Leukoencephalopathy with neuroaxonal spheroids (LENAS), also known as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD) is an extremely rare kind of leukoencephalopathy and is classified as a neurodegenerative disease. LENAS is a cause of severe and subacute dementia that results from damage to certain areas of the brain. This damage is to a type of brain tissue called white matter and axon damage due to swellings which are termed spheroids.
The rarity and unknown prevalence of this disease may be due to most symptoms being similar to other common disorders, leading to misdiagnosis. LENAS normally has an adult onset (but also can be present in childhood), which can present on MRIs that mimics progressive multiple sclerosis and is thus misdiagnosed for this instead.
The genetic etiology of LENAS is known to follow an autosomal dominant pattern through a mutation in the CSF1R gene.
Signs and symptoms The signs and symptoms that are present vary with each individual as some may have all symptoms while some may only have some listed below. However, the progression of this disease is different with each individual which reflects how the symptoms change over time. Further, the damage that we see to the myelin and axons is thought to contribute to many of the neurological signs and symptoms that are shown in this condition. The most frequent symptoms are categorized into psychiatric, psychotic and neurologic. +Predominant Symptoms Based on CategoryCategorySymptomsPsychiatricDepression, Anxiety, Alcohol use disorder, Irritability, and AggressivenessPsychoticConfusion, Delusions, and HallucinationsNeurologicDementia, Seizures, Impaired Balance, Retropulsion, Gait Apraxia, Spasticity, Ataxia, and Urinary Incontinence
General symptoms Personality changes Loss of social inhibitions Depression Memory loss Loss of executive function The ability to plan and use problem-solving skills inhibits normal life skills such as impulse control and appropriately paying attention in general Seizures Severe decline in thinking and reasoning abilities (dementia). Motor skills become affected, many may have difficulty walking Patterns of movement abnormalities can occur as well such as: Parkinsonism: Generally will see bradykinesia, tremors, and muscle rigidity.
While these vary among individuals as mentioned, over time, almost all patients with this condition will be unable to walk, speak and care for themselves.
Causes
Leukoencephalopathy with neuroaxonal spheroids (LENAS) is believed to occur when presence of white matter degeneration and axonal spheroids are seen with a brain biopsy or an MRI.
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.
The result of spheroids in the brain leads to this significant decline of functioning that progressively worsens the brain function and leads to varied symptoms. However, why this occurs is still not entirely understood, thus more research is continuously being done to this day.
There have been identifiable genetic differences that are better understood. This disease is inherited while following an autosomal dominant pattern.
Genetic Etiology There are identifiable genetic causes that are better understood with this disease. LENAS is caused by a mutation in a gene, specifically the CSF1R gene. This mutation changes protein receptors on the gene which normally plays a role in important cell signaling pathways; however, this altercation inhibits the regular function.
Normal Function of CSF1R Gene
The colony stimulating factor 1 receptor (CSFR1) gene regularly functions by giving instructions for making a protein termed the colony stimulating factor 1 receptor (CSF-1 receptor). Proteins in general attach (bind) to their specific receptor which "turns on" (activates) to stimulate a cascade of cellular signaling pathways crucial for cell function to occur. These events occur with the specific CSF-1 protein. As it binds and is activated, it allows for important cellular processes to occur which include cell growth, division, and maturation of cells to in turn take on specific functions.
Glial cells, located in the brain, are responsible for protection and maintenance of neurons. In a healthy brain, the membrane of glial cells are abundant with the CSF-1 receptor gene and is also thought to be an important player in the proliferation and differentiation of these cells.
Mutated CSF1R Gene There are several types of mutations that occur in genes. The majority of CSF1R genetic mutations in LENAS occur due to a type of mutation which is called a missense mutation. Missense mutations occur when there is a change in a single amino acid of a protein. This single change can result in problems with functions of the protein, like the CSF-1 receptor. The kinase domain, which is the region of CSF-1 receptor where the mutation occurs, is altered and thus the normal function that activates other proteins is compromised and cannot stimulate cell signaling pathways properly.
Although this is the primary type of mutation in LENAS, other types may occur as well but it is not as well understood for this disease.
This genetic mutation is related to LENAS and said to be the main cause but how these lead to damage in the white matter and associated symptoms (cognitive and movement impairment symptoms) is still not fully clear.
Inheritance LENAS is inherited in an autosomal dominant pattern. This means that one copy of the mutated gene in each cell is sufficient to cause the disorder.
If one parent who is unaffected and one parent who is affected with LENAS give birth to four children, at least two of the four will become affected and have the disorder because the affected parent would pass on the one copy of the gene. In most cases, an affected person does inherit the mutation from one affected parent but not all cases.
