Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration.

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.     

Infant stroke and beta-2-glycoprotein 1 antibodies: six cases

The binding of autoimmune anticardiolipin antibodies to phospholipid has been shown to require a plasma cofactor, beta-2-glycoprotein 1 (2-GPI). Antibodies against 2-GPI are associated with both venous and arterial thrombosis in adults and have been suggested as a new antiphospholipid syndrome marker. We present six children with cerebral thrombosis at the age of 0–12 months, who had IgG antibodies to 2-GPI (titers 26, 29, 31, 39, 101 and 109 SGU, when 20 SGU was the cut-off). In at least four patients, the conventional antiphospholipid markers (lupus anticoagulant and IgG and IgM anticardiolipin) were negative. All six children had normal results in the other routine thrombophilia assays (thrombin time, antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin mutation). Conclusion: the anti-beta-2 glycoprotein 1 assay, requiring only 5 l serum, may be a useful addition to antiphospholipid-antibody diagnostics in cases of paediatric stroke.Abbreviations a2-GPI anti-beta-2-glycoprotein 1 antibodies - aCL anticardiolipin antibodies - LA lupus anticoagulant     

Nonketotic hyperglycinemia A genetic study of 13 Finnish families

In Finland, 19 children, born 1964--1977, from 13 families, have been diagnosed as suffering from nonketotic hyperglycinemia (NKH). This gives an incidence for NKH in the Finnish population of 1:55,000 newborns. The majority of these children were born in the northern part of the country, where the incidence is 1:12,000. The geographical distribution of the birth-places of the grandparents also seems to point towards an enrichment of the gene in northern Finland. An autosomal recessive mode of inheritance for this disease seems probable, since the corrected proportion of affected siblings (Apert's a priori method) is 0.288. Abnormally high plasma glycine concentration and elevated glycine urinary excretion in the parents of the NKH-children suggest the existence of a minor metabolic defect in heterozygotes of this disease. Some of the healthy siblings of the NKH-patients also show similary elevated levels. However, a definite diagnosis of the NKH-heterozygote state cannot easily be made on the basis of these laboratory findings, as the levels in some individuals are very close to, or even overlap corresponding values in a normal material.     

Ultrasound Arthroscopy of Human Knee Cartilage and Subchondral Bone in Vivo

Arthroscopic ultrasound imaging enables quantitative evaluation of articular cartilage. However, the potential of this technique for evaluation of subchondral bone has not been investigated in vivo. In this study, we address this issue in clinical arthroscopy of the human knee (n = 11) by determining quantitative ultrasound (9 MHz) reflection and backscattering parameters for cartilage and subchondral bone. Furthermore, in each knee, seven anatomical sites were graded using the International Cartilage Repair Society (ICRS) system based on (i) conventional arthroscopy and (ii) ultrasound images acquired in arthroscopy with a miniature transducer. Ultrasound enabled visualization of articular cartilage and subchondral bone. ICRS grades based on ultrasound images were higher (p < 0.05) than those based on conventional arthroscopy. The higher ultrasound-based ICRS grades were expected as ultrasound reveals additional information on, for example, the relative depth of the lesion. In line with previous literature, ultrasound reflection and scattering in cartilage varied significantly (p < 0.05) along the ICRS scale. However, no significant correlation between ultrasound parameters and structure or density of subchondral bone could be demonstrated. To conclude, arthroscopic ultrasound imaging had a significant effect on clinical grading of cartilage, and it was found to provide quantitative information on cartilage. The lack of correlation between the ultrasound parameters and bone properties may be related to lesser bone change or excessive attenuation in overlying cartilage and insufficient power of the applied miniature transducer.     

Neuroradiological findings in the northern epilepsy syndrome

Neuroradiological findings are presented of 19 patients with the northern epilepsy syndrome, a recessively inherited childhood epilepsy with associated mental deterioration. The first signs of cerebellar-brainstem atrophy already appeared in young adulthood, with atrophy tending to increase with age. Findings of cerebral atrophy were detected later: four of the seven patients under 30 years of age displayed central or cortical atrophy, while all 12 patients over 30 were affected. The degree of mental deterioration correlated well with the severity of cerebral atrophy. One half of the patients with either central or cortical atrophy were moderately to severely retarded, whereas all patients with both central and cortical atrophy were moderately to profoundly retarded.     

