The differential diagnosis of this leukodystrophy includes neuroaxonal dystrophy (see below), cases of early-onset inherited polyneuropathy, late-onset Krabbe disease, and childhood forms of Gaucher disease and Niemann-Pick disease. A variant of metachromatic leukoencephalopathy, caused by a deficiency of the isoenzymes of arylsulfatase A, B, and C, was described by Austin in 1973 and called multiple sulfatase deficiency. The neurologic manifestations resemble those of metachromatic leukodystrophy but, in addition, there are facial and skeletal changes similar to those of a mucopolysaccharidosis. Deafness, hepatic enlargement, ichthyosis, and beaking of lumbar vertebrae are additional findings in some cases. Metachromatic material is found in the urinary sediment. Pathologically, in addition to metachromasia of degenerating white matter in cerebrum and peripheral nerve, there may be storage material (sulfated glycolipids), like that found in the gangliosidoses in neurons as well as in liver, gallbladder, and kidney. Granules are demonstrable in neutrophilic leukocytes. There has also been described a state of “arylsulfatase pseudodeficiency,” which exists as a polymorphism in approximately 7 percent of Europeans and makes the point that low enzyme levels alone are insufficient to be expressed as a phenotype of metachromatic leukodystrophy.
Forms of metachromatic leukodystrophy developing in adult years are discussed further on.
This is a rare disease, inherited as an autosomal recessive trait. In the largest group of cases (77 collected by Aicardi and Castelein), the onset was near the beginning of the second year in 50 patients and before the third year in all instances. The clinical constellation comprised psychomotor deterioration (loss of ability to sit, stand, and speak), marked hypotonia but brisk reflexes and Babinski signs, and progressive blindness with optic atrophy but normal retinae. Seizures, myoclonus, and extrapyramidal signs were rare. Loss of sensation was found later in some cases. Terminally, bulbar signs, spasticity, and decerebrate rigidity often supervened. The course was relentlessly progressive, with fatal issue in a decorticate state in 3 to 8 years. There were no abnormalities of the liver and spleen and no facial or skeletal changes.
Pathologic examination reveals eosinophilic spheroids of swollen axoplasm in the posterior columns and nuclei of Goll and Burdach and in the Clarke column, substantia nigra, subthalamic nuclei, central nuclei of brainstem, and cerebral cortex. There is cerebellar atrophy, affecting the granule cell layer predominantly, and increased iron-containing pigment in the basal ganglia (like that observed in the PANK2 mutation type of iron deposition discussed in a later section).
The CT and CSF are normal, and there are no biochemical or blood cell abnormalities. MRI may show decreased signal intensity of the pallidum bilaterally corresponding to iron deposition. Some reports are confusing in reporting an area of necrosis around a high signal that is characteristic of the aforementioned PANK2 mutation, with which it has overlapping clinical and pathologic features. After the age of 2 years, however, the EEG shows characteristic high-amplitude fast rhythms (16 to 22 Hz). Evoked responses may be abnormal. Nerve conduction velocities are normal despite EMG evidence of denervation. The diagnosis can be reliably established during life by electron microscopic examination of skin and conjunctival nerves, which show the characteristic spheroids within axons.