Antiphospholipid syndrome in patients with retinal venous occlusion

INTRODUCTION: We conducted a prospective study to determine the prevalence and the prognosis of antiphospholipid syndrome (APS) in patients with retinal venous occlusion (RVO). PATIENTS: Consecutive patients presenting with retinal vein occlusion were screened for vascular risk factors (diabetes mellitus, hypertension, hyperlipidemia) and for antiphospholipid antibodies (aPL): anticardiolipin (aCL), anti-beta2-glycoprotein I, and lupus anticoagulant. Patients with a serum sample positive for aPL returned at least 6 weeks later for a new screening to determine the prevalence of antiphospholipid syndrome. All patients were followed to determine the outcome. RESULTS: Sixty-eight patients presented with RVO, 16 had vascular risk factors for RVO. After two screenings for aPL, nine cases of antiphospholipid syndrome associated with RVO were diagnosed (13.2%). Eight patients were over age 50 years and none had a previous thrombotic event before RVO. All patients were treated with aspirin (160 mg/day). With a mean follow-up of 26.1+/-8.2 months (range, 16-36 months), there were no recurrences. CONCLUSION: Retinal venous occlusion is multifactorial in origin. In patients aged 50 years and older, without previous thrombotic event, aPL might not be predictive of recurrences and treatment with aspirin might be sufficient. In such patients, the routine screening for aPL does not appear warranted, but a randomized study should be conducted to really ascertain the pathogenic role of aPL and the most appropriate treatment in RVO.     

经基因确诊的单纯型遗传性痉挛性截瘫6型的临床和磁共振成像特征

目的 探讨单纯型遗传性痉挛性截瘫(PHSPG)6型的临床和MRI特征.方法 回顾性分析1个家系中6例SPG6型患者的MRI图像,并与6例MRI表现正常且同性别、同年龄的健康对照者进行对照研究.12例受试者均进行颅脑、颈髓及上胸髓MRI检查,分别测量颈2(C2)、C3、C7、胸1(T1)、T2、T3、T4、T9椎体水平脊髓横断面面积、椎管前后径及横径,测量结果进行统计学分析.结果 6例SPG6型患者中,5例患者的颅脑MRI表现未见明显异常,1例表现为老年性脑改变.6例患者颈髓及上胸髓MRI呈不同程度变细,灰质、白质均受累,蛛网膜下腔扩大;在变细明显的脊髓节段灰白质分界显示清楚,横轴位T2WI上灰质呈边界清楚、左右对称的点状或点片状高信号,矢状位上表现为连续纵行的条状高信号.6例患者的C2～3、C7、T1～4椎体水平的脊髓横断面面积、前后径及横径明显小于对照组,二者间差异有统计学意义,而T9水平仅横径的差异有统计学意义(患者组7.22±0.80,对照组8.17±0.41,t=2.870,P=0.046).结论 SPG6型患者的颅脑MRI可表现为正常;颈髓及上胸髓变细,而且灰白质分界清楚,下胸髓受累较轻,其MRI表现有一定的特征性.     

Anti-prothrombin antibodies are associated with thrombosis in children

Introduction

This investigation aimed to evaluate thrombotic risk factors in children, with special reference to autoantibodies against prothrombin and protein S.

Materials and methods

We studied 57 consecutive Swedish children and adolescents referred with a radiologically confirmed acute thrombotic event. Clinical data were collected and a thrombophilia investigation was performed, including analysis of autoantibodies against protein S (anti-PS) and prothrombin (anti-PT). The anti-PS and anti-PT autoantibodies were also investigated in sera from 47 healthy controls. Detection of autoantibodies was performed by quantitative enzyme-linked immunosorbent assays.

