Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): A misdiagnosed disease entity

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Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US.

We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS.

HDLS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis.

Introduction

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) was first identified in a Western Swedish family reported in 1984 [1]. There have been 13 kindreds [2], [3], [4], [5] and 11 sporadic cases [2], [6], [7], [8], [9] since that first report. HDLS is probably closely related to familial pigmentary orthochromatic leukodystrophy (POLD) or is within the same disease spectrum [2]. The pathological hallmark of this disease is the presence of brain white matter changes with neuroaxonal spheroids present [1]. Inheritance is autosomal dominant with variable penetrance, but the causative genes are unknown. HDLS is characterized by a constellation of symptoms including personality changes, cognitive dysfunction and motor impairments such as gait dysfunction, tremor, bradykinesia and rigidity. Brain MRI shows white matter lesions in a frontal predominant distribution, spreading out from the periventricular and deep white matter into the subcortical areas with enlarged ventricles and often signal changes in corpus callosum. Van Gerpen et al. reported a HDLS case with serial MRI's. In the presymptomatic stage, MRI demonstrated subtle patchy abnormalities in the periventricular white matter, which later on subsequent MRI, performed when patient was in advance stage of disease, became widespread and confluent [3]. This important observation suggests that the disease process in the brain starts locally and then becomes more widespread with disease progression.

An international consortium on HDLS was established in 2005 by one of the authors (ZKW) after the first Mayo Clinic kindred with HDLS was reported [10]. Since then, 14 additional families have been collected at the Mayo Clinic and 4 have been reported [2], [3]. In our research study brains and brain biopsy specimens have been collected both retrospectively and prospectively. All have been examined by DWD, and only those demonstrating pathological features of HDLS were included in our study. Based on our collection we found that all of the 20 cases were misdiagnosed (unpublished data). Therefore, we describe here the HDLS cases from the smallest families as the evidence of familial clustering indicating a genetic disorder is not always obvious. Phenotypic variability may occur in the affected members of a given kindred, and can misleadingly be interpreted as two unrelated sporadic disorders. Diagnoses of HDLS in small families can therefore be challenging and particularly difficult since there is often not a convincing family history.

However, there is strong evidence that HDLS is a genetic disorder due to the larger families, both reported and unpublished, who show an autosomal dominant heredity [1], [3], [10].

Based on our Mayo Clinic HDLS collection and published reports, HDLS patients may be misdiagnosed with Alzheimer's disease (AD), frontotemporal dementia (FTD), atypical parkinsonism (AP), Multiple Sclerosis (MS) and/or small vessel diseases. Herein we report three new HDLS families to increase the awareness of this disorder and discuss the differential diagnoses from the clinical, imaging, and pathological perspective.

Section snippets

Clinical and genealogic studies

We retrospectively reviewed the medical records of three kindreds that were previously collected from a world-wide collaboration on HDLS organized by the Mayo Clinic Florida by one of the authors (ZKW).

The probands of our families included in this report were identified and longitudinally followed in Norway, Germany, and the US. A written informed consent approved by the Mayo Clinic Institutional Review Board was obtained in order to perform the reviews of clinical, radiological and

Results

Short case reports are provided below. Summary of the clinical characteristics and laboratory investigations of our probands are provided in Table 1. Pedigrees are presented in Fig. 1.

Discussion

HDLS is a devastating neurodegenerative disease with adult onset. The disease is inherited in an autosomal dominant fashion, but the genetic defect has not yet been identified. It is thought that HDLS is caused by primary disruption of the axon integrity, neuroaxonal damage, and focal axonal swelling (axonal spheroids) leading to secondary demyelination [10], [11]. However, demyelination may precede the axonal damage [12], triggering an autonomous neurodegenerative process.

Neuropathology of our

Conflict of interest

Sundal: Anna-Lisa och Bror Björnssons-, Sven and Dagmar Saléns-, Signe och Olof Wallenius- and Gamla Tjänarinnor Foundations, Sweden. The Swedish Society of Medicine Gothenburg (GLS), Sweden, The Swedish Society of Medicine Sweden, The Swedish and Gothenburg Societies for the Neurologically Disabled and The Gothenburg Foundation for Neurological Research.

Lash: None

Aasly: None

Øygarden: None

Roeber: BMBF (Brain-Net-Germany 01GI0505)

Kretzschman: BMBF (Brain-Net-Germany 01GI0505)

Garben: None

Tselis:

Acknowledgements

Work was partially supported by the NIH/NINDS, , , Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052).

CS was sponsored by Anna-Lisa och Bror Björnssons, Sven and Dagmar Saléns, Signe och Olof Wallenius and Gamla Tjänarinnor Foundations, Sweden. The Swedish Society of Medicine Gothenburg (GLS), Sweden, The Swedish Society of Medicine Sweden, The

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