Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset.For new cases (n = 184), our resulting clinically relevant detection rate remained *Kathie J. Ngo and Jessica E. Rexach contributed equally to this work. ORCIDJennifer E. Posey http://orcid.org/0000-0003-4814-6765 James R. Lupski http://orcid.org/0000-0001-9907-9246 Brent L. Fogel http://orcid.org/0000-0001-9831-1576 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ngo KJ, Rexach JE, Lee H, et al. A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders. Human Mutation. 2020; 41:487-501. https://doi.

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Pigs have become important animal models in voice research. Several objective parameters exist to characterize the pig voice, but it is not clear which of them are sensitive to the impaired voice quality after laryngeal injury or surgery. In order to conduct meaningful voice research in pigs, it is critical to have standard functional voice outcome measures that can distinguish between normal and impaired voices. For this reason, we investigated 17 acoustic parameters before and early after surgery in three Yucatan mini pigs. Four parameters showed consistent changes between pre- and post-surgery recordings, mostly related to decreased spectral energy in higher frequencies after surgery. We recommend two of these, 50% spectral energy quartile (Q50) and Flux, for objective functional voice assessment of pigs undergoing laryngeal surgery. The long-term goal of this process is to enable quantitative voice outcome tracking of laryngeal surgical interventions in porcine models.

Background Partial gland ablation (PGA) is a new option for treatment of prostate cancer (PCa). Cryotherapy, an early method of PGA, has had favorable evaluations, but few studies have employed a strict protocol using biopsy endpoints in men with clinically significant prostate cancer (csPCa). Methods 143 men with unilateral csPCa were enrolled in a prospective, observational trial of outpatient PGA‐cryotherapy. Treatment was a 2‐cycle freeze of the affected prostate part. Participants were evaluated with MRI‐guided biopsy (MRGB) at baseline and at 6 months and 18 months after treatment. Absence of csPCa upon MRGB was the primary endpoint; quality‐of‐life at baseline and at 6 months after treatment was assessed by EPIC‐CP questionnaires in the domains of urinary and sexual function. Results Of the 143 participants, 136 (95%) completed MRGB at 6 months after treatment. In 103/136 (76%), the biopsy revealed no csPCa. Of the 103, 71 subsequently had an 18‐month comprehensive biopsy; of the 71 with 18‐month biopsies, 46 (65%) were found to have no csPCa. MRI lesions became undetectable in 96/130 (74%); declines in median serum PSA levels (6.9 to 2.5 ng/mL), PSA density (0.15 to 0.07), and prostate volume (42 to 34cc) were observed (all p < 0.01). Neither lesion disappearance on MRI nor PSA decline correlated with biopsy outcome. Urinary function was affected only slightly and sexual function moderately. Conclusion In the near to intermediate term, partial gland ablation with cryotherapy was found to be a safe and moderately effective treatment of intermediate‐risk prostate cancer. Eradication of cancer was better determined by MRI‐guided biopsy than by MRI or PSA.

SYNOPSIS A case of transient global amnesia in a nine year old child with a history of recurrent episodes of vertigoand a family history of migraine headache is described. The possibility that acute confusional state inchildren, presenting as transient global amnesia may represent a variant of basilar migraine is discussed.

ObjectivePatients with advanced laryngeal cancer are typically presented with divergent treatment options, namely chemoradiation versus total laryngectomy. This study aims to understand general perspectives of the factors involved in this decision‐making process.MethodsSurveys were constructed using specialized conjoint analysis software. Seven attributes integral to the decision‐making process for advanced laryngeal cancer treatment were included.ResultsThree hundred one healthy adult volunteers completed the decision‐making program. The relative impact of each treatment attribute on decision making across all participants was scored with an average importance score (standard deviation) as follows: Lifespan 22.2% (±8.5), Voicing 21.4% (±5.9), Swallowing 19.1% (±7.3), Cancer Cure 14.9% (±6.2), Mode of Breathing 11.0% (±3.7), Self‐Image 6.7% (±2.9), and Treatment Type 4.8% (±3.0).ConclusionsGeneral public opinion ranked lifespan, voicing, and swallowing aspects as similarly important, and all were ranked more important than probability of cure. These data demonstrate a variety of priorities among participants and the need for tailored discussions when determining treatment choice for advanced laryngeal cancer.Level of EvidenceLevel 4.

INTRODUCTION AND OBJECTIVE: We sought to determine the value of MRI and serum PSA levels in prediction of targeted biopsy results after partial gland ablation (PGA) of intermediate-risk prostate cancer (PCa) using cryotherapy (CRYO). METHODS: In a prospective, observational trial (NCT03503643), 143 men with unilateral PCa (all>GG2) were enrolled. PSA and MRI-guided biopsy (MRGB) was performed before and after PGA with CRYO. CRYO treatment was a 2-cycle freeze of the affected prostate part using argon gas delivered via transperineal needles under image guidance. Participants underwent MRI/US fusion biopsy at baseline to determine eligibility; at 6 months to determine technical success; and at 18 months. Fusion MRGB in follow-up at 6 and 18 months employed tracking technology (JAMA Open: 31509206). Successful ablation[absence of PCa >GG2 on MRGB. Effects on urinary and sexual function were studied via EPIC-CP. RESULTS: 95% of enrollees (136/143) completed f/u MRGB at 6 mo; 103 had a successful ablation (74%). Of the 103, 71 then had 18mo f/u MRGB; success rate at 18 mo was 46/71 (65%); among 25 failures at 18 months, PCa was ipsilateral in 8, contralateral in 12, and bilateral in 5. Baseline MRI lesions (PIRADS>3) disappeared post-CRYO in 96/130 men (74%); PCa was found in 22/96 (23%) with no lesion and 11/34 (32%) with lesions (p[NS). In a mult-variate analysis, lesion diameter was the only parameter related to biopsy outcome. PSA levels were similar (p[NS) before and after CRYO in successful and failed treatments (FIGURE), as was PSA density. After CRYO, urinary function changed but little, or improved; overall sexual function decreased in 53/143 (39%), but only 10/143 men reported a severe decrement (>6 point decline). CONCLUSIONS: In the near to intermediate term, PGA with cryotherapy is a safe and moderately effective treatment of intermediate-risk PCa, when outcome is judged by MRGB. Neither PSA nor MRI, at baseline or during follow-up, appear reliable as indicators of post-treatment tissue findings. We postulate the treatment per se alters prostate anatomy and physiology in a manner that obscures a relationship between either test and pathological outcome.