Computational structural genomics and clinical evidence suggest BCKDK gain-of-function may cause a potentially asymptomatic maple syrup urine disease phenotype.

Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acid metabolism caused by a defect in the branched-chain α-ketoacid dehydrogenase (BCKD) complex (OMIM #248600). The hallmark presentation is encephalopathic crisis in neonates, but can also present with metabolic decompensation, developmental delays, and feeding difficulties. Biochemical evidence for MSUD includes elevated branched-chain amino acids (BCAA) and the pathognomonic presence of alloisoleucine. The BCKD complex contains several subunits associated with autosomal recessive MSUD, while its regulatory proteins have less well-defined disease associations. We report on two families with the same BCKDK variant (c.1115C>G (p.Thr372Arg)). Probands were detected on newborn screening and demonstrated biochemical evidence of MSUD. The variant was identified in reportedly asymptomatic parents and additional family members who had elevated BCAA and alloisoleucine, following an autosomal dominant pattern of inheritance. To better define the functional effect of the variant on the kinase, we completed molecular modeling using sequence-based (2D), structural-based (3D), and dynamic-based (4D) analyses. The BCKDK variant modeling indicated a gain-of-function which leads to impaired BCAA catabolism consistent with the biochemical evidence in this cohort. Combining the evidence gained from molecular modeling with the absence of metabolic decompensation in our patients and several adult family members, despite encountering stressors typically problematic in classic MSUD, we suggest that heterozygous gain-of-function variants in BCKDK may represent a novel biochemical phenotype of MSUD with a benign clinical course.

Perspectives of genetic counseling supervisors regarding genetic counseling students' attainment of practice-based competencies in clinical care through remote supervision.

There are limited studies regarding the attainment of the Accreditation Council for Genetic Counseling Practice-Based Competencies by genetic counseling students who complete clinical rotations in an in-person setting versus in a remote setting that incudes telephone and/or video patient encounters. This study explored the perceptions of 17 patient-facing genetic counselors who had served as supervisors for genetic counseling students regarding student attainment of practice-based competencies in in-person compared to remote rotations. Participants were recruited through an American Board of Genetic Counseling eblast and were required to have at least 2 years of clinical experience and experience providing genetic counseling supervision for at least one in-person rotation and one remote rotation. Four focus groups were created comprising genetic counselors from various practice disciplines. Discussion focused on potential differences and similarities in supervisor perceptions of student attainment of each clinical practice-based competency, and whether there were any concerns about students being able to attain each competency in remote rotations. Overall, participants discussed that genetic counseling students' attainment of clinical competencies through remote rotations was comparable to in-person rotations; however, 15 themes were identified illustrating differences reported by participants in how they observed these skills being performed by students in in-person versus remote clinical settings. The findings of this study highlight important considerations when developing a remote rotation, as well as ways in which certain clinical skills may be further enhanced through a combination of both in-person and remote clinical experiences. A noted limitation of remote rotations is that students have less of an opportunity to interact with other providers, and so may require other opportunities for interprofessionalism and to understand their role as part of a larger organization. Further study is required to elucidate differences between telephone and video clinics, as well as potential differences pertaining to various specialty areas of practice.

Telemedicine in the Amish and Mennonite communities of Wisconsin.

The Plain Community (PC) is a medically underserved group found predominantly in the northeastern and midwestern USA. Due to the community's founder population with few converts and infrequent outside marriage, metabolic and genetic disorders are more prevalent. Individuals in the PC experience geographic, financial, and cultural barriers when accessing healthcare. In Wisconsin, a collaboration between clinicians at a rural community health clinic and the academic medical clinic established an outreach clinic for medical genetics located in a rural location closer to a Wisconsin PC which consists of both Amish and Mennonite communities. However, patients with acute medical concerns requiring more urgent genetics care must travel to the academic center. Telemedicine (TM) is a technology that increases access to healthcare, often reducing financial and travel barriers. Using survey tools, we explored whether TM could be used to provide genetic services to individuals in the Wisconsin PC at an outreach clinic. Results indicated that 36% of survey participants responded favorably to receiving services by TM at a clinic designed for the PC. Members of the Mennonite community are significantly more likely to consider receiving services via TM than those of the Amish community. The results of the surveys indicate potential utility of TM at the outreach clinic as alternative way to improve access to genetic and other subspecialty services for the PC.

Newborn Screening for Inherited Metabolic Disorders: Early Identification and Long-Term Care for Patients in the Plain Community, Wisconsin, 2011-2017.

The Plain community is the fastest-growing religious minority in Wisconsin. This community has a high incidence of genetic disorders, many of which are identifiable through newborn screening. We describe efforts by the Wisconsin Newborn Screening Program (WNSP) to improve health care in the Plain community by targeting early identification of, and intervention for, patients with inherited metabolic disorders. WNSP formed partnerships with families and health care providers to increase awareness of screening procedures and the intended benefits of screening, modify testing algorithms to enhance detection, and establish medical homes for patients with confirmed disorders. The estimated number of Plain newborns screened increased by 25.5% during the study period, from 547 in 2011 to 736 in 2017; 122 persons underwent carrier testing, and 143 newborns received second-tier testing. From 2014 to 2017, affected patients received 71 metabolic evaluations in their community medical home without travel to major health centers. This article demonstrates how a comprehensive public health program can help increase screening rates, enhance detection, and establish follow-up care in a hard-to-reach religious community. A key lesson learned was the importance of communication among all stakeholders to develop an effective public health program.

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy.

Ethylmalonic encephalopathy (EE) is a rapidly progressive autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the ETHE1 gene that encodes the mitochondrial sulfur dioxygenase. It is characterized by neurodevelopmental delay and regression, pyramidal and extrapyramidal signs, recurrent petechiae, chronic diarrhea, and orthostatic acrocyanosis. Laboratory findings include elevated serum levels of lactate and C4-C5 acylcarnitines, and elevated urinary excretion of ethylmalonic acid and C4-C6 acylglycines, notably isobutyrylglycine and 2-methylbutyrylglycine. These findings are attributed to deficiency of the mitochondrial sulfur dioxygenase resulting in toxic accumulation of hydrogen sulfide metabolites in vascular endothelium and mucosal cells of the large intestine. Medical management has thus far been directed toward decreasing the accumulation of hydrogen sulfide metabolites using a combination of metronidazole and N-acetylcysteine. More recently, orthotopic liver transplant (OLT) has been reported as a new therapeutic option for EE. Here, we report two additional cases of EE who achieved psychomotor developmental improvement after 7- and 22-months following OLT. The second case serves as the longest developmental outcome follow-up reported, thus far, following OLT for EE. This report provides additional evidence to validate OLT as a promising therapeutic approach for what was considered to be a fatal disease.

Genotypes of patients with phenylalanine hydroxylase deficiency in the Wisconsin Amish.

In the Plain Community, there is an increased frequency of genetic disorders including phenylalanine hydroxylase (PAH) deficiency. Common pathogenic variants have been observed due to founder effect and closed community. This study obtained genotypes of 12 Plain individuals with PAH deficiency, identified through newborn screen or diagnosed by symptomatic presentation, who are receiving medical care at the University of Wisconsin metabolic clinic. Genotype and phenotypic data were evaluated to characterize genotype-phenotype correlations. Results can inform the need for confirmatory testing for the disorder and provide a better understanding of the biochemical phenotype, which may help with management.