Adult-onset Leukoencephalopathies Research Articles

Chapter 7 - White matter disorders with cerebral calcification in adulthood

This chapter provides a comprehensive overview of adult-onset leukoencephalopathies with cerebral calcification (CC), emphasizing the importance of age at presentation, systemic clinical features, and neuroimaging patterns for accurate diagnosis. CC is a multifaceted phenomenon associated with various neurologic, developmental, metabolic, and genetic conditions, as well as normal aging. Here, we explore the distinction between primary familial brain calcification (PFBC) and secondary forms, including metabolic and mitochondrial causes. We discuss genetic causes, e.g., SLC20A2, XPR1, PDGFB, PDGFRB, MYORG, NAA60 and JAM2, in the context of autosomal dominant and recessive PFBC and other inherited conditions. The chapter delineates the diagnostic approach involving family history, clinical assessments, and detailed investigations of calcium-phosphate metabolism. Neuroimaging modalities, including computed tomography and magnetic resonance imaging, are crucial for assessing calcification patterns and localizations. Genetic testing, especially next-generation sequencing, plays a pivotal role in providing a final molecular diagnosis. The management of patients with CC encompasses symptomatic treatment and cause-specific approaches, requiring a multidisciplinary care approach. In conclusion, this chapter highlights the complexity of leukoencephalopathies with CC, emphasizing the need for integrated and evolving management to optimize patient care.

Adult-Onset Genetic Leukoencephalopathies With Movement Disorders

Genetic leukoencephalopathies (GLEs) are a group of white matter abnormalities with heterogeneous radiological and phenotypic features. Although these conditions have mostly been described in children, adult-onset cases are increasingly recognized owing to the widespread use of neuroimaging and advances in molecular genetic testing. The disease course is often progressive with a varied spectrum of presentations, trapping neurologists in the dilemma of differential diagnosis. Movement disorders are among the most common symptoms, and their diversity makes diagnosis challenging. In this review, we focus on adult-onset GLEs with movement disorders and offer a step-by-step diagnostic approach by clarifying the phenomenology of movement, advising investigations for acquired causes, describing the clinical and radiological clues to each disease, emphasizing the limitations of advanced molecular testing, and discussing the future application of artificial intelligence. We provide a list summarizing the leukoencephalopathies associated with different categories of movement disorders. In addition to guiding clinicians on how to narrow the list of differential diagnoses with the tools currently available, another aim of this review is to emphasize the inevitable trend toward applying advanced technology in diagnosing these difficult diseases.

Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy.

Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.

Distinctive diffusion-weighted imaging features in late-onset genetic leukoencephalopathies.

Genetic leukoencephalopathies are inherited disorders characterized by progressive white matter involvement. Although most are paediatric conditions, late-onset adult leukoencephalopathies are being increasingly recognized. Adult leukoencephalopathies may present as neurodegenerative diseases with cognitive decline and motor symptoms. Similar to their paediatric counterparts, different adult leukoencephalopathies often have distinctive MRI appearances. In particular, DWI has been recently shown to demonstrate specific patterns of persistent diffusion restriction in several adult-onset leukoencephalopathies. As such, DWI may provide important clues to the diagnosis of adult-onset leukoencephalopathy. The purpose of this review is to discuss characteristic DWI features in some late-onset leukoencephalopathies.

An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids

Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after a systematic and recent assessment of several family members. We also report the results from exome sequencing analyses indicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult-onset CSF1R-negative leukoencephalopathies.

