Hereditary diffuse leukoencephalopathy with spheroids is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in ... Hereditary diffuse leukoencephalopathy with spheroids is an autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes (summary by Rademakers et al., 2012).
Lanska et al. (1994) presented clinical and pathologic information on 2 large multigenerational families with a form of autosomal dominant adult-onset dementia termed progressive subcortical gliosis. Affected individuals presented in the fifth or sixth decade of life with ... Lanska et al. (1994) presented clinical and pathologic information on 2 large multigenerational families with a form of autosomal dominant adult-onset dementia termed progressive subcortical gliosis. Affected individuals presented in the fifth or sixth decade of life with personality change and degeneration of social ability which later developed into a profound dementia with mutism, dysphagia, and extrapyramidal signs. The presentation was similar to that of Pick disease. Autopsies were done on 7 affected individuals. These showed moderately severe atrophy with preferential involvement of the frontal and temporal lobes but without the knife edge pattern characteristic of Pick disease. The most striking microscopic finding was a marked fibrillary astrocytosis, particularly in the area of the short cortical association tracts (U fibers) at the junction of cortical lamina VI and the subcortical white matter, and in the subpial cerebral cortex (lamina I). There was also laminar spongiosis, particularly in laminae II and III similar to that observed in Pick disease and Alzheimer disease, but different from the pancortical spongiform change in Creutzfeldt-Jakob disease which is usually most prominent in deeper layers. Neuronal inclusions and amyloid deposits, which are pathologic hallmarks of Alzheimer disease and Pick disease, were uniformly absent. One of the families reported by Lanska et al. (1994) was found by Goedert et al. (1999) to have a mutation in the MAPT gene (157140.0006), thus confirming a diagnosis of MAPT-related frontotemporal dementia (FTD; 600274). Van der Knaap et al. (2000) reported a father and daughter with adult-onset deterioration of frontal lobe function, spasticity, ataxia, and mild extrapyramidal signs. MRI showed cerebral atrophy and patchy white matter changes. Postmortem examination showed leukoencephalopathy with numerous neuroaxonal spheroids. The frontal and frontoparietal lobes were most affected. Baba et al. (2006) reported a kindred in which 6 individuals had dementia, depression, and frontal lobe signs variably associated with parkinsonism, apraxia, and seizures. The mean age at onset was 54 years. Postmortem examination of the brains showed loss of myelinated fibers, bizarre astrocytosis, white matter gliosis, and axonal spheroids. Inheritance was autosomal dominant. Molecular analysis excluded mutations in the MAPT gene and in several genes involved in leukoencephalopathy with white matter disease (603896). Swerdlow et al. (2009) reported a multigenerational family with frontotemporal dementia associated with subcortical gliosis inherited in an autosomal dominant pattern. Age at onset ranged from the forties to sixties in affected individuals. The phenotype was characterized mainly by progressive behavioral changes, disorientation, frontal release signs, and memory loss. Later symptoms and signs included dementia, mutism, and incontinence. Some individuals developed parkinsonism. Neuropathologic studies showed frontotemporal cortical atrophy, ventriculomegaly, neuronal loss, hypertrophic astrogliosis in the superficial and deep white matter, loss of axons, dystrophic axons, and axonal spheroids containing neurofilaments. Immunohistochemical studies did not identify tau, ubiquitin, or prion (PRNP; 176640) inclusions. Swerdlow et al. (2009) noted that the disorder shared some characteristics with leukoencephalopathy with neuroaxonal spheroids, as described by van der Knaap et al. (2000) and Baba et al. (2006). Rademakers et al. (2012) reported 14 families with HDLS, including those