Novel Hypomyelinating Leukoencephalopathy Affecting Early Myelinating Structures

Abstract

To describe 4 children with a novel hypomyelinating leukoencephalopathy, defined by a distinct pattern of magnetic resonance imaging (MRI) abnormalities.Design: In our ongoing study on leukoencephalopathies of unknown origin, MRIs of patients are rated in a standardized manner. Patients are grouped according to their MRI abnormalities. The clinical and laboratory data are retrospectively reviewed. Subjects:The MRIs of approximately 3000 patients with a leukoencephalopathy of unknown origin were initially evaluated. Four unrelated patients (all male, aged 1.8-7.4 years) displayed similar MRI alterations.Results: Patients displayed mild T2 hyperintensity of the medulla oblongata, caudal part of the pons, hilus of the dentate nucleus, peridentate white matter, subcortical cerebellar white matter, optic radiation, and frontoparietal periventricular white matter. The posterior limb of the internal capsule showed alternating T2 hyperintensehypointense-hyperintense stripes in 3 patients. The T1weighted images showed hyperintensity, isointensity, or mild hypointensity of T2 hyperintense structures. The thalamus had a neonatal appearance with a mildly hyperintense signal except for a darker lateral part. Clinically, patients presented with nystagmus between ages 6 and 20 months. Over time, cerebellar ataxia and mild spasticity developed. All achieved unsupported walking. Cognition and language were normal. Known causes of hypomyelination were excluded. Conclusions:The patients share a striking pattern of MRI abnormalities and have a similar clinical picture, suggesting that they have the same disorder. The hypomyelination in this disorder specifically occurs in structures that normally myelinate early. We hypothesize that the disease is caused by a defect in a gene involved in early myelination.

Novel Hypomyelinating Leukoencephalopathy Affecting Early Myelinating Structures: Clinical Course in Two Brothers

“…We described two new patients presenting a clinical and radiologic picture consistent with the recently described leukoencephalopathy, named HEMS. 4 The clinical picture was similar to that of the previously reported patients, although our patients, who have never achieved the ability to walk, were more severely affected. From the neuroradiologic point of view, the findings of the first MRI examinations performed in the two brothers are similar to the neuroradiologic pictures of the previously described patients.…”

“…The fact that our two patients are both males lends weight to the hypothesis that inheritance of this disorder could be X-linked. 4 It is of note that the older of our two patients has the longest clinical and MRI follow-up available to date. None of the patients reported to date was older than 6 years.…”

“…3 At the start of 2012, Steenweg et al described a novel leukoencephalopathy, which they termed hypomyelinating leukoencephalopathy affecting early myelinating structures (HEMS). 4 They reported 4 male patients who presented with nystagmus between 6 and 20 months of age and thereafter developed cerebellar signs and mild spasticity, predominantly affecting the legs. The boys were all sporadic observations except for one, who had a brother and two maternal relatives probably affected by the same disease.…”

Advances In the Diagnosis of Leukodystrophies

“…A new distinct pattern of hypomyelination has been recently described in four boys [26]. Hypomyelinating leukoencephalopathy affecting early myelinating structures is presumed to be X-linked.…”

POLR3A and POLR3B Mutations in Unclassified Hypomyelination

“…There is no cerebral or cerebellar atrophy (I-L). patient was diagnosed with hypomyelination of early myelinating structures (HEMS), 22 one with hypomyelination with brain stem and spinal cord involvement and leg spasticity 23 after the radiological criteria of these entities had been defined. Three patients from two families were found to have RARS-associated hypomyelination, also by wholeexome sequencing.…”