Hereditary Diffuse Leukoencephalopathy With Axonal Spheroids Research Articles

Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids Mistaken for Stroke: A Case Report

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disorder that is caused by colony stimulating factor 1 receptor gene mutation degenerating the cerebral white matter. It is characterized by various symptoms such as progressive cognitive decline, personality changes, and motor disorders. Since these clinical features are not consistent, HDLS is often underdiagnosed or misdiagnosed. This case report presents a patient priorly diagnosed with cerebral infarction by clinical features, but eventually with HDLS by a genetic test.

A novel mutation in CSF1R associated with hereditary diffuse leukoencephalopathy with spheroids.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant disorder with high penetrance characterized by progressive cognitive and motor dysfunction. The objective of the study was to describe a new variant of the colony stimulating factor-1 receptor (CSF1R) gene causing HDLS in a Chinese family. Physical examinations, laboratory tests, structural neuroimaging studies, and whole-exome sequence analysis were carried out. Three patients in this family exhibited typical manifestations of HDLS, including progressive cognitive impairment, language and motor dysfunctions, and urinary and bowel incontinence. Genetic analysis identified a heterozygous missense mutation (c.2264T>C, p.L755P) in exon 17 of the CSF1R gene that cosegregated with the HDLS phenotype in an autosomal-dominant pattern. Brain MRI of the proband and her father showed diffuse white matter changes. The proband's 10-year-old son, a gene carrier, remains clinically asymptomatic at present. Our findings identify a novel missense mutation, p.L755P, in the CSF1R gene within a Chinese family with autosomal-dominant HDLS and broaden the genetic spectrum of CSF1R-associated HDLS.

P1-14-04. Pyramidal tract evaluation by transcranial magnetic stimulation in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

P1-14-04. Pyramidal tract evaluation by transcranial magnetic stimulation in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

P2‐288: TWO NOVEL MUTATIONS IN CSF1R CAUSING HEREDITARY DIFFUSE LEUKOENCEPHALOPATHY WITH AXONAL SPHEROIDS (HDLS)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a neurodegenerative disease presenting in midlife and associated with rapidly progressive cognitive, behavioral and motor symptoms. HDLS results from mutations in the CSF1R gene and is inherited in an autosomal dominant pattern. We describe the clinical and neuroimaging features of two cases of HDLS evaluated at our medical center.and compare them with previously reported cases. Both patients had clinical genetic testing done revealing mutations in CSF1R. Patient 1 is a 46 year old woman who initially presented with gait changes and dysarthria, with rapid progression of bulbar and cognitive symptoms over 18 months, and was found to have a mutation in exon 19, c.2519C>G (p.Ser840Cys). Patient 2 is a 56 year old man presenting with 3 years of depression and memory problems without significant motor symptoms in the context of a family history of early onset dementia syndrome in his mother and prior diagnosis of HDLS in his maternal aunt; he was also found to have a mutation in exon 19, c.2480T>A (p.Ile827Asn). Both patients demonstrated extensive white matter hyperintensities and thinning of the corpus callosum on their MRIs with Patient 1 having cavitary lesions. Both mutations are located in the tyrosine kinase domain of the protein at or near the location of previously described mutations. Both mutations are predicted to be probably damaging by Polyphen with a score of 1.0. To our knowledge, these are the first reported cases of HDLS associated with these mutations. As has been described in the literature, the female patient had a younger age of onset than the male. Clinicians should be aware of the diversity of clinical presentations of HDLS and consider genetic testing for atypical dementia syndromes associated with significant white matter changes.

Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu-Hakola disease: lesion staging and dynamic changes of axons and microglial subsets.

The brains of 10 Japanese patients with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) and eight Japanese patients with Nasu-Hakola disease (N-HD) and five age-matched Japanese controls were examined neuropathologically with special reference to lesion staging and dynamic changes of microglial subsets. In both diseases, the pathognomonic neuropathological features included spherically swollen axons (spheroids and globules), axon loss and changes of microglia in the white matter. In ALSP, four lesion stages based on the degree of axon loss were discernible: Stage I, patchy axon loss in the cerebral white matter without atrophy; Stage II, large patchy areas of axon loss with slight atrophy of the cerebral white matter and slight dilatation of the lateral ventricles; Stage III, extensive axon loss in the cerebral white matter and dilatation of the lateral and third ventricles without remarkable axon loss in the brainstem and cerebellum; Stage IV, devastated cerebral white matter with marked dilatation of the ventricles and axon loss in the brainstem and/or cerebellum. Internal capsule and pontine base were relatively well preserved in the N-HD, even at Stage IV, and the swollen axons were larger with a higher density in the ALSP. Microglial cells immunopositive for CD68, CD163 or CD204 were far more obvious in ALSP, than in N-HD, and the shape and density of the cells changed in each stage. With progression of the stage, clinical symptoms became worse to apathetic state, and epilepsy was frequently observed in patients at Stages III and IV in both diseases. From these findings, it is concluded that (i) shape, density and subsets of microglia change dynamically along the passage of stages and (ii) increase of IBA-1-, CD68-, CD163- and CD204-immunopositive cells precedes loss of axons in ALSP.

