In the late encephalopathic forms of the metabolic and mitochondrial diseases, the diagnosis is usually made only after symptoms have been present for months or years, the disease having been mistaken for some other condition, particularly depression or a degenerative dementia. Even a manifest psychosis may have occurred in relation to some of these disorders, but such occurrences are admittedly rare. For example, one of our patients with metachromatic leukodystrophy, a 30-year-old man, began failing in college years and was later unsuccessful in holding a job because of carelessness and mistakes in his work and indifference to criticism, irritability, and stubbornness (clearly traceable to a mild dementia). Only when Babinski signs and loss of tendon reflexes in the legs were detected was the correct diagnosis entertained for the first time. By then he had been ill for nearly 10 years. Bosch and Hart described a patient with the onset of dementia at 62 years of age and drew attention to 27 other similar cases of adult-onset metachromatic leukoencephalopathy (see also the 7 cases reported by Turpin and Baumann). Overt signs of neuropathy are usually lacking in these adult-onset cases, but EMG and sural nerve biopsy will disclose the characteristic abnormalities.
One of our adult patients with Wilson disease had been committed to a psychiatric hospital because of paranoid tendencies and fighting with his family; the presence of a tremor and mild rigidity of the limbs had been attributed at first to phenothiazine drugs. In some of Griffin’s cases of adrenomyeloneuropathy, a spastic weakness of the legs and sensory ataxia progressing over several years were the main clinical manifestations; a spinocerebellar degeneration was suspected. One of our patients with Kufs lipid storage disease began to deteriorate mentally in early adult life and only much later showed an increasing rigidity, with athetotic posturing of limbs and difficulty in walking; he succumbed to his disease after more than a decade of symptoms. Another recent patient with Kufs disease presented at age 51 with vague visual difficulty, which was followed by spasticity of the legs, behavioral disinhibition, and dementia spanning 6 years. Josephs and colleagues describe 2 of 5 patients with adult-onset Niemann-Pick disease type C who had a psychosis beginning at ages 61 and 27, respectively (see also Sevin et al).
We have observed cerebellar ataxia, polymyoclonus, and progressive blindness in adolescents and adults with a variant of GM2 gangliosidosis; cherry-red macular spots provided the clue to diagnosis. Several such cases have been reported in the last decade, particularly among the Japanese (Miyatake et al). Nine cases of a spinocerebellar ataxia with dementia or psychosis of adult onset were described by Wilner and colleagues. Also in our service were 2 adult patients with progressive spinal muscular atrophy who proved to have this same GM2 hexosaminidase deficiency; the process was clinically almost indistinguishable from a very slowly progressive lower motor neuron form of motor neuron disease but they had no macular changes and displayed the additional features of ataxia and an intermittent and atypical psychosis. An asymmetrical corticospinal syndrome with areflexia had advanced so slowly in one of our cases of Krabbe disease that she became disabled only in her sixties.
Another of our patients, an adolescent with severe diffuse myoclonus and seizures and slight intellectual deterioration, was found after several years to have one of the rare variants of Gaucher disease. Another with dementia, rigidity, choreoathetosis, slight cerebellar ataxia, and Babinski signs had a variant of Niemann-Pick disease. Rarely, Gaucher disease may be associated with an early and severe parkinsonian syndrome. Cases of familial adult-onset Leigh disease have been described by Kalimo and colleagues. Adrenoleukodystrophy presenting in adult life as a spinocerebellar or olivopontocerebellar syndrome has already been mentioned.