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Our objectives are to report on the outcomes of adrenal insufficiency (AI) and cerebral ALD (cALD) in children diagnosed with X-linked adrenoleukodystrophy (ALD) identified by newborn screening (NBS) in Minnesota in the first 5 years following initiation of NBS in 02/2017. A retrospective chart review was conducted for children diagnosed with ALD via Minnesota NBS from 02/06/2017 through 02/06/2022. Data reviewed included newborn screening data, diagnostic very long chain fatty acid levels, ABCD1 molecular testing results, serial measurements of ACTH and cortisol, and serial brain MRI results. Thirty-two boys and 11 girls were molecularly and/or biochemically confirmed to have ALD. Of these 32 boys, six (2-7 years; median age:18 months) developed AI. Two boys developed cALD and underwent stem cell transplantation, one of whom also has been diagnosed with AI. All the pathogenic/likely pathogenic variants detected during the first 5 years had initial C26:0 lysophosphatidylcholine (C26:0 lysoPC) values over 0.3 μmol/L at the time of newborn screening. The addition of ALD to NBS in Minnesota has allowed for early detection of asymptomatic AI in six young patients and asymptomatic cALD in two patients. Data from our study shows a positive correlation between high newborn screening LysoPC levels and variant pathogenicity., (© 2025 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Background: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability., Methods and Results: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes ( ACAN and LTBP4 ) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size., Conclusions: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Maple syrup urine disease (MSUD) is an intoxication-type inherited metabolic disorder in which hyperleucinemia leads to brain swelling and death without treatment. MSUD is caused by branched-chain alpha-ketoacid dehydrogenase deficiency due to biallelic loss of the protein products from the genes BCKDHA, BCKDHB, or DBT, while a distinct but related condition is caused by loss of DLD. In this case series, eleven individuals with MSUD caused by two pathogenic variants in DBT are presented. All eleven individuals have a deletion of exon 2 (delEx2, NM_001918.3:c.48_171del); six individuals are homozygous and five individuals are compound heterozygous with a novel missense variant (NM_001918.5:c.916 T > C [p.Ser306Pro]) confirmed to be in trans. Western Blot indicates decreased amount of protein product in delEx2;c.916 T > C liver cells and absence of protein product in delEx2 homozygous hepatocytes. Ultrahigh performance liquid chromatography-tandem mass spectrometry demonstrates an accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes. Individuals with these variants have a neonatal-onset, non-thiamine-responsive, classical form of MSUD. Strikingly, the entire cohort is derived from families who immigrated to the Washington, DC, metro area from Honduras or El Salvador suggesting the possibility of a founder effect., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis. He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years). Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I). The FDX2 gene encodes a mitochondrial protein, ferredoxin 2, that is involved in the biogenesis of Fe-S clusters. Biallelic pathogenic variants in FDX2 have previously been associated with episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy. Only two cases with FDX2-related rhabdomyolysis as a predominant feature have been reported in medical literature. Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis. He does not have optic atrophy or leukoencephalopathy. This is the oldest patient reported with FDX2-related disorder and he has significantly elevated CK during episodes of rhabdomyolysis. In addition, we describe untargeted global metabolomic findings during an episode of metabolic decompensation, shedding light on the biochemical pathway perturbation associated with this ultra-rare genetic disorder., (© 2021 Wiley Periodicals LLC.)

Williams-Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26-28 genes. An estimated 2-5% of patients have "atypical" deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p = .001), with higher (more impaired) scores for social motivation (p = .005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)