Duplication of Chromosome 16p13.11-p12.3 with Different Expressions in the Same Family.

The knowledge about genetic involvement in neurodevelopmental disorders, and especially in autism, is currently rising. To date, more than 100 gene mutations related to autistic syndromes have been described. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited. Recently, array comparative genomic hybridization (aCGH) has identified sub microscopic deletions and duplications as a common cause of mental retardation and autism. In this article we report the occurrence of the same genetic finding (chromosome 16p13.11-p12.3 duplication) in a family with four small children, where two older siblings manifested a global neurodevelopmental delay associated with an autism spectrum disorder (ASD), but younger twin brothers with the same mutation, have typical development. Genetic analysis showed that the chromosomal duplication was inherited from the father, in which phenotype and functioning are quite typical. As is known, the duplication can pass from parents to children. The 16p13.11 micro duplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance.

MMPI for personality characteristics of patients with different diseases.

In the field of psychosomatic medicine the relationship between personality characteristics and diseases is supposed to be an important issue. The aim of this article is to present group's MMPI profiles obtained for patients with different chronic diseases and to discuss about possible specific features of these different groups. We summarized results obtained by psychological testing of following groups of patients: adult patients treated with chronic maintenance dialysis, patients with diabetic retinopathy, general anxiety group, attack panic syndrome, parents of children with rheumatoid arthritis, as well as adolescents with mental anorexia, cystic fibrosis, diabetes mellitus and leukemia. Two control groups comprised adults and adolescents, both without any health problems, selected randomly. As a psychometric test MMPI-201 was used. Statistic 10 package is used for statistical analysis. In our presentation it can be seen some typical personality characteristics for patients with chronic conditions. These findings could be helpful for clinicians concerning treatment planning and follow-up. In general, the MMPI helps us to obtain a global, factual picture from the self-assessment of the patient, explained in a psycho-technical language. Group's profile could be used in clinical practice for planning treatment and to suppose the prognosis of the illness.

The need for regular screening of postpartum depression.

AIM: The aim of this study was to examine the level of depression during the first week of the postpartum period in a sample of women hospitalized for childbirth at the University Obstetric Clinic in Skopje and correlate it with some demographic characteristics. METHOD AND SAMPLE: The sample comprised 150 randomly selected women with a mean age of 29.23 years (SD±5.11). As a psychometric test the Beck Depression Inventory was used. It is a multiple choice, self-report inventory for measuring the severity of depression. For statistic evaluation (descriptive analysis and correlations) software Statistica 7 was used. RESULTS: The random study showed that 68% of postpartum women have minimal, 25% mild and 5% moderate depression. Fortunately only 2% manifested severe depression. Our findings showed that depression is negatively correlated with the level of education (r=-0.17), as well as with age (r=-0.15). The comparison of the level of depression with a group of chronic dialyzed patients showed that PPD is not so serious a problem. However, this study shows that PPD is under diagnosed. CONCLUSION: As a common mental health problem PPD is not systematically screened in our country. The study showed the presence of minimal (68%) and mild (25%) depression in the examined women. The age of the woman is important for PPD; younger women are more susceptible to depressive reactions. The level of education is negatively correlated with depression. It was pointed out that PPD must be recognized, treated and followed for a long period because it is a risk not only to the mental health of the mother but also for the development of child.

Aldosterone synthase deficiency type II with hypospadias.

Aldosterone synthase deficiency (ASD) type II was diagnosed in a 3 week old boy with severe dehydration. Elevated plasma renin activity, low-normal aldosterone, increased levels for 18-OH corticosterone (18-OHB) and 18-OH-deoxycorticosterone were measured. Sequencing revealed a homozygous mutation for c554C > T in exon 3 (p.T185I) (CYP11B2). Hypospadias has so far not been reported in ASD.

Personality profiles and depression in haemodialysis patients.

