Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene.

Inherited bone marrow failure syndromes (IBMFS) are group of disorders that lead to inadequate production of blood cells. Mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle cause IBMFS. ERCC6L2 gene mutations have been associated with bone marrow failure that includes developmental delay and microcephaly. We report 2 cases of bone marrow failure with no extra-hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described.

A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss.

Mutations in GLE1, RNA export mediator (GLE1) gene have previously been shown to cause motor neuron diseases such as lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD), including arthrogryposis, fetal akinesis and motor neuron loss as common clinical features. The homozygous FinMajor mutation p.T144_E145insPFQ has been described as one of the causes for LCCS1 whereas LAAHD is caused by a heterocompound FinMajor mutation together with p.R569H, p.V617M or p.I684T missense mutation. None of these heterocompound missense mutations have previously been reported as homozygous states. Here we present the clinical features of 2 siblings with a homozygous p.I684T mutation in GLE1. The patients suffered from similar, but milder symptoms than in LCCS1 and LAAHD, surviving up to 6 months before they died due to a progressive disease course including respiratory failure. Arthrogryposis, lack of spontaneous movements, and epilepsy were notable in both cases and lack of anterior horn cells was identified in autopsy samples. Our studies on patient-derived fibroblasts show that the homozygous p.I684T impairs the nuclear localization of GLE1 further confirming the pathogenic role of this mutation.

Identification of C12orf4 as a gene for autosomal recessive intellectual disability.

Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034-429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co-segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub-isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID.

Analysis of mitochondrial DNA sequences in patients with isolated or combined oxidative phosphorylation system deficiency.

BACKGROUND: Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA. OBJECTIVE: To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying genetic defect. RESULTS: Three novel non-synonymous substitutions in protein-coding genes, 4681T-->C in MT-ND2, 9891T-->C in MT-CO3 and 14122A-->G in MT-ND5, and one novel substitution in the 12S rRNA gene, 686A-->G, were found. The definitely pathogenic mutation 3460G-->A was identified in an 18-year-old woman who had severe isolated complex I deficiency and progressive myopathy. CONCLUSIONS: Bioinformatic analyses suggest a pathogenic role for the novel 4681T-->C substitution found in a boy with Leigh's disease. These results show that the clinical phenotype caused by the primary Leber's hereditary optic neuropathy mutation 3460G-->A is more variable than has been thought. In the remaining 23 patients, the role of mtDNA mutations as a cause of the OXPHOS system deficiency could be excluded. The deficiency in these children probably originates from mutations in the nuclear genes coding for respiratory enzyme subunits or assembly factors.

Lifetime use of psychiatric medications and cognition at 43years of age in schizophrenia in the Northern Finland Birth Cohort 1966.

BACKGROUND: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. METHODS: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. RESULTS: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11months) before the cognitive examination was associated with better cognitive performance (P=0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P=0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. CONCLUSIONS: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia.

Long-term antipsychotic use and its association with outcomes in schizophrenia - the Northern Finland Birth Cohort 1966.

BACKGROUND: Due to the paucity of previous studies, we wanted to elucidate the pharmacoepidemiology of antipsychotics in schizophrenia in a general population sample, and the association between long-term antipsychotic use and outcomes. METHODS: The sample included 53 schizophrenia subjects from the Northern Finland Birth Cohort 1966 with at least ten years of follow-up (mean 18.6 years since illness onset). Data on lifetime medication and outcomes (remission, Clinical Global Impression [CGI], Social and Occupational Functioning Assessment Scale [SOFAS]) were collected from medical records, interviews, and national registers. RESULTS: During the first two years 22 (42%), between two to five years 17 (32%), and between five to ten years 14 (26%) subjects had used antipsychotics less than half of the time. Drug-free periods became rarer during the follow-up. The mean lifetime daily dose of antipsychotics was 319mg in chlorpromazine equivalents. A high lifetime average and cumulative dose and antipsychotic polypharmacy were associated with a poorer outcome in all measures, whereas having no drug-free periods was associated with a better SOFAS score and a low proportion of time on antipsychotics with a better CGI score. CONCLUSIONS: In our population-based sample, the use of antipsychotics increased during the first five years of illness and was relatively stable after that. Our results suggest that both low dose and proportion of use, and having no drug-free periods, are associated with better outcomes, which concords with current treatment recommendations and algorithms. High long-term doses and polypharmacy may relate to poor outcomes.

