Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3–4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Background and Objectives To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. Methods This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy in individuals who were diagnosed with and received care for EDMD, LGMD, CMD, and DD from January 1, 2008, through December 31, 2016, in the 6 areas of the United States covered by the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). Variants of unknown significance (VUSs) from the original genetic test reports were reanalyzed for changes in interpretation. Results Among 243 individuals with definite or probable muscular dystrophy, LGMD was the most common diagnosis (138 cases), followed by CMD (62 cases), DD (22 cases), and EDMD (21 cases). There was a higher proportion of male individuals compared with female individuals, which persisted after excluding X-linked genes (EMD) and autosomal genes reported to have skewed gender ratios (ANO5, CAV3, and LMNA). The most common associated genes were FKRP, CAPN3, ANO5, and DYSF. Reanalysis yielded more definitive variant interpretations for 60 of 144 VUSs, with a mean interval between the original clinical genetic test of 8.11 years for all 144 VUSs and 8.62 years for the 60 reclassified variants. Ten individuals were found to have monoallelic pathogenic variants in genes known to be primarily recessive. Discussion This study is distinct for being an examination of 4 types of muscular dystrophies in selected geographic areas of the United States. The striking proportion of resolved VUSs demonstrates the value of periodic re-examinations of these variants. Such re-examinations will resolve some genetic diagnostic ambiguities before initiating repeat testing or more invasive diagnostic procedures such as muscle biopsy. The presence of monoallelic pathogenic variants in recessive genes in our cohort indicates that some individuals with muscular dystrophy continue to face incomplete genetic diagnoses; further refinements in genetic knowledge and diagnostic approaches will optimize diagnostic information for these individuals.

Adrenoleukodystrophy (ALD) is caused by pathogenic variants in the ABCD1 gene, encoding for the adrenoleukodystrophy protein (ALDP), leading to defective peroxisomal β-oxidation of very long-chain and branched-chain fatty acids (VLCFA). ALD manifests in both sexes with a spectrum of phenotypes, but approximately 35% of affected males develop childhood cerebral adrenoleukodystrophy (CCALD), which is lethal without hematopoietic stem cell transplant performed before symptoms start. Hence, ALD was added to the Recommended Uniform Screening Panel after the successful implementation in New York State (2013–2016). To date, thirty-five states have implemented newborn screening (NBS) for ALD, and a few programs have reported on the successes and challenges experienced. However, the overall impact of NBS on early detection of ALD has yet to be fully determined. Here, we conducted a retrospective analysis of VLCFA testing performed by our reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA) over 10 years. Rate of detection, age at diagnosis, and male-to-female ratio were evaluated in patients with abnormal results before and after NBS implementation. After NBS inclusion, a significant increase in abnormal results was observed (471/6930, 6.8% vs. 384/11,670, 3.3%; p < 0.0001). Patients with ALDP deficiency identified via NBS were significantly younger (median age: 30 days vs. 21 years; p < 0.0001), and males and females were equally represented. ALD inclusion in NBS programs has increased pre-symptomatic detection of this disease, which is critical in preventing adrenal crisis as well as the severe cerebral form.