Characterization of spheroids in hereditary diffuse leukoencephalopathy with axonal spheroids

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a neurodegenerative disease clinically characterized by slowly progressive cognitive decline and motor dysfunction. Neuropathology shows diffuse degeneration in the white matter, with prominent presence of widespread axonal spheroids. To investigate the mechanism underlying HDLS neurodegeneration, we characterized spheroids and examined their development in the degenerated white matter. Analysis revealed that the spheroids are an early neuropathological manifestation in the white matter degeneration and involve axonal component proteins and α-synuclein. The development of spheroids facilitates in initiating neurodegeneration in HDLS.

Adult-Onset Genetic Leukoencephalopathies. Focus on the More Recently Defined Forms.

Inherited white matter (WM) disorders include a heterogenous group of disorders affecting brain white matter and associated with myelin, axonal and glial cells or vascular pathology. Often a wide range of overlapping neurological manifestations possibly associated with variable systemic involvement are found in these disorders making clinical diagnosis challenging. Advances in molecular genetics enabled the identification of the responsible genes of an increasing number of previously undefined forms. This review focuses on genetic leukoencephalopathies with exclusive adulthood presentation, most of which have an autosomal dominant inheritance. The most common forms are related to vascular pathology, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy (RVCL), and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). Also cerebroretinal microangiopathy with cysts and calcifications (CRMCC), which presents a prevalent infantile onset, will be detailed because of the vascular based myelin damage and the recent genetic characterization. Other adult onset (AO) leukoencephalopathies, such as the recently genetically defined hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), adult-onset autosomal dominant leukodystrophy (ADLD) due to LMNB1 duplication, adult polyglucosan body disease (APBD), and fragile X-associated tremor/ataxia syndrome (FXTAS) will be detailed shortly. Short notes on the clinical and MRI features of late onset variants of the classical infantile-onset leukodystrophies mostly related to metabolic disorders will also be given. Finally, palliative, curative and experimental treatment options are here summarized.

Imaging features in conventional MRI, spectroscopy and diffusion weighted images of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease caused by mutations within the colony stimulating factor 1 receptor (CSF1R) gene. While a small number of reports on imaging findings in routine MRI exist, reported imaging findings in DWI and spectroscopy are scarce, and limited to not genetically proven case reports. We assessed MRI including DWI and MR spectroscopy in six patients with HDLS and two asymptomatic mutation carriers. A total of 13 MRIs were evaluated and a score of the white-matter lesion (WML) load was calculated. The course of MR abnormalities was followed for 6-19 months in four patients and 95 months in one carrier. MRI revealed widespread white-matter lesions of patchy or confluent pattern especially in the frontal and occipital lobe. The pyramidal tract was less affected than the surrounding tissue in all symptomatic patients on conventional T2WI. Three of four cases with DWI showed small dots of diffusion restriction within WML. Spectroscopy showed increased levels of mIns, Cho and lactate while NAA was decreased. Asymptomatic mutation carriers had, for the age of the patients, unusually pronounced unspecific WMLs. No diffusion restriction or alterations in metabolite levels could be detected in asymptomatic mutation carriers. Microbleeds were not found in any patient. Diffusion restriction seems to be a typical imaging pattern visible in patients with active disease progression in HDLS. Spectroscopic findings and the absence of microbleeds differ clearly from reported findings in CADASIL and subcortical arteriosclerotic encephalopathy. While the distribution and character of WMLs in asymptomatic cases remain unspecific they are likely to represent subclinical markers of HDLS.

Enlarging the Nosological Spectrum of Hereditary Diffuse Leukoencephalopathy with Axonal Spheroids (HDLS)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment-containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.

Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings ("spheroids"). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25-83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.

