Early Recognition of Patients with Neuronopathic Forms of Mucopolysaccharidosis Type II in Clinical Practice

Background: Mucopolysaccharidosis type II (MPS II) is a progressive, rare, X-linked inherited disease with multi-organ involvement and a restricted life expectancy. The disease has two main forms: neuronopathic (severe) and non-neuronopathic (attenuated). Aim: To compare the two main forms of MPS II to identify signs for early recognition of severe disease forms in daily practice. Methods: In this retrospective cohort study, clinical and laboratory data, as well as enzyme replacement therapy data, for approximately 162 patients were extracted and analyzed from the Russian MPS II registry. Patients with insufficient clinical information (23 patients) and children under 5 years of age (15 patients) were excluded. We compared patients with MPS II neuronopathic (n = 82, 66.1%) and non-neuronopathic forms (n = 42, 33.9%) based on the presence of cognitive deficits after age 6 years and on remaining committed to the phenotype throughout follow-up. Results: The patients with both forms had the following symptoms with similar frequency: Hurler phenotype, hernias, hepatosplenomegaly, short neck, orthopedic problems: spinal pathology (curvature), chest deformity, joint stiffness, deformity of the hand, hand contractures, wrist joint deformity and contractures, elbow joint deformity and contractures, shoulder and knee deformity and contractures, hip contractures, cardiomyopathy, obstructive respiratory tract diseases, noisy breathing, hearing loss, carpal tunnel syndrome. Highly specific symptoms (frequency of occurrence above 80%) for the diagnosis of the neuronopathic form of MPS II were: delayed intellectual disability at the age of 1-3 years, epilepsy, and the presence of gross rearrangements in the IDS gene. Highly sensitive symptoms (above 80%) were: psychomotor development delay of up to 1 year of age and delayed intellectual disability at the ages of 1-3 years, heart damage, and myxomatous degeneration of the valves (79.5%). A symptom with high sensitivity and specificity is delayed mental and speech development between the ages of one and three, with respective sensitivities and specificities of 94.8 and 86.5. Conclusions: Identifying symptoms characteristic of neuronopathic forms of MPS is important not only for determining the clinical form of the disease but also for developing various approaches to treating such patients. Early diagnosis of severe forms of MPS II will make it possible to use currently approved methods of intraventricular enzyme replacement therapy, or primarily use of ERT capable of crossing the brain-blood barrier which could improve the prognosis for such patients. Symptoms that predict the risk of developing the neuronopathic form can be used in clinical practice.