Brain morphometry of individuals with schizophrenia with and without antipsychotic medication ­ The Northern Finland Birth Cohort 1966 Study.

BACKGROUND: In schizophrenia, brain morphometric changes may be associated with antipsychotic medication. Only limited data is available concerning individuals with schizophrenia without antipsychotic medication. We aimed to study the associations of: use versus no use of antipsychotic medication; length of continuous time without antipsychotic medication; cumulative dose of lifetime antipsychotic medication; and type of antipsychotic medication; with brain morphometry in schizophrenia after an average of 10 years of illness. METHODS: Data of 63 individuals with schizophrenia (mean duration of illness 10.4 years) from the Northern Finland Birth Cohort 1966 were gathered by interview and from hospital and outpatient records. Structural MRI data at age 34 years were acquired and grey matter volume maps with voxel-based morphometry were analyzed using FSL tools. RESULTS: Of the individuals studied, 15 (24%) had taken no antipsychotic medication during the previous year. Individuals with antipsychotic medication had lower total grey matter (TGM) volume compared with non-medicated subjects, although this association was not statistically significant (Cohen's d=-0.51, P=0.078). Time without antipsychotic medication associated with increased TGM (P=0.028). Longer time without antipsychotic medication associated with increased regional volume in right precentral gyrus and right middle frontal gyrus. There were no associations between cumulative dose of lifetime antipsychotic medication or type of antipsychotic medication and brain morphometry. CONCLUSIONS: Unlike some previous investigators, we found no association between cumulative dose of lifetime antipsychotic medication and brain morphological changes in this population-based sample. However, longer continuous time without antipsychotic medication preceding the MRI scan associated with increased gray matter volume.

Serum and follicular fluid leptin during in vitro fertilization: relationship among leptin increase, body fat mass, and reduced ovarian response.

The satiety factor leptin is expressed in several reproductive tissues, but its role in the control of reproductive physiology is not well understood. We studied leptin concentrations in the sera and follicle fluids of 52 women [body fat mass percentage (BFM%) range, 19.6-38.8%] undergoing pituitary down-regulation and ovarian hyperstimulation for in vitro fertilization (IVF) treatment. Fasting serum samples were collected 1) at maximal suppression before the initiation of gonadotropin treatment, 2) at maximal ovarian hyperstimulation, 3) at the time of oocyte retrieval, and 4) 16 days later when all subjects were under exogenous luteal support using 600 mg progesterone daily. Follicular fluid (FF) was obtained at oocyte retrieval from two representative preovulatory follicles in both ovaries. During ovarian hyperstimulation there was a significant 60% increase in serum leptin concentrations from 10.9 +/- 1.1 (SEM) to 15.7 +/- 1.5 ng/mL (P < 0.01) between suppression and maximal hyperstimulation, demonstrating that the ovarian functional state can affect serum leptin concentrations. A serum leptin increase of 22-198% during ovarian hyperstimulation was evident in 43 subjects, whereas in 9, leptin concentrations remained unchanged. A positive correlation between leptin change and BFM% (r = 0.55; P < 0.0005) was observed in the 43 leptin responders. The follicular fluid leptin level was similar to that in serum. In separate linear regression analysis, BFM% contributed to 59-64%, body mass index to 46-56%, and weight to 46-55% (all P < 0.001) of the variability in leptin concentrations at the 4 time points. The 20-fold increase in serum estradiol concentrations during IVF was not significantly correlated with changes in leptin concentrations. On the contrary, the relative serum leptin increase was negatively associated with the ovarian response to hyperstimulation, as revealed by the numbers of follicles (b = -0.28; r2 = 8.1%; P < 0.05) and oocytes retrieved (b = -0.39; r2 = 15.2%; P < 0.01). This relationship was further reflected in a positive correlation between the percent increases in leptin and FSH concentrations (r = 0.39; P < 0.01). The significant relationship of high leptin and reduced ovarian response was also maintained when the cumulative dose of FSH was used as a covariable. Reduced ovarian response was not a function of body mass index, BFM%, basal leptin levels, or insulin concentrations. Fasting serum insulin concentrations remained unchanged in response to IVF, but were positively correlated to serum leptin concentrations at all four time points. Our data suggest that leptin production may be influenced by the ovarian functional state. During IVF a high relative leptin increase is associated with adiposity and a reduced ovarian response. These observations support the possibility that high leptin concentrations might reduce ovarian responsiveness to gonadotropins. Hence, leptin might explain in part why obese individuals require higher amounts of gonadotropins than lean subjects to achieve ovarian hyperstimulation.

