The standard course of lessons and exercises in the tonic sol-fa method of teaching music (Founded on Miss Glover's "Scheme for rendering Psalmody Congregational," 1835) : with additional exercises /

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Aspects of tonic accommodation and tonic vergence

Under conditions of reduced visual stimulation, the systems of accommodation and vergence tend towards physiological resting states that are intermediate within their functional range. The terms tonic accommodation (TA) and tonic vergence (TV) are used in the study to describe these stimulus-free, intermediate adjustments and to represent the systems as being in a state of innervational tonicity. The literature relating to TA and TV and the various experiments of this thesis are reviewed. Methodology has been developed enabling the determination of TA and TV under conditions of total darknessl laser optometry for TA and ~ernier-alignment for TV. The thesis describes a series of experiments designed to investigate various aspects of TA and TV, and their role in ametropia, binocular vision and their adaptation to sustained visual tasks. Measurements of TA were also utilised to investigate the effect of various autonomic effector drugs on the ciliary muscle. The effects of ethanol on binocular function are shown to be directly proportional to the .initial level of TVJ which is itself unaffected. These results support the concept of TV as the reference point for normal vergence responses. The results of the pharmacological investigations indicate the presence of a small but significant, beta-receptor mediated inhibitory sympathetic input to the ciliary muscle, and that the wide distribution in TA is a consequence of inter-observer variations in parasympathetic, rather than sympathetic tone. Following interaction with visual tasks of t5mins duration, the levels of TA and TV are found to be biased in the direction of, and proportional to, the task position: except during near-task viewing where the task-to-TA stimulus-distance exceeds 1.5D (for TA) and 3.5deg (for TV). Under these conditions the expected level of bias is attenuated, Adaptive models are discussed, proposing TA and TV as the reference points of the accommodative and vergence system.

Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons

Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15–30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage -clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states.

Acoustic characterisation of the tonic syllable in portuguese

A particular problem for the automatic prediction of prosody in speech synthesis is the realisation of accented syllables since these are affected by many parameters and are perceptually very salient. For the Portuguese language, in Europe, a set of comprehensive quantitative characterisation data and rules is totally lacking. The present paper is intended to be a quantitative contribution to the solution of this problem. In this paper, a preliminary modelling of duration, intensity and variation of F0 in the tonic syllable will be presented. The dependencies of the model with the syllable position in the word and the word position in the phrase are also presented.

The effect of prolonged reading on visual functions and reading performance in students with low vision