Results

Results for anti-PT antibodies were positive in 21% (12/57) of the patients and 2.1% (1/47) of the controls (OR 12.0, 95% CI 1.7-534; p = 0.005). Seven percent (4/57) of the patients and 2.1% (1/47) of the controls were positive for anti-PS antibodies (OR 3.4, 95% CI 0.3-174; p > 0.30). The FV G1691A mutation was found in 25% (14/57), and 44% (25/57) had 2 or more prothrombotic risk factors. Sixty percent (34/57) of the thrombosis patients were female. Peaks in frequency of thromboembolic events were found in the neonatal and the adolescent periods. Fifty-three percent (30/57) had thrombosis in the lower venous system. Associated clinical conditions occurred in 91% (52/57): systemic illness in 31% (18/57), infections in 26% (15/57), and oral contraceptive use in 25% (14/57). Four percent (2/57) had no apparent clinical or prothrombotic risk factors.

Conclusions

This study suggests that anti-PT autoantibodies may be common risk factors for thrombosis in children, and it confirms the multifactorial nature of pediatric thrombosis.     

Sneddon's syndrome (livedo reticularis and cerebrovascular lesions) with antiphospholipid antibodies and severe dementia in a young man: a case report

We present the case of 37-year-old man with Sneddon's syndrome and antiphospholipid antibodies. His chief neurological manifestation was rapidly progressive dementia, which developed 6 years after the appearance of livedo reticularis.     

A pilot study of eptifibatide for treatment of acute pain episodes in sickle cell disease

Introduction

The contribution of platelet activation to the pathogenesis of sickle cell disease (SCD) remains uncertain. We evaluated the safety and efficacy of eptifibatide, a synthetic peptide inhibitor of the αIIbβ3 receptor, in SCD patients during acute painful episodes.

Materials and Methods

In this single site, double-blind, placebo-controlled trial, eligible patients with SCD admitted for acute painful episodes were randomized to receive eptifibatide or placebo at a ratio of 2:1.

Results

Thirteen patients (SS - 10, Sβ⁰ - 2, SC - 1) were randomized to receive either eptifibatide (N = 9; 6 females; median age - 25 years) or placebo (N = 4; 3 females; median age - 31 years). In the intent-to-treat analysis, there were no major bleeding episodes in either the eptifibatide or placebo arms (point estimate of difference: 0.00, 95% CI; -0.604, 0.372). There was one minor bleeding episode in the eptifibatide arm (point estimate of difference for any bleeding: 0.11, 95% CI: -0.502, 0.494). There was no significant difference in the proportion of patients with thrombocytopenia between the treatment groups (point estimate of difference: 0.11, 95% CI: -0.587, 0.495). There were no differences in the median times to discharge, median times to crisis resolution or the median total opioid use.

Conclusions

In this small study, eptifibatide appeared to be safe, but did not improve the times to crisis resolution or hospital discharge. Adequately powered studies are required to evaluate the safety and efficacy of eptifibatide in SCD. Clinicaltrials.gov Identifier: NCT00834899.     

Evaluation of the procoagulant activity of endogenous phospholipids in the platelet-free plasma of children with sickle cell disease using functional assays

Background

The mechanisms of hypercoagulability in sickle cell disease (SCD) are poorly understood.

Objective

We aimed to explore the procoagulant activity of endogenous phospholipids (ePL) in the platelet-free plasma of SCD children.

Methods

A factor Xa clotting time (XACT), thrombin generation (TG) and a capture-based assay for the detection of procoagulant microparticles (PMP) were used. Forty three SCD children (35 SS, 6 SC and 2 Sβ +) were evaluated at steady-state and compared to 20 controls. Fourteen patients were also evaluated during vaso-occlusive crisis. TG was performed using 10pM tissue factor without addition of exogenous phospholipids. A control condition was also performed using 10pM tissue factor and 4 μM phospholipids. Percentages of the test/control conditions were calculated for the peak height (% peak), endogenous thrombin potential (% ETP) and velocity index (% VI).