Chronic haemodyalisis is an established treatment of end stage renal disease which maintains the lives of individuals who otherwise would have succumbed to a uraemic death. However, this method of treatment raises certain psychological, social and ethical issues, where depression and stress are the most common. This article is concerned with the evaluation of depression and the psychological characteristics of patients treated by chronic maintenance haemodyalisis. Using two psychometric tests (Beck Depression Inventory and MMPI-201) we obtained a significant incidence of depression (90.63%) in patients recruited from two centres for dia-lysis in Skopje, where even the severe form was unrecognized and untreated. The psychological profiles confirmed hypersensitivity, depressive mood, frequent interpersonal problems, and withdrawal from friends and relatives. Latent aggressiveness could be destructive for their social communications. In order to overcome the depression some response measures such as relaxation training, psychological support, music therapy or peripheral biofeedback are recommended.

Rare diseases with renal involvement in the Republic of Macedonia.

Rare diseases (RDs) pose a significant set of problems for patients, since their disease and general social and health situation are often not recognized by the medical community and shunned by health insurance. The sheer number of RDs (5000-8000) and the number of patients (6-8% of the population) are challenging for every society. We wanted to get a better understanding of the rare diseases affecting the kidneys and urinary tract (RDAKUT) in the Republic of Macedonia and we investigated principally the PubMed Central articles of Macedonian medical professionals dealing with RDAKUT, but we also used information on RDAKUT from local sources. A significant number of RDs have been published, demonstrating the awareness and skill of Macedonian medical professionals despite pretty limited diagnostic facilities. We still feel that RDAKUT are underdiagnosed (e.g. Fabry's disease has not yet been reported), and that many patients with RDs have a long way to go before an accurate diagnosis. Increased awareness and ameliorated education are needed by the physicians; while health insurance must include RDAKUT covering their diagnosis and treatment costs. Neonatal screening for ~30 diseases (instead of just hypothyroidism) is also required. Patients' organizations exist and they are active in promoting their interests before of the health authorities.

Alpha asymmetry in QEEG recordings in young patients with anxiety.

UNLABELLED: Anxiety is defined as a subjective sense of worry, apprehension, fear and distress. When severe, it can affect a child's thinking, decision-making ability, perceptions of the environment, learning and concentration. Basal instability in cortical arousal, as reflected in measures of quantitative electroencephalography (qEEG), is common in most of the anxiety disorders. SUBJECTS AND METHODS: The sample was composed of 26 children and teenagers aged 11.73±4.03 years, F:M=1:2. The group was diagnosed as having Generalized Anxiety Disorder (GAD). EEG was recorded with Quantitative EEG equipment--Mitsar-amplifier[with 19 electrodes with 250 Hz sampling rate in the 0.3-70 Hz frequency range in the following conditions: eyes opened and eyes closed, at least 5 minutes each. RESULTS AND CONCLUSIONS: A statistically significant difference of spectra power in alpha band between left and right hemisphere was obtained. The right frontal asymmetry is specific to the right-handed. In eyes-open condition the percentage of children manifesting right asymmetry is up to 92.31% and in the eyes-closed condition it is 88.46%. Left frontal asymmetry was typical of left-handed children. We did not confirm the posterior right asymmetry suggested by other authors. The correlations between asymmetry and hand preference of children was very strong (r=0.68-0.85) and statistically significant (p<0.05) only for frontal regions of the brain. For parietal regions this was weak and statistically not significant.

Early-onset ocular ochronosis in a girl with alkaptonuria (AKU) and a novel mutation in homogentisate 1,2-dioxygenase (HGD).

Alkaptonuria (AKU) is a disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD). This recessive disease is caused by mutations in the HGD gene. We report a 14-year-old girl who was referred after presenting black urine. Careful examination revealed ochronosis of the conjunctiva. There was no affection of the cardiac valves. Elevated excretion of homogentisic acid in urine was found. Sequence analysis of the HGD gene from genomic DNA revealed that the patient is a compound heterozygote with a previously described mutation (c.473C>T, p.Pro158Leu), and a novel one (c.821C>T, p.Pro274Leu). Her mother is heterozygous for the novel mutation, while the brother is heterozygous for the previously described mutation. In summary, we describe an alkaptonuric patient with ocular ochronosis and a novel HGD mutation, c.821C>T, p.Pro274Leu.

