Csf1r-Related Adult-Onset Leukoencephalopathy With Axonal Spheroids And Pigmented Glia

Clinical characteristics.

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by executive dysfunction, memory decline, personality changes, motor impairments, and seizures. A frontal lobe syndrome (e.g., loss of judgment, lack of social inhibitors, lack of insight, and motor persistence) usually appears early in the disease course. The mean age of onset is usually in the fourth decade. Affected individuals eventually become bedridden with spasticity and rigidity. The disease course ranges from two to 30 or more years (mean: 8 years).

Diagnosis/testing.

The diagnosis is suspected in individuals with characteristic clinical and brain MRI findings and is confirmed by identification of a heterozygous pathogenic variant in CSF1R.

Management.

Treatment of manifestations: Supportive management includes: attention to general care and nutritional requirements; antiepileptic drugs for seizures; and antibiotic treatment for general and recurrent infections.

Prevention of secondary complications: Information about and support systems for the social problems and suicidal tendencies often associated with disease progression.

Surveillance: Periodic brain MRI and clinical evaluation to monitor disease progression.

Agents/circumstances to avoid: Use of first-generation neuroleptics due to increased seizure risk and risk of additional parkinsonian signs; medications used to treat multiple sclerosis as they are of no benefit and have major side effects.

Genetic counseling.

CSF1R-related ALSP is inherited in an autosomal dominant manner. Individuals with CSF1R-related ALSP usually have an affected parent; de novo mutation can occur. Each child of an individual with CSF1R-related ALSP has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in a family is known.

Suggestive Findings

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) should be suspected in individuals with the following clinical and brain findings.

Clinical

• Progressive neurologic decline; presenting signs may include the following:
  • Personality changes, cognitive impairments, memory decline, and depression
  • Motor impairments including paresis, gait dysfunction, bradykinesia, rigidity, and tremor
  • On rare occasions, seizures
  Later signs usually include dementia, seizures, and pyramidal and extrapyramidal signs.
• Family history consistent with autosomal dominant inheritance

Brain

• On MRI [Van Gerpen et al 2008, Sundal et al 2012b, Bender et al 2014, Konno et al 2014, Konno et al 2017]
  • The white matter lesions are hyperintense on T₂-weighted and FLAIR images, and hypointense on T₁-weighted images.
  • Bifrontal or bifrontoparietal T₂-weighted/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. Early lesions are patchy and focal, but with time become confluent. T₂-weighted and FLAIR hyperintensities are present in other areas, including the corpus callosum and corticospinal tracts.
  • Cerebral atrophy manifesting as enlarged ventricles is typical, as is cerebral atrophy corresponding to the white matter lesions.
  • The following are absent:
    • Significant gray matter pathology
    • Brain stem atrophy
    • Contrast uptake in the parenchyma
  • Cerebellar abnormalities are minimal.
• On CT. Brain calcifications in the white matter are seen in up to half of individuals. Frequently they have a characteristic pattern of “stepping stone appearance” in the frontal pericallosal area, and punctate appearance in the frontal white matter adjacent to the anterior horns of the lateral ventricles and the parietal subcortical white matter [Konno et al 2017].

Establishing the Diagnosis

The diagnosis of CSF1R-related ALSP is established in a proband by identification of a heterozygous pathogenic variant in CSF1R by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of CSF1R is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes CSF1R and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is characterized by a constellation of findings including executive dysfunction, memory decline, personality changes, motor impairments, 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 a family harboring the same pathogenic variant. 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 2012b]. The disease course may be from two to 30 years or more with a mean of eight years.

Signs and symptoms that usually occur during the disease course include the following:

• Personality problems, memory decline, executive dysfunction
• Disturbances of higher cortical function such as motor aphasia, agraphia, acalculia, and apraxia
• Depression
• Gait disturbance
• Pyramidal signs such as spasticity, hyperreflexia, extensor plantar response, hemiparesis, or quadriparesis
• Sensory 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 myoclonus
• Cerebellar signs with ataxia, dysmetria, and intention tremor
• Visual field defects such as homonymous quadrantanopsia or hemianopsia
• Other signs of a movement disorder: dystonia, myoclonic twitches, dyskinesia, and akathisia
• Seizures in some individuals (at times only a single episode at the onset of the illness)
• Progressive course

