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The ‘Cerebral’ In Organic Acidurias: From Basics To Treatment

Introduction, biochemical basis and pathogenetic aspects of Cerebral OA using GA1 as a prototype
Asuri Prasad

Organic acidurias (OAD) are a heterogeneous group of inherited disorders resulting in life-threatening “intoxications” or encephalopathies with a large burden of neurological sequelae.  The disorders involve genes that encode enzymes that regulate amino acid catabolism. They include the systemic OAs, the cerebral OAs, and the ketogenic/ketolytic ones. The biochemical basis of these disorders involves several pathways and are characterized by the accumulation of organic acids, CoA, glycine esters generated upstream of the enzymatic block.  Single or multiple organ systems may be affected in this group of metabolic disorders. The clinical phenotypes are often highly variable and range from encephalopathy to movement disorders, epilepsy, ataxia, and intellectual and motor disability. GCDH deficiency represents a prototype amongst the OAD.  The speaker will give a brief introduction to the biochemical basis for OAD, and delve into the genetics and neuropathogenesis of providing the basis for the development of interventions in isolated aboriginal population with GCDH deficiency in Canada.

 

Neurological presentations and case illustrations of cerebral OA
Juan Darío Ortigoza-Escobar

OAD’s are a distinct subset of neurometabolic disorders that are often missed clinically as well as in the academic programs. This section will discuss the neurological presentation of cerebral OA, ranging from the milder phenotype to acute metabolic crisis, late-onset phenotypes, highlighting the associated movement disorder and other neurological (seizures, ID, psychiatric symptoms, etc.) and non-neurological symptoms. Pediatric neurologists and researchers will familiarize themselves of the state of the art in terms of therapeutic interventions in these disorders, which may be partially or totally preventable. Several of them present as common childhood neurological and neurodevelopmental problems such as developmental delay, movement disorders, cerebral palsy and epilepsy, and hence are likely to present to paediatricians. Many of these disorders include later age of onset in presentation, thus of significance to the audience of adult neurologists.Hence, this symposium will provide a timely update for this purpose.

 

Neuroimaging aspects of cerebral organic acidurias
Ajay Taranath

Neuroimaging is complementary to the clinical examination and lab tests in the diagnosis of OAD. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. Advanced techniques such as Diffusion tensor imaging and Magnetic resonance spectroscopy (MRS) will help narrow down possibilities. Involvement of the basal ganglia, thalami, brainstem, dentate nuclei is usually seen in addition to the involvement of the cerebral and cerebellar cortices and subcortical white matter. Whilst most of these are manifestations can be expected in OAD’s, the speaker will present imaging findings with identification of distinctive and discriminating features that will aid learners to develop a better understanding of the utility of neuroimaging in OAD.

 

Therapeutic interventions and challenges in the management of Organic acidemia
Arushi Saini

It is recognized that OAD’s continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. In this session, we attempt to discuss the overall management approach to organic acidemia, with a special focus on the cerebral organic acidemia. The speaker will focus shall be on recent published guidelines and interventions targeting pathophysiology (e.g., nutraceutical, pharmacological, surgical, etc.) of these disorders. Although there are gaps in patient care between developed and developing countries, yet with rapid economic progress and for sustainable developmental goals, it is imperative for the wider audience of pediatric care providers to be familiar with the state of the art in terms of therapeutic interventions in these disorders, which may be partially or totally preventable. This symposium will cover the biochemical and pathogenetic aspects in children with a focus on the cerebral and neurological presentations of selected OA disorders (e.g Glutaric aciduria Type 1, L2 and D2 OH glutaric aciduria, Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency 3-hydroxyisobutyryl-CoA hydrolase deficiency 3-hydroxyisobutyrate dehydrogenase deficiency).