Hunter syndrome (Muccopolysaccharridosis Type II) in Macedonia and Bulgaria.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is caused by a deficiency of iduronate-2-sulfatase (IDS; EC 3.1.6.13). METHODS AND RESULTS: We describe 11 boys from Bulgaria and Macedonia detected in the period from 1998 to 2008. The mean age at diagnosis was 4.77+/-1.29 years. All children were severely retarded: IQ ranged from 34-80, and they all had coarse faces and hepatomegaly. In addition, splenomegaly was found in 81.81% patients, dysostosis in 45.45%, kyphosis in 27.27%, deafness in 18.08%, growth below the third percentile in 45.45%, growth below the parental target height in all patients, stiff joints in 56.56% and hypertrophic myocardiopathy in 18.18% children. Two patients died at the age of 11 and 35 years. Plasma iduronate-2-sulfatase was low in all probands and normal in parents and relatives. Two new mutations were discovered: p.K236N (c.708G>C) in a child with a moderately severe phenotype, and p.Q80K (c.238C>A) which resulted in a severe phenotype and early death at the age of 11 years. Heterozygote carriers of the pathogenic allele were 29 female relatives. The calculated incidence rate for MPS II in Macedonia (censuses 1994 and 2002, children under 14 years: 483,923 and 426,280) and Bulgaria (censuses 1992 and 2006, children under 14 years: 1 126, 598 and 1,077,020) are 0.36 and 0.46 respectively, while the calculated prevalence rate are 3.6 and 4.6 per 1,000,000 boys (aged 0-14 years). Correlating phenotype and genotype remains a complex endeavour. CONCLUSIONS: We report calculated incidence and prevalence rates in two South Eastern European countries, and 2 novel genetic alterations correlated with their phenotypes.

Acute Gallbladder Hydrops and Arthritis: unusual initial manifestations of Wilson's Disease (WD): Case Report.

Wilson disease (WD) is an autosomal recessive disorder, in which copper is deposited in the liver, brain, cornea and kidneys. The clinical presentation is variable, with fully expressed disease manifesting cirrhosis, neurologic damage and Kayser-Fleischer (K-F) ring on the cornea. A 24-year-old patient developed right upper quadrant pain with a palpable mass and a swelling of the right talocrural articulation. X-rays were uneventful, but the routine examination of hepatic enzymes discovered a 6-8 fold increase in SGPT, SGOT and AST. Antibodies for hepatitis B, C were normal, as well as the ANA, ANCA, antimytochondrial and anti-smooth muscle antibodies. Ultrasound of the abdomen revealed extremely dilated hepatic, cystic ducts as well as gallbladder. A large, oedematous gallbladder with yellow green bile was removed, the liver was found to be cirrhotic, but as the operative bleeding was abundant a biopsy was not done. Serum ceruloplasmin was low [0.160 g/l (normal 0.204-0.407)], serum copper 12.7 µmol/l (11.0-24.4), transaminasis: always very high, in the last months normal/slightly elevated. Urine copper: 1.0 µmol/24 h (>9.44). As first seen the proband had tremor, dysarthria, dystonia and K-F ring on the cornea. After 10 months of treatment with penicillamine his transaminases normalized, the tremor, dysarthria, dystonia initially got worse and then ameliorated. The coagulation times are ameliorated, but not yet normalized. Mutational analysis has shown that the proband is homozygote for c.3207 C->A, p.H1069Q while his parents are heterozygotes. His sister is a healthy non-carrier. In brief, we describe an unusual presentation of WD, with gallbladder hydrops and talocrural arthritis in a patient with complete clinical manifestations of the disease.

A giant osteochondroma in a boy with multiple exostoses.

Hereditary multiple exostoses (HME) is an inherited autosomal dominant disorder characterised by the presence of multiple exostoses, in fact benign cartilaginous tumors (enchondromata on the long bones). A six-year-old boy was found to have multiple osteochondromas on the legs, arms and ribs. Unusually, one of the osteochondromas on the right arm was huge (5 x 6 cm) and painful. X ray confirmed the benign nature of the osteochondromas. The family history was uneventful as well as the pregnancy and delivery. His intelligence is normal, and ultrasound did not detect any anomalies of the heart or kidneys. The occurrence of a large osteochondroma in a young boy is rare. In spite of its size and growth the lesion is so far benign. Frequent follow-up is recommended for the timely detection of eventual malignant transformation.