Results

XACT times were shorter, PMP levels, peak height and velocity index of thrombin generation were higher in SCD patients than controls. Lag time and ETP were not different between the two groups. % peak, % ETP and % VI were higher in patients than controls. Significant correlations were found between PMP levels and XACT, also between PMP levels and peak height, velocity index, ETP and their respective percentages to the control condition, but not with lag time. Double heterozygous patients showed intermediate values for XACT and TG parameters. No significant difference was observed when comparing patients at steady-state versus vaso-occlusive crisis.

Conclusion

High procoagulant activity of ePL was observed in the platelet-free plasma of SCD children, probably borne by procoagulant microparticles. This may contribute to a high hemostatic potential and predisposition to thrombotic complications in these patients.     

ATL3 gene mutation in a Chinese family with hereditary sensory neuropathy type 1F

Hereditary sensory neuropathy (HSN) comprises a group of progressive peripheral neuropathies predominantly affecting the sensory nerves. To date, two different ATL3 gene mutations have been reported to be responsible for HSN type 1F (HSN1F). Here, we report a family in which the members presented numbness of the lower limbs and recurrent foot ulceration. Symptoms of foot ulcers disappeared in the years after onset, which suggests that the family members showed benign and mild symptoms compared with the affected patients reported previously. Laboratory examinations and electrophysiological data suggested axonal degeneration of the peripheral sensory nerves, while motor neurons were not involved. Exome sequencing revealed the previously reported c.C1013G (p.Pro338Arg) mutation of the ATL3 gene. This is the first report of ATL3 mutation in Chinese patients with HSN. Cells expressing mutant ATL3 exhibited disruption of the endoplasmic reticulum network, suggesting a dominant‐negative effect. There was no significant difference in the expression of the endoplasmic reticulum stress marker binding immunoglobulin protein (BiP) between cells expressing wild‐type or mutant ATL3. Further studies are required to ascertain the relevance of the changes in endoplasmic reticulum morphology to axonal degeneration of sensory nerves.     

Clinical phenotype and neuroimaging findings in a French family with hereditary ferritinopathy (FTL498‐499InsTC)

To describe a family with a hereditary ferritinopathy (HF) due to a mutation in the ferritin light chain gene (FTL498‐499InsTC mutation). Case reports of the clinical features, MRI, ¹⁸FDG PET, and pathological findings observed in this family with two patients described in more details. Postural tremor (phenotype‐1) or cerebellar signs (phenotype‐2) were the first neurological symptoms detected. Parkinsonian, cerebellar and pyramidal syndromes, abnormal involuntary movements, dementia were observed in both phenotypes at more advanced stages. Beside characteristics T2* hypointense signals suggestive of iron accumulation in the striatum, mesencephalon, and cerebellum, we detected more diffuse changes including cerebellar, cortical and subcortical atrophy, cortical iron deposition, and severe leukoencephalopathy. ¹⁸FDG PET showed frontal and cerebellum hypometabolism with more severe frontal defect in patients with cognitive decline. Pathological examination showed ferritin and iron deposition in the liver, kidney, muscle, skin, and in the central nervous system. Members of this family affected by HF due to the FTL498‐499InsTC mutation have a specific clinical presentation with initial postural tremor or cerebellar ataxia, followed by pyramidal and extrapyramidal motor syndromes and late severe subcortical dementia. © 2009 Movement Disorder Society     

Novel SPG6 mutation p.A100T in a Japanese family with autosomal dominant form of hereditary spastic paraplegia.

We describe a Japanese family in which inheritance of a novel mutation p.A100T in SPG6 resulted in an autosomal dominant form of hereditary spastic paraplegia (ADHSP). Clinical investigation showed a pure form of HSP. Our study demonstrates further allelic heterogeneity of SPG6.     

