Igor Prpić

Triple A syndrome: genotype–phenotype assessment

The triple A or Allgrove syndrome is an autosomal‐recessive disease (MIM*231550) characterized by the triad of achalasia, alacrima and adrenocorticotropic hormone (ACTH)‐resistant adrenal insufficiency. Associated features of the syndrome are neurological and dermatological abnormalities. Until the discovery of the AAAS gene as the responsible gene in triple A syndrome, the diagnosis was based on characteristic clinical features. Here we present the clinical and molecular genetic data which demonstrated the marked phenotypic variability in three unrelated patients with triple A syndrome. The final diagnosis of triple A syndrome was confirmed by molecular analysis. In one patient with isolated achalasia, the diagnosis of triple A syndrome could only be made on the basis of the molecular genetic analysis of the AAAS gene. We therefore suggest that the diagnosis of triple A syndrome should be considered in patients who exhibit only one or two of the main symptoms (i.e. alacrima, achalasia or adrenal insufficiency). These patients require careful neurological investigation, and mutation analysis of the AAAS gene should be performed.

Relationship between the prenatal exposure to low-level of mercury and the size of a newborn’s cerebellum

Exposure to methylmercury at any stage of central nervous system development could induce alterations and result in severe congenital abnormalities. Total mercury level in maternal hair during pregnancy correlates well with blood levels of methylmercury and with total mercury levels in fetal brain. A prospective study has been conducted and a total of 137 childbearing women living at the coastal region with term, normal pregnancies were included and their newborns evaluated by ultrasonography. Mothers and their newborns are divided in two groups according to their hair mercury levels; examined group with high body levels of mercury (≥ 1 μg/g) and control group with low body levels of mercury (<1 μg/g). Neurosonographic examination was conducted to all newborns. Two dimensions of cerebellum in the sagital-medial plane have been measured: maximum height and width starting from the roof of the fourth chamber. Majority of mothers had hair mercury levels lower than 1 μg/g (N = 107). Mean value was 0.88 μg/g (SD 1.24), ranging from 0.02 to 8.71 μg/g. There was no significant difference between the two groups when it comes to the width of cerebellum (Mann-Whitney test: Z = 1471; p = 0.141). However, comparison related to the length of cerebellum shows statistically significant smaller cerebellum in newborns whose mother had hair mercury levels higher than 1 μg/g (Mann-Whitney test: Z = 2329; p = 0.019). Our results lead to a conclusion that prenatal exposure to, what we consider to be, low-levels of methylmercury does influence fetal brain development detected as decreased size of newborns cerebellum. From a clinical point of view, a question related to the influence of prenatal low-level methylmercury exposure on fetal neurodevelopment remains open. Our further objectives are to direct the research towards performing detailed neuropshychological tests on children at the age of 18 months. Such tests could indicate the presence of subtle neurological or neuropsychological deficits.

MTHFR C677T and A1298C polymorphisms as a risk factor for congenital heart defects in Down syndrome

Background:  Congenital heart defects (CHD) are present in most, but not all, cases of Down syndrome (DS). The presence of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms has been reported as a risk factor for CHD in DS. The aims of the present study were to assess (i) the frequency of MTHFR C677T and A1298C polymorphisms in DS individuals in the Croatian population; (ii) the relationship between the two maternal MTHFR polymorphisms and CHD‐affected DS children; and (iii) the transmission frequencies of the variant alleles of the two MTHFR polymorphisms in CHD‐affected DS.

Achalasia, alacrima, adrenal insufficiency, and autonomic dysfunction: double A, triple A, or quaternary A syndrome?

In 1978, Allgrove et al. (1) described simultaneous occurrence of achalasia, adrenocortical insufficiency, and alacrima—a triple A syndrome. More recent reports emphasize neurologic abnormalities and autonomic dysfunction as distinct features that very often accompany the three main symptoms (2–4). It has therefore been suggested that this disease be named 4A syndrome (3). Recently, the gene for the triple A syndrome (AAAS) has been cloned and characterized, permitting the molecular confirmation of the diagnosis (5,6).