ADHD as an executive dysfunction.

Attention-deficit/hyperactivity disorder [ADHD] is a neuropsychiatric disorder characterized by inattention, hyperactivity and impulsivity that affects from 3-5% of school-aged children. In some cases it may persist into adulthood. Prominent theories about ADHD suggest that inattention, hyperactivity and impulsivity may be due to underlying deficits of the components of attention, including alerting, orienting and executive control. The aim of this study was to investigate neuropsychological characteristics of ADHD children, especially their executive functions [EFs]. The sample is comprised of 30 ADHD children from 6 to 14 years old [10, 45±22, 2], only boys, diagnosed at the department of psychophysiology, University Children's Hospital. The diagnosis was established according to ICD-10 criteria. All children had an IQ over 90 and were medication free. Psychological assessment of the children was performed with the Wechsler Intelligence Scale for Children [WISC-IV] and ADD-H Comprehensive Parent Rating Scale [ASTeRS]. Neuropsychological assessment was performed with the Stroop test and the Wisconsin Card Sorting Test [WCST]. Results showed an average IQ, manifested symptoms of hyperactivity and executive dysfunction, confirmed by the Stroop test and WCST.

Four generations in a family with neurofibromatosis 1: precocious puberty and optic nerve tumor (OPT).

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with varied clinical manifestations. The proband is a 6-year-old boy with signs of precocious puberty. His penis was 10 cm, testicles 8 ml, pubic hair P2-3, and the genital skin was hyperpigmented. Multiple cafe au lait spots well above 5 mm were noticeable on his skin, as well as hard subcutaneous nodules, mostly on his trunk. His intelligence and hearing are normal. He has no history of seizures. Laboratory analysis showed: LH LH 1.4 mIU/ml, FSH 6.2 mIU/ml, testosterone 183 ng/ml. Bone age was 9 years. LHRH stimulation was characteristic of true precocious puberty (LH 9.8 mIU/ml and FSH 8.9 mIU/ml after 30 minutes). The MRI of the brain showed a tumor of the suprasellar region with compression of the pituitary stalk. At present the boy is 6 years old and has been treated with triptoreline acetate for 3 months. The volume of the testicles has decreased to 7 ml and a slight loss of pubic hair was noted. In addition, his mother and his grandfather exhibited dermal masses, and focal cutaneous and subcutaneous growths. The great-grand father had had the same cutaneous changes and died at the age of 75 from unrelated causes. It has already been well documented that NF is associated with an increased risk of malignancy and precocious puberty. Hence, we emphasize the need for a close and regular clinical follow-up of the OPT, puberty and patterns of growth.

Psychological assessment and biofeedback mitigation of tension-type headaches in children.

(Full text is available at http://www.manu.edu.mk/prilozi). The research concerned a group of 59 children, 22 girls and 37 boys, mean age 12.5 +/- 1.24 years, with tension type headaches. Their clinical results (neurological, neuropsychological, radiological and laboratory) were normal, suggesting psychosomatic etiology. The characteristics of the headache correspond to a nosologic entity known as tension-type headache. The aim of this study was to evaluate the psychological characteristics of these children and their families, especially the profile of the mothers. The psychological assessment, consecutively applied, comprised: Eysenck Personality Questionnaire (EPQ), Emotions Profile Index (EPI), General Anxiety State (GAS) and Human Values Rank (HVR). The mothers were examined by Family Inventory Life Events (FILE) and Minnesota Multiphasic Personality Inventory (MMPI) and also checked with the Child Behavior Check List (CBCL). The results obtained showed a non-negligible level of actual anxiety in all the children, who were mostly the first-born and lived in families with accentuated stress. The emotional profile of the children was characterized by impulsiveness, a feeling of fear, moderate aggression, but still with a great level of acceptability. The EPQ confirmed their extroversion, moderate neurotic manifestations and a need for social acceptance. These results suggest that in preadolescents emotional stress, combined with a "model" for somatization, could provoke specific involuntary contraction of the head and neck muscles causing local ischaemia, which may be the pathophysiologic cause of a tension-type headache. The therapy comprised EDR and EMG biofeedback, applied once per week, of 50-minute duration. The results obtained after 20 sessions are very satisfactory. In addition, some response-measures involving a change and adjustment of family relations and school environment are recommended. Key words: headache, children, biofeedback, psychophysiology.