Relative fitness of carriers of the mitochondrial DNA mutation 3243A > G.

Deleterious point mutations in mitochondrial DNA (mtDNA) have been found in many human populations and always at a low frequency suggesting that they are under strong negative selection. It is assumed that this selection is caused by reduced genetic fitness of mutation carriers, but the fitness of carriers of any mtDNA mutation has not been determined. We estimated the reproductive disadvantage caused by the mitochondrial DNA mutation 3243A > G in a population-based group of female carriers (n = 32). The person-years method, Kaplan-Meier survival analysis and population statistics were used to estimate net reproduction rates of the mutation carriers and the general population. We found that women with 3243A > G reproduced at the same rate as women in the general population, suggesting that on average host-level selection against women harbouring the 3243A > G mutation is not strong.

Effects of oleoresin capsicum pepper spray on human corneal morphology and sensitivity.

PURPOSE: To examine the potential harmful effects on corneal structure, innervation, and sensitivity of a spray containing the neurotoxin capsaicin (oleoresin capsicum, OC). METHODS: Ten police officers who volunteered for the study were exposed to OC. Clinical signs were assessed. Corneal sensitivity was measured using a Cochet-Bonnet or a noncontact esthesiometer that provides separate measurements of mechanical, chemical, and thermal sensitivity. Tear fluid nerve growth factor (NGF) was measured. Corneal cell layers and subbasal nerves were examined by in vivo confocal microscopy. The subjects were examined before application and 30 minutes, 1 day, 1 week, and 1 month after OC exposure. RESULTS: OC spray produced occasional areas of focal epithelial cell damage that healed within 1 day. Each eye showed conjunctival hyperemia and in two subjects, mild chemosis. All except one eye had unchanged best corrected visual acuity (BCVA). A transient decrease (day 1) of mechanical sensitivity was observed with the Cochet-Bonnet esthesiometer. With the gas esthesiometer, mechanical sensitivity remained below normal values for 7 days. Chemical sensitivity to CO2 was high for as much as 1 day and decreased below normal 1 week later, whereas sensitivity to cold was unaffected. Two subjects had measurable tear NGF that increased after exposure. Basal epithelial cell morphology suggested temporary corneal epithelial swelling, whereas keratocytes, endothelial cells, and subbasal nerves remained unchanged. CONCLUSIONS: Although OC causes immediate changes in mechanical and chemical sensitivity that may persist for a week, a single exposure to OC appears harmless to corneal tissues. The changes are possibly associated with damage of corneal nerve terminals of mainly unmyelinated polymodal nociceptor fibers.

Autosomal recessive cornea plana: in vivo corneal morphology and corneal sensitivity.

PURPOSE: Autosomal recessive corneal plana (RCP) is a rare corneal anomaly with unknown pathogenesis and a high incidence in Finland. The aim was to examine corneal sensitivity and the morphology of different corneal layers and subbasal nerves in RCP patients. METHODS: Three patients with a diagnosed autosomal recessive cornea plana were examined. Corneal sensitivity to different modalities of stimulation was tested in four corneas using noncontact esthesiometry. Tissue morphology of three corneas was evaluated, and in two corneas thickness of corneal layers was measured using in vivo confocal microscopy. RESULTS: Corneas of RCP patients appear to have mechanosensory, polymodal, and cold-sensitive nerve terminals. RCP patients had normal sensation thresholds for chemical, heat, and cold stimulation but a high threshold for mechanical stimulation. Their capacity to discriminate increasing intensities of stimulus was reduced, except for cold stimuli. Thickness of the epithelial layer was reduced, whereas total corneal and stromal thicknesses were slightly reduced or close to normal values. In all cases Bowman's layer was absent. Subbasal nerves had abnormal branching patterns. The arrangement of anterior keratocytes was altered, showing clustered and irregularly shaped nuclei. Increased backscattering of light in confocal microscopy through focusing (CMTF) profiles was observed throughout the stroma. Epithelial and endothelial cells appeared to be regular in shape. CONCLUSIONS: The present study revealed qualitative and quantitative alterations in corneal sensitivity, cellular morphology, and the thickness of corneal layers in RCP patients.

Corneal morphology and sensitivity in lattice dystrophy type II (familial amyloidosis, Finnish type).

PURPOSE: To describe the corneal abnormalities and to measure different modalities of corneal sensitivity in corneal lattice dystrophy type II (familial amyloidosis, Finnish type, also known as gelsolin-related amyloidosis and originally as Meretoja syndrome). METHODS: Twenty eyes of 20 patients were examined by in vivo confocal microscopy and noncontact gas esthesiometry. RESULTS: Pleomorphism of, and dense deposits between or posterior to, the basal epithelial cells were frequently observed, as well as a reduction of long nerve fiber bundles in the subbasal nerve plexus. The anterior stroma was altered in most cases, with fibrosis and abnormal extracellular matrix. In 15 corneas, thick anterior and midstromal filaments, corresponding to lattice lines, and in 11 corneas, thin undulated structures were observed. The average mechanical sensitivity threshold of 12 subjects was increased, and in the remaining 8 subjects there was no response, even to the highest intensity of stimuli used. Three patients did not respond to CO(2), 11 to heat, and 2 to cold, but those patients who responded had normal thresholds. Patients with more long nerve fiber bundles per confocal microscopic image had better mechanical and cold sensitivity than patients with fewer nerve fiber bundles. CONCLUSIONS: Lattice lines seem to be related to amyloid material and not to corneal nerves. However, the subbasal nerve density appears reduced, which results mainly in a decrease in mechanical and, to a lesser extent, thermal sensitivity. The location of stromal filaments and undulated structures changes with increasing age.

Photorefractive keratectomy in ophthalmic residents.

PURPOSE: To find out how ophthalmologists themselves experience the correction of myopia after photorefractive keratectomy. Visuomotor functions were of special interest. METHODS: Four ophthalmology residents and one medical engineer underwent photorefractive keratectomy for myopia. Objective measurements including refraction, corneal topography, perimetry, contrast sensitivity, pattern visual evoked potentials, in vivo confocal microscopy, and a car driving simulator test were performed preoperatively, postoperatively, and at 6 months. Subjective evaluation was reported. RESULTS: Performing ophthalmological examinations and microsurgery without spectacles was easier postoperatively and was appreciated by the four ophthalmology residents. Minimal haze formation, good accuracy, and normal performance in the car driving simulator were also observed. Visual fields, contrast sensitivity, and pattern visual evoked potentials did not show changes. Negative observations included postoperative pain for 2 to 4 days, dry eye symptoms, a period of anisometropia between operations, and hypersensitivity of the lids. CONCLUSIONS: The four ophthalmic residents were satisfied with the outcome of their refractive surgery. Low to moderate myopic correction did not affect the objective measurements of high and low contrast sensitivity, pattern visual evoked potentials, or simulated car driving in dark illumination.

Characteristics of subjects with schizophrenia spectrum disorder with and without antipsychotic medication - a 10-year follow-up of the Northern Finland 1966 Birth Cohort study.

OBJECTIVE: To estimate the prevalence of non-medicated subjects having schizophrenia spectrum disorder and to study how they differ from medicated subjects in terms of sociodemographic and illness-related variables. We also aim to find the predictors for successful antipsychotic withdrawal. METHODS: Data of 70 subjects with schizophrenic psychoses (mean duration of illness 10.4 years) from the Northern Finland 1966 Birth Cohort were gathered by interview at the age of 34 and from hospital records. The stability of remission was assessed by comparing hospitalization rates between non-medicated and medicated subjects over an 8.7-year additional follow-up period. RESULTS: Twenty-four (34%) subjects were currently not receiving medication. They were more often males, less often on a disability pension, more often in remission, and had better clinical outcomes. Relapses during the follow-up were equally frequent between non-medicated and medicated subjects (47% vs. 56%). Not having been hospitalised during previous 5 years before the interview predicted long-term successful antipsychotic withdrawal without relapse. CONCLUSIONS: Despite a lack of precise predictors, there might be subgroup of schizophrenia spectrum subjects who do not need permanent antipsychotic medication, and a fewer previous psychiatric treatments may indicate such a subgroup.

