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Expanding Phenotypic Spectrum of NKX2-1–Related Disorders Letters RESEARCH LETTER The proband’s second child developed choreiform move- ments at 2 months. She had delayed motor development. Neu- Expanding Phenotypic Spectrum rologic examination showed hypotonia and chorea. Labora- of NKX2-1–Related Disorders— tory evaluation revealed hypothyroidism and cerebrospinal Mitochondrial and Immunologic Dysfunction fluid 5-methyltetrahydrofolate deficiency levels below refer- Autosomal dominant NKX2-1–related disorders present with ence range. Brain magnetic resonance imaging spectroscopy a spectrum of manifestations that includes benign hereditary findings were normal. chorea, hypothyroidism, and pulmonary dysfunction (brain- lung-thyroid syndrome).1,2 Multisystem involvement varies Muscle Biopsies. Muscle biopsy in the daughter at age younger substantially,3 likely stemming from the mutated protein’s than 3 years showed infrequent necrotic and regenerating fi- function. NKX2-1 is a transcription factor expressed during de- bers with no histological evidence of mitochondrial dysfunc- velopment of the central nervous system, especially the basal tion. Activity of muscle mitochondrial RC complexes I, I+III, ganglia and hypothalamus, thyroid, and lung.4 and IV was markedly reduced after normalization for citrate We describe a family with 2 individuals harboring a novel synthase activity (Table). The proband’s muscle biopsy showed NKX2-1 mutation associated with reduction of muscle mito- normal histological findings and mitochondrial RC complex chondrial respiratory chain (RC) complex activity and recur- activities. Muscle mitochondrial DNA analysis revealed no rent meningitis. pathogenic point mutations or deletions. Methods | Clinical and laboratory findings of 2 affected family Genetic Results. Whole-exome sequencing identified a novel het- members with childhood-onset chorea were reviewed. Whole- erozygousmutationinexon3oftheNKX2-1 gene (c. 727C>T; exome sequencing was performed in the proband (Baylor Col- p.Arg243Cys) in affected individuals (Figure). The mutated lege of Medicine). NKX2-1–targeted Sanger sequencing was done arginine, which is located in the homeobox domain of in the proband, daughters, and mother. Muscle mitochondrial NKX2-1 and highly conserved across species, is predicted to DNA analysis was performed by whole-genome sequencing and be deleterious. No potential disease-modifying alleles were Southern blot. Mitochondrial RC measurements were performed identified. in a commercial laboratory (Columbia University). This study was approved by the Mayo Clinic institutional Discussion | We report a family with 2 individuals affected review board (IRB 10-000229). with benign hereditary chorea due to a novel NKX2-1 muta- tion. In line with previous studies, early-onset chorea and Results | Case Histories. The proband was born at 36 weeks with hypotonia were the predominant neurologic features in respiratory distress. She had hypotonia and delayed motor de- both patients. velopment but was cognitively normal. Examination when she A novel finding is the reduction in mitochondrial RC com- was a child revealed ataxia with myoclonus. She developed per- plex activity. Such biochemical abnormality, in conjunction sistent chorea in her late teens. In her 20s, she developed IgA with neurologic and endocrine manifestations, mimics mito- nephropathy and Henoch-Schönlein purpura. In her early 30s, chondrial diseases. However, the predicted pathogenic NKX2-1 she had multiple episodes of aseptic meningitis character- mutation segregates with disease. To our knowledge, no ized by severe headache, meningismus, photophobia, and low- mitochondrial dysfunction has been linked to NKX2-1. Al- grade fevers. Cerebrospinal fluid lymphocyte counts were though mitochondrial RC complex deficiencies are often con- 135/μL, 3/μL, 1/μL, and 26/μL (to convert to ×109 per liter, mul- sidered diagnostic of mitochondrial disease, there is growing tiply by 0.001) during episodes with normal protein levels, glu- evidence that such abnormalities can occur in nonmitochon- cose levels, and viral studies (including herpes simplex vi- drial neurologic disorders.5 ruses 1 and 2 polymerase chain reaction). Electromyography Another notable feature is the recurrent aseptic menin- showed subtle myopathic changes. gitis, which, to our knowledge, has not been reported in Table. Mitochondrial Respiratory Chain Activity in the Affected Daughter Enzyme Complex Activity, μm/min/g Controls, Mean (SD), μm/min/g Cytochrome c oxidase IV 1.66 2.8 (0.52) Succinate cytochrome c reductase II + III 0.66 0.70 (0.23) NADH-cytochrome c reductase I + III 2.43 3.15 (1.11) NADH-CoQ reductase I 0.54 1.18 (0.11) Abbreviations: CoQ, coenzyme Q; NA, not applicable; NADH, Citrate synthase NA 12.93 9.66 (2.55) nicotinamide adenine dinucleotide. jamaneurology.com (Reprinted) JAMA Neurology February 2016 Volume 73, Number 2 237 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Letters Additional Contributions: We thank Fan Xia, PhD (Molecular and Human Figure. Pedigree and Results of Molecular Analysis Genetics, Baylor College of Medicine, Houston, Texas), for providing copies of the Sanger sequencing raw data. Dr Xia did not receive compensation. A Pedigree showing B Chromatogram affected individuals 280 1. Willemsen MA, Breedveld GJ, Wouda S, et al. Brain-Thyroid-Lung syndrome: C A C C G C T A a patient with a severe multi-system disorder due to a de novo mutation in the thyroid transcription factor 1 gene. Eur J Pediatr. 2005;164(1):28-30. I ? I-2 12 2. Patel NJ, Jankovic J. NKX2-1-related disorders. GeneReviews. http://www.ncbi .nlm.nih.gov/books/NBK185066/. Published February 20, 2014. Accessed January R Y H R/C Y 8, 2015. H II c.725 280 c.730 3. Peall KJ, Lumsden D, Kneen R, et al. Benign hereditary chorea related to C A C N G C T A 12 NKX2.1: expansion of the genotypic and phenotypic spectrum. Dev Med Child Proband Neurol. 2014;56(7):642-648. II-1 4. Lazzaro D, Price M, de Felice M, Di Lauro R. The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted 280 285 regions of the foetal brain. Development. 1991;113(4):1093-1104. III C A C C G C T A 5. Pyle ANH, Griffin H, Abicht A, et al. Respiratory chain deficiency in 12 III-1 nonmitochondrial disease. Neurol Genet. 2015;1(1):e6. Male Chorea 6. Maeda Y, Chen G, Xu Y, et al. Airway epithelial transcription factor NK2 Female Hypotonia homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation. Am J Respir 280 285 Proband Immune Crit Care Med. 2011;184(4):421-429. dysfunction C A C N G C T A Respiratory chain dysfunction III-2 COMMENT & RESPONSE The pedigree is shown in A. B, The chromatogram demonstrates a C>T in exon 3 Varicella-Zoster Virus in Giant Cell Arteritis of NKX2-1, resulting in p.Arg243Cys. The mutated arginine is in the homeobox 1 domain, highly conserved across species, and predicted to be deleterious. To the Editor We read with interest the article by Nagel et al. The authors investigated the frequency and localization of vari- cella-zoster virus (VZV) antigen in the temporal arteries of NKX2-1–related disorders. Recurrent fevers in NKX2-1 are con- patients diagnosed as having giant cell arteritis (GCA). Accord- sidered a hypothalamic symptom, but our patient had evi- ing to the authors’ findings, there was an increased fre- dence of meningitis. Additionally, her history of IgA nephropa- quency of VZV antigen in both patients with biopsy-positive thy and Henoch-Schönlein purpura suggests an immunologic and biopsy-negative GCA compared with the control group. dysfunction. NKX2-1 regulates inflammatory pathways in the They reported VZV antigen was particularly localized in the ad- 6 lung and could similarly affect inflammatory responses in the ventitial layer. A report from the United Kingdom did suggest brain. NKX2-1 also represses NR1D1, which may be involved GCA had a strong association with herpes zoster infection (rela- in regulating metabolic and inflammatory processes, offering tive risk, 2.6; 95% CI 1.6-4.1).2 potential mechanisms for immunologic dysfunction. However, we have a few comments and queries in regard In this family, whole-exome sequencing was an effective to the methods and conclusions of this study. First, the au- tool to diagnose a multisystem disorder, broadening the phe- thors studied both GCA-positive, GCA-negative, and control notypic spectrum of NKX2-1 mutations. groups. However, it is not clear on which basis the diagnosis of GCA was made clinically and what was the final diagnosis Elizabeth A. Coon, MD for the biopsy-negative GCA group. Perhaps, aging and immu- J. Eric Ahlskog, PhD, MD nosuppression (steroid use) are the main factors for the reac- Marc C. Patterson, MD tivation of latent VZV.Lack of such information is a major limi- Zhiyv Niu, PhD tation to this study. Margherita Milone, MD, PhD Second, the use of postmortem control individuals raises the question of whether there could be any artifactual ele- Author Affiliations: Department of Neurology, Mayo Clinic, Rochester, Minnesota (Coon, Ahlskog, Patterson, Milone); Department of Laboratory ments introduced postmortem. Perhaps a better control would Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Niu). have been temporal artery biopsies taken from patients who Corresponding Author: Margherita Milone, MD, PhD, Department of were deemed not to have GCA in the final analysis. It is not Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 usual for atherosclerotic changes in the temporal artery to be ([email protected]). found on biopsy. Published Online: December 7, 2015. doi:10.1001/jamaneurol.2015.2976. Third, another intriguing question is whether VZV involve- Author Contributions: Drs Coon and Milone had full access to all of the data in ment is indeed a factor in GCA disease pathogenesis and, if the study and take responsibility for the integrity of the data and the accuracy of the data analysis. so, is it only restricted to GCA or does it also play a role in other Study concept and design: Coon, Patterson, Milone.
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