The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm of chromosome 8.

A recently delineated childhood epilepsy has hitherto been observed only in a small geographic region in northern Finland, where, with the exception of one, both parents of all of the 11 sibships with affected individuals descend from one or two founding couples. The disease is characterized by generalized tonic-clonic seizures with onset at 5-10 years and progressive, severe mental retardation with onset 2-5 years after the first seizures. In this study the gene locus is assigned to the telomeric region of chromosome 8p by linkage. Analyses of recombinations place the locus in the 7-centimorgan interval between AFM185xb2 and D8S262 in which three markers, D8S504, D8S264, and AFM077yg5, show no recombinations with the phenotype. Haplotypes comprising alleles at the above five loci support the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who has a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. This study raises to three the number of heritable epilepsies whose gene loci have been mapped and provides a starting point for the cloning of the gene. It also suggests the possibility that the disease might not be limited to the northern Finnish population.     

Neurophysiological findings in the northern epilepsy syndrome

We describe the neurophysiological findings in the northern epilepsy syndrome (NES), an autosomal recessively inherited childhood onset epilepsy with associated mental deterioration. Sixty-five EEGs of 18 patients (10 females and 8 males) from the age of 5 years to 52 years were analyzed. EEG showed relatively slight changes at the outbreak of epilepsy at the mean age of 6.6 years (range 5–10 years). Slowing of the background activity to 6–7 Hz theta activity, abundant diffuse or intermittent theta and delta activity and disappearance of sleep-specific activity characterized the EEGs at puberty. The amount of diffuse delta and theta activity diminished in adulthood. Epileptiform findings were scanty. Spikes and sharp waves occurred in 43% of the recordings with varying localization, form and extent. Intermittent 2–4 Hz sharp and slow wave rhythm was seen in 32% of the recordings. Of the three ictal recordings, one showed a primarily generalized discharge pattern, while two were clearly asymmetric. Clonazepam was the most effective antiepileptic drug, and it also normalized the EEG when started in childhood or at the onset of puberty. Visual evoked potentials were abnormal in 44% and brainstem auditory evoked potentials in 35%. The neurophysiological findings suggest an extensive, probably multifocal degenerative brain process, which reaches its peak at puberty. Although the abnormal features of EEG often decreased in adulthood, the clinical course of NES showed slow progression throughout the lifetime.     

Trabecular Homogeneity Index Derived From Plain Radiograph to Evaluate Bone Quality

Radiographic texture analysis has been developed lately to improve the assessment of bone architecture as a determinant of bone quality. We validate here an algorithm for the evaluation of trabecular homogeneity index (HI) in the proximal femur from hip radiographs, with a focus on the impact of the principal compressive system of the trabecular bone, and evaluate its correlation with femoral strength, bone mineral density (BMD), and volumetric trabecular structure parameters. A semiautomatic custom‐made algorithm was applied to calculate the HI in the femoral neck and trochanteric areas from radiographs of 178 femoral bone specimens (mean age 79.3 ± 10.4 years). Corresponding neck region was selected in CT scans to calculate volumetric parameters of trabecular structure. The site‐specific BMDs were assessed from dual‐energy X‐ray absorptiometry (DXA), and the femoral strength was experimentally tested in side‐impact configuration. Regression analysis was performed between the HI and biomechanical femoral strength, BMD, and volumetric parameters. The correlation between HI and failure load was R² = 0.50; this result was improved to R² = 0.58 for cervical fractures alone. The discrimination of bones with high risk of fractures (load <3000 N) was similar for HI and BMD (AUC = 0.87). Regression analysis between the HIs versus site‐specific BMDs yielded R² = 0.66 in neck area, R² = 0.60 in trochanteric area, and an overall of R² = 0.66 for the total hip. Neck HI and BMD correlated significantly with volumetric structure parameters. We present here a method to assess HI that can explain 50% of an experimental failure load and determines bones with high fracture risk with similar accuracy as BMD. The HI also had good correlation with DXA and computed tomography–derived data. © 2013 American Society for Bone and Mineral Research.