This study is the first to investigate the effect of prolonged reading on reading performance and visual functions in students with low vision. The study focuses on one of the most common modes of achieving adequate magnification for reading by students with low vision, their close reading distance (proximal or relative distance magnification). Close reading distances impose high demands on near visual functions, such as accommodation and convergence. Previous research on accommodation in children with low vision shows that their accommodative responses are reduced compared to normal vision. In addition, there is an increased lag of accommodation for higher stimulus levels as may occur at close reading distance. Reduced accommodative responses in low vision and higher lag of accommodation at close reading distances together could impact on reading performance of students with low vision especially during prolonged reading tasks. The presence of convergence anomalies could further affect reading performance. Therefore, the aims of the present study were 1) To investigate the effect of prolonged reading on reading performance in students with low vision 2) To investigate the effect of prolonged reading on visual functions in students with low vision. This study was conducted as cross-sectional research on 42 students with low vision and a comparison group of 20 students with normal vision, aged 7 to 20 years. The students with low vision had vision impairments arising from a range of causes and represented a typical group of students with low vision, with no significant developmental delays, attending school in Brisbane, Australia. All participants underwent a battery of clinical tests before and after a prolonged reading task. An initial reading-specific history and pre-task measurements that included Bailey-Lovie distance and near visual acuities, Pelli-Robson contrast sensitivity, ocular deviations, sensory fusion, ocular motility, near point of accommodation (pull-away method), accuracy of accommodation (Monocular Estimation Method (MEM)) retinoscopy and Near Point of Convergence (NPC) (push-up method) were recorded for all participants. Reading performance measures were Maximum Oral Reading Rates (MORR), Near Text Visual Acuity (NTVA) and acuity reserves using Bailey-Lovie text charts. Symptoms of visual fatigue were assessed using the Convergence Insufficiency Symptom Survey (CISS) for all participants. Pre-task measurements of reading performance and accuracy of accommodation and NPC were compared with post-task measurements, to test for any effects of prolonged reading. The prolonged reading task involved reading a storybook silently for at least 30 minutes. The task was controlled for print size, contrast, difficulty level and content of the reading material. Silent Reading Rate (SRR) was recorded every 2 minutes during prolonged reading. Symptom scores and visual fatigue scores were also obtained for all participants. A visual fatigue analogue scale (VAS) was used to assess visual fatigue during the task, once at the beginning, once at the middle and once at the end of the task. In addition to the subjective assessments of visual fatigue, tonic accommodation was monitored using a photorefractor (PlusoptiX CR03™) every 6 minutes during the task, as an objective assessment of visual fatigue. Reading measures were done at the habitual reading distance of students with low vision and at 25 cms for students with normal vision. The initial history showed that the students with low vision read for significantly shorter periods at home compared to the students with normal vision. The working distances of participants with low vision ranged from 3-25 cms and half of them were not using any optical devices for magnification. Nearly half of the participants with low vision were able to resolve 8-point print (1M) at 25 cms. Half of the participants in the low vision group had ocular deviations and suppression at near. Reading rates were significantly reduced in students with low vision compared to those of students with normal vision. In addition, there were a significantly larger number of participants in the low vision group who could not sustain the 30-minute task compared to the normal vision group. However, there were no significant changes in reading rates during or following prolonged reading in either the low vision or normal vision groups. Individual changes in reading rates were independent of their baseline reading rates, indicating that the changes in reading rates during prolonged reading cannot be predicted from a typical clinical assessment of reading using brief reading tasks. Contrary to previous reports the silent reading rates of the students with low vision were significantly lower than their oral reading rates, although oral and silent reading was assessed using different methods. Although the visual acuity, contrast sensitivity, near point of convergence and accuracy of accommodation were significantly poorer for the low vision group compared to those of the normal vision group, there were no significant changes in any of these visual functions following prolonged reading in either group. Interestingly, a few students with low vision (n =10) were found to be reading at a distance closer than their near point of accommodation. This suggests a decreased sensitivity to blur. Further evaluation revealed that the equivalent intrinsic refractive errors (an estimate of the spherical dioptirc defocus which would be expected to yield a patient’s visual acuity in normal subjects) were significantly larger for the low vision group compared to those of the normal vision group. As expected, accommodative responses were significantly reduced for the low vision group compared to the expected norms, which is consistent with their close reading distances, reduced visual acuity and contrast sensitivity. For those in the low vision group who had an accommodative error exceeding their equivalent intrinsic refractive errors, a significant decrease in MORR was found following prolonged reading. The silent reading rates however were not significantly affected by accommodative errors in the present study. Suppression also had a significant impact on the changes in reading rates during prolonged reading. The participants who did not have suppression at near showed significant decreases in silent reading rates during and following prolonged reading. This impact of binocular vision at near on prolonged reading was possibly due to the high demands on convergence. The significant predictors of MORR in the low vision group were age, NTVA, reading interest and reading comprehension, accounting for 61.7% of the variances in MORR. SRR was not significantly influenced by any factors, except for the duration of the reading task sustained; participants with higher reading rates were able to sustain a longer reading duration. In students with normal vision, age was the only predictor of MORR. Participants with low vision also reported significantly greater visual fatigue compared to the normal vision group. Measures of tonic accommodation however were little influenced by visual fatigue in the present study. Visual fatigue analogue scores were found to be significantly associated with reading rates in students with low vision and normal vision. However, the patterns of association between visual fatigue and reading rates were different for SRR and MORR. The participants with low vision with higher symptom scores had lower SRRs and participants with higher visual fatigue had lower MORRs. As hypothesized, visual functions such as accuracy of accommodation and convergence did have an impact on prolonged reading in students with low vision, for students whose accommodative errors were greater than their equivalent intrinsic refractive errors, and for those who did not suppress one eye. Those students with low vision who have accommodative errors higher than their equivalent intrinsic refractive errors might significantly benefit from reading glasses. Similarly, considering prisms or occlusion for those without suppression might reduce the convergence demands in these students while using their close reading distances. The impact of these prescriptions on reading rates, reading interest and visual fatigue is an area of promising future research. Most importantly, it is evident from the present study that a combination of factors such as accommodative errors, near point of convergence and suppression should be considered when prescribing reading devices for students with low vision. Considering these factors would also assist rehabilitation specialists in identifying those students who are likely to experience difficulty in prolonged reading, which is otherwise not reflected during typical clinical reading assessments.

