Central Sulcus Misfolding: Polarity Reversal of SSEP N20 Potential in "Layered" Polymicrogyria.

Paradoxical cortical potential polarity of the upper extremity somatosensory evoked potential (SSEP) has been reported in cases of polymicrogyria (PMG) syndrome. To date, the pathophysiological basis of this electrophysiological aberration remains under investigation. Here we present a case of mild PMG that showed "layered" microgyri in the left frontoparietal cortices affecting both hand and foot sensorimotor areas. The SSEP recordings revealed an isolated polarity reversal of N20 from the dysplastic cortex. We postulate a central sulcus misfolding theory to explain the "positive" N20 potential recorded in the PMG cortex.

Site-dependent thenar compound muscle action potential: Comparison between surface and needle recordings.

BACKGROUND: Within the thenar eminence, the median nerve innervates three muscles: abductor pollicis brevis (APB), flexor pollicis brevis (FPB), and opponens pollicis (OP). Of these muscles, APB was often considered as the sole contributor to the thenar compound muscle action potential (CMAP). OBJECTIVE: To evaluate subcomponents of the thenar CMAP from the median nerve innervated muscles. METHODS: Surface and needle CMAPs were recorded in normal human subjects from three recording sites: proximal (site-I), middle (site-II), and distal (site-III) aspects of the thenar eminence when the median nerve was activated at the wrist. RESULTS: In the site-I and -II, both the surface and needle CMAPs shared many similar characteristics although the needle CMAPs were larger (∼ 5 folds) and briefer (∼ 60%, needle/surface duration). In addition, on the surface recording, the CMAP was larger (by ∼ 1.9 mV) when recorded from the site-I comparing to that of the site-II. In the site-III, the surface recordings registered a delayed (by ∼ 3.8 ms) CMAP. The muscle fiber action potential (MFAP) study suggested a predominant FPB contribution in the site-III. CONCLUSION: The optimal recording site for APB derived thenar CMAP is the site-I and for FPB is the site-III. The CMAPs registered by the needle recordings are more robust than the surface ones.

A Comparison of Interside Asymmetries of Lower Extremity Somatosensory Evoked Potentials in Anesthetized Patients with Unilateral Lumbosacral Radiculopathy.

STUDY DESIGN: Prospective cohort study. PURPOSE: This study was to investigate interside asymmetries of three lower extremity somatosensory evoked potentials (SSEPs) in anesthetized patients with unilateral lumbosacral radiculopathy. OVERVIEW OF LITERATURE: Although interside asymmetry is an established criterion of abnormal SSEP, little is known which of the lower SSEPs is more sensitive in detecting interside asymmetry in anesthetized patients. METHODS: Superficial peroneal nerve SSEP (SPN-SSEP), posterior tibial nerve SSEP (PTN-SSEP), and sural nerve SSEP were obtained in 31 lumbosacral surgery patients with unilateral lumbosacral radiculopathy, and compared with a group of 22 control subjects. RESULTS: The lumbosacral group showed significant larger interside asymmetry ratios of P37 latencies in SPN-SSEP and PTN-SSEP, and significant larger interside asymmetry ratio of P37-N45 amplitude in SPN-SSEP, when comparing with the control group. Within the lumbosacral group but not the control group, SPN-SSEP displayed significant larger interside asymmetry ratio in P37 latency. When referencing to the control group, more patients in the lumbosacral group displayed abnormal interside SPN-SSEP latency asymmetries which corroborated the symptom laterality. CONCLUSIONS: The data suggested that SPN-SSEP was more sensitive in detecting interside latency asymmetry in anesthetized patients.

Intraoperative Loss of Tibialis Anterior Transcranial Electrical Motor Evoked Potentials Predicted Postoperative Footdrop.

BACKGROUND: Footdrop secondary to L5 root injury is a rare complication associated with lumbar surgery. It is unclear whether intraoperative neuromonitoring can detect such an injury. CASE DESCRIPTION: A 54-year-old man who had had bilateral chronic L5 radiculopathy underwent L4-S1 lumbosacral decompression and fusion. During surgery, the patient lost transcranial electrical motor evoked potentials (tceMEPs) from the left tibialis anterior (TA) at the time of L5-S1 intervertebral cage placement. Neither intraoperative free-run electromyography nor somatosensory evoked potentials detected any changes. In addition, contralateral TA tceMEPs remained stable. Postoperatively, the patient presented with left-sided footdrop that has persisted for >1 year. CONCLUSIONS: Intraoperative TA tceMEPs could detect L5 root iatrogenic injury.

URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews.

BACKGROUND: Hereditary renal hypouricemia may be complicated by nephrolithiasis or exercise-induced acute renal failure. Most patients described so far are of Japanese origin and carry the truncating mutation W258X in the uric acid transporter URAT1 encoded by SLC22A12. Recently, we described severe renal hypouricemia in Israeli patients with uric acid transporter GLUT9 (SLC2A9) loss-of-function mutations. Renal hypouricemia in Iraqi Jews has been previously reported, but its molecular basis has not been ascertained. METHODS: Three Jewish Israeli families of Iraqi origin with hereditary hypouricemia and hyperuricosuria were clinically characterized. DNA was extracted and the URAT1 gene was sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of URAT1 mutants found. RESULTS: A missense URAT1 mutation, R406C, was detected in all three families. Two affected siblings were found to carry in addition a homozygous missense URAT1 mutation, G444R. Both mutations dramatically impaired urate uptake into X. laevis oocytes. Moreover, we demonstrate for the first time that URAT1 facilitates urate efflux, which was abolished in the mutants, indicating also a secretion defect. Homozygous patients had serum uric acid concentrations of 0.5-0.8 mg% and a fractional excretion of uric acid of 50-85%. Most individuals studied were asymptomatic, two had nephrolithiasis and none developed exercise-induced acute renal failure. CONCLUSIONS: The URAT1 R406C mutation detected in all three families is likely to be the founder mutation in Iraqi Jews. Our findings contribute to a better definition of the different types of hereditary renal hypouricemia and suggest that the phenotype of this disorder depends mainly on the degree of inhibition of uric acid transport.

Truncating mutations in the chloride/proton ClC-5 antiporter gene in Seven Jewish Israeli families with Dent's 1 disease.

Dent's disease is an X-linked hereditary renal tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure. About 60% of patients have mutations in the CLCN5 gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the OCRL1 gene (Dent 2). The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent's disease and to characterize the associated clinical syndromes. We studied 17 patients from 14 unrelated Israeli families with a clinical diagnosis of Dent's disease. LMWP was detected in all patients. Most of the affected individuals had hypercalciuria and nephrocalcinosis. Renal stones were found in 1 patient, and renal insufficiency developed in 2 patients. We identified six different truncating CLCN5 mutations that were segregated with the disease in 7 families: three nonsense mutations (Arg28stop, Arg467stop and Arg637stop), one deletion mutation (505delA) and two novel mutations, consisted of one deletion mutation (1493delG) and one insertion mutation (409insC). All the mutations cause premature termination of protein translation and result in a non-functional truncated protein. The clinical characteristics of patients with different mutations were, in general, similar.

Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients.

INTRODUCTION: The mortality rate in diabetic dialysis patients (DDPs) is over 15% per year, with the cause of death most often attributed to cardiovascular disease (CVD) or bacterial infection (sepsis). Identification of genetic markers predictive of early mortality would be useful in the evaluation of therapies for the reduction of mortality rate in this population. Haptoglobin (Hp) is a polymorphic protein which appears to confer differential susceptibility to bacterial infection and CVD. We therefore proposed that Hp phenotype can predict mortality in DDPs. METHODS: We tested this hypothesis prospectively in a longitudinal study of 392 dialysis patients from eight medical centres in Israel. Hp was determined by polyacrylamide gel electrophoresis. Patients were followed for all-cause mortality over a 3-year period. RESULTS: We found that Hp phenotype was a significant predictor of mortality in DDPs stratified by age. In diabetic individuals over 60 years of age there was a decrease in mortality associated with the Hp 1-1 phenotype (P = 0.03). However, in younger DDPs the Hp 2-2 phenotype was associated with a decreased mortality rate (P = 0.003). CONCLUSION: Hp phenotype may be useful in the risk stratification algorithm and management of DDPs.

A novel missense mutation in the sodium bicarbonate cotransporter (NBCe1/SLC4A4) causes proximal tubular acidosis and glaucoma through ion transport defects.

