Clinical Neuroscience

Neurogenetic Diseases - Diagnostic and Therapy Issues Report of the 1st Scientific Meeting on Neurogenetics

NOVEMBER 20, 1997

Clinical Neuroscience - 1997;50(11-12)

Basic molecular genetics concepts. Basic concepts of non-traditional inheritance. The importance of Southern hybridisation and PCR techniques in the diagnosis of genetic diseases. The study of a gene in a specific disease. How to investigate inherited neurodegenerative diseases in children. Factors complicating the detection of a new transthyretin mutation (TTRAsp18Gly). The role of genetic testing in neurology. Structure of the genetic laboratory. Neurogenetic tests that can be performed in Hungary. Newer possibilities for genetic diagnosis of spinal muscular atrophy. Experience of prenatal testing. Neurological pathologies caused by trinucleotide repeat expansion. Molecular genetic diagnosis of Huntington's disease and its problems. Introduction of molecular genetic detection of fragile X disease in our country. Genetic aspects of von Hippel-Lindau disease. Advances in molecular genetics in inherited neuromuscular diseases. First domestic experience in molecular genetic diagnosis of Charcot-Marie-Tooth type 1 peripheral neuropathy. Heterozygote testing problems in Duchenne-Becker-type myopathies. Analysis of IQ and genotype in Duchenne and Becker muscular dystrophy. Primary mitochondrial myopathies. Non-primary mitochondriopathies based on aberrations of mtDNA. Our experience in processing Hungarian cases of Leber's hereditary optic neuropathy. Detection of mitochondrial deletions by PCR. Recent data on the genetic basis of some epilepsy syndromes. New insights into the genetics of epilepsy. Lysosomal patients in the ten-year patient database of our department. Biochemical diagnosis of inherited neuro-metabolic diseases. Neurogenetics in Germany. Prospect for gene therapy for the nervuous system and muscle. Preclinical research on gene therapy for Duchenne muscular dystrophy. Absence of apoe e4 allele in the neurofibrillary tangle subset of senile dementia. Mitochondrial DNA sequence variiaton of complex I genes in Parkinson's disease. Aging in epilepsy - a Hungarian multicentre study. Decrease in antiepileptic effect in pregnant women with epilepsy given a folic acid-containing multivitamin. Molecular genetic study of heredoataxia (SCAl, SCA2, SCA3, FA). Atrophy olivopontocerebellaris (Déjeriné-André-Thomas). Diagnostic problems. Hereditary Motor and Sensory Neuropathies (HMSN) in Southern Burgenland and Vicinity. Apolipoprotein E e4 allele frequency in patients with multiple system atrophy. Expression of nitric oxide synthase (NOS) isoforms in skeletal muscle of patients with mitochondrial. Pedigree analysis of hungarian Rett syndrome girls. Epidemiological studies in a population with Huntington's disease in Western Transdanubia. The role of psychological factors in the counselling and care of individuals at risk for Huntington's disease. Lesch-Nyhan syndrome . Clinical analysis of type II spinal muscular atrophy. Familial scapuloperoneal syndrome and mitochondrial DNA defects. The use of rilutes in familial ALS. Addison's disease and symptoms - adrenoleukodystrophy Case report. On familial hemiplegic migraine. Examination of somatic mutations in cadaveric brain samples. EMG and genetic diagnosis of paramyotonia congenita. CTG-triplet expansion study in a three-generation family with myotonia dystrophy.

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Clinical Neuroscience

[Pedigree analysis of hungarian rett syndrome girls]

HOLLÓDY Katalin, BORVENDÉG Katalin, KOSZTOLÁNYI György

[Rett syndrome is a neurodevelopmental disorder that has been reported exclusively in females. It was first described by Andreas Rett in 1966. The disorder is characterized by a progressive loss of cognitive and motor skills as well as the development of stereotypic hand movements, occurring after an apparently normal 6 to 18 months of development. The aetiology of the syndrome is still unknown. Since genetic origin can be presumed we examined the potential gene sources of the Hungarian Rett syndrome patients. Genealogical tests were carried out based on 22 Hungarian families with Rett syndrome girls. None of our 23 probands was born to first-cousin couples, but we found an increased number of consanguineous marriages among the ancestors of the patients: in two families first-cousin marriages among the great grandparents on the maternal sides; in one family, one second-cousin marriage on the maternal side. Considering the rate of the consanguineous marriages in Hungary the observed rate is highly increased. On investigating the place of origin of the Rett families we found a predominance in the north east part of Hungary. Our results support the findings of a Swedish analysis.]