Spatial and developmental heterogeneity of calcium signaling in olfactory ensheathing cells

Olfactory ensheathing cells (OECs) are specialized glial cells in the mammalian olfactory system supporting growth of axons from the olfactory epithelium into the olfactory bulb. OECs in the olfactory bulb can be subdivided into OECs of the outer nerve layer and the inner nerve layer according to the expression of marker proteins and their location in the nerve layer. In the present study, we have used confocal calcium imaging of OECs in acute mouse brain slices and olfactory bulbs in toto to investigate physiological differences between OEC subpopulations. OECs in the outer nerve layer, but not the inner nerve layer, responded to glutamate, ATP, serotonin, dopamine, carbachol, and phenylephrine with increases in the cytosolic calcium concentration. The calcium responses consisted of a transient and a tonic component, the latter being mediated by store-operated calcium entry. Calcium measurements in OECs during the first three postnatal weeks revealed a downregulation of mGluR(1) and P2Y(1) receptor-mediated calcium signaling within the first 2 weeks, suggesting that the expression of these receptors is developmentally controlled. In addition, electrical stimulation of sensory axons evoked calcium signaling via mGluR(1) and P2Y(1) only in outer nerve layer OECs. Downregulation of the receptor-mediated calcium responses in postnatal animals is reflected by a decrease in amplitude of stimulation-evoked calcium transients in OECs from postnatal days 3 to 21. In summary, the results presented reveal striking differences in receptor responses during development and in axon-OEC communication between the two subpopulations of OECs in the olfactory bulb.

Structure of Raster in Melolonthine Larvae

Ultrastructural and electrophysiological investigations carried out on larval rasters of Rhopaea magnicomis Blackburn, Lepidiota frerzclzi Black, and Antitr-ogus consanguineus Blackburn revealed that the raster is a complex of mechanoreceptive setae. Chemical and morphological investigations provide no evidence that the raster is a site for chemical emissions; however, species differences in hydrocarbon profiles were found among larval cuticle samples. Ultrastructure of the setae (pali) show that each seta is innervated by a single dendrite which ends in a tubular body at the base of the seta. The connection with the seta is on the proximal side, which corresponds to the production of a phasic-tonic electrophysiological signal on downward deflection. The dendrite is surrounded by a granular, electron-dense sheath which has inwardly directed arms distally and outwardly directed arms proximally. Two sheath cells are present, 1 forming a large receptor lymph cavity which is lamellate and lined with electron-dense material.

Aavan meren täällä puolen : Arkkityyppiset piirteet ja amerikkalaisvaikutteet suosituimmissa suomalaisissa molli-iskelmissä

