Fucosidosis Chapter 12

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12.1 Clinical Features

and Laboratory Investigations Fucosidosis is a very rare, autosomal recessive neuro- visceral storage disorder. Two clinical variants have been described, but in fact the two types represent a continuous clinical spectrum. Mild and severe forms can occur within the same family.

Type I manifests before the end of the first year of life with frequent respiratory infections. From the age of about 1 year, mental and motor regression occurs.

Initially, the children show signs of hypotonic weak- ness, but later hypertonia and spasticity develop.

Seizures may occur. In the end stage decorticate and decerebrate postures are seen. The children’s facial appearance resembles that seen in mucopolysaccha- ridosis type I, with coarse features and a protruding tongue. Other similarities between these disorders are growth retardation and a mild to moderate dysos- tosis multiplex. Hepatosplenomegaly, cardiomegaly, and anhidrosis with a marked increase in the sodium chloride content of sweat are present. Death occurs in the first decade of life.

Type II has a milder and more prolonged course.

Mental retardation becomes evident between the ages of 1 and 2 years. The coarse facies, growth retarda- tion, and skeletal deformities are very similar to those seen in mucopolysaccharidosis type I. Angioker- atoma corporis diffusum is a very special characteris- tic of this type and is identical to that occurring in Fabry disease. The content of sodium chloride in sweat is normal, although anhidrosis may be present.

The patients suffer from similar but milder neurolo- gical signs than in type I. These patients survive much longer and often reach adulthood.

In the urine of patients with fucosidosis, an in- creased level of fucose-containing glycoconjugates is found, including fuco-oligosaccharides and fucogly- copeptides. There is evidence that fucosidosis types I and II can be distinguished by the pattern of urinary excretion. Cytoplasmic vacuolation in circulating lymphocytes is common in type I, less frequent in type II. Definite diagnosis is established by the demonstration of a deficiency of the lysosomal en- zyme a-fucosidase in leukocytes, cultured fibro- blasts, or other tissue cells. Prenatal detection is pos- sible by assessing enzyme activity in amniotic fluid cells. DNA-based prenatal diagnosis is possible when

the mutations responsible in the family at risk have been identified.

12.2 Pathology

The brain may be enlarged or small, depending on the stage of the disease. The most striking feature is dif- fuse neuronal ballooning and neuronal loss. The cy- toplasm of remaining neurons is packed with small vacuoles. These neuronal changes are seen every- where in the gray matter. There are prominent white matter abnormalities, variably described as deficient myelination or demyelination. The white matter is deficient in myelin and gliotic.

Electron microscopy demonstrates that the vac- uoles present in brain cells are membrane-bound.

Many vacuoles contain two different components, moderately electron-dense reticular materials and parallel lamellae. The vacuoles are present in neu- rons, astrocytes, and oligodendroglia.

Enlargement of many internal organs is found, in- cluding liver, spleen, heart, pancreas, thymus, thyroid, and kidneys. Marked vacuolar storage is present in hepatocytes, Kupffer cells, and bile duct epithelium.

The gall bladder may be “strawberry-like” and non- functioning and the adrenals may be small and at- rophic. Granulovacuolar storage is seen in almost all organs, including kidney, spleen, lymph nodes, lungs, heart, endocrine glands, and sweat glands. In addi- tion, vacuoles are present in vascular endothelial cells, fibroblasts, bone marrow cells, and circulating lymphocytes.

12.3 Pathogenetic Considerations

Fucosidosis is caused by a deficiency of the lysosomal enzyme acidic a-

L

-fucosidase. This enzyme hy- drolyzes a-fucose from glycolipids and glycoproteins.

Fucose is a normal sugar constituent of many tissue mucopolysaccharides, plasma glycoproteins, and tis- sue mucolipids. In fucosidosis, tissues store fucose- rich glycolipids, sphingolipids, glycoproteins, oligo- saccharides, and mucopolysaccharides. The major part of the stored material consists of ceramide con- taining fucose and other hexoses. This material is derived from secretor antigens and blood group anti-

Fucosidosis

Chapter 12

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gens, which are fucose-rich glycolipids and glycopro- teins. In the liver, there is a major accumulation of gly- colipids. These are only present to a minor extent in the brain, where oligosaccharides predominate as storage material.