Endothelial function is impaired in patients with primary antiphospholipid syndrome

INTRODUCTION: The aim of this study was to evaluate endothelial function in patients with primary antiphospholipid syndrome (PAPS). PATIENTS AND METHODS: Flow mediated (FMD) and glyceryl trinitrate (GTN) induced dilation of the right brachial artery were studied in 25 patients with PAPS and 25 controls matched by age, sex and conventional risk factors for atherosclerosis. Fibrinogen, D-dimer, adhesion molecules, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigens and activities were measured. RESULTS: Mean (SD) FMD was significantly lower in PAPS than in controls (8+/-5% vs. 15+/-6%, P<0.001); GTN-induced dilation did not differ between the groups. There was a correlation between the baseline diameter of the brachial artery and duration of the disease (-0.56, P<0.05) and between GTN induced dilation and duration of the disease (0.51, P<0.05). Concentrations of vascular cell adhesion molecule-1 (P<0.001), intracellular adhesion molecule-1 (P<0.001) and fibrinogen (P<0.05) were higher in patients than in controls but no differences were observed for D-dimer, t-PA and PAI-1 antigens and activities. There was correlation between concentration of vascular cell adhesion molecule-1 and FMD (-0.35, P<0.05) and between intracellular adhesion molecule-1 and FMD (-0.41, P<0.05). CONCLUSIONS: This study shows that endothelial function is impaired in patients with primary APS, possibly contributing to accelerated atherosclerosis and thromboembolic complications in these patients.     

The association of antiphospholipid antibodies with intrauterine fetal death: a case-control study

Introduction

Over the past few decades it has been recognized that antiphospholipid antibodies are associated with pregnancy loss. Other placenta-mediated pregnancy complications have also been associated with the presence of antiphospholipid antibodies. Most studies have measured antiphospholipid antibodies near the time of the event investigated.

Objectives

To investigate the association of antiphospholipid antibodies and a history of intrauterine fetal death (IUFD) in a case-control design.

Materials and methods

A case-control study of 105 women with a history of IUFD after 22 gestational weeks and 262 controls with live births. The prevalence of lupus anticoagulant, anticardiolipin- and anti-β2-glycoprotein 1 antibodies were measured 3-18 years after the event of IUFD.

Results

Total 9.5% of women with a history of IUFD and 5.0% of controls had at least one positive test for antiphospholipid antibodies (OR 2.0; 95% confidence interval (CI) 0.9-4.8). Women with a history of IUFD were significantly more often positive for lupus anticoagulant compared to controls (OR 4.3; 95% CI 1.0-18.4). The association of lupus anticoagulant with a history of IUFD was confined to women positive for other antiphospholipid antibodies in addition to lupus anticoagulant. Being positive for anti-β2-glycoprotein 1 or anticardiolipin antibodies alone was not significantly associated with a history of IUFD.

Conclusions

Women with a history of IUFD after 22 gestational weeks were more often lupus anticoagulant positive. The association was confined to women with multiple positivity for antiphospholipid antibodies, although firm conclusions on the importance of multiple positivity cannot be made from this study.     

Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy

Mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene have been identified in families with distal hereditary motor neuropathy (dHMN) and in families with SPG17-linked Silver syndrome. We studied the first Korean families with clinical features resembling classic Silver syndrome and dHMN type V. Direct sequencing analysis of the BSCL2 gene revealed a Ser90Leu mutation in the proband, a younger sister, and one of two sons of the proband. The clinical patterns in this family include presentation with lower-limb and hand-muscle involvement early in the disease course as well as the presence of Babinski signs with nonprogressive mild spastic paraparesis, resembling classic Silver syndrome and dHMN type V. This study reaffirms the clinical phenotype of the disorders associated with a BSCL2 Ser90Leu mutation and describes a genetically proven family with Silver syndrome and dHMN type V in Asia.     