reported previously by Swerdlow et al. (2009) and Baba et al. (2006). Clinical features of 24 affected individuals showed that the mean age at onset was 47.2 years (range, 18-78 years), with a mean age of death at 57.2 years (range, 40-84 years). One patient was described in detail. He developed mild depression and forgetfulness at age 50 years. Two years later, he had a flat affect, inappropriate behavior, poor concentration, executive dysfunction, restless legs syndrome, and insomnia. There was psychomotor slowing, and ideomotor and constructional apraxia. He had a slow, shuffling gait, postural instability, rigidity, and bradykinesia. Brain imaging showed hyperintense foci in both the frontal and parietal lobes, involving the periventricular, deep and subcortical white matter, but sparing the subcortical U fibers. At the end of his illness, he was mute and in a vegetative state; death occurred at age 55 years. Neuropathologic examination showed myelin loss, axonal spheroids containing neurofilaments, astrocytes, gliosis, and ballooned neurons. There was inter- and intrafamilial variability, with different ages at onset and death, as well as variable clinical features. Antemortem clinical diagnoses in mutation carriers included frontotemporal dementia (FTD; 600275), corticobasal syndrome, Alzheimer disease (AD; 104300), multiple sclerosis (MS; 126200), atypical cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310), and Parkinson disease (PD; 168600). - Neuroradiologic Findings Sundal et al. (2012) reviewed 20 brain MRI scans of 15 patients from 9 HDLS families, all of Caucasian descent with genetically confirmed disease, and assigned a severity score based on the lesion load. The mean age at onset was 44.3 years and the mean age at death was 53.2 years. All patients had a progressive clinical course, except 1, who had mild disease burden on initial MRI. At onset, 14 of 15 patients had localized white matter lesions (WML) with deep, subcortical, and periventricular involvement, whereas 1 more severely affected patient had generalized WML. All lesions were bilateral, but asymmetric, and predominantly in the frontal/parietal regions. There was cortical atrophy and involvement of the corpus callosum, but gray matter pathology and brainstem atrophy were absent; corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Indicators of rapid disease progression included onset before age 45 years, female sex, WML extending beyond the frontal regions, an MRI severity score greater than 15 points, and deletion mutations. Sundal et al. (2012) concluded that recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments.
By linkage analysis followed by whole-exome sequencing of the family with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous mutation in the CSF1R gene (164770.0001). Sequencing of this gene in 13 additional ... By linkage analysis followed by whole-exome sequencing of the family with HDLS reported by Swerdlow et al. (2009), Rademakers et al. (2012) identified a heterozygous mutation in the CSF1R gene (164770.0001). Sequencing of this gene in 13 additional probands with HDLS identified a different heterozygous mutation in each (see, e.g., 164770.0002-164770.0005). The mutations cosegregated with the disorder in all families for which DNA from multiple affected individuals was available, including the family reported by Baba et al. (2006). In vitro functional expression studies of some of the missense mutations indicated that the mutant proteins did not show autophosphorylation, suggesting a defect in kinase activity that likely also affects downstream targets. The mutant proteins probably also act in a dominant-negative manner, since CSF1R assembles into homodimers. Overall, the findings indicated that a defect in microglial signaling and function resulting from CSF1R mutations can cause central nervous system degeneration.
CSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) should be suspected in individuals with the following clinical and brain MRI findings. Definite diagnosis relies on identification of a disease-causing CSF1R mutation....
DiagnosisCSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) should be suspected in individuals with the following clinical and brain MRI findings. Definite diagnosis relies on identification of a disease-causing CSF1R mutation.Progressive neurologic declinePresenting signs may include:Personality changes, cognitive impairments, memory decline, and depression;Motor impairments including gait dysfunction, bradykinesia, rigidity and tremor; In rare individuals, seizure.Later signs usually include dementia, pyramidal signs, and seizures.Family history consistent with autosomal dominant inheritance Brain MRI [Van Gerpen et al 2008, Sundal et al 2012c]The white matter lesions are hyperintense on T2- and FLAIR-weighted images, and hypointense on T1-weighted images.Bifrontal or bifrontoparietal T2/FLAIR hyperintensities in the deep, subcortical, and periventricular areas are typical. The white matter lesions are often asymmetric, especially in the early stages of the disease. Also early on they are patchy and focal, but with time become confluent. T2 and FLAIR hyperintensities are present in other areas, including the corpus callosum and corticospinal tracts.Cerebral atrophy manifesting as enlarged ventricles is typical, as well as cerebral atrophy corresponding to the white matter lesions. The following are absent: Significant grey matter pathologyBrain stem atrophyContrast uptake in the parenchyma Cerebellar abnormalities are minimal. TestingBrain pathology. Prior to the definition of the molecular basis of HDLS, the only method of definitive diagnosis was the demonstration of white matter lesions with axonal spheroids on brain biopsy or at autopsy [Axelsson et al 1984, Baba et al 2006, Sundal et al 2012b].White matter changes are typically vacuolated and demyelinated. The histopathologic hallmarks are axonal spheroids in the white matter lesions that are immunoreactive for neurofilament, amyloid precursor protein (APP), and ubiquitin. Bizarre astrocytes and lipid-laden and myelin-laden macrophages are also observed.The basal ganglia, thalamus, hypothalamus, hippocampus, substantia nigra, raphe nucleus, reticular formation, and cerebellar grey matter are usually unaffected or very mildly affected. Amyloid angiopathy is not significantly present in parenchymal or leptomeningeal vessels. Note: Molecular genetic testing practically eliminates the need for performing brain biopsy for diagnosis.Molecular Genetic Testing Gene. CSF1R is the only gene in which mutations are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS).Evidence for locus heterogeneity. Families with phenotypes that suggest HDLS but without an identifiable CSF1R mutation have been observed [Authors, personal observation]. Although this finding could result from the inability of current molecular genetic testing methods to detect pathogenic CSF1R mutations, locus heterogeneity is also possible.Table 1. Summary of Molecular Genetic Testing Used in CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCSF1RSequence analysisSequence variants 214/14 probands 3, 41/1 proband 4, 53/4 probands 4, 63/3 probands 4, 7Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Rademakers et al [2011]4. Each family has a unique CSF1R mutation that is distributed in exons 12-22 [Kinoshita et al 2012, Kleinfeld et al 2012, Mitsui et al 2012, Rademakers et al 2011].5. Kinoshita et al [2012]6. Mitsui et al [2012]7. Kleinfeld et al [2012]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. Sequence analysis of CSF1R is recommended to confirm the diagnosis in a proband with suggestive clinical and brain MRI findings.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) requires prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No phenotypes other than those described in this GeneReview have been associated with mutations in CSF1R.
CSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairment, and seizures. A frontal lobe syndrome (including loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. ...
