Clinical Aspects

KD is traditionally classified into three major forms on the basis of the age of onset: (1) early-infantile, (2) late-infantile or juvenile, and (3) adult form. These forms also differ in their clinical severity, and the late-onset forms are characterized by a milder and more protracted course. The emergence of molecular genetic advances in the metabolic diseases has blurred these discrete boundaries between categories and consolidated the concept of a continuum of disease expression from infancy to adulthood based on the different impact of the specific mu-tational events (3).

The most frequent and common form of KD is the infantile form, which begins in the first 6 mo of life and rapidly progresses leading to death before the child reaches the age of 2. Children with KD present rapid psychomotor regression, generalized rigidity, and peripheral neuropathy; they subsequently develop optic atrophy, deafness, and cachexia. Increased proteins in the cerebrospinal fluid is a constant finding; cell count is usually normal. Nerve conduction velocity is always abnormal.

The late-onset forms of KD are clinically more heterogeneous, progress more slowly and have a milder clinical picture. Various clinical signs are observed including hemiparesis, spastic paraparesis, intellectual impairment, cerebellar ataxia, visual failure, peripheral polyneuropathy and talipes cavus. The increase in cerebrospinal fluid proteins and the reduction in nerve conduction velocity are less constant (5). An adult-onset form can be reasonably, although arbitrarily, isolated from this group.

Adult KD presenting as a pure spastic paraparesis, which may reach variable degrees of severity, is a rare phenotype that we shall now discuss.

These patients present an indolent course that may start even in their 40s; a few patients were diagnosed in their 50s or 60s. However, clinical onset sometimes goes back to childhood or adolescence if we consider the long-standing history of the presence of pes cavus. The deformity of talipes cavus is caused by an increase in the tone of the plantar flexor muscles, which probably indicates a very subtle involvement of the corticospinal tract (6). Most of the patients reported in the literature (2,711) as well as four of the five patients diagnosed at our Institute also had minimal neurological signs consisting of pes cavus (three of our five patients), subtle signs of peripheral neuropathy (three of five), slight dysarthria (two of five), and mild cognitive impairment (two of five). In addition to spastic para-paresis, other mild neurologic signs occasionally reported in the literature include visual impairment, pallor of the optic disc, tremor, and ataxia.

3. GENETIC CONSIDERATIONS

Molecular studies have demonstrated the heterogeneous nature of KD. Cloning of the GALC gene (12,13) has demonstrated that different mutations within this gene are associated with different severity of the disease (14). One common mutation has been found in 40-50% of the mutant alleles in infantile cases of European or Mexican descent (14). Sixty-five disease-causing mutations and polymorphic changes within the GALC gene have been described (14). Most of the mutations causing the late-onset or adult form are located in the region of the GALC gene coding for the 50-kDa subunit (2). However, some adult cases exhibited mutations located in the region encoding the 30-kDa subunit (2,7,15). The phenotypic variation of the disease may depend on the amount of residual GALC activity associated with differing mutant alleles (14). On the basis of in vitro studies, the correlation between residual enzymatic activity and clinical expression also has been proposed by Percy (3), who pointed out, however, that the available enzymatic data did not fully support this hypothesis. A different expression or stability of the mutant enzyme within various brain regions also might play a role (3). Other genetic factors not related to the GALC gene and, in particular, differing rates of psychosine turnover may also have an influence on the variable severity of different forms of KD (3).

4. RADIOLOGICAL FINDINGS

In the classic infantile form of KD, MRI scan shows diffuse abnormalities in the cerebral white matter and progressive atrophy. The white matter lesions may be difficult to recog nize at a very early age when the white matter is still normally hyperintense in T2-weighted images. At this stage, computed tomography studies may be more helpful because they may show hyperdense areas in the thalami or in the posterior periventricular regions that probably correspond to the clusters of globoid cells in which the galactocerebroside and psychosine accumulate; calcium deposits may contribute to the hyperdensity (16). In children in whom the white matter has become sufficiently hypointense in T2-weighted images, the MRI changes are more easily recognizable; they mostly involve the white matter of the parieto-occipital regions, with sparing of the subcortical arcuate fibers. An almost constant involvement of the pyramidal tracts (one of the first white matter pathways to myelinate) may be recognizable even within a diffusely unmyelinated white matter. Similarly, the cerebellar white matter is often affected. A frequent, although subtle, involvement of the basal ganglia and thalami is present, whereas the dentate nuclei appear more markedly abnormal (9). The brains of these children become progressively atrophic, and microcephaly ensues.

Children who are diagnosed at age 3 or 4 have more restricted and clear MRI abnormalities. They present hyperintense signal in T2-weighted images mostly in the posterior periventricular regions with involvement of the splenium of the corpus callo-sum, which may shrink.

Correlative MRI and neuropathologic studies have shown that the areas of hyperintensity on T2-weighted images correspond to the areas of demyelination with globoid cell infiltration (16). In long surviving patients, the white matter may be totally gliotic and devoid of macrophages (17).