In humans and terrestrial vertebrates, the kidney controls systemic pH in part by absorbing filtered bicarbonate in the proximal tubule via an electrogenic Na+/HCO3- cotransporter (NBCe1/SLC4A4). Recently, human genetics revealed that NBCe1 is the major renal contributor to this process. Homozygous point mutations in NBCe1 cause proximal renal tubular acidosis (pRTA), glaucoma, and cataracts (Igarashi, T., Inatomi, J., Sekine, T., Cha, S. H., Kanai, Y., Kunimi, M., Tsukamoto, K., Satoh, H., Shimadzu, M., Tozawa, F., Mori, T., Shiobara, M., Seki, G., and Endou, H. (1999) Nat. Genet. 23, 264-266). We have identified and functionally characterized a novel, homozygous, missense mutation (S427L) in NBCe1, also resulting in pRTA and similar eye defects without mental retardation. To understand the pathophysiology of the syndrome, we expressed wild-type (WT) NBCe1 and S427L-NBCe1 in Xenopus oocytes. Function was evaluated by measuring intracellular pH (HCO3- transport) and membrane currents using microelectrodes. HCO3- -elicited currents for S427L were approximately 10% of WT NBCe1, and CO2-induced acidification was approximately 4-fold faster. Na+ -dependent HCO3- transport (currents and acidification) was also approximately 10% of WT. Current-voltage (I-V) analysis reveals that S427L has no reversal potential in HCO3-, indicating that under physiological ion gradient conditions, NaHCO3 could not move out of cells as is needed for renal HCO3- absorption and ocular pressure homeostasis. I-V analysis without Na+ further shows that the S427L-mediated NaHCO3 efflux mode is depressed or absent. These experiments reveal that voltage- and Na+ -dependent transport by S427L-hkNBCe1 is unfavorably altered, thereby causing both insufficient HCO3- absorption by the kidney (proximal RTA) and inappropriate anterior chamber fluid transport (glaucoma).

Role of haptoglobin phenotype in end-stage kidney disease.

BACKGROUND: We recently reported that haptoglobin (Hp) phenotype 1-1 is protective against the development of nephropathy in normal creatinine diabetics. In the present study, we sought to determine if Hp phenotype also plays a role in renal deterioration by determining Hp phenotypes in a consecutive series of patients with chronic renal failure (CRF) in hemodialysis (HD) and predialysis clinics. METHODS: Three hundred and ninety-two patients on HD for less than 2 years and 182 predialysis patients (creatinine clearance time [CCT] <35 ml/min) were subjected to Hp phenotyping. Age, gender and presence of diabetes or hypertension were recorded. Patients were stratified according to age (above and below 60 years) and severity of renal dysfunction (CRF or HD). RESULTS: We observed a markedly lower prevalence of the Hp 1-1 phenotype in HD patients under 60 years of age compared to patients with CRF or compared to the general population. This was not due to differences in the threshold for dialysis initiation among patients with different Hp types or to decreased survival of patients with Hp 1-1 prior to entering HD. In HD patients 60 years and over, Hp 1-1 prevalence was increased, as observed with other diseases in this age group. CONCLUSIONS: The prevalence of Hp 1-1 is decreased in HD patients less than 60 years of age. This may be due to a fundamental difference in the rate of renal deterioration in patients with different Hp types. In addition, Hp 1-1 may provide a protective effect against mortality in elderly patients.

Search for peptidic "middle molecules" in uremic sera: isolation and chemical identification of fibrinogen fragments.

According to the "middle molecule" (MM) hypothesis, the uremic solutes ranging from 500 to 5,000 Da are insufficiently eliminated by conventional hemodialysis and may act as uremic toxins. However, because of the methodological difficulties of MM purification, their chemical analysis is complicated and the precise structure of these molecules remains obscure. In the present study, a new micro-preparative procedure including SDS electrophoresis and liquid chromatography was applied for isolation of MM peptides from uremic sera. Microsequencing and MS/MS analyses of these peptides showed that most of the identified MM (22 out of 23) represented the N- and C-terminal fragments of the alpha- and beta-chains of fibrinogen. The obtained data provide new information on the precise structure of fibrinogen fragments accumulating in uremic serum as MM.