Natural HistoryCSF1R-related hereditary diffuse leukoencephalopathy with spheroids (HDLS) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairment, and seizures. A frontal lobe syndrome (including loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The presenting problems and rate of progression vary among individuals and even within the same family harboring the same mutation. The mean age of onset is usually in the fourth decade, but ranges from early adulthood to the eighth decade of life [Sundal et al 2012c]. The disease course may be from two to 11 years or more with a mean of six years. Signs and symptoms that usually occur during the disease course include the following:Personality problems, memory decline, executive dysfunctionDisturbances of higher cortical function such as motor aphasia, agraphia, acalculia, and apraxiaDepressionGait disturbancePyramidal signs such as spasticity, hyperreflexia, extensor plantar response, hemiparesis, or quadriparesisSensory deficits including some impairment of vibration, position, tactile and pain perception. The higher integrative sensory functions such as graphesthesia, stereognosis, and double simultaneous stimulation are also impaired.Parkinsonian signs such as rigidity, bradykinesia, tremor (resting and/or kinetic), shuffling gait and postural instability. Hypomimic face and hypophonic voice are common. Lack of beneficial response to levodopa defines the parkinsonian signs as atypical.Bulbar/pseudobulbar signs: dysphagia, dysarthria, slurred speech, and palatal myoclonusCerebellar signs with ataxia, dysmetria, and intension tremorVisual field defects such as homonymus quadrant- or hemi-anopsiaOther signs of a movement disorder: dystonia, myoclonic twitches, dyskinesia, and akathisiaSeizures in some (at times only a single episode at the onset of the illness)Progressive courseAffected individuals eventually become bedridden with spasticity and rigidity. They lose speech and voluntary movements, and appear to be generally unaware of their surroundings. In the last stage of the disease, individuals lose their ability to walk and progress to a vegetative state. Primitive reflexes, such as visual and tactile grasp and mouth-opening reflex, as well as the sucking reflex, are present.Death most commonly results from pneumonia or other infections. Other findings. Cerebrospinal fluid (CSF):Normal cell count, glucose concentration, and proteins No inflammatory cellsNormal isoelectric focusing and no oligoclonal bandsNo identified CSF biomarker. The following preliminary findings in two persons with HDLS need to be interpreted cautiously and require further research [Sundal et al 2012a]: Normal Aβ42 protein concentrationsMinimally increased levels of total Tau protein concentrations,Borderline normal phospho-Tau protein concentrationsSignificantly elevated neurofilament light chain (NF-L) proteins. (Note that NF-L proteins are markers of neuronal death and axonal damage.)
No genotype-phenotype correlation exists: individuals from the same family harboring the same CSF1R mutation do not necessarily share the same phenotype. In the end stage all have devastating multiple neurologic impairments....
Genotype-Phenotype Correlations No genotype-phenotype correlation exists: individuals from the same family harboring the same CSF1R mutation do not necessarily share the same phenotype. In the end stage all have devastating multiple neurologic impairments.
The clinical presentation of hereditary diffuse leukoencephalopathy with spheroids (HDLS) often overlaps with other neurologic disorders. HDLS should be considered in previously healthy individuals who develop cognitive decline, memory problems, and personality changes in midlife with a progressive course and white matter lesions evident on brain MRI. ...
Differential DiagnosisThe clinical presentation of hereditary diffuse leukoencephalopathy with spheroids (HDLS) often overlaps with other neurologic disorders. HDLS should be considered in previously healthy individuals who develop cognitive decline, memory problems, and personality changes in midlife with a progressive course and white matter lesions evident on brain MRI. Familial pigmentary orthochromatic leukodystrophy (POLD) is phenotypically and radiologically similar to HDLS [Wider et al 2009]. See Nomenclature.Because the signs and symptoms in the early stages of HDLS are nonspecific, HDLS can often be confused with the inherited and sporadic disorders listed below. In individuals with HDLS, laboratory and/or genetic testing for these other disorders is normal.Autosomal Dominant DisordersThe adult form of Alexander disease has extensive cerebral white matter abnormalities with a frontal predominance and a periventricular rim of decreased T2 and increased T1 signal intensities. Additionally, there are abnormalities in the basal ganglia, thalamus, and brain stem with contrast enhancement of the cerebrum or brain stem [Van der Knaap et al 2005, Sawaishi 2009].Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms is characterized by white matter changes in a frontoparietal distribution involving the corticospinal tracts from the supratentorial regions to the spinal cord. Additionally, it involves the superior and middle cerebellar peduncles [Sundblom et al 2009].Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has multiple cerebral infarcts and white matter lesions including the characteristic temporal pools [Tikka et al 2009].Frontotemporal dementia typically demonstrates frontal and/or temporal atrophy with far fewer white matter lesions than are seen in HDLS [Seelaar et al 2011]. A study comparing the pattern of cerebral atrophy suggests that the pattern of atrophy is more widespread in persons with mutations in GRN (encoding progranulin) than in persons with mutations in MAPT (encoding microtubule-associated protein tau). C9ORF72-related FTD is associated with symmetric atrophy predominantly involving dorsolateral, medial, and orbitofrontal lobes, with additional loss in anterior temporal lobes, parietal lobes, occipital lobes, and cerebellum. In contrast, striking anteromedial temporal atrophy is associated with MAPT mutations and temporoparietal atrophy was associated with GRN mutations. The sporadic frontotemporal dementia group is associated with frontal and anterior temporal atrophy [Whitwell et al 2012].Early-onset Alzheimer disease (EOAD) typically begins with subtle memory failure which becomes more severe leading to disability. Common findings include confusion, poor judgment, language disturbance, agitation, hallucinations, withdrawal, and mutism. Seizures, parkinsonism, myoclonus, and urinary incontinence can occur. The significant overlap in clinical presentation of EOAD with HDLS includes similar age of onset. The predominant finding of EOAD on brain MRI is evolving cortical atrophy; white matter changes are present, but much less pronounced than those of HDLS. CSF biomarker examination reveals elevated total-Tau and phosphorylated Tau protein concentrations and reduced Aβ42 concentrations. Heterozygosity for mutation of APP, PSEN 1, or PSEN 2 is causative [Andreasen et al 2003, Lopez et al 2011, Cohn-Hokke et al 2012].Autosomal Recessive DisordersPolycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease) is characterized by sclerosing leukoencephalopathy with progressive cerebral atrophy, cerebellar atrophy, or both. White matter lesions are diffuse and usually centrally located, with sparing of the arcuate fibers. Basal ganglia atrophy and calcifications are often present. Lytic foci are also often evident on bone radiographs [Paloneva et al 2001, Kaneko et al 2010].Vanishing white matter (VWM) and metachromatic leukodystrophy (MLD) both have more wide-spread and diffuse white matter changes and atrophy than HDLS [Eichler et al 2009, Bugiani et al 2010]. Lysosomal storage diseases that can present in adult life with white matter lesions include the adult form of Krabbe disease. Although it can present with parieto-occipital white matter [Loes et al 1999] and can be unilaterally diffuse [Lemmens et al 2011], upper corticospinal tract involvement can also be the first presenting change [Wang et al 2007].Leukoencephalopathy with brain stem and spinal cord involvement (LBSL) diagnostic MRI findings are white matter lesions that are either non-homogeneous/spotty or homogeneous and confluent [Scheper et al 2007]. Signal abnormalities are evident in the medullary pyramids, dorsal columns, and lateral corticospinal tracts. Additionally, signal abnormalities may be present in the splenium of the corpus callosum, superior/inferior cerebellar peduncles, and cerebellum. X-Linked DisordersX-linked adrenoleukodystrophy (X-ALD) rarely develops into a cerebral form; when it does, it may demonstrate symmetric, increased T2 signal intensities usually in the parieto-occipital region with contrast enhancement at the periphery of the demyelination zone [Eichler et al 2007].Fabry disease can present with white matter lesions together with grey matter pathology [Reisin et al 2011]; however, the clinical presentation is different from that of HDLS [Meschia et al 2011].Mitochondrial DisordersWhite matter lesions (WML) may also be present in adult mitochondrial diseases [Saneto et al 2008]. In Leigh syndrome the WML may involve the deep white matter, posterior centrum semiovale and corpus callosum. The progression of WML is from posterior to anterior [Lerman-Sagie et al 2005]. