Hereditary diffuse leukoencephalopathy with spheroids - a volumetric and radiological comparison with multiple sclerosis patients and healthy controls.

BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder caused by colony-stimulating factor 1 receptor (CSF1R) gene mutations, resulting in demyelination and axonal degeneration with spheroids. The clinical expression is variable, including behavioral changes, cognitive impairment, motor symptoms and parkinsonism. Magnetic resonance imaging (MRI) reveals white matter (WM) changes and atrophy. The indistinct phenotype has led to misdiagnoses. This study's aim was to compare brain volumetry and radiological ratings in HDLS with multiple sclerosis (MS) patients and controls. METHODS: Five HDLS patients with c.2562T>A p.Asn854Lys CSF1R mutation, five age- and gender-matched MS patients and five healthy controls were cross-sectionally studied. All patients were examined neurologically. HDLS patients underwent Mini-Mental State Examination (MMSE). Brain MRI scans were analyzed volumetrically with FreeSurfer and Lesion Segmentation Toolbox and neuroradiologically with the brain MRI scoring system for HDLS. RESULTS: Patients with HDLS had lower brain, grey matter and WM fractions (66.3%; 37.9%; 27.6%) compared with controls (78.5%, P = 0.008; 44.4%, P = 0.008; 32.0%, P = 0.008), but not compared with MS patients (65.7%, P = 0.7; 36.8%, P = 0.4; 27.3%, P = 0.7). Cerebellar WM changes and atrophy were not seen in the HDLS group. The HDLS lesion volume fraction correlated with MMSE scores (r = -0.90, P = 0.04). CONCLUSIONS: Brain volume fractions in HDLS were lower than in controls and similar to those seen in MS. The cerebellum was relatively spared in HDLS, which may help in differentiating HDLS WM changes from MS. The strong relationship of HDLS lesions with MMSE scores indicates that accumulating WM pathology in HDLS is associated with cognitive decline.

Update of the original HDLS kindred: divergent clinical courses.

BACKGROUND: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first identified among a Swedish kindred with 17 cases. The average age of onset was 36 years. Autopsy in four cases revealed the presence of axonal spheroids. The causative gene is unknown. METHODS: We performed genealogical and longitudinal observations of the original kindred. Forty members were examined, five telephone-interviewed, and one of the original HDLS cases from 1984 was neuropathologically examined. The clinical course was documented. The cerebrospinal fluid (CSF) findings of two recently affected cases were examined, and one of those autopsied. RESULTS: Of those examined, two developed HDLS during our survey and 38 were healthy. Those interviewed by telephone were healthy. One had symptoms suggestive of HDLS in 1984, but autopsy during our survey showed no spheroids. This patient, two relatives healthy at our examination and one without symptoms at telephone interview had HDLS diagnoses in the 1984 report. Thus, four HDLS diagnoses were unconfirmed. The number of identified patients amounts to 15 among 75 individuals in four generations, including two recent cases who demonstrated a subacute multisystem encephalopathy in Case 1 and an insidious course in Case 2. CSF showed signs of neurodegeneration without inflammation, and autopsy verified HDLS in Case 1. CONCLUSIONS: Some HDLS cases were misdiagnosed with unspecified psychiatric diagnoses in affected relatives from the original 1984 publication. However, HDLS is an encephalopathy dominated by a frontal lobe syndrome with an inexorably progressive and fatal course, where the different symptomatology in two recent cases confirmed the existence of acute and chronic variants.

White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings.

BACKGROUND: Leukoencephalopathies are a heterogeneous group of severe encephalopathy syndromes with myelin, axonal or vascular pathology, typically with extensive white matter lesions on MRI T2-FSE and/or -FLAIR sequences. OBJECTIVES: This review is restricted to leukoencephalopathies with onset in adult age and a dominant inheritance. These diseases are generally severe and often lethal and present with an exacerbating or insidiously progressive course. MATERIAL AND METHODS: The focus is on four syndromes with pure leukoencephalopathies, however, leukoencephalopathies with associated clinical features are included. RESULTS: T2 weighted MR imaging often show features common for leukoencephalopathies, yet shows distinguishing features in transthyretin amyloidosis. CONCLUSION: The diagnosis within the group of leukoencephalopathies thus characterized by MRI relies mainly upon clinical and genetic analysis. The differential diagnosis against treatable leukoencephalopathies is increasingly relevant.