Cognitive dysfunction and symptoms of movement disorders in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

Adult-onset leukoencephalopathies are clinically and genetically heterogeneous disorders that affect predominantly the cerebral white matter of the central nervous system. Clinical and neuroimaging-based approaches have been developed to improve diagnostic processes for adult-onset leukoencephalopathies. However, the differential diagnosis is often challenging. Recently, knowledge of the genetic basis of leukoencephalopathies has been accumulated rapidly, which provides powerful diagnostic approaches. The article provides an overview of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), focusing on the clinical presentations of cognitive impairment and symptoms of movement disorders. ALSP is a subtype of dominantly inherited leukoencephalopathy caused by CSF1R mutations. ALSP typically develop in adulthood, with cognitive decline, psychiatric symptoms, and motor symptoms of movement disorders. Cognitive symptoms in ALSP are characterized by frontal lobe dysfunctions such as executive dysfunction, attention deficits and indifference. The cardinal motor symptoms of movement disorders ALSP were gait disturbance and bradykinesia, which may appear as the initial symptoms. Thus, ALSP should be recognized as both a cognitive disorder and a movement disorder.

Letter re: Mystery Case: CSF-1R mutation is a cause of intracranial cerebral calcifications, cysts, and leukoencephalopathy.

Ayrignac et al.1 presented an interesting case that highlighted the importance of CSF-1R in adult-onset leukoencephalopathies. However, we are concerned that the discussion by Dr. Ganesh in the Mystery Case Responses section confused 2 different diseases as the same.1 This case clearly described a typical presentation of CSF-1R-related disease with apparent autosomal dominant inheritance. However, Dr. Ganesh described this as a case of Labrune syndrome (leukoencephalopathy with calcifications and cysts), an autosomal recessive disorder caused by mutations in SNORD118 .2 While calcifications occur in both syndromes, they are far more widespread and severe in Labrune syndrome and the imaging appearance of both conditions is distinctive. Dr. Ganesh incorrectly attributed 11% of adult-onset leukoencephalopathy to Labrune syndrome by referencing Guerreiro et al.,3 who clearly referred to CSF-1R-related disease.

Posterior fossa involvement in the diagnosis of adult-onset inherited leukoencephalopathies.

Adult-onset genetic leukoencephalopathies are increasingly recognized. They are heterogeneous groups of disorders that commonly have distinct pathologic mechanisms but they share the presence of supratentorial bilateral and symmetric white matter hyperintensities. Although these abnormalities are usually non-specific, some specific MRI findings exist and sometimes help to distinguish these disorders. In this review, our aim is to describe posterior fossa abnormalities seen in the main adult-onset genetic leukoencephalopathies enabling clinicians to perform oriented genetic/metabolic screening.

Adult-onset genetic leukoencephalopathies: a MRI pattern-based approach in a comprehensive study of 154 patients.

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.

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.

ADULT ONSET LEUKOENCEPHALOPATHY DUE TO CSF1R GENE MUTATION

We report on a 44 year old Afro-Caribbean lady who presented with progressive personality change and cognitive impairment over one year. She had progressive difficulty managing household tasks, lost interest in her hobbies and spoke very little. Her family described her behaviour as ‘child-like’. She had been diagnosed with anti-Ro positive mild Lupus 10 years previously and was taking mepacrine. Examination suggested a predominantly frontal subcortical pattern of cognitive impairment. MRI/A revealed confluent symmetrical white matter changes in the frontal and parietal lobes with patchy restricted diffusion in the basal ganglia. Extensive other investigations including metabolic tests, autoimmune tests, and CSF analysis were unrevealing. A right frontal brain biopsy revealed non-specific gliosis. She was treated empirically with steroids and cyclophosphamide for the possibility of cerebral vasculitis but there was no subsequent clinical improvement. She tested positive for a heterozygous mutation in the CSF1R gene, first described in Hereditary Diffuse Leukoencephalopathy with Spheroids. Adult onset leukoencephalopathies are difficult to investigate given their broad clinical presentation and wide variety of acquired and rare genetic aetiologies. This case is instructive because it highlights a novel genetic test which may obviate the need for brain biopsy or harmful immunosuppressive agents in rapidly progressive leukoencephalopathies.

Update on several/certain adult-onset genetic leukoencephalopathies: clinical signs and molecular confirmation.

