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August 2018; 4 (4) Clinical/Scientific NotesOpen Access

Atypical Alexander disease with dystonia, retinopathy, and a brain mass mimicking astrocytoma

Keren Machol, Joseph Jankovic, Dhanya Vijayakumar, Lindsay C. Burrage, Mahim Jain, Richard A. Lewis, Gregory N. Fuller, Mingchu Xu, Marta Penas-Prado, Maria K. Gule-Monroe, Jill A. Rosenfeld, Rui Chen, Christine M. Eng, Yaping Yang, Brendan H. Lee, Paolo M. Moretti, Undiagnosed Diseases Network, Shweta U. Dhar
First published July 20, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000248
Keren Machol
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Joseph Jankovic
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Dhanya Vijayakumar
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Lindsay C. Burrage
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Mahim Jain
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Richard A. Lewis
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Gregory N. Fuller
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Mingchu Xu
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Marta Penas-Prado
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Maria K. Gule-Monroe
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Jill A. Rosenfeld
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Rui Chen
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Christine M. Eng
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Yaping Yang
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Brendan H. Lee
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Paolo M. Moretti
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
Shweta U. Dhar
From the Department of Molecular and Human Genetics (K.M., L.C.B., M.J., R.A.L., M.X., J.A.R., R.C., C.M.E., Y.Y., B.H.L., P.M.M., S.U.D.), Department of Neurology (J.J., D.V., P.M.M), and Department of Ophthalmology (R.A.L.), Baylor College of Medicine; Department of Pathology (G.N.F.), Department of Neuro-Oncology (M.P.-P.), and Department of Diagnostic Imaging (M.K.G.-M.), The University of Texas MD Anderson Cancer Center; Michael E. DeBakey VA Medical Center (P.M.M.); Baylor Genetics (C.M.E., Y.Y.); and Department of Medicine (S.U.D.), Baylor College of Medicine, Houston, TX.
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Atypical Alexander disease with dystonia, retinopathy, and a brain mass mimicking astrocytoma
Keren Machol, Joseph Jankovic, Dhanya Vijayakumar, Lindsay C. Burrage, Mahim Jain, Richard A. Lewis, Gregory N. Fuller, Mingchu Xu, Marta Penas-Prado, Maria K. Gule-Monroe, Jill A. Rosenfeld, Rui Chen, Christine M. Eng, Yaping Yang, Brendan H. Lee, Paolo M. Moretti, Undiagnosed Diseases Network, Shweta U. Dhar
Neurol Genet Aug 2018, 4 (4) e248; DOI: 10.1212/NXG.0000000000000248

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Alexander disease (AD) is an autosomal dominant progressive astrogliopathy caused by pathogenic variants in glial fibrillary acidic protein (GFAP).1 Clinical presentation of AD includes infantile AD, characterized by psychomotor retardation, seizures, pyramidal signs, and megalencephaly; juvenile AD, characterized by bulbar/pseudobulbar signs, hyperreflexia, lower limb spasticity, ataxia, loss of intellectual function, and macrocephaly; and adult-onset AD, characterized by progressive bulbar symptoms, ataxia, palatal myoclonus, bladder dysfunction, and spastic paraparesis.1

Clinical report

The patient is a 35-year-old woman with progressive left hemidystonia, retinitis pigmentosa (RP), and history of brain tumor. At age 8 years, she developed vision loss, limp, afferent pupillary defect, and optic disc edema. A pilocytic astrocytoma, World Health Organization grade I, was diagnosed and resected. At age 14 years, she developed gait abnormality and progressive left hemidystonia that responded well to botulinum toxin injections. She then developed bilateral optic disc fibrosis, bitemporal hemianopia, and bilateral posterior subcapsular cataracts and was diagnosed with RP at 22 years (figure, A–D). She also reported chronic constipation, functional megacolon, uterine leiomyomas, and dysphagia.

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Figure Clinical, histologic, and imaging findings

A 35-year-old woman with juvenile-onset Alexander disease (AD) (A and B). Note relative macrocephaly (FOC 56 cm, 94th centile) and esotropia. The photomontage of the right (C) and left (D) eyes shows the atrophic gliosis from prior optic disc edema and the marked retinal atrophy and secondary pigmentary degeneration. The retinal vasculature appears to show glial sheathing and peripheral vaso-obliteration in each eye. Brain MRI with contrast at 29 years (E and F). (E) Axial T2 image demonstrates a T2 hyperintense lesion centered in the left middle cerebellar peduncle (yellow arrow). (F) Axial T1 image with contrast shows an area of central enhancement within the lesion (yellow arrow). Partially imaged is cystic encephalomalacia within the frontal lobes bilaterally (yellow asterisk) with surgical changes in the right frontal lobe not included. Slides from patient's brain lesion (G and H) demonstrating AD histologic features. The prototypical histologic feature of AD is prominent Rosenthal fiber formation (G, solid arrows). An additional feature unique to AD is the presence of Rosenthal fiber-like eosinophilic cytoplasmic inclusions in astrocyte cell bodies (G, open arrows). The cell body inclusions are generally not seen in other Rosenthal fiber–rich conditions such as low-grade primary brain tumors. Astrocytes with markedly atypical nuclei (H, solid arrow) are also a characteristic morphologic feature of AD and can mimic the neoplastic cells of astrocytoma or ganglioglioma. FOC = fronto-occipital circumference.