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) occasionally presents with diffuse WML involving the periventricular white matter, centrum semiovale, and corpus callosum [Apostolova et al 2005]. Alpers syndrome may show T2 hyperintensities in the occipital lobe, deep cerebellar nuclei, thalamus, and basal ganglia. MNGIE (mitochondrial neuro-gastro-intestinal encephalopathy) has diffuse WML (typically sparing the corpus callosum) and supratentorial cortical atrophy [Barragan-Campos et al 2005]. In contrast to HDLS, the cranial MRI in mitochondrial diseases may demonstrate symmetric T1 hypointense and T2 hyperintense signal abnormalities in deep grey matter. These abnormalities are not restricted to vascular territories and the lesions often fluctuate over the course of the disease. Additionally, varying degrees of cerebral and cerebellar atrophy may be present [Saneto et al 2008]. OtherPrimary progressive multiple sclerosis (PPMS) is initially dominated by progressive central paraparesis. With advanced disease the clinical picture is more multifocal with multiple sclerosis (MS) typical symptomatology including internuclear ophthalmoplegia (INO) and optic neuropathy. Cerebrospinal fluid enriched oligoclonal IgG bands support the diagnosis. MRI lesions tend to be periventricular with characteristic MS “right-angle lesions.” Diagnostic PPMS criteria are based on one year of steady clinical progression and MRI and CSF findings [Polman et al 2011]. Although HDLS can mimic MS, it does not fulfill the diagnostic criteria for MS [Keegan et al 2008].Susac’s syndrome typically presents with the triad of retino-cochleo-cerebral vasculopathy. MRI demonstrates centrally located lesions of the corpus callosum of varying shapes and sizes (without atrophy) that usually evolve into pathognomic central callosal “holes” [Saenz et al 2005]. Most affected individuals improve with immunosuppressive therapy [Mateen et al 2012].Frontotemporal lobar degeneration (FTLD) ranges from behavioral and executive impairments to language disorders and motor dysfunction. The clinical findings of FTLD differ from those of HDLS. Although the combination of FTD with atypical parkinsonism has features such as multisystem atrophy (MSA) and progressive supranuclear palsy (PSP), and the addition of amyotrophic lateral sclerosis (ALS) can mimic clinical HDLS, the neuroimaging is different. MRI demonstrates mainly cerebral atrophy without the characteristic white matter lesions found in HDLS.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with hereditary diffuse leukoencephalopathy with spheroids (HDLS), the following evaluations are recommended:Complete neurologic assessmentPsychological and psychiatric assessmentsBrain MRI to determine the extent and localization of white matter changes, presence of cortical atrophy, and involvement of the corpus callosum and corticospinal tractsAssessment of feeding/eating, digestive problems (constipation, incontinence), and nutrition based on patient historyEEG or video EEG if a seizure disorder is suspected; evaluation of the need for antiepileptic drugsLumbar puncture to measure neurofilament light protein (NFL) in the cerebrospinal fluid (CSF) to follow the disease progression. An increased level of NFL on repeat CSF examinations may suggest faster disease course and thus worse prognosis. Assessment of family and social structure to determine the availability of adequate support systemMedical genetics consultationTreatment of ManifestationsNo specific therapy is currently available for HDLS.Management is supportive and includes: attention to general care, nutritional requirements, antiepileptic drugs for seizures, and antibiotic treatment for general and recurrent infections such as pneumonia or urinary tract infections.Other:L-dopa or other dopaminergic therapies have not been beneficial in individuals with HDLS or in those with an atypical parkinsonian phenotype, but may be worth trying. Antidepressant medications can be tested for depression but reports so far have demonstrated no long-term benefit.Antipsychotics are in general not recommended due to extrapyramidal side effects, but may be used in aggressive individuals. Anti-seizure medications should be initiated in any individuals with seizures and are reported to be beneficial.Prevention of Secondary ComplicationsSocial problems (unemployment, divorce, financial troubles, and alcoholism) and suicidal tendencies are often associated with the progression of the disease. Some of the