Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), is a rare, progressive neurological disease that causes brain tissue known as a white matter to waste away (leukodystrophy), forming lesions in certain brain areas due to disease-causing variants in the CSF1R (colony-stimulating factor-1 receptor) gene. ALSP is one type of leukodystrophy disorder, estimated by some studies to account for 10 to 25% of adult-onset leukodystrophy. Lesions of this white matter lead to major changes in personality, thinking (cognition), and muscle function, eventually causing people with this disorder to develop dementia and later decline into a vegetative state. Aside from the presence of a specific gene variant, the brains of people with ALSP show characteristic microscopic changes and patterns of atrophy on brain imaging that distinguish ALSP patients from those with other neurological conditions. Symptoms of ALSP overlap with frontotemporal dementia and other disorders associated with dementia such as Alzheimer’s disease as well as other neurological disorders such as Parkinson’s disease, multiple sclerosis, schizophrenia, and several others, making diagnosis difficult unless genetic testing is done. Symptoms can vary considerably from one person with ALSP to the next (even in the same family). Currently, brain biopsy is not necessary for diagnosis because genetic testing is available.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a neurological condition characterized by changes to certain areas of the brain. A hallmark of ALSP is leukoencephalopathy, which is the alteration of a type of brain tissue called white matter. White matter consists of nerve fibers (axons) covered by a substance called myelin that insulates and protects them. The axons extend from nerve cells (neurons) and transmit nerve impulses throughout the body. Areas of damage to this brain tissue (white matter lesions) can be seen with magnetic resonance imaging (MRI). Another feature of ALSP is swellings called spheroids in the axons of the brain, which are a sign of axon damage. Also common in ALSP are abnormally pigmented glial cells. Glial cells are specialized brain cells that protect and maintain neurons. Damage to myelin and neurons is thought to contribute to many of the neurological signs and symptoms in people with ALSP.
ALSP was previously known as two separate disorders: hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). Once both disorders were linked to CSF1R gene variants, they became known as ALSP.
Symptoms
Early symptoms of ALSP often include mild psychological or cognitive changes, but, while rare, can present as disturbances in motor function, such as difficulty walking, falling, and slowness of movements. Eventually, as damage in the brain becomes more extensive, psychological, cognitive and motor symptoms exist together. Initial symptoms and rate of disease progression vary quite a bit from one individual to the next, including those within the same family when the condition is inherited.
Psychiatric features of ALSP include changes in personality and the development of anxiety, depression, lack of interest in things (apathy), irritability, distractibility, socially inappropriate behaviors (disinhibition), and cravings for certain types of food (for example eating only ice cream). Cognitive features include the development of dementia, with a general decline in mental functioning, including memory loss, word-finding and language difficulties (aphasia), difficulty planning voluntary muscle movements (apraxia), poor attention, poor judgment, and problem-solving, and reduced impulse control.
Brain degeneration in ALSP also affects what is known as the pyramidal system in the brain. These are nerve tracts that travel from the cerebral cortex (responsible for the control of voluntary movements) to the brainstem or the spinal cord. Damage to these tracts in ALSP causes overactive reflexes (hyperreflexia); increased muscle tone, meaning muscles stay stiff and contracted at rest (hypertonicity); muscle spasms with increased movement (spasticity); weakness of one side of the body (hemiparesis) or in all four limbs (quadriparesis); reduced coordination; vision changes; difficulty walking; difficulty swallowing; slurred speech; and heightened emotional responses, meaning patients may cry or laugh at inappropriate times (pseudobulbar palsy).
Symptoms similar to Parkinson’s disease, such as increased muscle stiffness (rigidity), tremors, a slowing of movement (bradykinesia), a shuffling gait, and a reduction or loss of facial expression (hypoxemic face or masked facies) can occur in ALSP as well. In ALSP, these symptoms are referred to as Parkinsonism and are not helped by increasing dopamine levels with medications like levodopa, which would ordinarily improve symptoms in Parkinson’s disease.
Changes to sensory nerves can also occur, making it more difficult for patients to sense pain, touch, vibration, and changes in body position. Frequently, the patients cannot recognize the right or left side of the body.
Less commonly, seizures can accompany ALSP, occurring in approximately 30% of patients with the diagnosis. The seizures usually occur at the onset of the illness.
As the disease worsens, patients enter a state where they can no longer walk or speak and need total care with all daily living functions. They also lose control of bladder and bowel sphincter functions (double incontinent). Most patients with ALSP die from pneumonia.
Causes
ALSP is caused by an abnormal CSF1R gene variant that codes for the protein colony-stimulating factor-1 receptor found on many cell membranes, including those in the central nervous system, or CNS (consisting of the brain and spinal cord). This receptor plays a role in cell growth and cell specialization where cells take on specific functions in the body. Without a normally-functioning CSF-1 receptor, structural changes to the nerve cell, or neuron, eventually occur. Axons, the portions of neurons that transmit signals to the next neuron, are covered in a myelin sheath, or the white matter that is destroyed in ALSP and other leukodystrophies. In ALSP, the formation of swellings known as spheroids within axons causes immune cells known as macrophages to destroy myelin sheathing, further damaging nerve cell function. Microglia, another type of macrophage immune cell of the CNS that’s responsible for maintaining brain tissue, is highly dependent on the CSF-1 receptor. When the receptor is inhibited, microglia become underactive and are destroyed. Macrophages and microglia take on a pigmented appearance in brain biopsies of ALSP patients.
