Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.

Creatine transporter deficiency: Novel mutations and functional studies.

X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients. Biochemical testing indicated normal plasma levels of creatine and guanidinoacetate, but an increased urine creatine/creatinine ratio. The diagnosis was confirmed by demonstrating absent ([14])C-creatine transport in fibroblasts. Molecular studies indicated that the first patient is hemizygous for a single nucleotide change substituting a single amino acid (c.619 C > T, p.R207W). Expression studies in HeLa cells confirmed the causative role of the R207W substitution. The second patient had a three base pair deletion in the SLC6A8 gene (c.1222_1224delTTC, p.F408del) as well as a single base change (c.1254 + 1G > A) at a splicing site in the intron-exon junction of exon 8, the latter occurring de novo. The third patient, had a three base pair deletion (c.1006_1008delAAC, p.N336del) previously reported in other patients with creatine transporter deficiency. These three patients are the first reported cases of creatine transporter deficiency in Israel.

SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum.

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

Synchronizing activity of basal ganglia and pathophysiology of Parkinson's disease.

Early physiological studies emphasized changes in the discharge rate of basal ganglia in the pathophysiology of Parkinson's disease (PD), whereas recent studies stressed the role of the abnormal oscillatory activity and neuronal synchronization of pallidal cells. However, human observations cast doubt on the synchronization hypothesis since increased synchronization may be an epi-phenomenon of the tremor or of independent oscillators with similar frequency. Here, we show that modern actor/ critic models of the basal ganglia predict the emergence of synchronized activity in PD and that significant non-oscillatory and oscillatory correlations are found in MPTP primates. We conclude that the normal fluctuation of basal ganglia dopamine levels combined with local cortico-striatal learning rules lead to noncorrelated activity in the pallidum. Dopamine depletion, as in PD, results in correlated pallidal activity, and reduced information capacity. We therefore suggest that future deep brain stimulation (DBS) algorithms may be improved by desynchronizing pallidal activity.

Women's attitudes to being asked about exposure to violence.

OBJECTIVE: to examine women's attitudes to being questioned by their midwife, during and after pregnancy, about exposure to violence. DESIGN: an explorative study using content analysis of one open-ended question. SETTING: all antenatal clinics in Uppsala, a medium-sized Swedish university town. PARTICIPANTS: all women registered for antenatal care before 32 weeks of pregnancy, during a period of 6 months. MEASUREMENTS: all women were assessed regarding abuse, using the Abuse Assessment Screen (McFarlane 1993) twice during pregnancy and once again more than four weeks after the birth. On the last occasion the women were asked to respond to an open-ended written question worded: 'Please describe how you felt about being questioned by your midwife at the antenatal clinic concerning violence' Those women who reported violence and those who did not were compared regarding their attitude to being asked about violence. FINDINGS: 879 women were presented with the open-ended question. Eighty per cent found the questioning acceptable, 12% neither acceptable nor unacceptable, 5% both acceptable and unacceptable, and only 3% found it unacceptable. There was no difference between those who reported abuse and those who did not, as to whether the questioning was unacceptable. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: the findings suggest that most pregnant women are not averse to being asked, by their midwife, about exposure to violence. As part of the identification of risk factors that is carried out in every pregnancy, the midwife should ask about exposure to violence at the antenatal clinic. To feel confident when raising the subject of abuse, midwives must be taught about the nature of intimate-partner violence, and appropriate referral and intervention strategies.

The prevalence of violence investigated in a pregnant population in Sweden.

All women registered for antenatal care within a Swedish municipality during a 6-month period were assessed regarding acts of violence. The Abuse Assessment Screen was used on two occasions during pregnancy, and once between 4 and 20 weeks after delivery. The efficacy of repeated interviews was investigated, and characteristics of abused and non-abused women were compared. The participation rate was 93% (1038 women). Physical abuse by a close acquaintance or relative during or shortly after pregnancy was reported by 1.3%, and by 2.8% when the year preceding pregnancy was included. The lifetime prevalence of emotional, physical or sexual abuse was 19.4%. Repeated questioning increased the detection of abuse. Women abused during pregnancy reported more preceding ill-health and more elective abortions than non-abused women. Intervention against sexual violence has been on the political agenda in Sweden for several decades. Even so, physical abuse is a risk factor comparable in frequency to obstetric complications such as gestational diabetes and pre-eclampsia. Routines need to be established to make questioning about violence an integral part of the standardized screening for risk factors during pregnancy.

Reinforcement-driven dimensionality reduction--a model for information processing in the basal ganglia.

