How to Diagnose and Treat Rare Movement Disorders
MIAMI—When evaluating a patient with a movement disorder that seems to be rare, neurologists should employ their clinical expertise and consider a broad range of possible causes, said Anthony E. Lang, MD, Professor and Director of Neurology at the University of Toronto.
“Not everything is going to be diagnosed with whole exome sequencing,” Dr. Lang said at the First Pan American Parkinson’s Disease and Movement Disorders Congress. “Think much more broadly than that, or you are going to miss some important diagnoses and, in some cases, miss quite treatable diagnoses.”
A patient’s history, the physical and neurologic exam, and laboratory and genetic testing are important tools in developing a differential diagnosis. Once a diagnosis has been made, certain disorders may entail a risk of long-term complications that require preventive measures and surveillance.
Dr. Lang cochairs an annual session at the International Congress of Parkinson’s Disease and Movement Disorders that features video presentations of unusual cases. “The more you are aware of and the more you have seen, the more you may have an impact on helping the patient,” he said.
Think Broadly
Approximately 80% of rare diseases are genetic, and modern molecular genetic tests increasingly allow neurologists to make accurate diagnoses. Other causes of rare movement disorders include autoimmune disease, infection, neoplasms, environmental exposures, degenerative disorders, and deficiency states.
Camilo Toro, MD, a neurologist with the NIH Undiagnosed Diseases Program, advises that the classical phenotypes of rare diseases often represent the worst-case scenario, Dr. Lang said. Neurologists increasingly are recognizing broader phenotypic variability and milder forms of rare genetic diseases. In addition, the boundaries between pediatric and adult genetic disorders are blurred, and a patient with more than one genetic disorder may have a blended phenotype. It is also possible that a patient has a rare presentation of a common disorder.
Patient and Family History
Neurologists should consider how a movement disorder began (eg, triggers or precipitants) and whether a patient has other neurologic or general medical illnesses. A patient’s old images, videos, and laboratory tests may offer insights. Genetic counselors can be a valuable resource for neurologists who are interested in learning how to take a careful family history.
Possible sources of confusion about the inheritance of genetic disorders include de novo mutations, missed family history of a disorder (eg, if a relative has a mild manifestation), incomplete penetrance of dominant disorders, incorrect attribution of paternity, and the possibility of pseudodominance in inbred families with recessive disorders. Other types of inheritance include maternal inheritance, maternal imprinting (eg, in myoclonus dystonia), and uniparental disomy.
General and Neurologic Examinations
A patient’s habitus, stature, and facial dysmorphism may be informative. After seeing a patient with Woodhouse-Sakati syndrome in a case that had been presented at a conference, Dr. Lang recognized that he had a patient with the same facial characteristics. “Sure enough, the patient has Woodhouse-Sakati syndrome,” he said.
Patients with 22q11.2 deletion syndrome may have variable craniofacial features, and Dr. Lang’s clinic is following a number of patients with parkinsonism or other movement disorders as a consequence of this disorder.
Skin and related features, including telangiectasia, pigmentation, and nails, may suggest a diagnosis (eg, blue lunula in Wilson’s disease), as can the heart and other organs.
In addition to movements, other information can be gleaned from the eye during an examination, such as the presence of a sunflower cataract (which may suggest Wilson’s disease), a cherry-red spot on the retina (sialidosis), or choreoretinitis with maculopathy and optic atrophy (eg, subacute sclerosing panencephalitis).
During the neurologic examination, neurologists can assess behavior, language, cranial nerves, upper and lower motor neuron signs, eye movement disorders (eg, opsoclonus, oculogyric crisis, oculomotor apraxia, and supranuclear gaze palsies), and the phenomenology, distribution, and timing of movement disorders. In addition, a sensory exam may be useful. Parkinsonism with pure dorsal column sensory abnormalities, for example, is characteristic of POLG1 mutations.
Laboratory Tests
Many laboratory tests are available, and neurologists should use them selectively. As a visiting professor, Dr. Lang sees many patients who have undergone unnecessary tests. “Do not use a shotgun approach,” Dr. Lang said. “Be focused. Use them intelligently.”
Various metabolic pathways can be altered in patients with inborn errors of metabolism, thus creating risk of decompensation. Tests for patients suspected of having an inborn error of metabolism may include blood gases, anion gap, ammonia, glucose, lactate, uric acid, creatine kinase, amino acids, insulin, urine organic acids, ketones, and reducing substances.
Blood can be tested for heavy metals, vitamin deficiencies, and antibodies. CSF testing may be invaluable, including real-time quaking-induced conversion in patients with a suspected prion disorder or, when warranted, evaluation for extremely rare disorders such as testing for folate in patients with suspected cerebral folate deficiency.
Tissue biopsies, EEG, and electroretinogram may reveal useful information, and movement disorders laboratory testing, including assessments for functional movement disorder studies (eg, back-averaging) can help diagnose selected conditions, including psychogenic movement disorders.
