Pathologic examination shows neuronal loss in the cerebral and cerebellar cortices (granule and Purkinje cells), and curvilinear storage particles and osmophilic granules are visible in the remaining neurons. Inclusions are also observed in cutaneous nerve twigs and endothelial cells of blood vessels, findings that permit diagnosis during life by electron microscopy of skin, conjunctival, or rectal mucosal biopsies.
In many patients with lipofuscinoses, diagnosis can be confirmed by demonstrating the presence of one of several recently identified gene mutations. There are no definite markers for the group in blood or urine, but in some patients a structural component of mitochondria is excreted in excess (the so-called C-fragment).
In the differential diagnosis, one must consider late infantile GM1 gangliosidosis, idiopathic epilepsy, Alpers disease, and other forms of neuronal ceroid-lipofuscinosis.
This is a group of diseases in which the storage of lipid in neurons is combined with that of polysaccharides in connective tissues. As a consequence, there is a conjunction of neurologic and skeletal abnormalities that is virtually unique. The nervous system may also be involved secondarily as a result of skeletal deformities and thickening and hyperplasia of connective tissue at the base of the brain, leading to obliteration of the subarachnoid space and obstructive hydrocephalus or compression of the cervical cord. The prevalence of mucopolysaccharides as a whole is approximately 1 per 8,000 births, according to Meikle and colleagues. Depending on the degree of visceral-skeletal and neurologic changes, at least 7 distinct clinical subtypes are recognized (see Table 36-7).
The basic abnormality is an enzymatic defect that prevents the degradation of acid mucopolysaccharides (now called glycosaminoglycans). The latter can be measured and are increased in serum, leukocytes, or cultured fibroblasts. The storage is, again, within lysosomes in the brain, spinal cord, heart, viscera, bone, and connective tissue. All forms of the disease except the Hunter syndrome, which is sex-linked, are inherited in an autosomal recessive pattern. Studies over a 50-year period have established that each type of mucopolysaccharidosis is caused by a defect in a different enzyme and in keeping with progress in the field, the mutation of each disorder has been established.
Hurler Disease (MPS I, IDUA Mutation)
This, the classic form, also known as MPS I, begins clinically toward the end of the first year. Mental retardation is severe, and skeletal abnormalities are prominent (dwarfism; gargoyle facies; large head with synostosis of longitudinal suture; kyphosis; broad hands with short, stubby fingers; flexion contractures at knees and elbows). Conductive deafness and corticospinal signs are usually present. Protuberant abdomen, hernias, enlarged liver and spleen, valvular heart disease, chronic rhinitis, recurrent respiratory infections, and corneal opacities complete the picture. The biochemical abnormalities consist of the accumulation of dermatan and heparan sulfate (glycosaminoglycans) in the tissues and their excretion in the urine, probably as a consequence of absence of activity of a-l-iduronidase. Also, there is an increase in the ganglioside content in nerve cells of the brains of these patients. In the milder Scheie (MPS V) variant of Hurler disease, intelligence and life span are normal. A few newborn screening programs in the United States test the infant’s blood for MPS I.