Authors :
First Author: Teppei Matsubara, MD, PhD – Athinoula A. Martinos Center for Biomedical Imaging
Presenting Author: Phillip Pearl, – Boston Children’s Hospital, Harvard Medical School
Sheraz Khan, Ph.D. – Athinoula A. Martinos Center for Biomedical Imaging; Padmavathi Sundaram, Ph.D. – Athinoula A. Martinos Center for Biomedical Imaging; Steven Stufflebeam, M.D. – Athinoula A. Martinos Center for Biomedical Imaging; Deniz Ayugun, Clinical Research Assistant – Boston Children's Hospital; Melissa Dibacco, M.D. – Boston Children's Hospital; Jean-Baptiste Roullet, Ph.D. – Washington State University; Phillip Pearl, M.D. – Boston Children's Hospital; Yoshio Okada, Ph.D. – Boston Children's Hospital
Rationale:
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder. In the absence of SSADH, GABA accumulates in the brain, leading to clinical manifestations including developmental delay, hypotonia, ataxia and seizures. Although GABA has been known to be elevated, very little attention has been paid to another type of abnormality. Multiple myelin deficiencies have been identified in post-mortem human analysis of SSADHD patients. However, whether myelin-sensitive physiologic processes are altered in the human SSADHD brain is not yet understood even though cognition clearly requires efficient neuronal signal conduction. Thus, we measured somatosensory evoked magnetic fields (SEF) produced by an electrical stimulation of the median nerve in SSADHD patients to determine functional alterations related to myelin abnormalities.
Methods:
We studied 12 affected patients (age 3–29 years; mean, 12.1 years), and eight healthy volunteers (age 6–24 years; mean, 16.8 years). MEG was obtained at Martinos Center using a whole-head MEG system (MEGIN, Helsinki, Finland). The median nerve was electrically stimulated at the wrist with an inter-stimulus interval of 3s. The peak latency of the initial component (N20m) was measured on the contralateral hemisphere, and its reliability was confirmed by the topographical pattern in the sensor-space analysis.
Results:
The average latency of N20m in SSADHD patients (n = 12) was 21.1 ± 3.0 ms (standard deviation) while that of controls (n = 8) was 17.8 ± 2.1 ms. The latency was longer in SSADHD patients than that in controls when controlled for ages (p = 0.05).
Conclusions:
The delayed latency of SEF in SSADHD patients suggests that myelination is reduced in this metabolic disease. This is concordant with a mouse SSADHD model which showed significantly reduced myelination. It is necessary to directly validate using an anatomical technique that myelin sheath is indeed thinner in SSADHD patients as suggested by our data.
Funding:
Overseas Research Fellow of Japan Society for the Promotion of Science; NIH 5R01HD091142-05 (Natural History of SSADHD); NIH U01 EB023820.