Prevalence of menopause symptoms and their association with lifestyle among Finnish middle-aged women.

BACKGROUND AND AIM OF THE STUDY: The aim of this study is to report the prevalence of menopausal symptoms by severity among the Finnish female population and the association of their symptoms with lifestyle (smoking, use of alcohol, physical activity) and body mass index (BMI). MATERIAL AND METHODS: Health 2000 is a nationally representative population-based study of Finnish adults. Data were collected by home interview, three self-administered questionnaires and a clinical examination by a physician. This study included women aged 45-64 years (n=1427). All symptoms included menopause-specific symptoms. Both univariate analysis and a factor analysis based on symptom factors were performed by menopausal group. Multiple regression analysis included each symptom factor as a dependent variable and confounding and lifestyle factors (age, education, smoking, alcohol use, physical activity, BMI, use of hormonal replacement therapy (HRT) and chronic disease status). RESULTS: Over one-third (38%) of the premenopausal, half of the perimenopausal, and 54% of both postmenopausal and hysterectomized women reported bothersome symptoms. The difference between pre- and perimenopausal women was largest and statistically most significant in the case of back pain and hot flushes. Physically active women reported fewer somatic symptoms than did women with a sedentary lifestyle. Smoking was not related to vasomotor symptoms. CONCLUSION: Bothersome symptoms are common in midlife, regardless of menopausal status. Inverse association between physical activity and menopausal symptoms needs to be confirmed in randomized trials.

Corneal recovery after lasik for high myopia: a 2-year prospective confocal microscopic study.

AIM: To quantify human corneal recovery after moderate to high myopic laser in situ keratomileusis (LASIK) in a 2-year prospective follow-up study. METHODS: Fifteen eyes of 15 patients (mean refraction -10.1 (SD 2.4) D) were examined preoperatively and postoperatively at day 1, 5 days, 2 weeks, 1, 3 and 6 months and 2 years. Biomicroscopy, visual acuity and refraction were examined prior to imaging studies. An in vivo tandem scanning confocal microscope was used to obtain images from the central cornea. Subbasal nerve density was measured as the total length of nerve trunks in confocal image per mm2. Keratocyte density was calculated manually from stromal sublayers. The thickness of the altered keratocyte zone was measured on both sides of the LASIK interface. RESULTS: At the end of the follow-up, all patients had a 20/20 BCVA, and nine of 15 patients were within +/-0.5 D of the intended correction. The total corneal thickness remained unaltered, but epithelial hyperplasia was seen at 2 years. Keratocyte density in the anterior stroma and posterior to the flap interface showed a slight decrease during the follow-up. Subbasal nerve density decreased 82% in 5 days after LASIK. A gradual increase was observed from 2 weeks postoperatively, but even 2 years after the operation the nerve density was only 64% from the preoperative values. CONCLUSIONS: Subbasal nerve fibre density shows a gradual recovery throughout the follow-up. However, only three subjects showed totally regenerated subbasal nerve fibres at 2 years. This may correlate with the observed decrease in the density of the most anterior keratocytes. Corneal remodelling seemed to continue for at least 2 years.

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

Excretion of alpha-tocopherol into human seminal plasma after oral administration.

In this open controlled study, we investigated the blood and seminal plasma concentrations of alpha-tocopherol in 15 unselected male volunteers, who received either 600, 800 or 1200 mg d-alpha-tocopherol per day for 3 weeks. During the intervention, both the blood and seminal plasma vitamin E concentrations increased significantly, although the increase did not correlate with the dose administered. The highest median blood and seminal plasma concentrations were achieved with 800 mg vitamin E per day, but the differences between the group medians were not significant, except in the blood plasma concentration after the first week of treatment between men receiving 600 and 800 mg per day (P < 0.05). No significant improvement was noted in the movement characteristics of spermatozoa, hypo-osmolar swelling of spermatozoa, or the velocity of deterioration in the parameters mentioned above. The seminal plasma vitamin E concentrations achieved during the treatment remained low (< 1 mumol l-1) compared to the concentrations found effective in protecting spermatozoa from peroxidative damage in vitro.