How to Diagnose and Treat Rare Movement Disorders

Imaging

Neurologists should be comfortable looking at neuroimaging to identify patterns of atrophy, the presence of heavy metals, or the occurrence of calcium, for example. Some rare movement disorders require vascular imaging. “Unexpected normal findings should be a clue as well,” he said. Dr. Lang described a patient who was thought to have cerebral palsy, but the patient’s MRI was normal. The patient ultimately was found to have ADCY5-related dyskinesia.

Basal ganglia lesions and recurrent episodes of encephalopathy may indicate that a patient has biotin-responsive basal ganglia disease. “This is a critical disorder for us to recognize,” Dr. Lang said, because a patient who is treated early enough with biotin and thiamine can make a striking recovery.

Punctate changes throughout the posterior fossa, the cerebellum, and the pons, as well as other regions, are characteristic of a vascular abnormality called chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), which can be treated with prednisone.

Genetic Testing

Genetic testing can help establish a diagnosis, but even in careful studies, whole exome sequencing may fail to provide a diagnosis in more than 40% of cases.

Problems with next-generation sequencing include incidental findings, variants of unknown significance, and the possibility of patients having two or more concomitant diseases or incompletely penetrant pathogenic variants. In addition, clinical exome sequencing does not detect repeat expansion disorders, copy number variations, structural variants, or abnormalities in the noncoding part of the genome.

A recently published case report further highlights the need for clinical expertise amid advances in genetic testing, Dr. Lang said. Zittel et al reported a case of a patient who came to a clinic with genetic test results showing that she had GCH1 and TH mutations. Clinically, however, neurologists determined that she had a functional movement disorder. When they went back to the original genetic testing laboratory, they discovered that the patient had doctored the form with the genetic test results. The authors deemed it a case of Munchausen syndrome by genetics.

Treatment

Neurologists should especially consider the possibility of movement disorders caused by autoimmune disease, infection, deficiency states, toxins, drugs, and treatable inborn errors of metabolism because treatment may alter the natural history of the disease and patient outcomes in these cases, Dr. Lang said.

Treatment of metabolic disorders typically requires a multidisciplinary team and may consist of substrate reduction, removal or enhanced clearance of toxic metabolites, replenishment of depleted metabolites, enzyme therapy, cell or organ replacement, and gene therapy.

Certain patients require long-term screening and follow-up to monitor for and prevent complications.

Avoiding infection, trauma, surgery, and vaccination may be important for patients with defects of small molecules. Patients with McLeod syndrome are at risk of transfusion reactions, and patients with ataxia-telangiectasia mutated gene variants should avoid ionizing radiation because of increased risk of malignancy. “If you are following patients with any of these rare disorders, you need to be aware of the long-term consequences,” Dr. Lang said.

In addition, online resources can provide useful information for neurologists who are evaluating patients with potentially rare movement disorders, including OMIM, GeneReviews, Orphanet, Face2Gene, SimulConsult, and MDSGene, Dr. Lang said.

—Jake Remaly

Suggested Reading

Gupta A, Lang AE. Psychogenic movement disorders. Curr Opin Neurol. 2009;22(4):430-436.

Sethi KD, Lang AE. Will new genetic techniques like exome sequencing obviate the need for clinical expertise? No. Mov Disord Clin Pract. 2017;4(1):39-41.

Ure RJ, Dhanju S, Lang AE, Fasano A. Unusual tremor syndromes: know in order to recognise. J Neurol Neurosurg Psychiatry. 2016;87(11):1191-1203.

Zittel S, Lohmann K, Bauer P, et al. Munchausen syndrome by genetics: Next-generation challenges for clinicians. Neurology. 2017;88(10):1000-1001.