age was 46 years in sifap1 versus 49 years in GQH. Slightly higher percentages for diabetes mellitus and hypertension in the GQH registry were noted. There were no differences in stroke severity as assessed by NIHSS (median 3) and mRS (median 2). In patients with ischaemic stroke or TIA (n = 4467 sifap1; n = 14522 GQH) higher rates of strokes due to small artery occlusion and atherosclerosis occurred in older age groups; cardioembolism and strokes of other determined cause occurred more frequently in younger patients. CONCLUSIONS: The comparison of baseline characteristics between the sifap1 study and the GQH registry revealed differences mainly determined by age.

GM2 gangliosidosis (Tay-Sachs disease) was diagnosed in 6- to 8-month-old pedigree Jacob lambs from two unrelated flocks presenting clinically with progressive neurological dysfunction of 10 day's to 8 week's duration. Clinical signs included hindlimb ataxia and weakness, recumbency and proprioceptive defects. Histopathological examination of the nervous system identified extensive neuronal cytoplasmic accumulation of material that stained with periodic acid-Schiff and Luxol fast blue. Electron microscopy identified membranous cytoplasmic bodies within the nervous system. Serum biochemistry detected a marked decrease in hexosaminidase A activity in the one lamb tested, when compared with the concentration in age matched controls and genetic analysis identified a mutation in the sheep hexa allele G444R consistent with Tay-Sachs disease in Jacob sheep in North America. The identification of Tay-Sachs disease in British Jacob sheep supports previous evidence that the mutation in North American Jacob sheep originated from imported UK stock.

GNE myopathy is a rare autosomal recessive myopathy without an approved treatment. Symptoms of distal leg weakness typically present in early adulthood and progressive weakness results in greater dependence and disability over time. The GNEM-FAS is a disease-specific measure of functional activity and independence in ambulatory patients. Mobility (MOB), Upper Extremity (UE) and Self-Care (SC) domains are assessed. A Total Score (TS) is calculated and higher scores represent greater independence. The GNEM-FAS was administered by clinical interview to 47 ambulatory subjects enrolled in a randomized, placebo-controlled, 48 week, Phase 2 study of extended release sialic acid (SA-ER). Subjects were randomized to receive placebo, 3g or 6g of SA-ER/ day and after 24 weeks, the placebo group crossed to 3g or 6g/day for the remaining 24 weeks. Strength and functional performance measures administered in the study included hand-held dynamometry to evaluate UE and lower extremity (LE) strength and a 6-minute walk test (6MWT). The GNEM-FAS was administered at 12 week intervals. At baseline, the mean TS was 69 out of 100 (range 22-94) with MOB scores indicating more limitations than in UE or SC function. Higher MOB scores were associated with greater LE strength (r = 0.85) and longer 6MWT distances (r = 0.83). A moderate association was seen between UE strength and the UE (r = 0.66) and MOB (r = 0.62) domains. At week 48, the differences between subjects treated with 6g and 3g doses are reported. Analysis of the GNEM-FAS TS demonstrated a 3.71 point difference favoring the high dose group (p = 0.08). Further analysis revealed a statistically significant difference in the MOB score (2.14; p = 0.02) although this effect was not evident in measures of LE strength or function. A positive trend in the UE domain score (1.60; p = 0.11) was also observed and supported by a statistically significant difference in UE strength (p = 0.003). No differences in SC domain scores were observed. The statistically significant differences observed in both the MOB domain and UE strength may reflect an increased reliance on UE use as the disease and weakness progresses. The GNEM-FAS shows promise in evaluating patient-reported change in functioning and for use in future studies of patients with GNE myopathy. Additional work is underway to further validate this version of the GNEM-FAS and expand it for use with more impaired patients

Headache as symptom of stroke is linked to gender, history of migraine, younger age, cerebellar stroke, and low blood pressure. These associations have been controversial, large scale studies are missing. We used the stroke in young fabry patients study to examine the association of demographic, clinical and imaging factors with the occurrence of headache in 4,431 young ischaemic stroke patients (18-55 years; mean: 44.7 years) with an ischemic cerebrovascular event (CVE) (ischemic stroke-IS 75.9 %, TIA 24.1 %). Headache in males occurred more frequently in bilateral localisation (right/left/bilateral: 27.5, 24.6, 39.2 %, p < 0.01), but not in females (40.3, 34.7, 39.6 %). Headache occurrence was more often associated in both genders with IS or TIA in the posterior cerebral territory (male: 33.2 %, p < 0.05; female: 51.0 %, p < 0.01) and vertebrobasilar arteries (male: 44.8 %, p < 0.001; female: 51.2 %, p < 0.001). The larger the size of the most prominent lesion the more likely patients were complaining headache during the IS (half lobe: 19.5 vs. 28.4 % in male, p < 0.001; 28.9 vs. 39.1 % in female, p < 0.01). Binary logistic regression analyses revealed lower age (p < 0.001), female sex (p < 0.001), larger size of the largest lesion (p < 0.001), and localization in the vertebrobasilar territory (p < 0.001) as predictors for headache during CVE. Headache at stroke onset is more common during IS in females, younger patients, with greater size of the acute lesion, and affected in posterior cerebral artery or vertebrobasilar system. Headache is a leading symptom in specific combination of stroke factors. These factors should be taken into account when patients report headache during IS or TIA.

BACKGROUND AND PURPOSE: Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. METHODS: Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. RESULTS: Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). CONCLUSIONS: Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov.Unique identifier: NCT00414583.