ALSP is an autosomal dominant genetic condition, meaning only a single copy of the disease-causing CSF1R gene variant is necessary to cause ALSP. The altered gene can be inherited from either parent or can be the result of a new mutation in the affected individual, known as a de novo mutation where the mutation has never before been present in the family. The latter case is referred to as a sporadic, rather than an inherited, case of ALSP. In autosomal dominant conditions, there’s a 50% chance the affected individual will pass the altered gene to their child, with the risk of inheritance being the same for males and females.
ALSP is caused by mutations in the CSF1R gene. This gene provides instructions for making a protein called colony-stimulating factor 1 receptor (CSF-1 receptor), which is found in the outer membrane of certain types of cells, including glial cells. The CSF-1 receptor triggers signaling pathways that control many important cellular processes, such as cell growth and division (proliferation) and maturation of the cell to take on specific functions (differentiation). CSF1R gene mutations in ALSP lead to an altered CSF-1 receptor protein that is likely unable to stimulate cell signaling pathways. However, it is unclear how the gene mutations lead to white matter damage or cognitive and movement problems in people with ALSP.
Diagnosis
Diagnosis of ALSP is made by a neurologist. ALSP is diagnosed through genetic testing that identifies a CSF1R gene variant associated with the disease. However, family history, clinical signs, and brain imaging results are integral in raising suspicions enough to order genetic testing. When symptoms affecting cognition and movements or when seizures combined with either cognitive or motor symptoms are present before or by age 60, suspicion of ALSP should be raised. Cognitive testing by psychiatrists, neurologists, or psychologists can identify behaviors that confirm frontal lobe dysfunction (e.g., reduced inhibition), especially when subtle, that is associated with ALSP.
Specific patterns of brain deterioration on MRI and CT scans can further raise suspicion. These include the existence of lesions of white matter on both sides of the cerebrum (the largest, most exterior part of the brain that controls more complex functions) that in earlier stages of ALSP are less symmetric but become more symmetric and extensive as the disease progresses. White matter lesions in ALSP are most common in the frontal and parietal brain lobes of the cerebrum and the white matter around the lateral ventricles (periventricular deep white matter), making the ventricles appear enlarged in imaging. Also apparent in brain scans is thinning of the corpus callosum (a bundle of white matter, or myelinated, nerve fibers that connect the right and left halves of the brain so that they can communicate with one another) and small calcifications (from calcium deposits) in the white matter around the frontal and parietal brain lobes.
Detection of high levels of neurofilament light chain, a protein that serves as an indicator of axonal damage, has been found in the blood and cerebrospinal fluid of ALSP patients and may aid clinicians in formulating their diagnosis.
CT
Small periventricular calcifications, often only seen on thin sagittal reconstructions with a bone kernel are a typical imaging finding. Affected areas show a low attenuation and no contrast enhancement.
MRI
Presymptomatic mutation carriers
Mutation carriers usually show non-specific T2 hyperintense lesions of the white matter that are pronounced for the age of the patient. MR spectroscopy in these lesions is usually normal without characteristic findings.
Symptomatic patients
Characterized by bilateral, asymmetric patchy, or confluent areas of subcortical and deep white matter signal change, usually most pronounced in the frontal lobe followed by the parietal lobe with a relative sparing of the temporal lobe. The corticospinal tract is usually affected late in the disease course. Progression leads to severe atrophy of the supratentorial white matter. The cerebellum and brainstem are usually spared 3,4.
- T1: affected areas are low in signal
- T1 C+ (Gd): no enhancement is visible
- T2/FLAIR: hyperintense
- DWI: small spots of diffusion restriction, that can be visible over months have been described as a characteristic finding 3
- MR spectroscopy: (in symptomatic patients)
- reduced N-acetyl aspartate (NAA)
- increased choline
- increased Myo-inositol
- increased lactate
Treatment
There are currently no FDA-approved treatments for ALSP. Researchers are further investigating underlying disease mechanisms and symptom progression to develop more effective treatment options. Current treatment options do not reverse brain damage but instead are meant to manage symptoms. For patients with ALSP who have seizures, anti-epileptic medications are useful for controlling seizures. Antibiotics may be prescribed to help control infections, such as pneumonia or urinary tract infections that may arise as patients grow progressively weaker. Muscle relaxers may be recommended to target spasticity. Anti-depressants are often prescribed to treat psychological symptoms of ALSP but are not especially effective. Anti-psychotic medications may be used to control aggression in ALSP but side effects are generally not well-tolerated. Nutritional supplements and physical therapy are often recommended to slow overall decline and maintain the most optimal overall health possible.
Genetic counseling is recommended to help patients and families understand the genetics and progression of ALSP and to provide psychosocial support.
Investigational Therapies
Bone marrow transplantation is the most promising and first potential treatment to modify the ALSP disease course. Results vary between each patient, but in some cases, bone marrow transplants have slowed the progression of motor and cognitive symptoms of the disease. Bone marrow transplants are thought to be beneficial for some individuals with ALSP by providing new immune cells from donors with normal CSF-1 receptors to develop into and increase levels of microglia in the brain.
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