Tausta: CP-vamma on sikiön tai pikkulapsen kehittyviin aivoihin tapahtuneen aivovaurion aiheuttama liikuntavamma. CP-vamma jaotellaan spastiseen, dyskineettiseen ja ataktiseen alatyyppiin. Anatomisen sijainnin perusteella CP-vamma jaotellaan edelleen kvadriplegiseen, diplegiseen ja hemiplegiseen muotoon. Lisäksi käytössä ovat määrittämätön ja muu CP-vamma. CP-vamma on yleensä diagnosoitu noin 1–2 vuoden iässä, mutta on mahdollista jo ennen 6 kuukauden ikää. Tanskassa mediaani-ikä diagnoosin asettamiselle on 11 kuukautta. Suomessa vastaava ikä on 1,5 vuotta, mutta eri alatyypeille tätä ikää ei ole selvitetty. Tavoitteet: Tutkimuksen tavoitteena on selvittää HYKS:n lastenneurologialla diagnosoitujen CP-vammaisten lasten diagnoosi-iän mediaani. Tämä määritetään koko tutkimuspopulaatiolle sekä eri alatyypeille huomioiden myös sukupuolien väliset mahdolliset erot. Menetelmät: Aineistona käytettiin HYKS:n lastenneurologialla ajalla 1/2009–6/2018 alle 9-vuotiaana diagnosoituja potilaita. Tiedot diagnoosista ja sen ajankohdasta haettiin potilastietojärjestelmästä. Lopullinen tutkittavien määrä oli 213, joista poikia oli 122 ja tyttöjä 91. Spastisia kvadriplegisiä potilaita oli 7, spastisia diplegisiä 37, spastisia hemiplegisiä 139, dyskineettisiä 29 ja ataktisia 1. Tulokset: Mediaani-ikä diagnoosivaiheessa oli kaikille 17 kuukautta, pojille 16,5 kk ja tytöille 17 kk. Mediaani-iät alatyypeissä olivat kvadriplegialle 17, diplegialle 22, hemiplegialle 14, dyskineettiselle 19 ja ataktiselle 42 kuukautta. Alatyypillä yleisesti tarkasteltuna oli tilastollisesti merkitsevä vaikutus diagnoosi-ikään, mutta sukupuolella ei. Pohdinta: Koko tutkimuspopulaation diagnoosi-iän mediaani oli hyvin yhtenäinen aiemmin tutkitun, koko Suomen kattavan diagnoosi-iän kanssa. Näiden perusteella diagnostiikka ei kuitenkaan ole Suomessa yhtä aikaista kuin Tanskassa. Aikainen diagnoosi on etu hoitointerventioiden aloituksen suhteen, mutta Suomen ja Tanskan eroja hoitointerventioissa ei kuitenkaan tämän perusteella voi arvioida. Tärkeää diagnostiikassa on myös diagnoosin pysyvyys myöhemmällä iällä.

Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative diseases in childhood. Its clinical onset, with visual failure as the first sign, is between the ages of 4 to 8 years. During the disease progress, epilepsy, motor symptoms, cognitive decline, and psychiatric symptoms become apparent. It leads to premature death between ages 15 and 30. Treatment consists of symptomatic drug administration and various forms of rehabilitation, but to date, no curative treatment exists. To gain a more comprehensive picture of psychiatric problems, symptoms were evaluated by the Child Behavior Checklist, the Teacher Report Form, and the Children s Depression Inventory. The JNCL patients had a great number of severe psychiatric symptoms, with wide inter-individual variability. The most common symptoms were social, thought, attention, and sleep problems, somatic complaints, and aggressive behaviour. Patients with psychotropic treatment had more problems than did those without psychotropic treatment, and female patients had more problems than did males. Between 10 and 20% of the patients reported depressive symptoms. In a 5-year follow-up, [123I]β-CIT SPECT and MRI revealed a tendency of decreasing serotonin transporter (SERT) availability and progressive brain atrophy. The correlation between changes in midbrain SERT and total brain volume was positive; no correlation appeared between SERT or brain atrophy and depressive symptoms. Thus, it seems likely that the low SERT availability is associated with progressive brain atrophy; it may also predispose towards depression, however. An open survey of psychotropic drugs and their efficacy was performed on JNCL patients in Finland. The most commonly used psychotropic drugs were the antidepressant citalopram and the antipsychotic risperidone. Their efficacy was good or satisfactory in the majority of cases and they seemed well tolerated. Quetiapine had a marked effect on one patient with a history of severe psychotic symptoms. Glutamate decarboxylase 65 autoantibodies (GAD65ab), found in JNCL patients, indicate that an immunomediated reaction against GAD or GABAergic neurons may play a part in the underlying pathogenetic mechanism. GAD65ab s also appeared in the serum of all eight JNCL patients included and intermittent corticosteroid therapy was initiated in all cases. After one year, the GAD65ab s had disappeared in the two oldest patients, who experienced an improvement in motor symptoms and alertness associated with their prednisolone therapy. Two younger patients experienced a significant IQ increase, but no change in GADab s. A randomized study with longer follow-up time is needed, however, to clarify the effect of prednisolone on disease progression.

Ataxia involves incoordination of balance, gait, extremity movements, eye movements, and dysarthria. Hereditary ataxia has a heterogeneous genetic background, with hundreds of associated genes. Over the last decade, utilization of next-generation sequencing methods have become common, initially in a research setting and then in clinical use, allowing for analysis of all gene coding regions or a subset of genes at once instead of sequencing genes one-by-one in a selective manner. This has changed the diagnostic process for rare diseases, including hereditary ataxia, with faster identification of known disease-causing variants and description of novel ones. The aims of this study were to characterize the genetic causes of undiagnosed childhood ataxia in a Finnish cohort, identify novel genetic causes of ataxia, evaluate the diagnostic yield of exome sequencing for genetic diagnosis of hereditary childhood ataxia, and describe the genotype and phenotype of individuals with specific ataxias. In this study, exome sequencing and a genome-wide genotyping array were used to analyze the genetic background of children with ataxia. Patient medical records were reviewed and the severity of ataxia evaluated in a subset of individuals using the Scale for the Assessment and Rating of Ataxia clinical scale. In a cohort of 50 families with childhood-onset ataxia, the diagnostic yield of exome sequencing was 46% and approximately half of diagnosed families had a de novo variant. Using exome sequencing, causative variants were found in 18 different genes, including two novel ataxia genes, and 17 previously unpublished causative variants were identified. The heterogeneous genetic background of childhood-onset ataxia seen elsewhere in the world is reflected in our cohort and de novo variants explain a large proportion of this disease group. Two novel ataxia genes, SQSTM1 and GPAA1 were identified as part of two international collaborations. This work describes two novel diseases; a childhood-onset neurodegenerative disease with ataxia; caused by bi-allelic pathogenic variants in the gene SQSTM1 and developmental delay, epilepsy and cerebellar atrophy caused by bi-allelic pathogenic variants in the gene GPAA1. This thesis provides new information on phenotype and genetic mechanisms in a recently described neurodevelopmental disorder caused by variants in the transcription factor EBF3 and describes eleven individuals with EBF3 variants, including an individual with a duplication/triplication mosaicism of a region that includes EBF3. After exome sequencing, nearly half of individuals with childhood-onset ataxia still remain without a genetic diagnosis. Emerging technologies including long-read sequencing and multi-omic strategies may help in the search of genetic variants overlooked by exome sequencing. However, periodic exome re-analysis has been shown to increase diagnostic yield and should be performed before applying additional and/or newer technologies. Although only few childhood-onset ataxias currently have treatments that affect the disease process, a genetic diagnosis has many benefits, including ending the laborious and stressful diagnostic odyssey, guiding management and giving prognosis; and aiding in family planning.