Diffuse Leukoencephalopathy and Ischemic Stroke in Hunter Syndrome: Interesting Case with Review of Literature
Year: 2025
Type: article
Abstract: Dear Editor, Mucopolysaccharidosis type II (MPS II, Hunter syndrome, #MIM 309900) is a rare, X-linked recessive, childhood-onset lysosomal storage disorder resulting from deficient activity of the iduronate 2-sulfatase enzyme (IDS) that results in intra- and extracellular accumulation of glycosaminoglycans heparan sulfate and dermatan sulfate in the body. The enzyme is encoded by the IDS gene (#MIM 300823) located on chromosome Xq28 and consists of nine exons. The disease is named after Charles Hunter, who first reported the condition in two brothers in 1917.[1] Progressive accumulation of glycosaminoglycans affects several organs in the body, resulting in a typical facial profile and musculoskeletal manifestations, which provide a clue to the underlying storage disorder.[2,3] Neurological manifestations are common in the severe or early progressive phenotype of Hunter disease and include initial early developmental delay or progressive cognitive decline after a few years of normal development, macrocephaly with or without hydrocephalous, and behavioral abnormalities. Ischemic stroke is uncommon in children with MPS II and is not considered a common complication. An 11-year-old boy with Hunter syndrome (not on enzyme replacement therapy (ERT)) presented with on-and-off high-grade fever for the past two months, progressive exertional dyspnea, and acute-onset left hemiparesis with left-sided facial palsy. He had been on oral and intravenous antimicrobials from the local hospital intermittently, but did not respond completely. There was no history of altered sensorium, seizures, extrapyramidal symptoms, or cerebellar involvement. He was 4th born to non-consanguineously married couple with a diagnosis of Hunter syndrome in an elder brother and maternal uncle; both expired in the second decade of life. On examination, he had coarse facial features [Supplementary Figure 1a] with clear cornea, hearing impairment, pallor, pandigital clubbing, and pansystolic murmur in the mitral area radiating to axilla and the back, hepatomegaly (6 cm below right costal margin), and splenomegaly (4 cm below left costal margin). Nervous system examination showed normal cognition, normal fundi, bilateral finger and ankle contractures, left hemiparesis (proximal power 3/5 and distal power 1/5) with ankle clonus, left-sided supranuclear facial palsy, and Babinski’s sign. A clinical diagnosis of infective endocarditis with acute ischemic stroke (cardioembolic/thrombotic or vasculitis) with congestive cardiac failure in Hunter syndrome was considered. He was initiated on subcutaneous enoxaparin and supportive care. Echocardiogram showed a thickened mitral valve with severe regurgitation, severe aortic regurgitation, mild tricuspid regurgitation, severe pulmonary artery hypertension, enlargement of all four chambers with normal biventricular function, and a healed vegetation of 3–4 mm on the anterior mitral leaflet. He was initiated on injection vancomycin (60 mg/kg/day) and meropenem (60 mg/kg/day) for infective endocarditis and injection furosemide, enalapril, and carnitine supplementation for cardiomyopathy, along with respiratory support. Magnetic resonance imaging (MRI) of the brain showed an acute infarct on the right side, ventriculomegaly, prominent perivascular spaces, and leukoencephalopathy [Figure 1a-f]. Radiographs showed dysostosis complex [Supplementary Figure 1b and c]. His course was complicated by health-care associated infection and calf muscle hematoma secondary to enoxaparin therapy.Figure 1: Axial T2w (a) and FLAIR (b) images show white matter hyperintensity in the periventricular regions (red arrows). Multiple dilated perivascular spaces in cribriform appearance are also seen (black arrows). Sagittal T1w image (c) shows J-shaped Sella (arrowhead). Axial FLAIR (d) and Axial DW images (e) show hyperintensity (stars) in the right MCA territory cortical subcortical region, suggestive of acute infarct. Time of Flight MR angiography image (f) shows attenuated right M1 segment of MCA (curved arrow). MCA: Middle cerebral artery, MR: Magnetic resonance, FLAIR: Fluid-attenuated inversion recovery, DW: Diffusion-weightedWe also searched PubMed literature using the search terms (((Mucopolysaccharidosis type II) OR (HUNTER SYNDROME)) OR (MPS II)) AND ((stroke) AND (infarction)) to look at the profile of children or adults with stroke. Fifty-three articles were retrieved in the English language. Cross-references were checked for any other reports of stroke in MPS II. The search strategy used above yielded three reports of anterior circulation stroke in patients with MPS II, which are compared with the present case in Table 1.