Kathryn J. Swoboda, MD
Dr. Swoboda received her medical degree at The Northwestern Feinberg School of Medicine. She completed her neurology residency at the Harvard Longwood Neurology Program at the Brigham and Women’s Hospital, and additional subspecialty training in Clinical Genetics and Neuromuscular disease/ Neurophysiology at Boston Children’s Hospital and the Lahey-Hitchcock Clinic. Dr. Swoboda’s research and clinical activities are dedicated to the diagnosis and treatment of neurologic disorders, especially neuromuscular diseases, movement disorders, and neurodegenerative disorders with childhood-onset.
Questions being addressed in the lab
- Targeted studies in patients and in patient-derived samples and tissues to clarify disease pathogenesis and identify novel therapeutic targets for rare neurogenetic diseases.
- Identify and validate predictive, prognostic and disease responsive biomarkers in patients to facilitate presymptomatic genetic diagnosis and treatment for infantile and childhood onset neurodegenerative disorders.
- Design clinical studies to understand disease pathogenesis and develop and test novel therapeutic approaches for children and adults with rare neurogenetic or metabolic disorders.
Projects underway to answer these questions
Diagram of our current research projects and research questions to generate results and publications. The clinical data show the path to research human samples to results for a more biochemical and informative data. Additional steps such as RNA seq and gene profiling are needed to conduct our research projects in combination with the clinical data.
We identified a de novo missense mutation in NALCN, c.1768C.T, in an infant with a severe neonatal lethal form of the recently characterized CLIFAHDD syndrome (congenital contractures of the limbs and face with hypotonia and developmental delay). When engineered into the C elegans ortholog, this mutation results in a severe gain-of-function phenotype, with hypercontraction and uncoordinated movement. We engineered 6 additional CLIFAHDD syndrome mutations into C elegans and the mechanism of action could be divided into 2 categories: half phenocopied gain-of-function mutants and half phenocopied loss-of function mutants.
We examined the impact of fasting and glucose tolerance on selected metabolic variables in children with spinal muscular atrophy (SMA) type II in a well state, secondary to reports of glucose regulation abnormalities in SMA. Based on the dual-energy x-ray absorptiometry scan, all 6 children were variably obese at baseline. All 6 exhibited hyperinsulinemia, and 3 of 6 met formal American Diabetes Association criteria for impaired glucose tolerance. According to homeostatic insulin resistance calculations, 5 of the 6 participants were insulin-resistant. All 6 participants tolerated a monitored fast for 20 hours without hypoglycemia (blood glucose <54 mg/dL). Free fatty acid levels increased significantly from prefasting to postfasting, whereas levels of several plasma amino acids decreased significantly during fasting.
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers’ questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported.