REVIEW Genetic Mimics of Cerebral Palsy Toni S. Pearson, MBBS,1* Roser Pons, MD,2 Roula Ghaoui, MBBS, FRACP, PhD3 and Carolyn M. Sue, MBBS, FRACP, PhD4* 1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA 2First Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sofia Hospital, Athens, Greece 3Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia 4Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, St Leonards, NSW, Australia ABSTRACT: The term “cerebral palsy mimic” is used to possibility of a cerebral palsy mimic, provide a practical describe a number of neurogenetic disorders that may pre- framework for selecting and interpreting neuroimaging, sent with motor symptoms in early childhood, resulting in a biochemical, and genetic investigations, and highlight misdiagnosis of cerebral palsy. Cerebral palsy describes a selected conditions that may present with predominant heterogeneous group of neurodevelopmental disorders spasticity, dystonia/chorea, and ataxia. Making a precise characterized by onset in infancy or early childhood of diagnosis of a genetic disorder has important implications motor symptoms (including hypotonia, spasticity, dystonia, for treatment, and for advising the family regarding prog- and chorea), often accompanied by developmental delay. nosis and genetic counseling. © 2019 International The primary etiology of a cerebral palsy syndrome should Parkinson and Movement Disorder Society always be identified if possible. This is particularly important in the case of genetic or metabolic disorders that have spe- Key Words: ataxia; cerebral palsy; dystonia; inborn cific disease-modifying treatment. In this article, we discuss errors of metabolism; spasticity clinical features that should alert the clinician to the The term cerebral palsy (CP) describes a group of perma- predominant spasticity, the body distribution: diplegia, nent disorders of the development of movement and pos- hemiplegia, or quadriplegia. In addition, motor symptoms ture, causing activity limitation, that are attributed to are frequently accompanied by a variety of nonmotor neu- nonprogressive disturbances that occurred in the develop- rological features, such as intellectual disability, behavioral ing fetal or infant brain.1 Motor features may include symptoms, and seizures. hypotonia, spasticity, weakness, and involuntary move- Historically, patients with CP have been classified based ments (most commonly dystonia or chorea), either alone on physical characteristics rather than etiology. Some his- or in combination. Clinical characterization involves a torical perspective is worth bearing in mind when consider- description of the motor features, and in the case of ing how our usage of the term “cerebral palsy” evolved. --------------------------------------------------------- The English surgeon William Little is credited with the first *Correspondence to: Dr. Toni S. Pearson, Department of Neurology, description, in 1843, of musculoskeletal complications Washington University School of Medicine, 660 S. Euclid Ave, Campus arising from injury to the infantile central nervous system Box 8111, St. Louis, MO 63110, USA; E-mail: [email protected] 2 Dr. Carolyn M. Sue, Department of Neurogenetics, Kolling Institute, (CNS). Other 19th century researchers described the clini- Royal North Shore Hospital and University of Sydney, Pacific Highway, cal features that distinguished the cerebral palsies from the St Leonards, NSW 2065, Australia; E-mail: [email protected] flaccid paralysis of poliomyelitis.3 Aclassification scheme Relevant conflicts of interest/financial disclosures: Nothing to report. based on the body distribution of motor symptoms devel- Full financial disclosures and author roles may be found in the online oped: hemiplegia, diplegia (bilateral hemiplegia), and para- 4,5 version of this article. plegia. A century later, in the 1980s, further delineation Received: 26 July 2018; Revised: 4 February 2019; Accepted: 10 of the clinical motor syndrome based on the predominant February 2019 type of motor involvement—spastic, ataxic, dyskinetic, or — 6 Published online 00 Month 2019 in Wiley Online Library hypotonic was adopted. The variety of possible underly- (wileyonlinelibrary.com). DOI: 10.1002/mds.27655 ing etiologies has been acknowledged since the 19th Movement Disorders, 2019 1 PEARSON ET AL century,5 but a universal etiological classification system 1. Symptom onset before age 2 years. In the great majority for CP remains elusive to this day. Given the manner in of children with CP, initial symptoms appear in infancy, which technological advances in neuroimaging and genetic and the diagnosis of CP is made between the ages of 8 testing in the early 