Prenatal exposure to low-level methylmercury alters the child's fine motor skills at the age of 18 months☆

Objectives To compare motor, cognitive and language characteristics in children aged 18 months who were prenatally exposed to low‐level methyl‐mercury (MeHg), and to analyze the eventual differences in these characteristics in relation to cord blood THg concentration. Patients and methods The total number of 205 child‐mother pairs was included in the study, and total cord blood mercury was measured in 198 of them. Out of the 198 already measured samples, 47 of them have also been tested for methyl‐mercury in cord blood. Data regarding the 47 samples of MeHg levels has been used for calculating the correlation between cord blood THg and cord blood MeHg. MeHg and THg showed a significant correlation (r=0.95, p<0.05). One month after the delivery, mothers were asked to complete the questionnaire regarding socioeconomic factors, breastfeeding of their infants, and dietary habits during pregnancy. Neurodevelopmental assessment of motor, cognitive and language skills were conducted on 168 children using The Bayley Scales of Infant and Toddler Development, Third Edition (BSID‐III). Regarding the cord blood THg concentration, 135 children were divided in 4 quartile groups. Their neurodevelopmental characteristics have been compared. Results The cord blood THg concentration median and inter‐quartile range was 2.98 ng/g (1.41–5.61 ng/g). There was a negative correlation between cord blood THg concentration and fine motor skills (rho=−0.22, p=0.01). It is evident that children grouped in 2nd,3rd and 4th quartile had statistically significant lower fine motor skills assessment related to those grouped in 1st quartile (2nd quartile −1.24, p=0.03; 3rd quartile −1.28, p=0.03; 4th quartile −1.45, p=0.01). The differences in fine motor skills assessments between children in 2nd and 3rd and 3rd and 4th quartile were not statistically significant. Conclusion Intrauterine exposure to low‐level THg (MeHg) is associated with alterations in fine motor skills at the age of 18 months. HighlightsPrenatal exposure to low‐level of methylmercury has a negative effect on fine motor skills in children at 18 months of age.Increase of methylmercury level in cord blood is in direct correlation with the decrease of fine motor skills.Cerebellum and its functions seems to be particularly affected by prenatal exposure to low level of methylmercury.

Mohr syndrome (oro‐facial‐digital syndrome II) ‐ a familial case with different phenotypic findings

We report on two male siblings with an oro‐facial‐digital syndrome. The parents and two other siblings, a boy and a girl, are unaffected. The clinical findings on the reported brothers were different. Patient 1 had typical oral, facial and digital anomalies plus hypoplastic genitalia and short limbs. Clinically he had marked hypotonia, convulsions and apneic episodes. He died shortly after birth. His brother, Patient 2, had OFD features with conductive hearing loss and normal psychomental development. He did not have syndactylous reduplication of the great toes, although the toes were disproportionately large. These two patients are classified as OFD type II‐Mohr syndrome. Involvement of the central nervous system in OFD type II is noted. Different phenotypic findings could be explained as variable gene expressivity. The patients described here support the hypothesis that the clinical variability of the Mohr syndrome is even wider than previously thought.

Prenatal mercury exposure, neurodevelopment and apolipoprotein E genetic polymorphism

Abstract The aim of the present study was to evaluate the association between prenatal exposure to mercury (Hg) and neurodevelopment of the child, taking into account genetic polymorphism of apolipoprotein E (Apoe) and other relevant confounders. Six hundred and one mother‐child pairs were recruited from the central Slovenia region and 243 from Rijeka, on the Croatian coast of the northern Adriatic. The total Hg in cord blood, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley‐III) assessment at 18 months of age and Apoe genotyping was performed on 361 children; 237 of them were from Slovenia and 124 from Croatia. The results showed negative association between low‐to‐moderate Hg exposure in children with normal neurodevelopmental outcome and cognitive and fine motor scores at 18 months of age as assessed by Bayley III. The Hg‐related decrease in cognitive score was observed only in children carrying at least one Apoe &egr;4 allele, while the decrease in fine motor scores was independent of the Apoe genotype. Adjusting for selenium (Se) and lead (Pb) levels, a positive association between Se and the language score and a negative association between Pb and the motor score was observed, but not in the subgroup of children carrying the &egr;4 allele. HighlightsApoe &egr;4 carriers showed negative association between cord blood Hg and cognitive score.Fine motor score was negatively associated with cord blood Hg in all children.Gene‐environment interaction was confirmed for the cognitive score..Se and Pb levels confounded the association between Hg and neurodevelopment.

