Skip to main content
Image
Scientists using microscopes in the laboratory

Bi-Allelic NOTCH3 Variants May Cause Early-Onset Vascular Leukoencephalopathy and More: RDCRN Research Roundup

May 3, 2022

Each week, we share summaries of recent Rare Diseases Clinical Research Network (RDCRN) grant-funded publications. Read new research on leukoencephalopathy, kidney diseases, and primary ciliary dyskinesia.


Bi-Allelic NOTCH3 Variants May Cause Early-Onset Vascular Leukoencephalopathy

Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN): Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

Cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. Heterozygous variants of the NOTCH3 gene are known to cause CADASIL, with patients typically presenting in adulthood.

In this study, researchers describe three patients from two unrelated families presenting at an early age with a vascular leukoencephalopathy. The team reviewed clinical records, MRI, and CT scans of the patients. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene.

These results indicate that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.


Review Discusses Sphingolipids in Kidney Diseases

Nephrotic Syndrome Study Network (NEPTUNE): Implications of Sphingolipid Metabolites in Kidney Diseases

Sphingolipids are lipids with complex structures that act as bioactive signaling molecules. They are involved in several cellular processes, including cell survival, proliferation, migration, and apoptosis.

Abnormalities in the levels of sphingolipids are associated with several human diseases, including kidney diseases. Studies demonstrate that sphingolipids play an important role in maintaining proper renal function. Sphingolipids can alter the glomerular filtration barrier (GFB, a membrane that prevents the passage of the majority of proteins into the urine) by affecting the functioning of podocytes, which are key cellular components of the GFB.

In this review paper, researchers summarize studies of the regulation of sphingolipid signaling in kidney diseases, especially in glomerular and tubulointerstitial diseases. Authors also discuss the potential to target sphingolipid pathways in developing therapeutics for the treatment of renal diseases.


Chest X-Rays Alone May Not Detect Organ Laterality Defects in Primary Ciliary Dyskinesia

Genetic Disorders of Mucociliary Clearance Consortium (GDMCC): Going beyond the chest X-ray: Investigating laterality defects in primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is an inherited condition in which mucociliary clearance is impaired in the upper and lower airways. Organ laterality defects are common in patients with PCD, ranging from situs inversus totalis (SIT, complete mirror image organ arrangement), to situs ambiguus (SA, any laterality defect other than SI). However, targeted investigations for these defects are not universally recommended in PCD consensus statements. Without investigations beyond chest radiography (CXR), clinically significant defects may go undetected, leading to increased morbidity.

In this study, researchers reviewed CXR images and reports of add-on, targeted investigations (computed tomography scans, abdominal ultrasounds, upper GI contrast studies, and splenic scintigraphy) from medical records collected at two PCD clinics. They compared situs classifications from CXR alone versus CXR with add-on, targeted investigations. Results showed that situs classification differed significantly from CXR images alone versus CXR with add-on, targeted investigations. Some of these additional organ laterality defects resulted in significant patient morbidity and even mortality when splenic dysfunction was present.

Authors conclude that in PCD patients, clinically significant SA defects may not be detected by CXR alone. These results suggest that the routine use of CXR with add-on, targeted investigations may be justified.


The Rare Diseases Clinical Research Network (RDCRN) is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). Now in its fourth five-year funding cycle, RDCRN is a partnership with funding and programmatic support provided by Institutes, Centers, and Offices across NIH, including the National Institute of Neurological Disorders and Stroke, the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute, the National Institute of Dental and Craniofacial Research, the National Institute of Mental Health, and the Office of Dietary Supplements.

View News by Topic

Recent Articles

FacebookTwitter ShareLinkedIn ShareEmail Share