Family history includes nonconsanguineous unaffected parents. Physical examination showed relative macrocephaly, absent ocular horizontal and vertical pursuit, dysarthria, circumduction gait and left-sided arm dystonia, muscle atrophy, hyperreflexia, and ankle clonus. Brain MRI demonstrated a frontal resection cavity, cystic encephalomalacia, and fluctuating enhancement of the hypothalamus. At age 29 years, a new left middle cerebellar peduncle lesion was identified (figure, E and F).

The patient was enrolled in the NIH Undiagnosed Diseases Network (UDN). Whole-exome sequencing (WES) for her and her mother was completed. Her father was deceased at the time of evaluation.

Results

WES revealed a novel heterozygous variant of uncertain significance (VUS) in GFAP (MIM_137780) c.989G>C (p.R330P, NM_002055) and a heterozygous VUS c.6196G>A (p.D2066N, NM_006269) in RP1 (MIM_603937), both absent in the mother. The parental origin of the GFAP mutated allele could not be concluded based on WES data and available DNA samples. The variant in RP1 was reported in 127 heterozygotes among 138,396 unrelated, unaffected individuals in gnomAD database (gnomad.broadinstitute.org). Both variants are predicted as damaging in SIFT (sorting intolerant from tolerant; sift.jcvi.org/) and Polyphen-2 (genetics.bwh.harvard.edu/pph2). No other contributory variants were detected in 256 known retinal disease genes.

Pathology slides from the initial brain mass were re-examined. Histologic examination showed features of AD, including profuse Rosenthal fiber formation, Rosenthal fiber-like eosinophilic cytoplasmic inclusions in astrocyte cell bodies, and scattered cells with markedly atypical nuclei (figure, G and H).

Discussion

Radiologic findings in AD vary with age at onset, and typical characteristics have been described for the various forms of AD. Serial radiologic imaging of our patient showed sequelae of right frontal lobe resection, development of periventricular white matter changes, and fluctuating brainstem and hypothalamic lesions. Waxing and waning imaging findings, in the absence of treatment, were inconsistent with a brain tumor. Therefore, despite her previous diagnosis of a brain tumor, these new findings were interpreted as non-neoplastic, and the working diagnosis was non-MS demyelinating lesions. Similar atypical MRI findings had been described before in patients with molecularly proven AD.2 Dystonia and retinal abnormalities have never been previously reported with AD. Left hemidystonia in our patient may be secondary to AD-related encephalomalacia or a possible delayed consequence of right frontal brain resection.3 The RP1 VUS in our patient is less likely to be pathogenic, given the presence of multiple heterozygous carriers in population databases. It is unclear whether RP is a phenotypic expansion of AD or an unrelated finding (i.e., dual genetic diagnosis).4

Several histologic features of AD can mimic brain tumors. Rosenthal fiber formation in astrocytes of the brain and spinal cord, a pathologic hallmark of AD, is also seen in several low-grade primary brain tumors (e.g., pilocytic astrocytoma, ganglioglioma, and pleomorphic xanthoastrocytoma). Cytologically atypical astrocytes, a recognized feature of AD,5 can also lead to misdiagnosis of pilocytic astrocytoma/ganglioglioma and unnecessary invasive interventions. The presence of Rosenthal fiber–like eosinophilic cytoplasmic inclusions in astrocyte cell bodies serves as a “red flag,” raising the index of suspicion of AD.

Over 120 pathogenic variants in GFAP have been reported with a possible dominant gain-of-function mechanism.6 GFAP p.R330P substitutes arginine, located in the evolutionarily well-conserved structure of GFAP, with proline. Another change in the same amino acid, p.R330G, was associated previously with adult AD.7 The potential functional significance of the p.R330P substitution, our patient's phenotype, and the histologic findings all strongly support GFAP p.R330P being a disease-causing variant.

