The pedigree is shown in A. B, The chromatogram demonstrates a C>T in exon 3 of NKX2-1, resulting in p.Arg243Cys. The mutated arginine is in the homeobox domain, highly conserved across species, and predicted to be deleterious.
Coon EA, Ahlskog JE, Patterson MC, Niu Z, Milone M. Expanding Phenotypic Spectrum of NKX2-1–Related Disorders—Mitochondrial and Immunologic Dysfunction. JAMA Neurol. 2016;73(2):237-238. doi:10.1001/jamaneurol.2015.2976
Autosomal dominant NKX2-1–related disorders present with a spectrum of manifestations that includes benign hereditary chorea, hypothyroidism, and pulmonary dysfunction (brain-lung-thyroid syndrome).1,2 Multisystem involvement varies substantially,3 likely stemming from the mutated protein’s function. NKX2-1 is a transcription factor expressed during development of the central nervous system, especially the basal ganglia and hypothalamus, thyroid, and lung.4
We describe a family with 2 individuals harboring a novel NKX2-1 mutation associated with reduction of muscle mitochondrial respiratory chain (RC) complex activity and recurrent meningitis.
Clinical and laboratory findings of 2 affected family members with childhood-onset chorea were reviewed. Whole-exome sequencing was performed in the proband (Baylor College of Medicine). NKX2-1–targeted Sanger sequencing was done in the proband, daughters, and mother. Muscle mitochondrial DNA analysis was performed by whole-genome sequencing and Southern blot. Mitochondrial RC measurements were performed in a commercial laboratory (Columbia University).
This study was approved by the Mayo Clinic institutional review board (IRB 10-000229).
The proband was born at 36 weeks with respiratory distress. She had hypotonia and delayed motor development but was cognitively normal. Examination when she was a child revealed ataxia with myoclonus. She developed persistent chorea in her late teens. In her 20s, she developed IgA nephropathy and Henoch-Schönlein purpura. In her early 30s, she had multiple episodes of aseptic meningitis characterized by severe headache, meningismus, photophobia, and low-grade fevers. Cerebrospinal fluid lymphocyte counts were 135/µL, 3/µL, 1/µL, and 26/µL (to convert to ×109 per liter, multiply by 0.001) during episodes with normal protein levels, glucose levels, and viral studies (including herpes simplex viruses 1 and 2 polymerase chain reaction). Electromyography showed subtle myopathic changes.
The proband’s second child developed choreiform movements at 2 months. She had delayed motor development. Neurologic examination showed hypotonia and chorea. Laboratory evaluation revealed hypothyroidism and cerebrospinal fluid 5-methyltetrahydrofolate deficiency levels below reference range. Brain magnetic resonance imaging spectroscopy findings were normal.
Muscle biopsy in the daughter at age younger than 3 years showed infrequent necrotic and regenerating fibers with no histological evidence of mitochondrial dysfunction. Activity of muscle mitochondrial RC complexes I, I+III, and IV was markedly reduced after normalization for citrate synthase activity (Table). The proband’s muscle biopsy showed normal histological findings and mitochondrial RC complex activities. Muscle mitochondrial DNA analysis revealed no pathogenic point mutations or deletions.
Whole-exome sequencing identified a novel heterozygous mutation in exon 3 of the NKX2-1 gene (c. 727C>T; p.Arg243Cys) in affected individuals (Figure). The mutated arginine, which is located in the homeobox domain of NKX2-1 and highly conserved across species, is predicted to be deleterious. No potential disease-modifying alleles were identified.
We report a family with 2 individuals affected with benign hereditary chorea due to a novel NKX2-1 mutation. In line with previous studies, early-onset chorea and hypotonia were the predominant neurologic features in both patients.
A novel finding is the reduction in mitochondrial RC complex activity. Such biochemical abnormality, in conjunction with neurologic and endocrine manifestations, mimics mitochondrial diseases. However, the predicted pathogenic NKX2-1 mutation segregates with disease. To our knowledge, no mitochondrial dysfunction has been linked to NKX2-1. Although mitochondrial RC complex deficiencies are often considered diagnostic of mitochondrial disease, there is growing evidence that such abnormalities can occur in nonmitochondrial neurologic disorders.5
Another notable feature is the recurrent aseptic meningitis, which, to our knowledge, has not been reported in NKX2-1–related disorders. Recurrent fevers in NKX2-1 are considered a hypothalamic symptom, but our patient had evidence of meningitis. Additionally, her history of IgA nephropathy and Henoch-Schönlein purpura suggests an immunologic dysfunction. NKX2-1 regulates inflammatory pathways in the lung6 and could similarly affect inflammatory responses in the brain. NKX2-1 also represses NR1D1, which may be involved in regulating metabolic and inflammatory processes, offering potential mechanisms for immunologic dysfunction.
In this family, whole-exome sequencing was an effective tool to diagnose a multisystem disorder, broadening the phenotypic spectrum of NKX2-1 mutations.
Corresponding Author: Margherita Milone, MD, PhD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email@example.com).
Published Online: December 7, 2015. doi:10.1001/jamaneurol.2015.2976.
Author Contributions: Drs Coon and Milone had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Coon, Patterson, Milone.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Coon.
Critical revision of the manuscript for important intellectual content: All authors.
Administrative, technical, or material support: Coon.
Study supervision: Ahlskog, Patterson, Milone.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank Fan Xia, PhD (Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas), for providing copies of the Sanger sequencing raw data. Dr Xia did not receive compensation.