Affected 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 cells
• Usually normal isoelectric focusing and no oligoclonal bands; however, oligoclonal bands have been demonstrated in samples from affected individuals with the pathogenic variant p.Asn854Lys or p.Val 838Leu [Karle et al 2013, Levin et al 2014, Schuberth et al 2014, Sundal et al 2015].
• No identified CSF biomarker. The following preliminary findings in four persons with ALSP need to be interpreted cautiously and require further research [Sundal et al 2012a, Sundal et al 2015]:
  • Normal Aβ42 protein concentrations
  • Minimally increased levels of total Tau protein concentrations
  • Borderline normal phospho-Tau protein concentrations
  • Elevated neurofilament light chain (NF-L) proteins (Note that NF-L proteins are markers of neuronal death and axonal damage.)
  • Slight increase in glial fibrillary acidic protein, indicating gliosis or astroglial cell damage

Brain pathology. The following features may be seen on brain biopsy or at autopsy:

• White matter changes that are typically vacuolated and demyelinated
• Axonal spheroids in the white matter lesions that are immunoreactive for neurofilament, amyloid precursor protein, and ubiquitin
• Bizarre astrocytes and lipid-laden and myelin-laden macrophages
• Unaffected or very mildly affected basal ganglia, thalamus, hypothalamus, hippocampus, substantia nigra, raphe nucleus, reticular formation, and cerebellar gray matter
• Absence or only traces of amyloid angiopathy in parenchymal or leptomeningeal vessels
• Pigmented changes of either iron or lipofuscin found in macrophages and other glia cells

Genotype-Phenotype Correlations

No genotype-phenotype correlation exists: individuals from the same family harboring the same CSF1R pathogenic variant do not necessarily share the same phenotype. In the end stage all have devastating multiple neurologic impairments.

Penetrance

Penetrance appears to be incomplete [Karle et al 2013, Sundal et al 2015, Konno et al 2017]; estimates have not been calculated given the limited number of families reported to date. Although CSF1R-related ALSP is a dominantly inherited disease, de novo mutation occurs and variable expressivity in terms of the phenotype and the disease course can be found in members of the same family sharing the same pathogenic variant.

Nomenclature

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is within the same disease spectrum as familial pigmentary orthochromatic leukodystrophy (POLD) [Wider et al 2009]. Because of the phenotypic and radiologic similarities of the two disorders, Wider et al [2009] proposed the following terminology for the combined entity: "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)." Families with POLD have recently been found to have CSF1R pathogenic variants [Nicholson et al 2013], providing evidence that HDLS and POLD are a single disease entity. Because a similar phenotype has been reported in individuals with biallelic AARS2 pathogenic variants, the authors propose new nomenclature: CSF1R-related ALSP.

Prevalence

CSF1R-related ALSP was previously thought to be a rare disease. However, recent expanded publications in this field have demonstrated that it is more common than previously recognized: it is now estimated to be responsible for 10%-25% of adult-onset leukodystrophy. However, actual prevalence figures have not been reported [Lynch et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), the following evaluations are recommended if they have not already been completed:

• Complete neurologic assessment
• Psychological and psychiatric assessments
• Brain MRI to determine the extent and localization of white matter changes, presence of cortical atrophy, and involvement of the corpus callosum and corticospinal tracts
• Assessment of feeding/eating, digestive problems (constipation, incontinence), and nutrition based on clinical history
• EEG or video EEG if a seizure disorder is suspected; evaluation of the need for antiepileptic drugs
• Lumbar 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 systems
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific therapy is currently available for ALSP. However, as CSF1R-related ALSP is a microglia-associated neurodegenerative disease it is suggested that hematopoietic stem cell transplantation may have a therapeutic role for this disease [Eichler et al 2016].

Management is supportive and includes attention to general care and 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 ALSP or in those with an atypical parkinsonian phenotype, but may be worth trying.
• Antidepressant medications may be prescribed for depression, although reports to date 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 individual with seizures and are reported to be beneficial.

Prevention of Secondary Complications

Social 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.

Surveillance

Periodic clinical evaluation to monitor for the following is appropriate:

• 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 every year can potentially help with prognosis, as during the disease course the more rapid the confluence of patchy or focal T₂-weighted hyperintensities and the progression of cortical atrophy, the poorer the prognosis appears to be [Van Gerpen et al 2008, Sundal et al 2012b].

Agents/Circumstances to Avoid

The 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 are of no benefit and have major side effects

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.