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Neurometabolic Disorders Hunter Syndrome Hunter Syndrome (Mucopolysaccharidosis II) – The Signs and Symptoms a Neurologist Needs to Know Hernan Amartino Head of Child Neurology Department, Hospital Universitario Austral, Buenos Aires, Argentina Abstract Hunter syndrome (mucopolysaccharidosis II) is a rare X-linked lysosomal storage disease caused by deficiency of the enzyme iduronate-2- sulfatase. The condition is one of a group of disorders, the mucopolysaccharidoses, which all result in accumulation of glycosaminoglycans. Hunter syndrome is a chronic progressive disorder whose clinical manifestations vary widely in severity and involve multiple organs and tissues. In addition to developing somatic symptoms, patients having the neuronopathic form of the disease also display developmental delay and cognitive impairment in early childhood that progressively worsens and that is severely life-limiting. Patients are at risk of developing secondary neurological manifestations, including hydrocephalus, vision and hearing loss, carpal tunnel syndrome and spinal cord compression. Common findings from brain magnetic resonance imaging (MRI) scans and at autopsy include neurodegenerative changes in white matter, the corpus callosum and basal ganglia; enlargement of periventricular spaces; ventriculomegaly; closed cephaloceles; and tissue atrophy. Though at present there is no specific treatment for the neurodegenerative aspects of the disease, hydrocephalus, carpal tunnel syndrome and spinal cord compression can be managed surgically. Patients who have Hunter syndrome should receive coordinated care from a multidisciplinary team: in light of the extensive neurological symptoms of the disease, neurologists play an important role in the diagnosis and management of this condition. Keywords Hunter syndrome, mucopolysaccharidosis II, lysosomal storage disorder, developmental delay, cognitive impairment, neurology, neurological symptoms, seizures, spinal cord compression, neuronopathic Disclosures: Hernan Amartino is a consultant to Shire and a principal investigator on Shire-sponsored clinical trials. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Acknowledgements: Editorial support was provided by Andy Sheridan from Oxford PharmaGenesis™ and funded by Shire. Received: 13 March 2015 Accepted: 17 April 2015 Citation: European Neurological Review, 2015;10(1):90–4 Correspondence: Hernan Amartino, Jefe del Servicio de Neurología Infantil,Hospital Universitario Austral, Juan Domingo Peron 1500, Pilar (B16641NZ), Buenos Aires, Argentina. E: hernan.amartino@gmail.com Support: The publication of this article was supported by Shire. The views and opinions expressed are those of the author and do not necessarily reflect those of Shire. Hunter syndrome (mucopolysaccharidosis II, OMIM 309900), is a rare progressive X-linked lysosomal storage disease caused by deleterious mutations in the iduronate-2-sulfatase (I2S) gene, leading to a deficiency of the enzyme. 1,2 I2S is required for the catabolism of the glycosaminoglycans (GAGs) dermatan sulphate and heparan sulphate; in the absence of I2S, these GAGs accumulate in tissues and organs. 1 Hunter syndrome occurs with a reported incidence of 0.3–0.71 per 100,000 live births 1,3,4 and almost exclusively affects males, though rare cases of females having the disease are known. Patients suspected of having Hunter syndrome are often first screened by assessing urinary GAGs (quantitative and qualitative tests are available). However, a definitive diagnosis requires enzyme assay in leukocytes, fibroblasts, dried blood spots or plasma, using substrates specific for I2S. Molecular testing can confirm the diagnosis and may be used to screen family members when the type of MPS and the family mutation is known. 5,6 Charles Hunter first described the condition in 1917 in two brothers presenting with developmental delay. 7 Hunter syndrome is associated with multiple somatic symptoms affecting nearly every organ, including the cardiovascular, respiratory, gastrointestinal and endocrine systems. 8 90 Patients also develop characteristic dysmorphic facial features and stunted growth (see Figure 1). 8 Although the clinical phenotype of Hunter syndrome covers a wide continuous spectrum from mild to severe disease, patients are usually considered to be in one of two groups: those having the severe (neuronopathic) form of the disease and those having the attenuated (non-neuronopathic) form. 5,9 Approximately two-thirds of patients have neuronopathic Hunter syndrome and develop both the somatic symptoms and cognitive impairment. 8 This form of the condition is characterised by developmental delay that generally becomes apparent at 2–4 years of age and cognitive decline that occurs from approximately 4 years of age onwards (see Figure 2). 8,9 Neuronopathic Hunter syndrome is life-limiting, and the natural course of the disorder results in death in the second decade of life. 8,10 Enzyme replacement therapy (ERT) has been available for almost 10 years in Hunter syndrome and positively affects specific somatic symptoms. 11–13 Patients having the non-neuronopathic form of Hunter syndrome are more likely to have normal cognitive abilities but may experience some Tou c h ME d ica l ME d ia