Although anatomical studies of the basal ganglia show the existence of extensive convergence and lateral inhibitory connections, physiological studies failed to show correlated neural activity or lateral interaction in these nuclei. These seemingly contradictory results could be explained with a model in which the basal ganglia reduce the dimensionality of cortical information using optimal extraction methods. Simulations of this model predict a transient change in the efficacy of the feed-forward and lateral synapses following changes in reinforcement signal, causing an increase in correlated firing rates. This process ultimately restores the steady-state situation with diminished efficacy of lateral inhibition and no correlation of firing. Our experimental results confirm the model's predictions: rate correlations show a drastic decrease between the input stage (cortex) and output stage (pallidum). Moreover, preliminary analysis revealed that pallidal correlations show a transient increase following discrepancies between the animal's predictions and reality. We therefore propose that by using a reinforcement-driven dimensionality reduction process the basal ganglia achieve efficient extraction of cortical salient information that may then be used by the frontal cortex for execution and planning of forthcoming actions.

DiHA Dextran Copolymer, a new biocompatible material for endoscopic treatment of stress incontinent women. Short term results.

BACKGROUND: This study was undertaken to investigate the safety and effect of DiHA, dextranomers in hyaluronan, a new biocompatible material for endoscopic treatment of stress incontinence, and to further develop the injection technique. METHODS: Twenty women aged 38 to 90 years with genuine stress incontinence participated. Seventeen were followed for a minimum of 6 months after treatment and three for a minimum of 3 months. The DiHA implants were administrered by transurethral endoscopically controlled submucosal injections under local anesthesia. Safety was assessed mainly in terms of infection, need for catheterization, residual urine and dysuria. The treatment efficacy was estimated objectively by a short-term pad test with standardized physical exercise and a 48 h pad-test, 7 days, and 1, 3 and 6 months after treatment. The patient's subjective experience of the effect was also studied. RESULTS: The implantation procedure was well accepted by the patients. Four patients required catheterization due to voiding problems during the first 24 postoperative hours. One patient had urinary retention 14 days postoperatively. No UTI or local infection was detected. Some patients had transient urgency. In 17 or 20 patients the treatment resulted in objective cure or improvement. CONCLUSIONS: This substance shows promising qualities for endoscopic treatment of stress incontinence.

Prevalence of postmenopausal symptoms in two age groups of elderly women in relation to oestrogen replacement therapy.

A cross-sectional study of the whole female population of ages 71 and 81 years in a defined part of Sweden was undertaken to investigate the prevalence of oestrogen treatment and postmenopausal symptoms. A questionnaire was mailed to 2245 women, of whom 1084 (87%) aged 71 years and 611 (62%) aged 81 years left evaluable responses. Of the responding 71- and 81-year-old women 25 and 16%, respectively were receiving oestrogen, and 4 and 2% of all women of the respective age groups were on systemic treatment. Nearly half of all the women reported urinary incontinence, which was considerate for approximately half of these women. Five and 11% of the respective age groups had experienced more than two urinary tract infections (RUTI) in the last year. RUTI had occurred both in the oestrogen-treated group and in the non-treated group. Vegetative symptoms were still encountered among these elderly women. Previous fractures were frequent, being experienced after menopause by 29 and 39% of the 71- and 81-year-old women respectively. Thirty-five and 39% of the women in respective age group had sought medical help for postmenopausal symptoms. Of the women with moderate, severe or unbearable urinary incontinence, 60 and 66% of the respective age groups had sought medical help. In only few of the totals of women on oestrogen had the treatment a complete effect. Only 2 and 1% of all women in respective age group had been offered and undergone surgery for their urinary incontinence.

Transvaginal ultrasonographic evaluation of the endometrium related to the histological findings in pre- and perimenopausal women.

OBJECTIVE: To evaluate the clinical usefulness of high-resolution transvaginal ultrasonography in pre- and perimenopausal women suspected to have endometrial pathology. PATIENTS AND METHODS: 196 women, aged between 32 and 57 years, were referred to the outpatient clinic for a dilatation and curettage (D&C). In 81% the clinical indication was irregular vaginal bleedings. Before the D&C an examination with transvaginal ultrasonography was performed, and the endometrial thickness and texture were determined. The ultrasonographic results were later compared with the histological diagnosis obtained from the D&C specimen. RESULTS: Ultrasonographically both normal and pathological endometrial changes could be detected, and 82% of the women had an endometrium characterized as normal. The endometrial phase determination correlated with the histological findings in approximately 50% of the women. Histologically 83% of the women had a normal endometrium. Endometrial hyperplasia was found in 12% and endometrial polyps in 4%. There were no malignancies found in this study. The hormone users (33% of the women) had no higher incidence of hyperplasias than non-users. CONCLUSION: Our data indicate that transvaginal ultrasonography is as effective as the D&C for depicting the endometrium in pre- and perimenopausal women with irregular bleedings.

