P.121 Leading the Way to the Future: Implementing Novel Therapeutics for Rare Pediatric Neurological Disorders

Background: Children and Adolescents with rare neurogenetic disorders often have no known cure or disease modifying treatments. Recent advancements in treatments are offering much needed hope to these patients and families. However, these treatments are extremely costly, have complex administration requirements and have many unknown long-term risks and outcomes. Methods: In this presentation, we will discuss our experiences with the implementation process, including developing intricate care pathways, collaborating with multiple disciplines and services, supporting and advocating for our patients and families, and interacting with government agencies and pharmaceutical companies. Case studies will highlight the positive impact these treatments are making on the lives of children and adolescents with rare neurological disorders. Results: Spinal muscular atrophy and Neuronal Ceroid Lipofuscinosis Type 2 are both rare and devastating neurodegenerative conditions with significant morbidity and mortality. Health Canada and government funding agencies recently approved Nusinersen, Onasemnogene abeparvovec for the treatment of SMA and Cerliponase alfa for the treatment of CLN2, leading us to swiftly integrate these treatments into our standard of care. Conclusions: While implementing these novel therapies into clinical practice can be both challenging and rewarding, neuroscience nurses are positioned at the forefront to be leaders in this process at both organizational, national, and international levels.

Expanding the Phenotype of the FAM149B1-Related Ciliopathy and Identification of Three Neurogenetic Disorders in a Single Family

Biallelic truncating FAM149B1 variants result in cilia dysfunction and have been reported in four infants with Joubert syndrome and orofaciodigital syndrome type VI, respectively. We report here on three adult siblings, 18 to 40 years of age, homozygous for the known FAM149B1 c.354_357delinsCACTC (p.Gln118Hisfs*20) variant. Detailed clinical examinations were performed including ocular and gait analyses, skeletal- and neuroimaging. All three patients presented with neurological and oculomotor symptoms since birth and mild skeletal dysplasia in infancy resulting in characteristic gait abnormalities. We document mild skeletal dysplasia, abnormal gait with increased hip rotation and increased external foot rotation, ataxia, variable polydactyly, ocular Duane syndrome, progressive ophthalmoplegia, nystagmus, situs inversus of the retinal vessels, olfactory bulb aplasia, and corpus callosal dysgenesis as novel features in FAM149B1-ciliopathy. We show that intellectual disability is mild to moderate and retinal, renal and liver function is normal in these affected adults. Our study thus expands the FAM149B1-related Joubert syndrome to a mainly neurological and skeletal ciliopathy phenotype with predominant oculomotor dysfunction but otherwise stable outcome in adults. Diagnosis of FAM149B1-related disorder was impeded by segregation of multiple neurogenetic disorders in the same family, highlighting the importance of extended clinical and genetic studies in families with complex phenotypes.

Mitochondrial Dysfunction: A Common Denominator in Neurodevelopmental Disorders?

Mitochondria, the organelles classically seen as the powerhouse of the cell, are increasingly associated with a wide variety of neurodevelopmental disorders. Although individually rare, a myriad of pediatric neurogenetic disorders have been identified in the last few years, thanks to advances in clinical genetic sequencing and data analysis. As this exponential growth continues, mitochondrial dysfunction is increasingly implicated in childhood neurodevelopmental disorders, with clinical presentations ranging from syndromic autism, intellectual disability, and epileptic encephalopathies to childhood onset neurodegeneration. Here we review recent evidence demonstrating mitochondrial involvement in neurodevelopmental disorders, identify emerging mechanistic trends, and reconsider the long-standing question of the role of mitochondria in light of new evidence: causation versus mere association.

Characterizing the Richness of Maternal Input for Word Learning in Neurogenetic Disorders

Promoting language abilities, including early word learning, in children with neurogenetic disorders with associated language disorders, such as Down syndrome (DS) and fragile X syndrome (FXS), is a main concern for caregivers and clinicians. For typically developing children, the quality and quantity of maternal language input and maternal gesture use contributes to child word learning, and a similar relation is likely present in DS and FXS. However, few studies have examined the combined effect of maternal language input and maternal gesture use on child word learning. We present a multidimensional approach for coding word-referent transparency in naturally occurring input to children with neurogenetic disorders. We conceptualize high-quality input from a multidimensional perspective, considering features from linguistic, interactive, and conceptual dimensions simultaneously. Using case examples, we highlight how infrequent the moments of word-referent transparency are for three toddlers with DS during play with their mothers. We discuss the implications of this multidimensional framework for children with DS and FXS, including the clinical application of our approach to promote early word learning for these children.

Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome

Background Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome—a sex chromosome aneuploidy that is known to increase risk for psychopathology. Methods We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. Results Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R2 ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. Conclusions We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. Trial registrations ClinicalTrials.govNCT00001246, “89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls.” Date of registry: 01 October 1989.

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders.

Breaking Boundaries in the Brain—Advances in Editing Tools for Neurogenetic Disorders

Monogenic neurological disorders are devastating, affecting hundreds of millions of people globally and present a substantial burden to individuals, carers, and healthcare systems. These disorders are predominantly caused by inherited or de novo variants that result in impairments to nervous system development, neurodegeneration, or impaired neuronal function. No cure exists for these disorders with many being refractory to medication. However, since monogenic neurological disorders have a single causal factor, they are also excellent targets for innovative, therapies such as gene therapy. Despite this promise, gene transfer therapies are limited in that they are only suitable for neurogenetic disorders that fit within the technological reach of these therapies. The limitations include the size of the coding region of the gene, the regulatory control of expression (dosage sensitivity), the mode of expression (e.g., dominant negative) and access to target cells. Gene editing therapies are an alternative strategy to gene transfer therapy as they have the potential of overcoming some of these hurdles, enabling the retention of physiological expression of the gene and offers precision medicine-based therapies where individual variants can be repaired. This review focusses on the existing gene editing technologies for neurogenetic disorders and how these propose to overcome the challenges common to neurogenetic disorders with gene transfer therapies as well as their own challenges.