The gene encoding a-fucosidase, FUCA1, is locat- ed on chromosome 1 at position 1p34. The observed clinical variability among patients cannot be ex- plained by the nature of the mutations in FUCA1 and must be secondary to unknown factors. A region showing homology to the fucosidase gene was identi- fied on chromosome 2 and designated FUCA1P.

FUCA1P does not encode for fucosidase enzyme activity and is a so-called pseudogene. Because of the wide variation in clinical severity of fucosidosis, even within families, it is of interest to know whether the FUCA1P gene could encode for a protein product that might affect fucosidase enzyme activity. A third gene, FUCA2 on chromosome 6, is thought to regulate the fucosidase activity, although it does not encode for the fucosidase enzyme.

12.4 Therapy

To date therapy has been entirely supportive. Hemato- poietic stem cell transplantation has been performed in fucosidase-deficient animals. Following successful engraftment, increased levels of fucosidase activity were found in leukocytes, plasma, and neural and visceral tissue. The enzyme reaches viscera and peripheral nerves rapidly via phagocytes, but it takes months to achieve substantial levels of enzyme activ- ity in the CNS. Long-term engraftment from an early age reduced the severity and slowed the progression of clinical neurological disease in these animals;

transplantation after the onset of clinical signs was not effective. Hematopoietic stem cell transplantation has been performed in a few patients and the results are promising in those undergoing the transplanta- tion early. At present, it is still uncertain whether ear- ly treatment will completely prevent the clinical signs of disease.

12.5 Magnetic Resonance Imaging

CT scan findings include hypodensity of the cerebral white matter and globus pallidus. Mildly increased density of the thalami has been reported.

The MR images obtained in a fucosidosis patient show symmetrical white matter abnormalities. In some patients, the white matter signal behavior on T

1

- and T

2

-weighted images is suggestive of moderate hypomyelination: the white matter is mildly hyperin- tense on both T

1

- and T

2

-weighted images (Fig. 12.1).

In other patients, however, the white matter has in some parts a higher signal intensity on T

2

-weighted images than is usual for hypomyelination, and its sig- nal on T

1

-weighted images is low in places, suggesting myelin loss (Fig. 12.2). The subcortical U fibers, inter- nal, external, and extreme capsules, and cerebellar white matter also have an abnormal signal intensity.

The corpus callosum is normal in signal, but may be thin. The cerebral white matter may have a decreased volume with enlarged CSF spaces. The internal medullary laminae of the thalamus and in some cas- es the lateral and medial medullary laminae of the globus pallidus and hypothalamus have a high signal on T

2

-weighted images. The globus pallidus, thala- mus, and substantia nigra tend to have an abnormal- ly low signal on T

2

-weighted images. Cerebral and cerebellar atrophy may be seen and may be marked, especially in older patients.

The involvement of a combination of cerebral hemispheric white matter, globus pallidus, and thala- mus is reminiscent of Canavan disease and later-on- set variants of maple syrup urine disease, but in the latter two conditions the white matter is swollen, whereas it is reduced in volume in fucosidosis. The images show resemblance with the pattern observed in infantile GM

1

and GM

2

gangliosidoses, although the hypointensity of central brain nuclei on T

2

- weighted images is not seen in the latter disorders.

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12.5 Magnetic Resonance Imaging 121

Fig. 12.1. The cerebral white matter in this 4-year-old patient with fucosidosis has a high signal on both T1- and T2-weighted images, suggestive of moderate hypomyelination. The globus pallidus, thalamus, and substantia nigra have a strikingly high

signal on T1-weighted images and low signal on T2-weighted images. Courtesy of Dr. S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto

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Chapter 12 Fucosidosis 122

Fig. 12.2. Part of the cerebral white matter in this 7-year-old patient with fucosidosis has a high signal on both T1- and T2-weighted images, suggestive of moderate hypomyelination, but parts of the deep cerebral white matter have a higher signal on T2-weighted images and a low signal on T1-weighted images, suggestive of myelin loss. Note the signal

abnormalities in the internal laminae of the thalamus. Also note the very low signal of the globus pallidus, thalamus, and substantia nigra on T2-weighted images. Courtesy of Dr.

S. Blaser, Department of Diagnostic Imaging, Hospital for Sick Children, Toronto