Analysis of antiepileptic drugs use at a university hospital in Croatia

To analyse the consumption rate of new generation antiepileptic drugs (AEDs) compared with traditional AEDs at a university hospital in Croatia. Antiepileptic drugs use was analysed retrospectively for two consecutive years, 2001 and 2002 at Departments of Neurology, Paediatrics, Psychiatry and Neurosurgery at the University Hospital Centre (UHC) Rijeka. The results obtained are expressed as number of defined daily doses (DDDs) per 100 bed days, as proposed by the WHO. The use of new generation AEDs was represented by 2% in 2001 and 5% in 2002. Majority of AEDs administered was taken by the barbiturates in both years. A wide spectrum of AEDs has been used at the Department of Paediatrics. At the Department of Neurology and Psychiatry use of barbiturates and carbamazepine predominated. The use of new AEDs at UHC has increased during the investigation period but it is still rather low compared with traditional AEDs. The similarity of our results with the result of the leading Croatian university hospitals might represent general routine AED prescription in country. Nationally based guidelines may bring more appropriate and rational approach for usage of modern AED. This task should be supported and promoted by international and national neurology associations.

Transorbital penetrating brain injury caused by a toy arrow: a case report

A case of a 9-year-old boy with a transorbital toy-arrow injury to the brain is presented. At admission he was in coma (Glasgow Coma Scale of 6) with right hemiparesis and had a completely prolapsed left eye. Computerized tomography revealed intracranial haemorrhage and fracture of the orbital wall, which were treated conservatively. His left eye was enucleated due to massive injury. At the 6-month check-up the boy still show neurological signs of latent right hemiparesis. Disturbances, mostly cognitive, were noted on his psychological tests. A survey of the literature reveals no report of this nature in the paediatric age group. The necessity of continuous monitoring of new environmental risks as they occur, and the requirement for the prevention of recreational brain injuries in children, is stressed.

Combination of vibroacoustic stimulation and acute variables of mFBP as a simple assessment method of low-risk fetuses

Objectives. To observe a rate of fetal breathing and gross body movement appearance as physiologic reactions to the external vibroacoustic stimulation (VAS) and to establish a rapid and reliable antepartal method for accurate selecting of non-compromised fetuses in the low-risk population. Methods. Actual condition of 742-term and near-term structurally normal and otherwise healthy singleton fetuses with favourable outcome was assessed by previously established combination of the modified fetal biophysical profile and VAS. Only inactive fetuses at the beginning of the testing were included in the study. The combined biophysical testing has been started by a transabdominal real-time ultrasound examination, followed by vibroacoustic stimulus applied over the fetal head for 5 s during fetal quiescence. Fetal breathing and gross body movements were observed with particular attention in each case at measured time intervals from the application of external VAS until the moment at which either the first 60-s episode of breathing movements or all three fetal gross body movements were detected. Obtained results have been presented numerically in 5-min periods and cumulative percentages. Results. After the external VAS, 84.5% of studied fetuses successfully manifested their normal breathing or gross body movements in the first 5 min of the modified biophysical testing. Furthermore, approximately 96% of them were able to demonstrate at least one of these two biophysical activities after 6–7 min. Discussion. Because of its simplicity, non-invasiveness, independence of precise gestational dating, reproducibility and immediate individual results, ultrasonographic observation of normal fetal breathing and/or gross body movements after the external VAS stands a real chance to become a nearly optimal antenatal test for accurate and rapid information of actual non-compromised fetal condition. Authors strongly believe that the described antenatal method should represent a rather efficient assessment procedure of fetal well-being in late pregnancy, performed during regular antenatal visits.