What are the musical features that turn a song into a hit? The aim of this research is to explore the musical features of hit tunes by studying the 224 most popular Finnish evergreens from the 1930s to the 1990s. It is remarkable, that 80-90% of Finnish oldies are in a minor key, though parallel major keys have also been widely employed within single pieces through, for example, modulations. Furthermore, melodies are usually diatonic, staying mostly in the same key. Consequently, chromatically altered tones in the melody and short modulations in the bridge sections become more prominent. I have concentrated in particular on the melodic lines in order to find the most typical melodic formulas from the data. These analyzed melodic formulas play an important role, because they serve as leading phrases and punchlines in songs. Analysis has revealed three major melodic formulas, which most often appear in the melodic lines of hit tunes. All of these formulas share common thematic ground, because they originate from the triadic tonic chord. Because the tonic chord is the most conventional opening chord in the verse parts, it is logical that these formulas occur most often in verses. The strong dominance of these formulas is very much a result of the rhythmic flexibility they possess; for instance, they can be found in every musical style from waltz to foxtrot. Alongside the major formulas lies a miscellaneous group of other tonic-related melodic formulas. One group of melodic formulas consists of melodic quotations. These quotations appear in a different musical context, for instance in a harmonically altered form, and are therefore often difficult to recognize as such. Yet despite the contextual manipulation, the distinctive character of the cited melody usually remains the same. Composers have also made use of certain popular chord-progressions in order to create new but familiar-sounding melodies. The most important individual progression in this case is what is known as a "circle of fifths" and its shortened, prolonged and altered versions. Because that progression is harmonically strong, it is also a contrastive tool used especially in chorus parts and middle sections (AABA). I have also paid attention to ragtime and jazz influences, which can be found in harmony parts and certain melody notes, which extend, suspend or alter the accompaning chords. Other influences from jazz and ragtime in the Finnish evergreen are evident in the use of typical Tin Pan Alley popular song forms. The most important is the AABA form, which dominates over the data along with the verse/chorus-type popular song form. To briefly illustrate the main results, the basic concept of the hit tune can be traced back to Tin Pan Alley songs, whereas the major stylistic aspects, such as minor keys and musical styles, bear influences from Russian, Western European, and Finnish traditions.

Psychophysiology of flow experience : An explorative study

This study explored the possibilities the psychophysiological methodology offer to flow research. Facial electromyography has often been used to index valence, and electrodermal activity to index arousal, the two basic dimensions of emotion. It was hypothesized that these measures can also be used to examine enjoyment, a basic component of flow experiment. A digital game was used to induce flow, and physiological activity of 32 subjects was measured continuously. Flow State Scale was used to assess flow. Activity of corrugator supercilii muscle, an index of negative valence, was negatively correlated with flow reports, as hypothesized. Contrary to hypothesis, skin conductance level, an index of arousal, was unrelated to self-reported flow. The results for association between flow and zygomaticus major and orbicularis oculi muscle activities, indices of positive valence, were inconclusive, possibly due to experimental design where only tonic measures were available. Psychophysiological methods are recommended for future studies of flow. Specifically, the time series approach may be particularly viable in examining the temporal aspects of flow, an area currently unexplored. Furthermore, it is suggested that digital game research would benefit from psychophysiological study of game-related flow.

Clinical signs and duration of cyanide toxicosis delivered by the M-44 ejector in wild dogs

Sodium cyanide poison is potentially a more humane method to control wild dogs than sodium fluoroacetate (1080) poison. This study quantified the clinical signs and duration of cyanide toxicosis delivered by the M-44 ejector. The device delivered a nominal 0.88 g of sodium cyanide, which caused the animal to loose the menace reflex in a mean of 43 s, and the animal was assumed to have undergone cerebral hypoxia after the last visible breath. The mean time to cerebral hypoxia was 156 s for a vertical pull and 434 s for a side pull. The difference was possibly because some cyanide may be lost in a side pull. There were three distinct phases of cyanide toxicosis: the initial phase was characterised by head shaking, panting and salivation; the immobilisation phase by incontinence, ataxia and loss of the righting reflex; and the cerebral hypoxia phase by a tetanic seizure. Clinical signs that were exhibited in more than one phase of cyanide toxicosis included retching, agonal breathing, vocalisation, vomiting, altered levels of ocular reflex, leg paddling, tonic muscular spasms, respiratory distress and muscle fasciculations of the muzzle.

Role of prolactin(prl) in regulation of the nocturnal surge of testosterone (t) in the bonnet monkey (macaca radiata)

Earlier studies from this lebordory have shown thet adult male bonnet monkeys exhibit nychthemrel rhythmicity la the secretion of serum 'T' the levele reehlng peek by 22OOhr. Of the gonedotropine cnelyeed only serum PRL showed a concommitent increme with T(Biol.of Reprod. 24,814, 1981). In the present study mMinietretion of l rgobromocryptin (EBC) either by i.v.route(2mg)or by naeel l pr~(100~)reeulted in blockade of nocturnal increase of both PRL end T(Controle T-18.6ng/ml: PRL 130=29ng/ml: EBC treated T-2.2&1.2ng/ml; PRL n.d.to 15nng/ml). Adminietretion of N oPRL could not reverse the effect of EBC. Although, increaeed serum PRL induced by injection of Chlorprommine did not result in increase in serum 'T' during the dey time, the nocturnel 'T' surge could not be obeeerved. EBC treeted monkeys, however, showed normal testosterone response to exogenous hCG. These IeSUlte a0 SwgeStive of high levels of PRL me&in6 reeponeiveneee of testes to tonic levels of serum IX. (Aided by grant8 from ICMR, Kew Delhi, WHO, Geneva eld FPF, India).