Although relative macrocephaly, spasticity, ocular movement abnormalities, and autonomic disturbance (functional megacolon), as seen in our patient, have been described in juvenile AD,1 the diagnosis of AD was delayed because of an atypical presentation, including RP, left hemidystonia, atypical MRI findings, and histologic features confounding the diagnosis. This case emphasizes the clinical, histologic, and radiologic challenges in diagnosing AD and demonstrates the importance of considering AD in the differential diagnosis of specific Rosenthal fiber–rich brain lesions such as pilocytic astrocytoma.

Author contributions

K. Machol: drafting the manuscript and analysis of whole-exome sequencing. J. Jankovic: neurologic management of the patient. D. Vijayakumar: drafting the manuscript. L.C. Burrage and M. Jain: analysis of whole-exome sequencing. R.A. Lewis: ophthalmologic evaluation of the patient and review and editing of the manuscript. G.N. Fuller: revision of histopathology and drafting the manuscript. M. Xu: review of RP-related genes in whole-exome sequence. M. Penas-Prado: oncologic management of the patient, drafting the manuscript, and critical revision of the manuscript. M. K. Gule-Monroe: radiology interpretation and drafting the manuscript. J. A. Rosenfeld: coordination of patient evaluation and critical revision of the manuscript. R. Chen: review of RP-related genes in whole-exome sequence. Y. Yang and C.M. Eng: analysis of whole-exome sequencing. B.H. Lee: critical revision of the manuscript. P.M. Moretti: neurologic evaluation of the patient and drafting the manuscript. S.U. Dhar: drafting the manuscript, critical revision of the manuscript, and patient management.

Study funding

This work was supported by the BCM Intellectual and Developmental Disabilities Research Center (HD024064) from the NICHD and NIH/NHGRI U01 HG007709 Clinical Site for a UDN. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing offered by Baylor Genetics.

Disclosure

K. Machol reports no disclosures. J. Jankovic has served on the scientific advisory boards of, received gifts from, and received funding for travel or speaker honoraria from Adamas Pharmaceuticals Inc., Allergan Inc., and Teva Pharmaceutical Industries; has served on the editorial boards of Acta Neurologica Scandinavica, the Journal of Neurological Sciences, Neurology Medlink, Neurotherapeutics, Journal of Parkinson's Disease, and Toxins; receives publishing royalties from Cambridge, Elsevier, Future Science Group, Hodder Arnold, Lippincott Williams and Wilkins, and Wiley-Blackwell; and has received research support from Allergan Inc., CHDI Foundation, Civitas/Acorda Therapeutics, Dystonia Medical Research Foundation, Huntington Study Group, Ipsen Limited, Kyowa Haako Kirin Pharma Inc., Lundbeck Inc., Medtronic, Merz Pharmaceuticals, Michael J. Fox Foundation for Parkinson Research, NIH, National Parkinson Foundation, Parkinson Study Group, Pfizer, Prothena Biosicneces Inc., Psyadon Pharmaceuticals Inc., St. Jude Medical, and Teva Pharmaceutical Industries Ltd.; D. Vijayakumar reports no disclosures. L.C. Burrage has received funding for travel or speaker honoraria from the Burroughs Welcome, the NIH, and the Society for Inherited Metabolic Disorders and has received research support from the NIH/NIDDK, the NIH RDCRN, the Burroughs Welcome Fund, and the Ligums Family. M. Jain, R.A. Lewis, G.N. Fuller, and M. Xu report no disclosures. M. Penas-Prado has received funding for travel from AGIOS and LILLY and serves on the editorial board of Neuro-Oncology Practice. M.K. Gule-Monroe reports no disclosures. J.A. Rosenfeld serves on the editorial board of Prenatal Diagnosis and Molecular Syndromology and receives research support from the NIH/National Human Genome Research Institute. R. Chen has received research support from the NIH. C.M. Eng is employed by Baylor College of Medicine, which has a joint venture with Miraca Genetics Lab. Y. Yang reports no disclosures. B.H. Lee serves on the editorial advisory boards of the Journal of Clinical Investigation, Human Molecular Genetics, and the Journal of Bone Mineral Research and holds a patent license for helper dependent adenoviral gene therapy for osteoarthritis and phenylbutyrate use in Maple Syrup Urine Disease. P.M. Moretti received research support from the NHGRI/NIH. S.U. Dhar is employed by the Baylor College of Medicine, which has a joint venture with Miraca Life Services. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

Acknowledgment

The authors thank the patient and her family for participating in this research. They thank Alyssa Tran, Deanna Erwin, and Alex Espana in the Molecular and Human Genetics Department, Baylor College of Medicine for administrative assistance.

Footnotes

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • The Article Processing charge was funded by NIH.

  • Coinvestigators are listed at links.lww.com/NXG/A59.

  • Received February 20, 2018.
  • Accepted in final form May 14, 2018.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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