Neuroaxonal Leukoencephalopathy with Axonal Spheroids (Hereditary Diffuse Leukoencephalopathy with Spheroids – HDLS)

What Causes Neuroaxonal Leukoencephalopathy with Axonal Spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant progressive disease. The disease was described for the first time in multiple members of a large Swedish pedigree in 1984 (Axelsson et al, 1984). In this family, 17 of 71 subjects from 4 generations were affected. The age at onset varied from 8 to 60 years with a mean of 36 years. The age at death was 39 to 89 years with a mean of 57 years. The time between onset and death varied from 3 months to over 30 years. Some patients rapidly developed severe dementia and died a few months after the onset of symptoms, whereas in others the course was prolonged with dementia developing over decades. Sporadic patients have also been reported.

The predominant clinical manifestations are psychiatric and include depression, anxiety, alcohol abuse, irritability, and aggressiveness. Psychotic symptoms may occur with confusion, delusions, and hallucinations. The most frequent neurologic symptoms are dementia, seizures, impaired balance, retropulsion, gait apraxia, spasticity, ataxia, and urinary incontinence. Extrapyramidal symptoms may occur with hyperkinesia, chorea, tremor and oral dyskinesia.

EEG usually shows nonspecific abnormalities with slowing of the background pattern and sometimes paroxysmal changes. The abnormalities often have a frontotemporal predominance. They may be asymmetrical. Routine and metabolic laboratory investigations reveal no abnormalities. The diagnosis is at present based on histopathologic findings.


External examination of the brain shows mild atrophy of the frontoparietal regions. The thalamus and the rostral part of the caudate nucleus may be mildly reduced in size. The lateral ventricles are moderately enlarged. The corticospinal tracts and the basis of the pons are atrophic. On microscopy, a widespread leukoencephalopathy is found, characterized by a commensurate loss of myelin sheaths and axons and the presence of numerous neuroaxonal spheroids in the affected white matter. Neuroaxonal spheroids are round to sausage-shaped axonal swellings, which are easily identified with Bielschowsky, Bodian, and anti-neurofilament immunostatins. The leukoencephalopathy is most severe in the frontal, frontoparietal and temporal areas and may be mildly asymmetrical. The U-fibres are relatively spared. The abnormalities tend to be most pronounced in the white matter below the pre- and postcentral gyri and extend through the posterior limb of the internal capsule into the pyramidal tracts of the brain stem. The corpus callosum is variably affected. The abnormal white matter may show vacuolization. Reactive astrocytes and macrophages are present, but no inflammatory cells. The cerebral cortex and basal ganglia are normal and contain no or only few spheroids. Within the cerebellum, a marked loss of Purkinje cells is seen, but the cerebellar white matter is normal. Electron microscopy of the spheroids reveals neurofilaments scattered among electron-dense material and mitochondria.

Pathogenetic Considerations

The homogeneity of the clinical picture and histopathologic findings strongly suggests that HDLS is a distinct disease entity. The disease has an autosomal dominant mode of inheritance. Isolated cases are probably the result of new mutations. The genetic defect and the pathophysiology of HDSL are as yet unresolved. Considering the more or less commensurate loss of axons and myelin sheaths, the preferential involvement of long tracts and the presence of axonal swellings, it is likely that axons are the primary target of the disease.

Axonal spheroids are pathologic findings characteristic of the neuroaxonal dystrophies. They occur most often in the context of neuronal degenerative disorders, such as infantile neuroaxonal dystrophy (Seitelberger disease) and Hallervorden-Spatz disease. The combination of a leukoencephalopathy and neuroaxonal spheroids in the abnormal white matter is rare. Apart from HDSL, this combination is observed in dermatoleukodystrophy with neuroaxonal spheroids (Matsuyama et al, 1978) and polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (Nasu-Hakola disease). Both disorders are clinically different form HDLS.

How is Neuroaxonal Leukoencephalopathy with Axonal Spheroids Treated?

Supportive care is the only therapeutic option.

Magnetic Resonance Imaging

MR images demonstrate signal abnormalities bilaterally within the cerebral white matter, either most pronounced within the white matter under the pre- and postcentral gyri, or within the frontal white matter. The signal abnormalities may be patchy or more confluent, and may be symmetrical or asymmetrical. They are ill-defined. The corpus callosum is thin and may contain areas of abnormal signal. The signal abnormalities extend downwards through the posterior limb of the internal capsule into the pyramidal tracts of the brain stem. The affected cerebral white matter is atrophic with widening of the lateral ventricles and subarachnoid spaces. The head of the caudate nucleus may be flattened. There may be cerebellar atrophy.

The above MRI findings may confirm the diagnosis within a pedigree with known HDLS. However, the MRI findings in itself are not specific and do not allow definite diagnosis. The diagnosis needs to be confirmed by histopathology.

The differential diagnosis of HDLS includes disorders with frontal cortical degeneration, such as frontotemporal dementia and Pick disease. In these disorders MRI shows atrophy of mainly the frontotemporal areas. Sometimes there are additional white matter changes, which are ill-defined and usually mild. If present, they make differentiation from HDLS difficult.

The differential diagnosis also includes disorders with frontal lobe dysfunction caused by white matter degeneration, such as metachromatic leukodystrophy, X-linked adrenoleukodystrophy with frontal predominance, Nasu-Hakola disease (PLOSL), Binswanger disease, CADASIL, orthochromatic pigmentary leukodystrophy, and adult onset autosomal dominant leukodystrophies. Most disorders can be ruled out by typical clinical, physical and laboratory findings and neuroimaging differences. Some disorders require histopathologic confirmation.

Courtesy of Van der Knaap et al, Neurology 2000; 54: 463-468, with permission

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