Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a recently identified rare disorder from the neurodegeneration with brain iron accumulation (NBIA) group¹. Symptoms include progressive spasticity, motor neuropathy, cognitive dysfunction, movement disorders, and optic atrophy. MPAN is putatively an autosomal recessive disorder caused by mutation in the c19orf12, a gene with yet unknown function. Information about possible subclinical changes in heterozygotes is lacking. Brain MRI in patients typically shows iron deposits in globus pallidus (GP) and substantia nigra (SN) without other abnormalities². Yet, spastic paresis heralding the clinical picture suggests impairment of corticospinal pathway. The aim of this study was to apply ¹H MR spectroscopy (MRS) in the white matter (WM) of the precentral region and quantitative susceptibility mapping (QSM) of basal ganglia at ultra-high (7T) field in patients (homozygotes) and non-manifesting heterozygotes to elucidate underlying metabolic and structural changes of MPAN.All scans were performed on a 7T whole-body system (Siemens Healthcare, Erlangen, Germany) using a 24 channel RF head coil (Nova Medical Inc., Wilmington, MA). Three patients (18, 19, 23 yrs), 9 heterozygotes (50.4±9.8 yrs), and 9 matched control subjects (42.3±17.8 yrs) were scanned (one control subject was excluded from MRS analysis due to poor data quality). For MRS, localized RF calibration was performed, and first- and second-order shims were adjusted using a vendor-supplied algorithm. Single volume data from the left precentral WM were acquired using the spin echo full intensity acquired localized (SPECIAL) MRS technique^3,4 with the following scan parameters: VOI = 20x20x20 mm³, TR/TE = 9000/11 ms, number of averages = 64, and Tacq = 512 ms. Metabolite quantification was performed using LCModel⁵. Resulting concentrations were corrected for the CSF content of each VOI. QSM maps were reconstructed from 3D gradient echo (GRE) acquisitions with TR/TE = 30/15.3 ms, flip angle = 30º, in-plane resolution = 0.3x0.3 mm², slice thickness = 1 mm, BW = 180 Hz/pixel. Phase images were reconstructed offline using a virtual reference coil approach⁶. The QSM reconstruction was performed using the STI Suite 2.2 and consisted of Laplacian unwrapping, variable SHARP filtering (starting radius=10 mm) and iLSQR inversion⁷. ROIs were manually drawn in GP and SN. Results from MRS and QSM were compared for control subjects and heterozygotes and patients, respectively using a non-parametric Mann-Whitney test.Localized shimming resulted in water linewidths of 11.4 ± 0.9 Hz, 11.4 ± 0.9 Hz, and 12.2 ± 0.4 Hz for controls, heterozygotes, and patients, respectively. The high signal-to-noise ratio (SNR) of the spectra (Fig.1) allowed the quantification of 13 individual and 5 combined metabolites with Cramér-Rao lower bounds (CRLBs) < 20% for all three groups, including GABA, glutamine (Gln), glutamate (Glu), and lactate (Lac). No significant differences between metabolite concentrations for heterozygotes and controls were detected, where only for total choline (tCho) the Mann-Whitney test result exactly yielded the limits of critical values. Performing a two-tailed Student’s t-test for tCho in addition yielded p>0.14 though, rather indicating no significant difference. Comparing patients versus controls resulted in significant increases for Glu, taurine (Tau), and Glu+Gln. Mean concentrations from heterozygotes and controls are shown together with the individual results for patients in Table 1.In this study, differences in metabolite quantification for patients versus controls were observed. These have to be considered with caution due to the small number of patient cases. The increase in Tau might be partially attributed to the relatively young age of the patient group, since Tau decreases with age⁸. However, for the first time, using MRS increased Glu levels in MPAN patients were detected. This suggests a dysfunctional regulation of excitatory neurotransmission. No differences between heterozygotes and controls with respect to results from 7T MRS and QSM were found indicating that one functional copy of gene c19orf12 is sufficient to prevent iron accumulation and metabolic changes in the brain of heterozygotes. In contrast, quantitative measurements suggest that iron concentration is 3-4 times increased in GP and SN of MPAN patients compared to controls.Using MRS and QSM at 7T allowed a more detailed characterization of MPAN heterozygotes and patients. While no abnormalities were detected in heterozygotes, metabolic changes in homozygotes detected by MRS indicated an underlying mechanism related to neurotransmission in corticospinal pathway.