In the patients with late onset of the disease reported in the literature, the radiological data are often incomplete because they are usually described in articles prevalently dealing with the clinical, biochemical, and genetic aspects of the disease (18,19). These patients show well-circumscribed, posterior, periventricular white matter abnormalities with frequent involvement of the corpus callosum. All these white matter areas are shrunk; the posterior parts of the lateral ventricles, therefore, are enlarged. The corticospinal tracts are often abnormal symmetrically or asymmetrically (2,6-11,20-32; Fig. 1). Loes et al. (9) in their series showed that pyramidal tract involvement is the most characteristic finding in both early- and late-onset KD. Mild cerebral atrophy may be present. However, in late-onset KD patients, MRI studies may show very subtle abnormalities (11) or be entirely normal (14).

In late-onset KD, MR-hyperintense lesions suggest demyelination (17). Neuropathological reports of late-onset cases are limited. Choi et al. (33) described the neuropathology of 18-yr-old twins who died of graft-vs-host disease 2 mo after allo-geneic bone-marrow transplantation. Their brains showed degeneration of the optic radiations, frontoparietal white matter, and corticospinal tracts. Multiple necrotic foci with calcium deposits were found within the lesions. Globoid cell infiltration was present in actively degenerating white matter. In the peripheral nerves of adult KD, loss of myelinated fibers, disproportionately thin myelin sheaths, and inclusions in Schwann cells have been described (17).

Fig. 1. Shown is a 53-yr-old female patient with onset of the disease at age 30. (A,B) Axial fluid-attenuated inversion recovery sections. (C,D) Sagittal SE T2-weighted sections. In A, hyperintense signal in the posterior periventricular regions and splenium of the corpus callosum is demonstrated. The corticospinal tracts are involved from the subcortical white matter within the precentral gyrus through the corona radiata down to the posterior limb of the internal capsule (arrowheads, A-C). On the midline sagittal section (D), involvement of the isthmus of the corpus callosum is also visible (arrow).

Recently, patients with adult-onset KD presenting with pure progressive spastic paraparesis and selective involvement of the corticospinal tracts, which are associated with segmental atrophy of the corpus callosum and occasional slight abnormalities in the parieto-occipital white matter, have been described (2,7-11). In more detail, the patients we observed presented signal abnormalities along the pyramidal tracts visible from the axis of the precentral gyrus down to the corona radiata, posterior limb of the internal capsule, and to variable levels of the brainstem. The spinal cords of two patients that we examined appeared slightly atrophic, but we could not detect any signal abnormalities, perhaps because of the suboptimal quality of the examinations. The neat involvement of the corticospinal tracts was very well appreciated in T2-weighted sagittal paramedian sections (Fig. 1C); coronal sections demonstrated that the involvement was more marked in the

Fig. 2. Shown is a 62-yr-old female patient with onset of the disease at age 32. (A,B) Axial T2-weighted sections show hyperintensity of the white matter in the motor strip, which is moderately atrophic on both sides. (C,D) Coronal fluid-attenuated inversion recovery images 5-mm apart demonstrate involvement of the corticospinal tracts (C) and corpus callosum. The opercular areas are spared.

upper part of the motor strip, thus explaining the involvement of the lower extremities (Fig. 2). The lower part of the motor strip, corresponding to the areas of representation of the hand and face, was affected to a lesser extent or not at all. The white matter at the opercula was always spared (Fig. 2C,D). The upper part of the precentral gyrus was always clearly atrophic and became as thin as the postcentral gyrus. The abnormal signal intensity extended across the corpus callosum at the isthmus, which appeared focally thinned (Figs. 1D and 2C). This finding probably corresponds to the degeneration of the association fibers connecting the motor cortex of both sides. The intensity of the signal abnormalities is variable in different cases, ranging from marked T2 hyperintensity to minimal alterations only in fluid-attenuated inversion recovery images.

It is difficult to understand why the corticospinal tracts are selectively involved in this disorder. It is noteworthy that the corticospinal tracts have some characteristics that are different from other white matter tracts (34). Van der Knaap postulated that in patients with dysmyelinating diseases the oldest myelin breaks down first (M. van der Knaap, Myelination and myelin disorders, Utrecht, the Netherlands: University of Utrecht; 1991, thesis). Because in KD the pathologic process does not involve the formation of myelin but its turnover, the myelin that is formed first, like in the corticospinal tract, will be the first to be affected (5).

Satoh et al. proposed that in patients with late-onset KD the selective vulnerability of the corticospinal tracts might depend on their more active myelin metabolism, compared with the white matter of other parts of the brain where the residual GALC activity is sufficient to maintain a normal or nearly normal myelin. Perhaps the more marked enzymatic defect justifies the more severe white matter involvement of infantile KD. So far, however, the reason for the selective vulnerability of the corticospinal tract still remains unknown. It must be pointed out that the corticospinal tract has some peculiarity compared with the rest of the white matter: in normal subjects, its signal may be slightly hyperintense in T2-weighted images in the posterior limb of the internal capsule, with some variability between subjects (35). In addition, within the corticospinal tract there are segments that can be affected for a certain length, whereas the adjacent segments are spared as seen in some cases of ALD.

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