Parkinsonism and Positive Dopamine Transporter Imaging in a Patient with a Novel KMT2B Variant
Year: 2020
Type: article
Study design: Case Report
Abstract: KMT2B-related dystonia (DYT-28) is a recently identified autosomal-dominant disorder caused by mutations in the KMT2B gene.1, 2 KMT2B encodes a histone lysine methyltransferase, which plays a central role in regulating gene expression through epigenetic modifications.3 The disorder is characterized by childhood-onset and progressive dystonia, commonly starting in the limbs with subsequent cervical, oromandibular and laryngeal involvement. The clinical phenotype further includes bulbar symptoms manifesting as dysarthria and dysphagia, developmental delay and dysmorphic features. We present a case of DYT-28 caused by a novel KMT2B mutation, initially with characteristic clinical features, who in early adulthood developed prominent parkinsonism, good response to dopaminergic therapy, and positive pre-synaptic dopamine transporter (DaT) SPECT imaging. A 33-year-old right-handed Caucasian male presented to our clinic for progressively worsening generalized dystonia. He had no history of birth trauma, toxin exposure or family history of dystonia, though his paternal grandfather developed parkinsonism and dementia in his 70s. His initial neurological symptom was right foot supination at age 3. At age 4, delays in verbal milestones were noted. Dystonia slowly progressed, involving his right upper extremity at age 6 and his neck and trunk at age 17. Trihexiphenidyl, lorazepam and botulinum toxin injections were trialed, but only trihexiphenidyl provided benefit. MRI brain was normal and genetic testing (ataxia panel and chromosomal microarray) were negative. At age 23 bilateral globus pallidus interna deep brain stimulation (DBS) surgery was performed, resulting in significant improvement in dystonia, particularly in his upper body and trunk. Our initial clinical evaluation noted dysmorphic features (broad nasal bridge, elongated face and low set ears), a nasal and dysarthric voice, generalized dystonia, elevation of the right shoulder and parkinsonism with rigidity, bradykinesia (left greater than right) and freezing of gait (FOG) with a MDS-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS) of 48 (Video 1). Extensive DBS reprogramming, including turning off the DBS, testing modifiable parameters and performing a monopolar review, was performed to ensure his parkinsonian symptoms were not stimulation-induced.4 A comprehensive dystonia panel from MNG Laboratories (NextGen Sequencing Panel and Copy Number Analysis; 192 Genes and mtDNA and HTT Repeat Expansion Analysis) and a DaT scan were acquired. Genetic testing identified a presumed de novo six-nucleotide deletion of KMT2B, introducing a premature stop codon (c.974_979del, p.Ser325Ter). The DaT scan revealed decreased uptake in the right greater than left putamen (Fig. 1). We also obtained a Hereditary Parkinson's Disease and Parkinsonism panel from Invitae Laboratories, which was negative. Carbidopa/levodopa up-titrated to 1 tablet (25 mg/100 mg) three times daily improved gait and parkinsonism. Further dosage increases worsened FOG and subsequently carbidopa/levodopa was discontinued. The patient transitioned to rotigotine, and at 4 mg gait significantly improved without worsening of FOG. Eight months later he continued to receive benefit from rotigotine with a MDS-UPDRS of 36 and significant improvement in his gait. Parkinsonism is a rarely cited feature of KMT2B-related dystonia,3, 5 and FOG has not previously been reported in the literature. Our patient's initial clinical course was consistent with prior KMT2B cases reported in the literature. Unusual, however, was the development of parkinsonism and FOG in his 30s. Even more distinct were his positive DaT scan and responsiveness to dopaminergic therapy.2, 3 All DaT scans thus far reported in KMT2B patients (three cases) showed normal radiotracer uptake.2 The etiology of our patient's suspected nigrostriatal degeneration is not known, but our patient was imaged at an older age than prior cases. Therefore, other patients may be at risk for dopaminergic neuronal loss as they age. Alternatively, the dopaminergic deficit may be, at least partially, due to our patient's unique KMT2B mutation. Several mutations in the same domain (AT-hook DNA binding domain) have been reported and none with parkinsonism.5 Genotyping of additional cases of DYT-28 with and without accompanying parkinsonism in adulthood will be needed to determine if mutation differences explain the development of parkinsonism and FOG in our patient. Interestingly, KMT2B mutations have been associated with decreased expression of THAP1 and TOR1A, both of which are known to be associated with dysfunctional dopaminergic systems.6 This may provide a link between KMT2B mutations and nigrostriatal degeneration, but the downstream consequences of KMT2B mutations are yet to be elucidated. This case rests in the company of other cases of genetic neurodevelopmental dystonias which have positive DaT scans and are dopamine responsive, including mutations in NR4A2,7 SPG118 and ACTB (p.Arg183Trp).9 Our case has important clinical implications. First, it will be important for clinicians caring for these patients to evaluate them for development of parkinsonism as these symptoms may be responsive to dopaminergic medication. Second, it highlights the need to potentially expand the phenotypic expression of KMT2B mutations especially in later stages of the disease. Third, it underscores the importance of ongoing mechanistic research which will elucidate the pathophysiology of DYT-28, and potentially other not yet identified causes of dystonia and parkinsonism, given the post-translational role of KMT2B. In summary, we report a new KMT2B mutation identified in a male with childhood-onset progressive generalized dystonia who developed parkinsonism and FOG in his 30s and was found to have an abnormal DaT scan and clinical response to dopaminergic medication. This is the first report of dopa-responsive parkinsonism and FOG accompanied by evidence of dopaminergic degeneration in a patient with DYT-28. Thank you to Jean Jirikowic, MSGC, for her help with this case. (1) Manuscript Preparation: A. Writing of first draft, B. Review and critique J.F.: 1A, 1B J.K.: 1B M.T.: 1B B.B.: 1A, 1B Ethical Compliance Statement: Ethical guidelines were followed in the absence of an IRB. Written patient consent was obtained. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest. Financial Disclosures for the Previous 12 Months: Dr. Brian D. Berman has the following disclosures to report: Employed by Virginia Commonwealth University and MCV Foundation; consultant for International Parkinson and Movement Disorder Society and the National Football League Players Association; medical advisory board member for the Benign Essential Blepharospasm Research Foundation and the National Spasmodic Torticollis Association and member of the American Academy of Neurology Clinical Research Subcommittee; and has received research grant support from the Parkinson's Foundation, Dystonia Coalition (receives the majority of its support through NIH grant NS065701 from the Office of Rare Diseases Research in the National Center for Advancing Translational Science and National Institute of Neurological Disorders and Stroke), Colorado Clinical and Translational Science Institute, Benign Essential Blepharospasm Research Foundation, and Tools4Patient. The authors declare that there are no additional disclosures to report.
DOI: 10.1002/mdc3.13140
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3117360596