The type of ceroid lipofuscinosis that develops later (15 to 25 years of age or older) is often unattended by visual or retinal changes and is even slower in its evolution. It is presented here for ease of exposition, but it becomes relevant mostly in relation to dementing illness in young adulthood. Personality change or dementia is one constellation, the other being myoclonic seizures with subsequent dementia and even later pyramidal and extrapyramidal signs. As the disease progresses, cerebellar ataxia, spasticity, rigidity or athetosis, or mixtures thereof, are combined with dementia. As a reflection of the variability of the clinical presentation, a recent patient of ours had vague visual difficulties at age 51 years and evolved a spastic quadriparesis with disinhibited behavior over 5 years. Additional comments regarding the unusual presentations of this disease can be found further on, under “Adult Forms of Inherited Metabolic Disease.” van Bogaert pointed out to our colleague R.D. Adams that relatives of these patients may have retinal changes without neurologic accompaniments. The mutations that give rise to this and related disorders are mentioned above. The difficulties in making the diagnosis in adults with dementia is discussed by Berkovic and coworkers (2016).
Of all the lipidoses, these cerebroretinal degenerations had for decades defied unifying biochemical definition. Our understanding of these diseases is difficult because they embody both enzymatic defects and structural protein dysfunctions. In a few of the early childhood types, mutations of one of several lysosomal enzymes have been identified. Zeman and coworkers showed that the cytoplasmic inclusions are autofluorescent and give a positive histochemical reaction for both ceroid and lipofuscin, but this material is not different biochemically from the lipid substance that accumulates in aging cells. In addition to the presence of curvilinear bodies in the cytoplasm of neurons and other tissues, some in a fingerprint pattern, there is a reduction in type II synapses in the distal parts of the axon. All these changes precede nerve cell loss. The genetics (CLN mutations) have been discussed above.
Instances of the recessive type of GM2 gangliosidosis may have their onset in this age period. Twenty-four such cases (from 20 kindreds) were collected from the medical literature by Meek and coworkers. Ataxia and dysarthria were frequently the presenting symptoms, followed by dementia, dysphagia, spasticity, dystonia, seizures, and myoclonus. Degeneration of anterior horn cells with progressive muscular atrophy may be a feature, although this is more characteristic of the adult-onset variety (see further on). Atypical cherry-red spots are observed in some patients. The biochemical abnormality, that is, a deficiency of hexosaminidase A, is the same as in Tay-Sachs disease, but not as severe or as extensive. Progression of the disease is slow, over a period of many years.
A type of Gaucher disease is occasionally encountered in which seizures, severe diffuse myoclonus, supranuclear gaze disorders (slow saccades, saccadic and pursuit horizontal gaze palsies), and cerebellar ataxia begin in late childhood, adolescence, or adult life. The course is slowly progressive. The intellect is relatively spared. The spleen is enlarged. The pathologic and biochemical abnormalities are the same as those of Gaucher disease of earlier onset.
Type 1, α-Neuraminidase Deficiency; NEU1 Mutation)
This is a genetically distinct class of disease characterized by the storage in nervous tissue of sialylated glycopeptides. It is caused by a deficiency of neuraminidase, a lysosomal enzyme. In some of the patients, the onset was in late childhood or adolescence, and in others, even later. In addition to the patients initially reported by Rapin and coworkers, a few dozen similar cases have appeared in the medical literature.