Adult-onset leukoencephalopathies are clinically and pathologically heterogeneous diseases, characterized by overlapping clinical and neuroradiological features and a difficult diagnostic process. Nevertheless, knowledge of the metabolic and genetic basis of leukoencephalopathies is constantly increasing. This article provides an overview of currently known leukoencephalopathies in adulthood, emphasizing, in addition to the classical forms, their atypical clinical presentations. In particular, we review the clinical spectrum and the molecular pathogenesis of certain adult-onset leukoencephalopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebroretinal microangiopathy with calcifications and cysts (CRMCC), hereditary diffuse leukoencephalopathy with spheroids (HDLS), fragile X-associated tremor/ataxia syndrome (FXTAS), vanishing white matter disease (VWM), autosomal dominant leukodystrophy due to lamin B1 duplication (ADLD), and vascular leukoencephalopathy mapping to chromosome 20q13.

Observational Study for MRI Characteristics in HDLS with a Known Gene Mutation on Chromosome 5 (P06.180)

Objective: To describe the MRI characteristics of HDLS patients with a known gene mutation on chromosome 5. Background Adult-onset leukoencephalopathies are a heterogeneous group of rare disorders, with natural histories ranging from being asymptomatic to inexorably progressive and fatal. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first described in 1984, and is an autosomal dominant disorder. Currently, 23 HDLS reports have been published. The pathological hallmark of HDLS is cerebral white matter lesions (WML) with axonal spheroids.Recently, a chromosome 5 mutation, CSF1R , was identified. Design/Methods: Twenty brain MRIs of 15 patients with autopsy/biopsy verified HDLS and chromosome 5 mutations were reviewed. Sagittal T1-, axial T1-, T2- weighted, and FLAIR images were assessed for distribution of WML, grey matter involvement, and atrophy. Results: In this study, the mean age of onset was 44 years (range, 19-71); mean disease duration was 5 years (range, 3-11); and the mean age at death was 50 years (30-75). 80 % (12/15) demonstrated focal WML, whereas in two the lesions were patchy. One patient had generalized WMLs. All patients had bilateral, though slightly asymmetric lesions. WMLs with frontal predominance, involving deep and subcortical regions, were found in all cases. 93 % (14/15) had periventricular involvement, while 73% (11/15) had involvement of the corpus callosum. Of the latter, seven had more than one callosal segment affected and five had involvement of the entire corpus callosum. Typically, brain atrophy was present in the same region as the WMLs; however, in three cases isolated atrophy of the parietal, occipital and temporal cortices were found, respectively. Central atrophy was invariably present. Corticospinal tract involvement occurred late in the disease course. The grey matter, brain stem and cerebellum were spared, and enhancement was absent. Conclusions: MRI is valuable in helping to define the natural history of HDLS and will be useful in assessing future treatment responses. The MRI patterns of HDLS are sufficiently typical to aid in diagnosis. Supported by: ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, 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). SF is partially supported by MCF Research Committee CR program ( MCF #90052030). CS was partially supported by Anna-Lisa och Bror Bjornssons-, Sven and Dagmar Salens-, Signe och Olof Wallenius- and Gamla Tjanarinnor 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. Disclosure: Dr. Sundal has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Van Gerpen has nothing to disclose. Dr. Wider has nothing to disclose. Dr. Aasly has nothing to disclose. Dr. Shuster has nothing to disclose. Dr. Ghetti has received personal compensation for activities with Bayer Pharmaceuticals Corporation. Dr. Ghetti has received research support from the National Institute of Health. Dr. Garbern has received personal compensation for activities with Genzyme Corporation, Lundbeck Research USA, Inc., StemCells, Inc, and Serono, Inc. as a consultant and/or speaker. Dr. Garbern has received personal compensation in an editorial capacity for Medlink Neurology. Dr. Garbern has received research support from Genzyme Corporation. Dr. Tselis has received research support from Teva Neuroscience and Biogen Idec. Dr. Swerdlow has received personal compensation for activities with Eisai, Inc. as a consultant. Dr. Miller has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Broderick has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Roeber has nothing to disclose.

Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5

Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5