There have been very few reports of cases that result from new mutations have been seen as well as cases in which there has been no history of LENAS. These few reports are not as concrete or well understood yet and further studies should be conducted.
Pathophysiology
Neuropathology
LENAS is seen with damage to the white matter and axons within the brain. The external human LENAS brain shows findings in several major structures. There is mild atrophy of the frontoparietal regions of the brain and a mild reduction of the thalamus and rostral (front) part of the caudate nucleus (which is located in an area of the brain called the basal ganglia). Abnormalities in the frontal, frontoparietal, and temporal lobes are most severe and predominant with LENAS and asymmetry of the cerebral hemispheres has sometimes been found. LENAS also may show moderately enlarged lateral ventricles and atrophy in corticospinal tracts as well as in the pons.
The area where it is seen to be the most pronounced abnormalities appear in the white matter below the pre- and postcentral gyri that extend through the posterior limb of the internal capsule into pyramidal tracts of the brain stem. The corpus callosum is variably affected. Reactive astrocytes and macrophages are present, but no inflammation appears. The cerebral cortex and basal ganglia are normal and contain no or only few spheroids. Within the cerebellum, there is a marked loss of Purkinje cells seen but cerebral white matter is normal. Specific Immunostains are used as the easiest identification of neuroaxonal spheroids in LENAS which appear as round to oval shaped swellings and are seen in affected white matter. If there appears to be a large amount of loss in myelin sheaths on axons and these spheroids, LENAS progressed to become widespread.
Electron Microscopy has also been used to identify spheroids. In LENAS, evidence of the spheroids may show neurofilaments that are scattered amount electron-dense material and mitochondria.
Subcortical U-fibers in the brain appear to be relatively spared, meaning they seem to not be involved in most cases but this does not mean they are not always/eventually involved. U-fibers represent connections which are between adjacent areas of the brain located within the cortex or deep in the white matter that are one of the last parts of the brain to be myelinated. In LENAS, it has been found that because these U-fibers are last to myelinate normally, they are also last to be affected as the disease progresses.
Biochemistry The primary biochemical defect in LENAS disrupts normal states and may involve oxidative stress. Ceroids, which are essentially products of unsaturated fatty acids that build up, are found in macrophages and other glia is thought to be an end-product of oxidative damage, indicative of membrane damage from abnormal accumulation.
The high levels of Iron is also present in LENAS which can be associated to cause an increased level of toxic free radicals and causing oxidative damage to the body, causing failure in our cellular energy systems.
Disease Mechanism The mechanism of LENAS still seems to remain unclear and it varies as more research on this is being done. Some mechanisms that can be of clinical importance of why individuals show certain symptoms and which area of the brain has been shown to be consistent.
Normally, the frontal lobe in our brain are important for our higher level executive functions. Predominance of white matter damage in this lobe has been found to be consistent with both the psychiatric and behavioral signs and symptoms pertaining to LENAS. The underlying symptoms seen of frontotemporal dementia seen commonly in LENAS is associated with the temporal lobe damage. There is a large disconnect in the brain between the lobes that reflect the neuropsychiatric symptoms that are common with the disease.
Ataxia, which is related to our daily voluntary movements of muscles, are often present even in patients without cerebellar involvement which could reflect either minimal damage to the cerebellum or diffuse cerebral white matter lesions.
Diagnosis The diagnosis of LENAS is usually based on medical and family history, genetic testing, extensive imaging and other supplemental testing. As this disease is extremely rare, diagnosis is still very complex as many of these diagnostic criteria for LENAS can be mistaken for similar neurodegenerative disorders. The differential diagnosis of leukoencephalopathy in general is very extensive and specialized investigations are required to make an accurate diagnosis.
Diagnostic Criteria Note: These criteria were established by a group consisting of board-certified neurologists from the Mayo Clinic, Niigata University, Shinshu University School of Medicine, Kyoto Prefectural University of Medicine, and Tokushima University Graduate School.
Core Features
Age at onset ≤ 60 years old More than 2 findings of the following clinical signs and symptoms: Cognitive Impairment or Psychiatric Symptoms Pyramidal Signs Parkinsonism Epilepsy Autosomal Dominant inheritance or sporadic occurrence Brain CT/MRI findings: Bilateral Cerebral white matter lesions Thinning of the Corpus Callosum Other causes of Leukoencephalopathy including vascular dementia, multiple sclerosis, or leukodystrophy can be excluded.
Exclusionary Findings
Age at onset ≤ 10 years Stroke-like episodes more than twice except for epilepsy Prominent peripheral neuropathy
Supportive Findings
Frontal lobe dysfunction shown by clinical features or cognitive battery test Rapidly progressive course. Become bedridden within 5 years after onset Spotty small calcifications in the white matter shown by brain CT Neuropathologic findings compatible to LENAS