Baylor Research Institute

McNeill, N., A. Nasca, A. Reyes, B. Lemoine, B. Cantarel, A. Vanderver, R. Schiffmann and D. Ghezzi (2017). “Functionally pathogenic ears2 variants in vitro may not manifest a phenotype in vivo.” Neurol Genet 3(4): e162.

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OBJECTIVE: To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC). METHODS: Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity. RESULTS: Whole-exome sequencing uncovered compound heterozygous mutations in EARS2, c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an approximately 11% decrease in the oxygen consumption rate and approximately 43% decrease in the maximum respiratory rate in the patient’s skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient’s fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA (SNORD118) responsible for LCC. CONCLUSIONS: Here, we report seemingly pathogenic EARS2 mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant.

Asadollahi, R., M. Zweier, L. Gogoll, R. Schiffmann, H. Sticht, K. Steindl and A. Rauch (2017). “Genotype-phenotype evaluation of med13l defects in the light of a novel truncating and a recurrent missense mutation.” Eur J Med Genet: 2017 Jun [Epub ahead of print].

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A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in approximately 30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

Martin, H. D., A. N. Khoury, R. Schroder, J. Gomez-Hoyos, S. Yeramaneni, M. Reddy and I. James Palmer (2017). “The effects of hip abduction on sciatic nerve biomechanics during terminal hip flexion.” J Hip Preserv Surg 4(2): 178-186.

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Terminal hip flexion contributes to increased strain in peripheral nerves at the level of the hip joint. The effects of hip abduction and femoral version on sciatic nerve biomechanics are not well understood. A decrease in sciatic nerve strain will be observed during terminal hip flexion and hip abduction, independent of femoral version. Six un-embalmed human cadavers were utilized. Three Differential Variable Reluctance Transducers (DVRTs) sensors were placed on the sciatic nerve while the leg was flexed to 70 degrees with a combination of – 10 degrees , 0 degrees , 20 degrees and 40 degrees adduction/abduction. DVRT placement included: (i) under piriformis, (ii) immediately distal to the gemelli/obturator, (iii) four centimeters distal to sensor two. A de-rotational osteotomy to decrease femoral version 10 degrees was performed, and sciatic nerve strain was measured by the same procedure. Data were analyzed with three-way analysis of variance and Bonferroni post-hoc analysis to identify differences in the mean values of sciatic nerve strain between native and decreased version state, hip abduction angle and DVRT sensor location. Significant main effects were observed for femoral version (P = 0.04) and DVRT sensor location (P = 0.01). Sciatic nerve strain decreased during terminal hip flexion and abduction in the decreased version state. An 84.23% decrease in sciatic nerve strain was observed during hip abduction from neutral to 40 degrees in the presence of decreased version at terminal hip flexion. The results obtained from this study confirm the role of decreased femoral version and hip abduction at terminal hip flexion to decrease the strain in the sciatic nerve.

Yahagi, K., E. Ladich, R. Kutys, H. Mori, L. G. Svensson, M. J. Mack, H. C. Herrmann, C. R. Smith, M. B. Leon, R. Virmani and A. V. Finn (2017). “Pathology of balloon-expandable transcatheter aortic valves.” Catheter Cardiovasc Interv: 2017 Jun [Epub ahead of print].

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BACKGROUND: The Placement of AoRtic TraNscathetER Valves trials (PARTNER) showed favorable safety and efficacy versus medical or surgical therapy in inoperable, high, and intermediate surgical risk patients with severe aortic stenosis. However, the biological responses to transcatheter aortic valves have not been well characterized. OBJECTIVES: The aim of this study was to perform pathologic assessment of Edwards SAPIEN transcatheter aortic valves removed either at autopsy or surgically during the PARTNER I and II clinical trials. METHODS: Explanted valves and frame were evaluated for pathologic responses including extent of thrombus, inflammation, neointima, and leaflet degeneration/calcification according to semiquantitative grading by implant duration (90 days). RESULTS: A total of 22 cases (median age 82.0 years, 45% men) were included, with a duration of implantation that ranged from 0 to 1739 days (median duration 16.5 days [interquartile range, 2.8-68.3]). Valve thrombosis resulting in severe aortic stenosis was observed in one case. Moderate leaflet thrombus was seen in 14% of cases (n = 3) and all were asymptomatic. Calcification was seen in two valves: one with severe leaflet calcification had severe aortic stenosis requiring surgical replacement, while the other showed early calcification. Mild structural leaflet changes were exclusively seen in valve implants >90 days. Valve inflammation and thrombus formation was mild in majority of the cases. CONCLUSIONS: Overall, our study demonstrates moderate thrombus formation in 14% and calcification in only 2 valves, >/=4 years duration. In this short-duration study, acceptable durability and biocompatibility of the Edwards SAPIEN transcatheter valve system was demonstrated; however, further studies are required to confirm the significance and application of our findings.

Driver, S., M. Reynolds, M. Douglas and M. Bennett (2017). “Describing weight loss attempts and physical activity among individuals with tbi prior to participation in a weight-loss program.” J Head Trauma Rehabil: 2017 May [Epub ahead of print].

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OBJECTIVE: Describe (1) weight loss history, (2) perceptions about lifestyle changes, and (3) physical activity among a sample of individuals with traumatic brain injury prior to a 12-month lifestyle change program. SETTING: Community-based. PARTICIPANTS: Individuals enrolled in a lifestyle change program, 6 months or more post-traumatic brain injury, body mass index of 25 or greater, 18 to 64 years of age, with physician’s clearance to participate. DESIGN: Convenience sample. MAIN MEASURES: Self-report data were collected before beginning the lifestyle change program including descriptive, weight loss history and physical activity behavior using the Modifiable Activity Questionnaire. RESULTS: The final sample included 22 participants (M age = 46 years) injured a median of 8 years ago. Mean weight was 208.5 lb (SD = 40.2), with average body mass index of 31.84 (SD = 4.4). Since injury, 72.7% reported prior weight loss attempts, with 50% gaining 10 lb or more. All participants indicated high motivation for lifestyle changes. Perceived benefits included feeling better, improving overall health, and increased energy. Barriers included physical health complications. Types of physical activity completed included walking (68%, 180 min/mo) and swimming (32%, 79 min/mo). CONCLUSION: Results indicate that many individuals gained weight since injury and attempted weight loss, demonstrating a need for evidence-based lifestyle interventions. Future research is needed to determine whether individuals with traumatic brain injury are able to achieve and maintain weigh loss through intervention.