Clinical Neuroscience

[Antecendents and epilepsy in dyskinetic/dystonic cerebral palsy]

BALOGH Erzsébet, KOZMA Gyuláné, VARGÁNÉ Kiss Anna

[The rate of cerebral palsy (1-3/1000) is not diminishing, but the prevalence of athetosis seems to be decreasing. 234 athetosis cases (born 1972–1992) have been studied in Budapest (n=149) and in London (n=85) for birth weight, icterus, hypoxia and/or neonatal convulsion and epilepsy. The majority of athetosis cases were born with a birth weight above 2500 g. Kernicterus has not been found, but 43.3% (Budapest) and 75.3% (London) of the cases showed clinical signs of hypoxia with or without perinatal convulsion. Hypoxia and icterus were rarely found together. Athetosis with epilepsy occurred in one fourth and one third of the cases, respectively. Long term hypoxia of mature infants has to see the most relevant risk factor for the severe cerebral palsy with (29.5% Budapest, 23.5% London) and without epilepsy.]

Clinical Neuroscience

[Advances in the diagnostics of spinal muscular atrophy]

HERCZEGFALVI Ágnes, KARCAGI Veronika, TÍMÁR László

[The three most common types of childhood spinal muscular atrophy (SMA) are type I or Werdnig Hoffmann disease, type II or intermediate form, and type III or Kugelberg-Welander disease. The clinical features of these three types are characteristic, profound limb hypotonia, wasting of muscles and areflexia. All three forms of SMA reveal an autosomal recessive mode of inheritance. The gene responsible for all three types of SMA is located on the long arm of chromosome 5 in the region of 5q11.2-913.3. Starting from 1993 blood samples were collected from 87 Hungarian families with all 3 types of SMA. DNA samples of all family members were analysed with the currently available highly informative microsatellite DNA markers in the locus 5q11.2 q13.3. Moreover, affected persons and their family members have been analysed for deletions of the survival of motor neuron gen (SMN). Prenatal diagnoses were performed in 28 cases at the request of the affected families. The possibility of prenatal diagnosis is a major step forward in helping these families, as the risk of recurrence of this devasting, untreatable disease is 25% in affected families.]

Clinical Neuroscience

[Prognosis of newborns of very low birthweight]

BEKE Anna, FEHÉRNÉ Szekszárdi Márta, CSIKY Erzsébet, KUCSERÁNÉ Gráf Rózsa, NÉMETH Tünde, SZABÓ Györgyné

[Development of 357 ventilated newborns born from January 1989 to 30 September 1996, who weighed 1500 gm or less at birth, was investigated in follow-up studies. Of the 357 infants, 9 died after one month of age. The outcome of 348 survivors was followed up by a team after the same protocol. Infants were divided into two groups according to year of birth. In the first four-year group, there were 168 children (from 1989 to 1992), in the second one there were 180 children (from 1993-1996). The two periods are different in the obstetrical and neonatological therapeutic methods. Comparing the results of follow-up studies, the authors investigated the influence of the new therapeutic methods on the neonatal morbidity and prognosis of newborns of very-low birthweigt. Although the survival rate increased from 61% to 78% between the two four-year periods, and the survival rate of newborns of very very low birth weight became two times higher (from 19.8% to 41 %), the neurological morbidity (rate of cerebral palsy), did not changed essentially. Important improvement was found in the ophthalmological outcome. The conclusion is that the quality of life for infants and children born of very-low birthweight has not yet improve significantly in every area of development.]

Clinical Neuroscience

[99 M TC HMPAO SPECT in children with intractable epilepsy]

NEUWIRTH Magdolna, BORBÉLY Katalin, KOPCSÁNYI Zsuzsanna

[We examined the role of HMPAO SPECT examinations in presurgical evaluation of children with intractable partial epilepsy. SPECT studies (ictal, interictal) were performed on 31 children aged 1-18 years. The focus was restricted in 18 cases and extensive, ie, a whole hemisphere or some lobes, in 4 cases. SPECT indicated pathological changes in the relevant areas in 15 of 18 cases, but in 9 children with temporal epilepsy in all. The focus was extensive in 4 cases, e.g. in 3 children with Rasmussen syndrome. SPECT was pathologic in all of them when MRI did not yet show hemiatrophy of the brain. In 3 cases of partial epilepsy MRI did not demonstrate lesion, the focus was not well-defined by EEG, in contrast to SPECT. Thus it can be stated that SPECT provides valuable information on presurgical evaluation in children with intractable partial epilepsy.]