[4-6]Table 1: Review of published cases of stroke in children and adults with MPS II and comparative findings with the index caseDiffuse cerebral atrophy, ventriculomegaly (or hydrocephalous), and variable leukoencephalopathy with widened perivascular spaces are the commonly described neuroimaging features in MPS II. However, cerebral infarction is a rare complication in MPS II, both in children and adults.[7] The presence of ischemic strokes has been described more commonly in MPS I, both as a neurological and post-operative complication.[8] Our case is probably the first report of ischemic stroke in a child with untreated MPS II from India. We found only three other reports of ischemic stroke in children (one case) and young males (two cases) with MPS II. Based on the disease pathophysiology and ensuing cardiac complications, several risk factors may contribute to the occurrence of ischemic strokes in MPS II. Cardiac valvulopathy resulting in thickening and fibrosis may generate cardiac thrombi, which embolize to the cerebral circulation.[5,7] Such valves are also predisposed to infective endocarditis, which may lead to endocarditis/embolism-associated stroke as seen in our case. Extracellular dermatan sulfate deposition affects matrix assembly, leading to pan-arterial vasculopathy with myointimal proliferation and luminal narrowing. This may occur in the cerebral, cardiac, and aorta, leading to stroke, myocardial infarction, and systemic hypertension. Disease-associated obesity, hyperlipidaemia, and atheromatous disease have also been postulated as possible contributory factors. Systemic infection and chronic pro-inflammatory state via activation of toll-like receptor-4 (TLR-4) can also contribute to focal arteritis. It is postulated that vasculopathy may slowly progress despite early ERT, which explains the occurrence of stroke in stabilized patients with MPS II on ERT. Hence, the incidence of ischemic strokes as a neurological complication can be expected to increase due to the increased survival of MPS II patients on treatment. Hence, knowledge about this potential complication and timely measures are needed to improve the care of children with MPS II.[6] Acute management of stroke in MPS includes MRI/magnetic resonance angiography (MRA) for diagnosis, supportive care, and initiation of antithrombotic therapy—aspirin for arterial ischemia or anticoagulation if cardioembolism is suspected. Thrombolysis is generally avoided due to vascular fragility and limited evidence. Secondary prevention involves long-term antithrombotics, disease-modifying treatments like enzyme replacement therapy or hematopoietic stem cell transplantation, and management of comorbidities. Regular neuroimaging, cardiac evaluations, and sleep studies are essential for monitoring and individualized stroke prevention in affected children. Another interesting feature in our case was the typical but florid leukoencephalopathy, probably related to disease progression.[9] White matter changes are typically periventricular and patchy in distribution.[10] A characteristic “honeycomb-like” appearance in the basal ganglia and thalami is also described, which is probably secondary to multiple mechanisms such as glycosaminoglycans accumulation in neuronal cells leading to oligodendrocyte dysfunction, impaired myelination, neuroinflammation, increased fluid in periventricular spaces, lacunar infarction, glycosaminoglycans-induced microglial activation, and mitochondrial stress. Secondary axonal degeneration and blood-brain barrier disruption further exacerbate demyelination, manifesting as T2 hyperintensities and cerebral atrophy on neuroimaging. Sometimes, cystic enlargement of Virchow-Robin spaces in the periventricular regions, and occasionally in the corpus callosum, thalami, basal ganglia, and subcortical regions, gives a “cribriform” or “sieve-like” appearance and Hurler holes.[9,11] Other neuroimaging findings include hydrocephalus, dilated subarachnoid spaces, posterior fossa abnormalities, and myelopathy.[9,10] One or several of these mechanisms results in the typical presentation in our case. In conclusion, our interesting case highlights the presence of ischemic strokes in neurometabolic disorders such as MPS II often due to combined injury to the heart and the cerebral vessels. The management in such cases can be extremely difficult and hinges on the early initiation of enzyme replacement therapy. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.Supplementary Figure 1: Index case (a) clinical picture of the face showing coarseness of facial features (b) skull radiograph showing J-shaped sella turcica (c) chest radiograph showing cardiomegaly and oar-shaped ribs
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4413138310