Prevalence of genitourinary and other climacteric symptoms in 61-year-old women.

In a population-based cohort study, 1280 women, aged 61, were interviewed regarding their genitourinary and other postmenopausal symptoms by means of an anonymous questionnaire. The group selected was to constitute all women of 61 years of age living in Uppsala county, Sweden. The response rate was 84%. All were postmenopausal women. Seventy-three percent of the women answering admitted some degree of urinary incontinence and 33% more severe degree. Forty-nine percent reported some degree of stress incontinence, 25% a more severe degree. Thirty-one percent experienced urge incontinence, 14% severely. A minority (4%), had had more than two urinary infections during the last year. The majority (67%) had changed urinating habits, going to the toilet at night and a minority complained of increased frequency of micturation (8%). Of the participating women, 59% were still sexually active, 43% had trouble with vaginal dryness and 10% with vaginal burning. Vasomotor problems such as hot flushes (30%), daily (33%) and nightly sweating (36%) were all common troubles. Forty-seven percent of the women had asked for medical help for estrogen deficiency problems, 82% were satisfied with the help they had received. Thirty-four percent were on estrogen therapy, 16% had systemic therapy 18% low dose estrogen treatment.

A national center for sexually abused women in Sweden.

Sexual violence is a significant global problem. The unequal power between men and women is considered to be the main reason for violence against women. Women who are exposed to sexual assault are great consumers of medical and social care. The Swedish government has reacted to the problem by establishing an expert center for battered and raped women. The center has three main tasks: treatment in a professional and empathic way; research into and development of medical and psychosocial treatment of patients and the underlying causes of sexual violence; education and information of the general public.

[Health service's responsibility for sexually abused victims]. / Vårdens ansvar för sexualiserat Våld.

The abuse of women is a global problem, a women's health problem, and an egalitarian issue. In Sweden alone, 15,000 cases of the abuse of women, where victim and perpetrator were acquainted, were reported in 1994. In 1995, the National Women's Centre was inaugurated at the University Hospital, Uppsala, for the care of woman exposed to assault, abuse and sexual violence. Both care, research and training of personnel are carried out at the centre. Every abused woman coming to the hospital is now taken care of by specially trained personnel. The centre works in close cooperation with the police and the voluntary crisis centre, where battered women can receive support and help--for instance with temporary accommodation.

Effects of vaginally delivered estrogens.

INTRODUCTION: Atrophic condition in the vagina and lower parts of the urethral tract are common in elderly women. From population based surveys it has been estimated that 40% or more of women over 60 complain of insufficient control of micturation. In addition, lower urinary tract infections are common in this age group and recurrent cystitis is a scourge for many women (1, 2). Vaginal problems such as vaginal dryness, dyspareunia as well as infectious and non infectious disorders in the vagina may be even more common in elderly women (3) Vasomotor symptoms such as sweats and hot flushes commonly commence around the time of the menopause. In the majority of cases urogenital dysfunction does not become a problem until a decade later. Endogenous estrogens decline during the climacteric and the fall of estradiol levels from the time of onset of vasomotor symptoms until commencement of urogenital problems cannot be disregarded. In other words, it seems as if urogenital integrity can be maintained at lower estrogen levels than those required to resist vasomotor symptoms and conserve bone mass. Further evidence for this concept is achieved from numerous clinical studies in which various estrogens have been administered both orally and vaginally to elderly women with signs of urogenital atrophy which have resulted in amelioration. Such an alleviation of urogenital symptoms can be achieved without provoking endometrial growth.

The prevalence of urogenital symptoms in postmenopausal women.

Lower urogenital tract disorders, such as vaginal athropy, urethritis, dyspareunia, recurrent urinary tract infections and urinary incontinence symptoms, are more prevalent in postmenopausal women. While these disorders are attributed to the ageing process as well as estrogen deficiency, knowledge of the relationship between estrogen status and symptomatology is scarce and hard to investigate due to the complexity of the problem. Little is known about the epidemiology of urogenital symptoms and their relationship to estrogen status and treatment. Studies of the prevalence of urogenital symptoms in postmenopausal women have been rare and results divergent. Through reviewing existing literature and relating findings to our own prevalence studies of 61-, 71- and 81-year-old women, we can conclude that many of the symptoms accounted for in our study are those known to be due to the loss of estrogen and easily dealt with by estrogen therapy. However, there is a need for more adequate information about postmenopausal symptoms and the effect of estrogens, as only a minority of postmenopausal women are currently treated.