Molecular biology of progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1)

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited disorder characterized by age of onset at 6-15 years, stimulus-sensitive myoclonus, tonic-clonic epileptic seizures and a progressive course. Mutations in the cystatin B (CSTB) gene underlie EPM1. The most common mutation underlying EPM1 is a dodecamer repeat expansion in the promoter region of CSTB. In addition, nine other mutations have been identified. CSTB, a cysteine protease inhibitor, is a ubiquitously expressed inhibitor of cathepsins, but its physiological function is unknown. The purpose of this study was to investigate CSTB gene expression and CSTB protein function in normal and pathological conditions. The basal CSTB promoter was mapped and characterized using different promoter-luciferase gene constructs. The binding activity of transcription factors to one ARE half, five Sp1 and four AP1 sites in the CSTB promoter was demonstrated. The CSTB promoter activity was clearly decreased using a CSTB promoter with "premutation" repeat expansions and in individuals with alike expansions. The expression of CSTB mRNA and protein was markedly reduced in patient cells. The endogenous CSTB protein localized to the nucleus, cytoplasm and lysosomes, and in differentiated cells merely to the cytoplasm. This suggests that the subcellular distribution of CSTB is dependent on the differentation status of the cells. The proteins representing patient missense mutations failed to associate with lysosomes, implying the importance of the lysosomal association for the proper physiological function of CSTB. Several alternatively spliced CSTB isoforms were identified. Of these CSTB2 was widely expressed with very low levels whereas the other alternatively spliced forms seemed to have limited tissue expression. In patients CSTB2 expression was reduced similarly to that of CSTB. The physiological relevance of CSTB alternative splicing remains unknown. The mouse Cstb transcript was shown to be present in all embryonic stages and adult tissues examined. The expression was highest at embryonic day 7 and in thymus, as well as in postnatal brain in the cortex, caudate putamen, thalamus, hippocampus, and in the Purkinje cell layer of the cerebellum. Our data implies that CSTB expression is tightly temporally and spatially regulated. The data presented in my thesis lay the basis for further understanding of the role of CSTB in health and disease.

Generation and Characterization of the Cation-Chloride Cotransporter KCC2 Hypomorphic Mouse

The cation-Cl- cotransporter (CCC) family comprises of Na+-Cl- cotransporter (NCC), Na+-K+-2Cl- cotransporters (NKCC1-2), and four K+-Cl- cotransporters (KCC1-4). These proteins are involved in several physiological activities, such as cell volume regulation. In neuronal tissues, NKCC1 and KCC2 are important in determining the intracellular Cl- levels and hence the neuronal responses to inhibitory neurotransmitters GABA and glycine. One aim of the work was to elucidate the roles for CCC isoforms in the control of nervous system development. KCC2 mRNA was shown to be developmentally up-regulated and follow neuronal maturation, whereas NKCC1 and KCC4 transcripts were highly expressed in the proliferative zones of subcortical regions. KCC1 and KCC3 mRNA displayed low expression throughout the embryogenesis. These expression profiles suggest a role for CCC isoforms in maturation of synaptic responses and in the regulation of neuronal proliferation during embryogenesis. The major aim of this work was to study the biological consequences of KCC2-deficiency in the adult CNS, by generating transgenic mice retaining 15-20% of normal KCC2 levels. In addition, by using these mice as a tool for in vivo pharmacological analysis, we investigated the requirements for KCC2 in tonic versus phasic GABAA receptor-mediated inhibition. KCC2-deficient mice displayed normal reproduction and life span, but showed several behavioral abnormalities, including increased anxiety-like behavior, impaired performance in water maze, alterations in nociceptive processing, and increased seizure susceptibility. In contrast, the mice displayed apparently normal spontaneous locomotor activity and motor coordination. Pharmacological analysis of KCC2-deficient mice revealed reduced sensititivity to diazepam, but normal gaboxadol-induced sedation, neurosteroid hypnosis and alcohol-induced motor impairment. Electrophysiological recordings from CA1-CA3 subregions of the hippocampus showed that KCC2 deficiency affected the reversal potentials of both the phasic and tonic GABA currents, and that the tonic conductance was not affected. The results suggest that requirement for KCC2 in GABAergic neurotransmission may differ among several functional systems in the CNS, which is possibly due to the more critical role of KCC2 activity in phasic compared to tonic GABAergic inhibition.