Comparison of visual and emotional continuous performance test related to sequence of presentation, gender and age.

(Full text is available at http://www.manu.edu.mk/prilozi). Continous Performance Tests (CPTs) form a group of paradigms for the evaluation of attention and, to a lesser degree, the response inhibition (or disinhibition) component of executive control. The object of this study was to compare performance on a CPT using both visual and emotional tasks in 46 normal adult subjects. In particular, it was to examine the effects of the type of task (VCPT or ECPT), sequence of presentation, and gender/age influence on performance as measured errors of omission, errors of commission, reaction time and variation of reaction time. From the results we can assume that there are significantly worse performance parameters for ECPT than VCPT tasks, with a probable explanation of the influence of emotional stimuli on attention and information-processing and no significant effect of order of presentation and gender on performance. Significant differences with more omission errors for older groups were obtained, showing better attention in younger subjects. Key words: VCPT, ECPT, omission errors, commission errors, reaction time, variation of reaction time, normal adults.

Type I Gaucher disease (GDI) in three siblings: enzyme replacement treatment (ERT) required.

(Full text is available at http://www.manu.edu.mk/prilozi). This is a family of three children, born to healthy Macedonian parents after uneventful pregnancies and delivery. The index child was an eight-year-old girl admitted for abdominal discomfort and distension: the spleen was 14cm below the costal margin (BCM), the liver 8cm BCM. No bone pain or pathology was reported. There was mild pancytopaenia (hemoglobin 11.2 gm/L; WBC counts 4.6 x 10;3; platelets 70 x 10;3). Liver function tests, renal ultrasound, bone scan, and a chest radiograph were within normal limits. Bone marrow analysis in this child and her two brothers (11 and 6.5 years old) revealed Gaucher cells. Both brothers had only mild anaemia, but the older brother had been splenectomized prior to diagnosis of GD1. Enzyme analysis revealed low activity (2.59, 1.62, and 2.55 nmol/h/mg protein, respectively); plasma chitotriosidase levels were also elevated. Genetic testing revealed homozygosity for the N370S/N370S mutation in all three siblings. In the absence of available enzyme replacement treatment (ERT), the girl was splenectomized. Removing an important immune organ (the spleen) introduces further risk for the patients. In addition, this does not solve the bone involvement characteristic for GD. ERT should be introduced for all GD1 patients in Macedonia. Key words: Gaucher disease, N370S mutation, siblings, enzyme replacement therapy.

Growth hormone deficiency (GHD) and small for gestational age (SGA): genetic alterations.

Short stature associated with GH deficiency has been estimated to occur in about 1 in 4000 to 1 in 10,000 in various studies. In the last decade new genetic defects have been described in all the levels of the growth hormone-releasing hormone (GH-RH)-GH-IGF (insulin-like growth factor) axis. Genetic defects in the GHRH and in various parts of the Insulin-like growth factor system have been demonstrated. Genetic defects causing isolated GH deficiency (GHD), as well as multiple pituitary hormonal deficiencies have been analysed in detail. Signalling molecules and transcription factors leading to the development of the pituitary gland have been discovered and their function recognized. In animal models and in humans the importance of the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3 has been extensively studied. Genetic alterations of those transcription factors dictate the highly variable phenotype: from isolated hypopituitarism to multiple pituitary hormonal deficiencies with or without malformations (e.g. septo-optic dysplasia or holoprosencephaly). Small for gestational age (SGA) children are increasingly recognized to be a heterogeneous group in which new mechanisms of growth retardation and metabolic disturbances have been proposed. Since SGA is considered to be the main reason for the short stature in 10% of short adults this is a large group with a great potential for novel insights into mechanisms of growth and metabolic disturbances. A group of signalling proteins are involved in prenatal (SGA) growth retardation: IRS-1, PDK1, AKT1, and S6K1. In addition, an attractive modern theory supposes that a disturbed mother-placenta-foetus relation results in the activation of the so-called "thrifty phenotype" of which the IGF system is a vital part. The mechanisms assure short-term postnatal survival in conditions of deficient nutritional supply. However, as a consequence, the abundant postnatal nutritional supply and the "thrifty phenotype" result in increased adult risk of metabolic syndrome, diabetes mellitus type 2 (DM2) and cardiovascular disease. The manuscript reviews in brief genetic alterations in humans leading to growth hormone deficiency (GHD), multiple pituitary hormone deficiencies (MPHD) and SGA.