21st century have transformed our diag- 12 and 24 months. nostic capability, the contemporary meaning and usage of 2. Stable clinical course with no developmental regres- cerebral palsy deserves some contemplation. sion. The existence of a nonprogressive lesion or dys- CP is best considered a descriptive, rather than a diagnos- function of the immature brain is a core feature of 9,10 tic, label. We would argue that, as neurologists, we should CP. This results in relatively stable neurological fea- not be satisfied with CP as a stand-alone diagnosis for any tures, but it is recognized that symptoms may evolve child with nonprogressive motor symptoms. Rather, it over time with growth and development even in the face 11 should be conceptualized as a syndrome with an underlying of a static brain insult. For example, spasticity and primary etiology in every case. The use of CP as a quasi- weakness may functionally increase as a result of body diagnostic label is likely to endure for several reasons, growth, and dystonia may emerge years after the initial 12,13 including its long-standing history, broad recognition by brain injury. We do include some slowly progres- the lay community, and the practical consideration that sive conditions in which progression may not be evident many non-neurological specialists are typically involved in in the first years of life because of the interaction the care of children with chronic motor disability. between disease progression and normal development. This brings us to the question: what should be considered Some, but not all, CP registries re-evaluate patients a “CP mimic?” If one considers CP to be a syndrome rather through age 5 years to confirm the diagnosis of CP, per- than a diagnosis, genetic diagnoses are not necessarily mitting the detection of both patients with progressive excluded. But, in practice, CP is often considered to be syn- disorders, and patients with mild symptoms that were 8,14 onymous with long-term neurological sequelae of a perina- not evident at an earlier age. tal or infantile brain injury: complications of prematurity 3. Normal or nonspecific neuroimaging findings. Although such as intraventricular hemorrhage and periventricular neuroimaging is not required to diagnose CP, it is of great leukomalacia, neonatal hypoxic-ischemic encephalopathy, assistance in the recognition of the etiology and patho- 14 CNS infection, or trauma. For the purposes of this review, genesis. It is known that over 80% of patients with CP we consider a CP mimic to be a condition that manifests attributed to acquired brain injury show evidence of 15 with a clinical syndrome consistent with CP, in the absence brain abnormalities on neuroimaging, with white mat- of documented risk factors or neuroimaging findings con- ter injury being the most common imaging pattern sistent with a history of brain injury or a congenital cerebral (19–45%), followed by gray matter injury (21–25%), malformation. focal vascular insults (10–13%), malformations 15,16 A number of genetic and metabolic disorders may pre- (11–17%), and miscellaneous findings (4–22%). sent with clinical features that fit a CP phenotype. Some of Characteristic lesions described in patients with typi- these disorders may be thought of as developmental (symp- cal CP attributed to acquired brain injury include per- tomatic from birth and nonprogressive), while others are iventricular leukomalacia (PVL), thalamic and basal neurodegenerative (onset at variable intervals postnatally, ganglia ischemic lesions, cerebral hemorrhage or with progressive symptoms). A precise etiological diagnosis ischemic stroke, and cerebral dysgenesis. should always be sought because, while symptomatic treat- 4. Exclusion of conditions that typically present with ments may be prescribed independent of the primary diag- predominant intellectual disability, autism, encepha- nosis, the confirmation of a genetic diagnosis has important lopathy, or epilepsy. We do, however, discuss some implications for the patient and family. Critically, some of the epileptic-dyskinetic encephalopathies in which neurometabolic conditions have disease-specifictreatments motor phenotypes with absent or mild epilepsy have that may dramatically improve symptoms and develop- been described in a number of patients. mental outcome. Determination of a genetic diagnosis can We aim to add our perspective to two previously publi- lead to an improvement of quality of life for the patient and shed systematic reviews on the topic of genetic and metabolic family, independent of treatment options, by relieving pos- 17,18 sible feelings of ambivalence or guilt.7 Genetic counseling disorders that may resemble CP by providing