Dissection of the genetic background of childhood onset progressive myoclonic epilepsies

The progressive myoclonic epilepsies (PMEs) are a clinically and etiologically heterogeneous group of symptomatic epilepsies characterized by myoclonus, tonic-clonic seizures, psychomotor regression and ataxia. Different disorders have been classified as PMEs. Of these, the group of neuronal ceroid lipofuscinoses (NCLs) comprise an entity that has onset in childhood, being the most common cause of neurodegeneration in children. The primary aim of this thesis was to dissect the molecular genetic background of patients with childhood onset PME by studying candidate genes and attempting to identify novel PME-associated genes. Another specific aim was to study the primary protein properties of the most recently identified member of the NCL-causing proteins, MFSD8. To dissect the genetic background of a cohort of Turkish patients with childhood onset PME, a screen of the NCL-associated genes PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8 and CTSD was performed. Altogether 49 novel mutations were identified, which together with 56 mutations found by collaborators raised the total number of known NCL mutations to 364. Fourteen of the novel mutations affect the recently identified MFSD8 gene, which had originally been identified in a subset of mainly Turkish patients as the underlying cause of CLN7 disease. To investigate the distribution of MFSD8 defects, a total of 211 patients of different ethnic origins were evaluated for mutations in the gene. Altogether 45 patients from nine different countries were provided with a CLN7 molecular diagnosis, denoting the wide geographical occurrence of MFSD8 defects. The mutations are private with only one having been established by a founder-effect in the Roma population from the former Czechoslovakia. All mutations identified except one are associated with the typical clinical picture of variant late-infantile NCL. To address the trafficking properties of MFSD8, lysosomal targeting of the protein was confirmed in both neuronal and non-neuronal cells. The major determinant for this lysosomal sorting was identified to be an N-terminal dileucine based signal (9-EQEPLL-14), recognized by heterotetrameric AP-1 adaptor proteins, suggesting that MFSD8 takes the direct trafficking pathway en route to the lysosomes. Expression studies revealed the neurons as the primary cell-type and the hippocampus and cerebellar granular cell layer as the predominant regions in which MFSD8 is expressed. To identify novel genes associated with childhood onset PME, a single nucleotide polymorphism (SNP) genomewide scan was performed in three small families and 18 sporadic patients followed by homozygosity mapping to determine the candidate loci. One of the families and a sporadic patient were positive for mutations in PLA2G6, a gene that had previously been shown to cause infantile neuroaxonal dystrophy. Application of next-generation sequencing of candidate regions in the remaining two families led to identification of a homozygous missense mutation in USP19 for the first and TXNDC6 for the second family. Analysis of the 18 sporadic cases mapped the best candidate interval in a 1.5 Mb region on chromosome 7q21. Screening of the positional candidate KCTD7 revealed six mutations in seven unrelated families. All patients with mutations in KCTD7 were reported to have early onset PME, rapid disease progression leading to dementia and no pathologic hallmarks. The identification of KCTD7 mutations in nine patients and the clinical delineation of their phenotype establish KCTD7 as a gene for early onset PME. The findings presented in this thesis denote MFSD8 and KCTD7 as genes commonly associated with childhood onset symptomatic epilepsy. The disease-associated role of TXNDC6 awaits verification through identification of additional mutations in patients with similar phenotypes. Completion of the genetic spectrum underlying childhood onset PMEs and understanding of the gene products functions will comprise important steps towards understanding the underlying pathogenetic mechanisms, and will possibly shed light on the general processes of neurodegeneration and nervous system regulation, facilitating the diagnosis, classification and possibly treatment of the affected cases.