social consequences may be avoided if family members are informed early about the nature of the disorder.SurveillanceThe following are appropriate:Periodic clinical evaluation to monitor for:Changes in mobility, communication, and behavior, which could indicate a need to alter care and support systems (wheelchair/ personal assistance);Onset of seizures and need for antiepileptic therapy; Contractures, which could indicate a need to change medical management and physical therapy;Behavioral changes, inappropriate emotions and actions, problems following directions, memory loss, incontinence, which indicate curtailing of independence;Difficulties in swallowing or weight loss, which trigger consideration for gastrostomy;Need for physical therapy to minimize contractures and maintain locomotion.Longitudinal MRI studies can potentially help with prognosis as during the disease course the more rapid the confluence of patchy or focal T2 hyperintensities and the progression of cortical atrophy, the poorer the prognosis appears to be [Van Gerpen et al 2008, Sundal et al 2012c]. Agents/Circumstances to AvoidThe following should be avoided:Use of first-generation neuroleptics, which increase seizure risk and risk of additional parkinsonian signs.Treatment agents for multiple sclerosis as these medications have no benefit and have major side effects.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameHGMDCSF1R5q32Macrophage colony-stimulating factor 1 receptorCSF1RData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for CSF1R-Related Hereditary Diffuse Leukoencephalopathy with Spheroids (View All in OMIM) View in own window 164770COLONY-STIMULATING FACTOR 1 RECEPTOR; CSF1R 221820LEUKOENCEPHALOPATHY, DIFFUSE HEREDITARY, WITH SPHEROIDS; HDLSNormal allelic variants. CSF1R comprises 22 exons. No normal allelic variants have been reported.Pathologic allelic variants. To identify the genetic basis of HDLS, an international consortium was established and one large kindred with clear autosomal dominant inheritance was selected for linkage analyses. Evidence for linkage was identified at loci on chromosome 5. Whole-exome sequencing identified CSF1R as the gene in which mutation is causative. Additional mutations were demonstrated in 13 probands with neuropathologically proven HDLS. CSF1R mutations cosegregated with the disease phenotype in all families with HDLS. Ten missense mutations, one single codon deletion, and three splice site mutations were identified in exons 12 to 22.The CSF1R mutation was absent in all 660 controls [Rademakers et al 2011].Table 2 shows the 18 CSF1R mutations reported to date [Kinoshita et al 2012, Kleinfeld et al 2012, Mitsui et al 2012, Rademakers et al 2011]. Table 2. Selected CSF1R Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.1754-2A>Gp.Gly585_Lys619delinsAla 2NM_005211.3 NP_005202.2c.1766G>Ap.Gly589Glu 2c.1897G>Ap.Glu663Lys 2c.2297T>Cp.Met766Thr 2c.2308G>Cp.Ala770Pro 2c.2320-2A>Gp.Cys774_Asp814del 2c.2324T>Ap.Ile775Asn 2c.2381T>Cp.Ile794Thr 2, 3, 4c.2442+5G>Cp.Cys774_Asp814delinsGlnGlyLeuGlnSerHisVal GlyProSerLeuProSerSerSerProGlnAlaGln 2c.2546_2548delTCTp.Phe849delc.2546T>Cp.Phe849Serc.2603T>Cp.Leu868Proc.2624T>Cp.Met875Thrc.2632C>Ap.Pro878Thrc.2345G>Ap.Arg782His 5c.2329C>Tp.Arg777Trp 3c.1958G>Ap.Cys653Tyr 3c.2483T>C (2775T>C)p.Phe828Ser 4See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. Rademakers et al [2011]3. Mitsui et al [2012]4. Kleinfeld et al [2012]5. Kinoshita et al [2012]Normal gene product. The CSF1R protein is a cell-surface receptor primarily for the cytokine CSF-1, which regulates the survival, proliferation, differentiation, and function of mononuclear phagocytic cells, including microglia of the central nervous system. CSF1R comprises a highly glycosylated extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Binding of CSF-1 to its receptor (CSF1R) results in the formation of receptor homodimers and subsequent autophosphorylation of several tyrosine residues in the cytoplasmic domain. CSF1R autophosphorylation precedes CSF1R-dependent phosphorylation of several proteins, including the phosphatase SHP-1 and the kinases Src, PLC-γ, PI(3)K, Akt, and Erk [Rademakers et al 2011]. In the brain, CSF1R is predominately expressed in microglial cells. The link between mutations in CSF1R and the neuronal/ glial dysfunction remains to be elucidated. Abnormal gene product. The CSF1R mutations that cause HDLS affect the kinase activity and potentially the phosphorylation of downstream targets.