The new diagnostic methods of CADASIL as differential diagnosis of HDLS

Both hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are autosomal dominant white matter diseases. First symptoms of HDLS are cognitive decline or dementia, while those of CADASIL are migraine or ischemic infarcts. Family histories of young patients with stroke are important, because most of patients with CADASIL have these family histories. Temporal pole lesions are specific for CADASIL. However, some of the patients have no such lesions. We should differ CADASIL from non-CADASIL by evaluation of family history or the other MRI findings such as confluent external capsular lesions or multiple white matter medullary infarcts. Coronal views of MRI are useful for differentiating ischemic lesions from demyelinated lesions, even if horizontal views of MRI give little information. In addition, evaluation of immunohistochemical staining of Notch3 by frozen skin samples is useful for diagnosis. We discovered the methods of detecting light microscopic findings of GOM in frozen section. To reveal the pathogenesis of CADASIL, it is indispensable to analyze the chemical nature of GOM by histochemical stainings. We are going to analyze coexist proteins or materials in small arterial granular degeneration by proteomics of LC/ MS/ MS.

De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.

CSF1R mutations link POLD and HDLS as a single disease entity

Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD. We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed. We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R. We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.

Clinical, Imaging and Histopathological Features of Adult Onset Leukoencephalopathy with Neuroaxonal Spheroids and Pigmented Glia: A Report of 4 Cases (P02.149)

Objective: To report on a series of 4 patients with Adult onset Leukoencephalopathy with Neuroaxonal Spheroids and Pigmented glia (ALSP). Background ALSP is a rare adult onset leukodystrophy, encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), which had previously been considered separate entities. Design/Methods: Retrospective chart review. Results: Four previously healthy women presented with a rapidly progressive neurological disorder with insidious onset at age 39, 37, 40, and 30 respectively, and were initially diagnosed as multiple sclerosis (MS). One patient had a sister who was diagnosed with MS and died 18 months later, and another had multiple female family members spanning four generations that died soon after being diagnosed with MS or dementia. The other 2 did not have a family history. The clinical courses of the 4 patients were stereotypical with progressive spastic quadriparesis and progressive neurological decline. The major features seen on brain MRI included diffuse cerebral atrophy with corpus callosal atrophy evident at an early stage, diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions, and involvement of pyramidal tracts from motor cortex to the brainstem in two patients who had late stage MRIs. Cerebrospinal fluid was normal in all cases. The correct diagnosis of ALSP was established by biopsy (2 cases) and autopsy (2 cases). Histopathology showed the presence of neuroaxonal spheroids in all cases and pigmented glia in two. Conclusions: ALSP may be suspected in adults with rapid to subacute progression of neurological disease, when (i) MRI shows corpus callosal atrophy on a background of generalized brain atrophy, diffuse white matter disease without postcontrast enhancement, (ii) CSF studies are normal, and (iii) studies for systemic inflammatory diseases and specific leukodystrophies are normal. However, despite suggestive MRI changes reported in our series, a brain biopsy remains essential for definitive diagnosis. Disclosure: Dr. Kleinfeld has nothing to disclose. Dr. Mobley has nothing to disclose. Dr. Wegner has nothing to disclose. Dr. Pawate has nothing to disclose.

HDLSの疾患概念と国内報告例のレビュー

Leukoencephalopathy or leukodystrophy is characterized pathologically by extensive degenerative and/or demyelinating lesions in cerebral white matter and produces various clinical manifestations such as behavioral and/or mood changes, dementia, motor impairment and epilepsy. The hereditary form of this disease is rare, but recent advances in diagnostic techniques have made it possible to make a correct pre-mortem diagnosis for some diseases including CADASIL and CARASIL. Recently, another unique form of the disease, hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) has been noted. The clinical picture of HDLS is as follows: age of onset ranging from 8 to 78 years (average: 39 years), autosomal dominant inheritance, and dementia. The presence of numerous neuroaxonal spheroid in cerebral white matter is one of the pathologic hallmarks of HDLS. Another term "familial pigmentary orthochromatic leukodystrophy (POLD)" has been also used for the patients showing similar clinical pictures and pathologic findings of the patients. Both disorders are now regarded as a single disease entity. Rademakers et al have just reported that HDLS is caused by mutation in the colony stimulating factor 1 receptor gene (CSF1R) and HDLS should be included in the differential diagnosis of familial occurrence of pre-senile dementia.

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

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.

Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD) present as adult-onset dementia with motor impairment and epilepsy. They are regarded as distinct diseases. We review data from the literature that support their being a single entity. Apart from a slightly older age at onset, a more rapid course, and more prominent pyramidal tract involvement, familial POLD is clinically similar to HDLS. Moreover, the pathologic hallmarks of the two diseases, axonal spheroids in HDLS and pigmented macrophages in POLD, can be identified in both conditions. This supports HDLS and POLD being referred collectively as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).