Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy

Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder

Delayed contrast extravasation MRI for depicting tumor and non-tumoral tissues in primary and metastatic brain tumors.

The current standard of care for newly diagnosed glioblastoma multiforme (GBM) is resection followed by radiotherapy with concomitant and adjuvant temozolomide. Recent studies suggest that nearly half of the patients with early radiological deterioration post treatment do not suffer from tumor recurrence but from pseudoprogression. Similarly, a significant number of patients with brain metastases suffer from radiation necrosis following radiation treatments. Conventional MRI is currently unable to differentiate tumor progression from treatment-induced effects. The ability to clearly differentiate tumor from non-tumoral tissues is crucial for appropriate patient management. Ten patients with primary brain tumors and 10 patients with brain metastases were scanned by delayed contrast extravasation MRI prior to surgery. Enhancement subtraction maps calculated from high resolution MR images acquired up to 75 min after contrast administration were used for obtaining stereotactic biopsies. Histological assessment was then compared with the pre-surgical calculated maps. In addition, the application of our maps for prediction of progression was studied in a small cohort of 13 newly diagnosed GBM patients undergoing standard chemoradiation and followed up to 19.7 months post therapy. The maps showed two primary enhancement populations: the slow population where contrast clearance from the tissue was slower than contrast accumulation and the fast population where clearance was faster than accumulation. Comparison with histology confirmed the fast population to consist of morphologically active tumor and the slow population to consist of non-tumoral tissues. Our maps demonstrated significant correlation with perfusion-weighted MR data acquired simultaneously, although contradicting examples were shown. Preliminary results suggest that early changes in the fast volumes may serve as a predictor for time to progression. These preliminary results suggest that our high resolution MRI-based delayed enhancement subtraction maps may be applied for clear depiction of tumor and non-tumoral tissues in patients with primary brain tumors and patients with brain metastases

Correlation with time to progression.

<p>The correlation between the late enhancement subtraction maps and time to progression was studied in a small cohort of 13 GBM patients post chemoradiation. Kaplan-Meier curves of time to progression in patients above and below the median of four predictors are shown: Initial fast volume (A), initial enhanced volume (B), initial fast growth rate (C) and initial enhanced growth rate (D). The curves are plotted for each predictor for patients above (black) and below (gray) the median. It can be seen that the initial fast growth rate predictor provides a near-significant difference between the two groups of patients, suggesting this predictor may be a candidate for prediction of time to progression.</p

Newly diagnosed GBM cohort.

<p>List of newly diagnosed GBM patients with post chemoradiation treatment follow-up.</p>*<p>Column #2: Patients were diagnosed with GBM prior to initiation of chemoradiation by histological analysis of either gross tumor resection (GTR), sub-total resection (STR) or stereotactic biopsy samples (STB).</p>*<p>Column #4: Stereotactic samples were taken from locations determined using the late enhancement subtraction maps calculated from the pre-surgical MRIs.</p>*<p>Column #5: In cases where progression was not reached, the duration of follow-up is listed in parenthesis.</p

Examples of progression and pseudoprogression in GBM patients post chemoradiation.

<p>Late enhancement subtraction maps of a patient (#6) with significant increase in the enhancing lesion due to increase in the red volume (A–C) and a patient (#3) with significant increase in the blue component (D–F) with minor changes in the enhancing volume are shown. In the first example, the total enhancing volume has increased by 34% from 3 weeks (A) to 4.2 months (B) post chemoradiation, and then decreased to 33% below the initial volume (C) 9 months post treatment. The blue volume slightly increased by 6% in the first 4 months (A, B) and then significantly decreased to 47% below the initial volume at 9 months (C) while the red volume increased by 51% in the first 4.2 months (A, B) and decreased to 13% above the initial volume by 9 months (C). This patient progressed 11.6 months post treatment. In the second example, the total enhancing volume has increased by 16% from 3 weeks (D) to 2.5 months (E) and then remained 17% above the initial volume (F) 6.5 months post treatment. The blue volume slightly increased by 2% in the first 2.5 months (D,E) and then significantly increased to 57% above the initial volume at 6.5 months (F) while the red volume increased by 39% in the first 2.5 months (D, E) and decreased to 61% below the initial volume by 6.5 months (F). This patient progressed 6.5 months post treatment when he was referred to surgery.</p