Familial Brain Calcifications With Leukoencephalopathy: A Novel PDGFB Variant
Jack Shen1, Amelle Shillington1, Alberto J Espay1
1Department of Neurology and Rehabilitation Medicine (J.S., A.J.E., E.J.H.), University of Cincinnati; and Department of Human Genetics (A.S.), Cincinnati Children's Hospital Medical Center, OH.
Insights
A novel PDGFB gene variant causes primary familial brain calcifications (PFBC) and leukoencephalopathy in a three-generation family. This study identifies a new genetic cause for these rare neurological disorders.
Area of Science:
- Neurogenetics
- Neurology
- Molecular Biology
Background:
- Primary familial brain calcifications (PFBC) are rare genetic disorders characterized by abnormal calcium deposition in the brain.
- Leukoencephalopathy involves white matter degeneration in the brain, often leading to neurological deficits.
- The genetic basis for many PFBC cases remains unknown, necessitating further research into causative genes.
Purpose of the Study:
- To describe a family exhibiting primary familial brain calcifications (PFBC) and leukoencephalopathy.
- To identify the genetic variant responsible for these neurological conditions within the family.
- To investigate the role of the PDGFB gene in the pathogenesis of PFBC and associated leukoencephalopathy.
Main Methods:
- Clinical evaluation of three generations of a family with neurological symptoms.
- Neuroimaging (CT scans) to assess brain calcifications and white matter abnormalities.
- Genetic analysis, including sequencing of the PDGFB gene and in silico pathogenicity prediction.
Main Results:
- A novel, previously unreported variant in the PDGFB gene (NM_002608.3:c.298C>T:p.Arg100Cys) was identified in affected family members.
- Affected individuals presented with basal ganglia and cerebellar calcifications, along with periventricular white matter disease.
- Clinical manifestations included migraine, bipolar disorder, cognitive impairment, parkinsonism, and dementia.
Conclusions:
- The identified novel PDGFB variant is associated with primary familial brain calcifications.
- This study highlights a rare association between leukoencephalopathy and PDGFB-related PFBC.
- The findings expand the understanding of genetic causes for PFBC and associated neurological conditions.
Objective:
To describe a family with primary familial brain calcifications (PFBCs) and leukoencephalopathy associated with a novel variant in PDGFB.
Methods:
We present 3 generations of a family with PFBC associated with a previously unreported variant in PDGFB.
Results:
A 24-year-old woman with migraine, bipolar disorder, and functional neurologic disorder was found to have bilateral calcifications of the basal ganglia and frontally predominant periventricular white matter disease. Her father had mild cognitive impairment and action tremor of the hands with basal ganglia and cerebellar calcifications found incidentally on head CT. Her paternal grandmother had severe parkinsonism and dementia with calcifications of the basal ganglia and cerebellum and diffuse, confluent periventricular white matter disease. Genetic testing in both the proband and her father revealed a PDGFB variant (NM_002608.3:c.298C>T:p.Arg100Cys) not reported in publicly available databases. Multiple in silico analysis tools support pathogenicity.
Discussion:
Our report identifies a novel PDGFB variant associated with PFBC and highlights the rare association of leukoencephalopathy with PDGFB-associated PFBC.