A novel small deletion in PMP22 causes a mild hereditary neuropathy with liability to pressure palsies phenotype

Introduction: In this study we examined a family with electrophysiological findings of hereditary neuropathy with liability to pressure palsies (HNPP) and a mild clinical presentation.Methods: Four members of a family were referred for diagnosis of HNPP. Electrophysiological studies included motor and sensory nerve conduction studies in the upper and lower extremities. Investigations of microsatellites, using polymorphic repeat markers flanking the gene, and multiplex ligation‐dependent probe amplification (MLPA) were performed for molecular studies. Results: The initial study of microsatellites did not detect any change, but MLPA demonstrated a small deletion of exon 5 in the PMP22 gene. Conclusion: Our findings demonstrate the important role of small deletions in the PMP22 gene in the etiology of HNPP with a normal microsatellite study. Muscle Nerve 45: 135–138, 2012     

A novel mutation in the <Emphasis Type="Italic">HSPD1</Emphasis> gene in a patient with hereditary spastic paraplegia

Abstract A mutation in the HSPD1 gene has previously been associated with an autosomal dominant form of spastic paraplegia in a French family. HSPD1 encodes heat shock protein 60, a molecular chaperone involved in folding and quality control of mitochondrial proteins. In the present work we have investigated 23 Danish index patients with hereditary spastic paraplegia (HSP) for mutations in the HSPD1 gene. One patient was found to be heterozygous for a c.1381C > G missense mutation encoding the mutant heat shock protein 60 p.Gln461Glu. The mutation was also present in two unaffected brothers, but absent in 400 unrelated Danish individuals. We found that the function of the p.Gln461Glu heat shock protein 60 was mildly compromised. The c.1381C > G mutation likely represents a novel low-penetrance HSP allele.     

New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype

Charcot-Marie-Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine-Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.     

Performance validity testing in a clinical sample of adults with sickle cell disease

Objective: Neuropsychologists utilize performance validity tests (PVTs) as objective means for drawing inferences about performance validity. The Test of Memory Malingering (TOMM) is a well-validated, stand-alone PVT and the Reliable Digit Span (RDS) and Reliable Digit Span-Revised (RDS-R) from the Digit Span subtest of the WAIS-IV are commonly employed, embedded PVTs. While research has demonstrated the utility of these PVTs with various clinical samples, no research has investigated their use in adults with sickle cell disease (SCD), a condition associated with multiple neurological, physical, and psychiatric symptoms. Thus, the purpose of this study was to explore PVT performance in adults with SCD. Method: Fifty-four adults with SCD (M_age = 40.61, SD = 12.35) were consecutively referred by their hematologist for a routine clinical outpatient neuropsychological evaluation. During the evaluation, participants were administered the TOMM (Trials 1 and 2), neuropsychological measures including the WAIS-IV Digit Span subtest, and mood and behavioral questionnaires. Results: The average score on the TOMM was 47.70 (SD = 3.47, range = 34–50) for Trial 1 and 49.69 (SD = 1.66, range = 38–50) for Trial 2. Only one participant failed Trial 2 of the TOMM, yielding a 98.1% pass rate for the sample. Pass rates at various RDS and RDS-R values were calculated with TOMM Trial 2 performance as an external criterion. Conclusions: Results support the use of the TOMM as a measure of performance validity for individuals with SCD, while RDS and RDS-R should be interpreted with caution in this population.     

Progressive dementia, without cerebral hemorrhage, in a patient with hereditary cerebral amyloid angiopathy

A now 58-year-old female patient, carrier of the point-mutation in the β-amyloid gene on chromosome 21 which causes hereditary cerebral hemorrhage with amyloidosis — Dutch type, developed progressive dementia after the age of 55 years. She never suffered from a cerebral hemorrhage. Dementia has been described as a feature of hereditary amyloid angiopathy before, but only in patients who also suffer from strokes. The clinical manifestation of the patient described here underlines the relation between the Dutch type of hereditary amyloid angiopathy and (familial) Alzheimer's disease.     

Refractory psychotic symptoms in a patient with homozygous sickle cell disease: a 24-month follow-up

The present report describes a case of a 33-year old male patient with homozygous sickle cell disease (SCD) with comorbid psychotic symptoms. The systematical evaluation revealed an intimate association between acute SCD complications, associated with hematological abnormalities, and psychotic symptoms worsening. Clozapine was effective in controlling psychotic symptoms refractory to previous antipsychotic trials.