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Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: A retrospective case-control study

NÉMETH Klára Zsófia, SZÛCS Anna , VITRAI József , JUHÁSZ Dóra , NÉMETH Pál János , HOLLÓ András

We aimed to investigate the association between fluoxetine use and the survival of hospitalised coronavirus disease (COVID-19) pneumonia patients. This retrospective case-control study used data extracted from the medical records of adult patients hospitalised with moderate or severe COVID-19 pneumonia at the Uzsoki Teaching Hospital of the Semmelweis University in Budapest, Hungary between 17 March and 22 April 2021. As a part of standard medical treatment, patients received anti-COVID-19 therapies as favipiravir, remdesivir, baricitinib or a combination of these drugs; and 110 of them received 20 mg fluoxetine capsules once daily as an adjuvant medication. Multivariable logistic regression was used to evaluate the association between fluoxetine use and mortality. For excluding a fluoxetine-selection bias potentially influencing our results, we compared baseline prognostic markers in the two groups treated versus not treated with fluoxetine. Out of the 269 participants, 205 (76.2%) survived and 64 (23.8%) died between days 2 and 28 after hospitalisation. Greater age (OR [95% CI] 1.08 [1.05–1.11], p<0.001), radiographic severity based on chest X-ray (OR [95% CI] 2.03 [1.27–3.25], p=0.003) and higher score of shortened National Early Warning Score (sNEWS) (OR [95% CI] 1.20 [1.01-1.43], p=0.04) were associated with higher mortality. Fluoxetine use was associated with an important (70%) decrease of mortality (OR [95% CI] 0.33 [0.16–0.68], p=0.002) compared to the non-fluoxetine group. Age, gender, LDH, CRP, and D-dimer levels, sNEWS, Chest X-ray score did not show statistical difference between the fluoxetine and non-fluoxetine groups supporting the reliability of our finding. Provisional to confirmation in randomised controlled studies, fluoxetine may be a potent treatment increasing the survival for COVID-19 pneumonia.

Clinical Neuroscience

Cases of inborn errors of metabolism diagnosed in children with autism

CAKAR Emel Nafiye, YILMAZBAS Pınar

Autism spectrum disorder is a neurodevelopmental disorder with a heterogeneous presentation, the etiology of which is not clearly elucidated. In recent years, comorbidity has become more evident with the increase in the frequency of autism and diagnostic possibilities of inborn errors of metabolism. One hundred and seventy-nine patients with diagnosis of autism spectrum disorder who presented to the Pediatric Metabolism outpatient clinic between 01/September/2018-29/February/2020 constituted the study population. The personal information, routine and specific metabolic tests of the patients were analyzed retrospectively. Out of the 3261 patients who presented to our outpatient clinic, 179 (5.48%) were diagnosed with autism spectrum disorder and were included in the study. As a result of specific metabolic examinations performed, 6 (3.3%) patients were diagnosed with inborn errors of metabolism. Two of our patients were diagnosed with classical phenylketonuria, two with classical homocystinuria, one with mucopolysaccharidosis type 3D (Sanfilippo syndrome) and one with 3-methylchrotonyl Co-A carboxylase deficiency. Inborn errors of metabolism may rarely present with autism spectrum disorder symptoms. Careful evaluation of the history, physical examination and additional findings in patients diagnosed with autism spectrum disorder will guide the clinician in the decision-making process and chose the appropriate specific metabolic investigation. An underlying inborn errors of metabolism may be a treatable cause of autism.

Clinical Neuroscience

Late simultaneous carcinomatous meningitis, temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting with mono-symptomatic vertigo – a clinico-pathological case reporT

JARABIN András János, KLIVÉNYI Péter, TISZLAVICZ László, MOLNÁR Anna Fiona, GION Katalin, FÖLDESI Imre, KISS Geza Jozsef, ROVÓ László, BELLA Zsolt

