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Trisomy 21, caused by triplication of human chromosome 21, is also known as Down syndrome (DS) and affects every 1 out of 800 births. DS causes morphometric deviations in the brain and face as well as behavioral changes, due to gene dosage imbalances. Since many DS studies focus on adults, there are very few that explore how DS influences children. This investigation helps to fill this void in the literature by seeking to understand the differences in brain morphometry in children with DS and euploid controls. To do this, we first obtained two age- and gender-matched sample groups composed of MRI images from 1) children with DS (n=31 images, 0-4 yrs.); 2) euploid children (n = 31 images, 0-4 yrs.). MRI images were provided by the Florida Hospital (now AdventHealth) and the National Institute of Health. On these MRI images, 36 anatomical landmarks were placed throughout the brain. With the 36 landmarks, Euclidean Distance Matrix Analysis was used to measure every unique linear distance between landmarks, resulting in a total of 630 linear distances. Out of 630 linear distances, 211 (33.49%) were significantly different between the two samples (p-value < 0.05), as determined by analysis of variance (ANOVA) calculations. From these 211 linear distances, 22 were extremely different between the two samples (p-value < 0.001) and were thoroughly analyzed. Based on our results, regions of the brain that were significantly different in children with DS include the following: frontal lobe, occipital lobe, ventricles, thalamus, striatum, and corpus callosum. Such morphometric changes are likely associated with behavioral changes such as social-cognitive defects and motor-related issues commonly seen in DS.

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Neurodegenerative diseases are becoming increasingly prevalent due to the ageing population, and are among the major contributors to disability and disease worldwide. The identification of the gene defects responsible for many of these conditions has played a major role in our understanding of the pathogenic processes involved, and provided opportunity to develop targeted treatment strategies. Cholinergic neurotransmission supports a wide range of physiological and behavioural processes and its dysfunction of cholinergic signalling has been associated with a number of disorders, including myasthenias, cardiovascular disease(1), attention-deficit hyperactivity disorder (ADHD) (2), Alzheimer’s disease (ADi), schizophrenia, addiction(3), and depression(4). SLC5A7 encodes the Na+/Cl- dependent, high-affinity choline transporter (CHT) which represents the rate limiting step in acetylcholine (Ach) synthesis and is critical for normal cholinergic signalling. The work in this thesis details two new inherited disorders, caused by distinct pathogenic disease mechanisms, associated with novel SLC5A7 mutations. Chapter three documents the discovery of two autosomal-dominantly acting SLC5A7/CHT mutations associated with adult onset motor neurone disorders. Initially we identified a frameshift mutation that results in premature truncation of the transporter protein in a large Welsh kindred affected with distal hereditary motor neuropathy type VII (dHMN-VII), in which neurodegeneration and muscle paresis is largely restricted to the distal limb muscles and vocal cords. The mutation responsible results in the dominant-negative interference of the mutant molecule with function of the wild type choline transporter, resulting in significantly reduced (although not completely abolished) transporter activity. This finding is further evidenced by the discovery of a second dHMN family associated with a distinct frameshift SLC5A7 mutation indicative of a similar dominant-negative disease mechanism. Together these findings corroborate a dominant-negative disease mechanism arising from C-terminal truncating SLC5A7 mutations associated with dHMN, and provide further insight into the role of aberrant choline transporter function in neurological disease. Chapter four describes N-terminal missense mutations located in the transmembrane spanning region of SLC5A7/CHT, associated with a severe infantile neuromuscular disorder characterised by predominantly central hypotonia and developmental delay. The phenotypic effects of these mutations are likely to result from the near abolition of CHT-mediated choline transport in homozygous individuals, and are in keeping with those observed in CHT knock-out mouse models(5). The development of a mouse model of the human motor neurone disease arising from SLC5A7 frameshift mutations should allow for further investigation of the mechanism by which truncated CHT leads to the dHMN phenotype. Chapter 5 details treatment hypotheses for dHMN, as well as the generation of a patient-specific knock-in mouse model carrying an Slc5a7 mutation orthologous to that identified in dHMN-VII families in chapter 3, and results from preliminary neurological phenotyping of the mouse model. This model will be crucially important for the exploration of treatment options in dHMN-VII motor neurone disease as a prelude to clinical trials in humans.

There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.