Neurofeedback treatment of children with attention deficit hyperactivity disorder.

BACKGROUND: Biofeedback is a modern computer-related technique used for assessment and therapy of many psychophysiological disorders, especially stress-related ones. After a short overview of the basic concepts of biofeedback, in this study the application of EEG biofeedback (neurofeedback) in the assessment of and therapy for attention deficit hyperactivity disorders (ADHD) is presented and discussed. METHODS: The study comprised 12 children diagnosed as ADHD, selected according to ICD-10, and assessed by WISC-R, Q-EEG, neurofeedback and Conner's questionnaire for parents and teachers. The mean age was 9.5 years (7 to 13), both sexes. Each of them participated in a five-month programme of neurofeedback training, performed two times weekly with Biograph/ProComp 2.0 protocols. RESULTS: Post-treatment results showed an improved EEG pattern expressed in increased 16-20 Hz (beta) activity and decreased 4-8 Hz (theta) activity. In parallel, higher scores on WISC-R, better school notes and improved social adaptability and self-esteem were obtained. CONCLUSIONS: EEG biofeedback operant conditioning is a good choice for treatment of ADHD children. The method is non-invasive and has high cost-benefit. Optimal results are obtained in children of higher age. Cooperation with family members and teachers is crucial.

Electrodermal biofeedback in treating psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures are operationally defined as episodes of altered movement very like epileptic seizures, but associated with psychological problems and not with ictal discharges. Children with psychogenic nonepileptic seizure (PNS) could be categorized either under somatoform in the ICD-10 or conversion disorders in DMS-IV. The history, psychometric evaluation and therapeutic approach concerning nonepileptic psychogenic seizures in a 13-year-old girl are presented and discussed. The novelty of the treatment is the electrodermal (EDR) biofeedback procedure combined with cognitive-behavioral therapy. We infered that biofeedback for PNE in pediatric patients is highly cost-effective, discriminative for the actual level of stress and gives good therapeutic results through enhancing self awareness and relaxation, when used in combination with standard psychometric and psychotherapeutic methods. The stabilization of the hypersensitivity, lower neurotic tendencies and emotional maturation were obtained after 10 sessions of EDR biofeedback, each with the duration of 45 minutes/day. Mean value of EDR before treatment was 4919 (+/- 145.5) and the last value obtained with training showed a mean value of 5400.8 (+/- 147.9) microOmega. The following controls showed no more attacks, stabilization of the neurotic tendencies, progression of the maturational process and good academic results.

Child trauma, attachment and biofeedback mitigation.

The aim of this study is to investigate the correlation between the quality of attachment in early infancy and the effects of child trauma, as well as to introduce some innovative therapeutic approaches. For this reason, a group of 10 children manifesting post-traumatic stress disorder (PTSD), diagnosed by ICD-10, was selected. The mean age of the patients was 9 +/- 3.05 years, from both sexes (girls 3, boys 7). Mothers and children were examined by a battery of psychometric instruments Minnesota Multiphasic Personality Inventory (MMPI), Child Behaviour Checklist (CBCL), Eysenck Personality Questionnaire (EPQ), and State Anxiety Inventory (STAI). In addition to the classical psychotherapeutic methods (supportive, behaviour and play therapy), the multimodal computerised biofeedback technique was introduced for both assessment and therapy. The results for the children showed a high level of anxiety and stress, somatisation and behavioural problems (aggressivity, impulsivity, non-obedience, and nightmares), complemented by hypersensitive and depressive mothers and miss-attachment in the early period of infancy. Consequently, the explanation of the early predisposition to PTSD was related to be the non-developed Right Orbitofrontal Cortex-ROFC. The latter resulted from insecure attachment confirmed in all the children examined. The therapeutic results obtained with biofeedback techniques are very encouraging.