Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified to date.

Source: GeneReviews — "CSF1R-Related Disorder"

Penetrance

Penetrance is estimated to be high but not complete .

Source: GeneReviews — "CSF1R-Related Disorder"

Diagnostic Criteria

Suggestive Findings

CSF1R-related disorder should be suspected in a proband with the following clinical and neuroimaging findings (that present in an age-dependent manner) and family history .

Early Onset (age 18 years)

Clinical findings. Most common neurologic manifestations include:

• Speech disturbances

• Developmental delay and/or cognitive decline

• Spasticity with abnormal reflexes and other pyramidal signs

• Parkinsonism

• Dysphagia

• Seizures

Radiographic features

• Diffuse osteosclerosis of the craniofacial bones, most prominent in the skull base

• Platyspondyly and sclerosis of the vertebral bodies

• Sclerotic pelvic bones most prominent in the iliac bodies, sclerosis of proximal femora

• Tubular bones: diaphyseal sclerosis and metaphyseal radiolucency with metaphyseal undermodeling

Source: GeneReviews — "CSF1R-Related Disorder"

Differential Diagnosis

CSF1R-related disorder may present with a range of non-motor and motor features, which may be nonspecific and overlap with other neurodegenerative genetic disorders and conditions that are often of unknown cause (e.g., multiple sclerosis and atypical parkinsonism, including corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, and frontotemporal lobal degeneration ). At present, there are several other clinical, radiologic, and pathologic mimics of CSF1R-related disorder, including those described below and in .

Early-Onset CSF1R-Related Disorder

Hereditary disorders that primarily affect the central nervous system and manifest with glial and/or myelin abnormalities may mimic early-onset CSF1R-related disorder .

Late-Onset CSF1R-Related Disorder

Primary progressiv...

Source: GeneReviews — "CSF1R-Related Disorder"

Management Guidelines

No clinical practice guidelines for CSF1R-related disorder have been published. Therefore, the following considerations are based on the authors' experience managing individuals with this disorder and should be viewed as personal opinions rather than recommendations. Note that the care of individuals with early-onset CSF1R-related disorder requires addressing issues of developmental delay and skeletal abnormalities that are typically addressed by developmental pediatricians and pediatricians and thus are not discussed further in this chapter. Rather, the assessment and management of the manifestations of neurodegeneration observed in all individuals with CSF1R-related disorder are discussed in detail.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CSF1R-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

CSF1R-Related Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic deficits

| Complete neurologic assessment | • Incl screening for cognitive impairment

• Assessment for motor impairment incl gait, bradykinesia, rigidity, tremor; sensory deficits; bulbar signs

• When seizures are suspected, an EEG or video EEG is recommended

Cognitive abilities neurobehavioral/psychiatric manifestations

Clinical Guidance

As many individuals with CSF1R-related disorder have gait problems and cognitive decline, sedatives, antipsychotics, and other medications that may decrease alertness and increase the risk of falling should be used cautiously.

Source: GeneReviews — "CSF1R-Related Disorder"

Therapies Under Investigation

In a retrospective cohort study, it was observed that glucocorticoids might protect against symptomatic disease onset in individuals at risk for late-onset CSF1R-related disorder (i.e., asymptomatic individuals with a heterozygous CSF1R pathogenic variant) . This effect was also observed in a mouse model of the disease . For a detailed discussion on the optimal dose, route of administration, type of glucocorticoid, and timing of therapy, see . Note that glucocorticoids are not beneficial in individuals with advanced disease . Currently, one interventional clinical trial is in progress, enrolling individuals age 18 years and older with the late-onset CSF1R-related disorder commonly known as adult-onset leukoencephalopathy w/axonal spheroids pigmented glia (ALSP) (NCT05677659).

Source: GeneReviews — "CSF1R-Related Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 6.

CSF1R-Related Disorder: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

neuropsychiatric deficits | By neurologist neuropsychologist for severity/ new manifestations1 | Symptomatic persons: every 6 mos or as needed

By specialist in physical medicine rehab/ PT

Brain MRI (preferably 3 or 7 Tesla) | Every 12 mos or as needed

Feeding/Nutrition(esp difficulty w/swallowing /or weight loss need to consider gastrostomy tube placement) | By feeding team | Per treating feeding team

Gastrointestinal issues

| By primary care doctor | Every 12 mos or as needed

Vision problems

| By ophthalmologist | Per treating ophthalmologist

Musculoskeletal/ADL(including development of contractures /or changes in mobility) | By PT/OT | Per treating PT/OT

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning). |

ADL = activities of daily living; OT = occupational therapist; PT = physical therapist

Source: GeneReviews — "CSF1R-Related Disorder"