Study Indicates Newborn Screening for Duchenne Muscular Dystrophy Can be Implemented by Birth Hospitals and May Lead to Improved Outcomes

Parents of babies born at the Brigham are now offered voluntary and free newborn screening for Duchenne Muscular Dystrophy (DMD), the most common pediatric muscular dystrophy condition. This screening program allows an opportunity for early initiation of recently approved U.S. Food & Drug Administration (FDA) therapies that may improve outcomes for the condition, according to the research team. DMD affects 300,000 children worldwide and about 15,000 American children, and primarily occurs in male newborns. Involving impaired function of the dystrophin protein, which normally protects muscle cells from contraction-induced damage, the condition manifests as clumsiness and delayed motor milestones in children aged three to six years and can lead to muscle weakness, respiratory insufficiency, cardiac failure, and premature death. In July 2021, the Brigham became the first birth hospital in the U.S. to implement this hospital-based screening program, which is supported by a gift from the non-profit CureDuchenne. The team found that 80 percent of parents agreed to it and over 2,400 babies have been screened to date. The screening algorithm combines the use of an FDA approved immunoassay for Creatine Kinase (CK) and reflex next-generation sequencing of the DMD gene when CK elevation is detected. When diagnosed early, those at risk for DMD can begin exon skipping therapy and steroidal therapeutics at an earlier age, which may improve long-term outcomes.

“We expect the experience from this screening effort will serve as a model that will allow further expansion to other hospitals and health care systems until universal public health screening is established,” said Richard Parad, MD, MPH, of the Departments of Pediatric Newborn Medicine and Newborn Genetic Medicine.

Read more in International Journal of Neonatal Screening.

New Bioengineering Approach Replicates Rare Kidney Tumor, Opens Path for Future Therapies

Researchers at the Brigham have designed a bioengineering strategy to study the in vivo mechanisms of a kidney tumor called renal angiomyolipoma (AML), by transplanting human kidney organoids that replicate AML into immunodeficient rats. AML is found in 80 percent of patients with Tuberous Sclerosis Complex (TSC), an incurable genetic disease that causes tumor growth in various organs. AML often leads to kidney failure or premature death caused by spontaneously bleeding vascular aneurysms. The understanding of AML biology has been greatly limited by the lack of appropriate experimental models. The transplanted organoids used in this study originated from human-induced pluripotent stem cells (hiPSCs), somatic cells that can be differentiated into many types of tissue, taken from TSC patients.  The research team tested rapamycin-loaded nanoparticles as a treatment for AML. Locally delivered nanoparticles rapidly shrank the transplanted organoids without affecting the healthy kidney, improving upon current rapamycin treatments, which only partially shrink kidney AMLs in TSC patients who often require life-long treatment.

“Our new human AML organoid transplant model is an innovative and scalable tissue-bioengineering strategy for modeling rare kidney disease in vivo,” said Dario Lemos, PhD, an assistant professor at Harvard Medical School and a principal investigator in the Brigham’s Renal Division. “We expect that this model may become a widely-used experimental platform for the study of disease mechanisms and for the development of new therapies targeting these tumors.”

Read more in Nature Communications.

Study Indicates Form of Kidney Disease Caused by Autoantibodies Against Crucial Protein

Autoantibodies against nephrin, a critical protein in the kidney filtration barrier, contribute to non-congenital acute nephrotic syndrome (NS) due to a condition termed “minimal change disease,” according to a recent study by researchers at the Brigham. Non-congenital NS, which affects both adults and children, can lead to elevated protein levels in the urine, deterioration of the kidney filtration barrier, and even kidney failure. However, little is known about its causes, leading to its designation as “The Holy Grail of Kidney Disease.” Because of similarities in structural changes between non-congenital NS and the skin-blistering autoimmune condition pemphigus, the research team hypothesized that circulating autoantibodies against nephrin weaken the connections among specialized kidney cells called podocytes and leads to a more porous kidney filter. When the researchers examined 62 serum samples from the Nephrotic Syndrome Study Network (NEPTUNE) of patients with non-genetic forms of nephrotic syndrome— roughly two-thirds children — they found nearly 30 percent (in similar proportions across children and adults) displayed these autoantibodies, compared to only 2 percent of control samples. In addition, of nine patients with minimal change disease who had a kidney biopsy reviewed at the Brigham and evidence of autoantibodies binding to the kidney filtration barrier, all displayed these circulating autoantibodies in serum.

“Our discovery adds fundamental insights into the causes of a disease that has been poorly understood for decades,” said Astrid Weins, MD, PhD, of the Department of Pathology. “Future studies will be needed to establish the prevalence of autoantibodies in all forms of non-congenital NS. Nevertheless, our work allows us to molecularly define those patients who stand to benefit most from the development of new, targeted therapeutic strategies for the disease.”

Read more in the Journal of the American Society of Nephrology.

New Grading System for Meningiomas Improves Prediction of Long-Term Outcomes

A joint research team from the Brigham and the Dana Farber Cancer Institute have developed an Integrated Grade for meningiomas, the most common primary brain tumors in adults. This new system for predicting the behavior of meningiomas adds valuable information to the longstanding grading system developed by the World Health Organization (WHO). The WHO’s meningioma index relies primarily on features identified by microscopic inspection of tumor tissues. Variability exists in how these characteristics are interpreted by pathologists and in how they manifest in each patient’s tumor. The new system uses genetic and molecular evidence in addition to tissue inspection and was developed by evaluating nearly 700 meningioma patients. The Integrated Scale reclassified nearly one-third of meningiomas into higher or lower-risk categories and significantly improved upon the WHO’s scale in terms of ability to predict tumor recurrence.

“Given the high incidence of meningiomas globally, the framework we present would influence the care of thousands of meningioma patients worldwide,” noted corresponding authors Wenya Linda Bi, MD, PhD, of the Department of Neurosurgery and Sandro Santagata, MD, PhD, of the Department of Pathology.

Read more in NeuroOncology.

Study Defines a Blood Group, Allowing for Screening Before Transfusion

A rare mutation in the PIGG gene leads to the absence of the Emm antigen, important to blood transfusion compatibility, reports a joint research team from the Brigham and the New York Blood Center. The team’s findings show that Emm is located on GPI-anchors which contain proteins protruding from red blood cells (RBCs). The lack of the Emm antigen, known as the Emm− phenotype, may be linked to seizures, developmental disabilities, intellectual disabilities, and hypotonia, although not all individuals with the phenotype display these traits. Importantly for blood transfusions, antibodies against Emm have been shown to occur naturally and can cause hemolytic transfusion reactions. The team performed whole gene sequencing (WGS) of blood samples taken from two South Asian Indian brothers with the Emm− phenotype. In addition, the team also sequenced previously collected samples from other individuals with familial incidences of the phenotype. The team detected 1,818 variants in the PIGG gene in the samples from the brothers, including one of high impact. The four additional individuals also had mutations in PIGG, although the placement of the mutations varied. Based on these findings, the International Society of Blood Transfusion has designated Emm as the 42nd blood group system.

“The findings here illustrate the power of using WGS with family cohorts to uncover the genetic basis of blood group systems,” said William J. Lane, MD, PHD, of the Department of Pathology. “The observation that Emm− RBC phenotype reveals underlying mutations in PIGG, provides an approach to find other individuals with Emm null phenotypes, and may offer a potential diagnostic.”

Read more in Scientific Reports.