Although vertigo is one of the most common complaints, intracranial malignant tumors rarely cause sudden asymmetry between the tone of the vestibular peripheries masquerading as a peripheral-like disorder. Here we report a case of simultaneous temporal bone infiltrating macro-metastasis and disseminated multi-organ micro-metastases presenting as acute unilateral vestibular syndrome, due to the reawakening of a primary gastric signet ring cell carcinoma. Purpose – Our objective was to identify those pathophysiological steps that may explain the complex process of tumor reawakening, dissemination. The possible causes of vestibular asymmetry were also traced. A 56-year-old male patient’s interdisciplinary medical data had been retrospectively analyzed. Original clinical and pathological results have been collected and thoroughly reevaluated, then new histological staining and immunohistochemistry methods have been added to the diagnostic pool. During the autopsy the cerebrum and cerebellum was edematous. The apex of the left petrous bone was infiltrated and destructed by a tumor mass of 2x2 cm in size. Histological reexamination of the original gastric resection specimen slides revealed focal submucosal tumorous infiltration with a vascular invasion. By immunohistochemistry mainly single infiltrating tumor cells were observed with Cytokeratin 7 and Vimentin positivity and partial loss of E-cadherin staining. The subsequent histological examination of necropsy tissue specimens confirmed the disseminated, multi-organ microscopic tumorous invasion. Discussion – It has been recently reported that the expression of Vimentin and the loss of E-cadherin is significantly associated with advanced stage, lymph node metastasis, vascular and neural invasion and undifferentiated type with p<0.05 significance. As our patient was middle aged and had no immune-deficiency, the promoting factor of the reawakening of the primary GC malignant disease after a 9-year-long period of dormancy remained undiscovered. The organ-specific tropism explained by the “seed and soil” theory was unexpected, due to rare occurrence of gastric cancer to metastasize in the meninges given that only a minority of these cells would be capable of crossing the blood brain barrier. Patients with past malignancies and new onset of neurological symptoms should alert the physician to central nervous system involvement, and the appropriate, targeted diagnostic and therapeutic work-up should be established immediately. Targeted staining with specific antibodies is recommended. Recent studies on cell lines indicate that metformin strongly inhibits epithelial-mesenchymal transition of gastric cancer cells. Therefore, further studies need to be performed on cases positive for epithelial-mesenchymal transition.

Clinical Neuroscience

Alexithymia is associated with cognitive impairment in patients with Parkinson’s disease

SENGUL Yildizhan, KOCAK Müge, CORAKCI Zeynep, SENGUL Serdar Hakan, USTUN Ismet

Cognitive dysfunction (CD) is a common non-motor symptom of Parkinson’s disease (PD). Alexithy­mia is a still poorly understood neuropsychiatric feature of PD. Cognitive impairment (especially visuospatial dysfunction and executive dysfunction) and alexithymia share com­mon pathology of neuroanatomical structures. We hypo­thesized that there must be a correlation between CD and alexithymia levels considering this relationship of neuroanatomy. Objective – The aim of this study was to evaluate the association between alexithymia and neurocognitive function in patients with PD. Thirty-five patients with PD were included in this study. The Toronto Alexithymia Scale–20 (TAS-20), Geriatric Depression Inventory (GDI) and a detailed neuropsychological evaluation were performed. Higher TAS-20 scores were negatively correlated with Wechsler Adult Intelligence Scale (WAIS) similarities test score (r =-0.71, p value 0.02), clock drawing test (CDT) scores (r=-0.72, p=0.02) and verbal fluency (VF) (r=-0.77, p<0.01). Difficulty identifying feelings subscale score was negatively correlated with CDT scores (r=-0.74, p=0.02), VF scores (r=-0.66, p=0.04), visual memory immediate recall (r=-0.74, p=0.01). VF scores were also correlated with difficulty describing feelings (DDF) scores (r=-0.66, p=0.04). There was a reverse relationship bet­ween WAIS similarities and DDF scores (r=-0.70, p=0.02), and externally oriented-thinking (r=-0.77,p<0.01). Executive function Z score was correlated with the mean TAS-20 score (r=-62, p=0.03) and DDF subscale score (r=-0.70, p=0.01) Alexithymia was found to be associated with poorer performance on visuospatial and executive function test results. We also found that alexithymia was significantly correlated with depressive symptoms. Presence of alexithymia should therefore warn the clinicians for co-existing CD.

Clinical Neuroscience

[The role of sleep in the relational memory processes ]

CSÁBI Eszter, ZÁMBÓ Ágnes, PROKECZ Lídia

[A growing body of evidence suggests that sleep plays an essential role in the consolidation of different memory systems, but less is known about the beneficial effect of sleep on relational memory processes and the recognition of emotional facial expressions, however, it is a fundamental cognitive skill in human everyday life. Thus, the study aims to investigate the effect of timing of learning and the role of sleep in relational memory processes. 84 young adults (average age: 22.36 (SD: 3.22), 21 male/63 female) participated in our study, divided into two groups: evening group and morning group indicating the time of learning. We used the face-name task to measure relational memory and facial expression recognition. There were two sessions for both groups: the immediate testing phase and the delayed retesting phase, separated by 24 hours. 84 young adults (average age: 22.36 (SD: 3.22), 21 male/63 female) participated in our study, divided into two groups: evening group and morning group indicating the time of learning. We used the face-name task to measure relational memory and facial expression recognition. There were two sessions for both groups: the immediate testing phase and the delayed retesting phase, separated by 24 hours. Our results suggest that the timing of learning and sleep plays an important role in the stabilizing process of memory representation to resist against forgetting.]