The onset is usually between 4 and 8 years, sometimes later; in the most common form of this disorder, only males are affected with the entire syndrome (women carriers may display a special myelopathy discussed further on). The signs of either the adrenal insufficiency or the cerebral lesion may be the first to appear. In the case described by Siemerling and Creutzfeldt, the first recorded example of this disorder, bronzing of the skin of the hands appeared at 4 years of age; quadriparesis, with dysarthria and dysphagia (i.e., pseudobulbar palsy), became evident at 7 years; a single seizure occurred at 8 years; and by 9 years, shortly before death, the patient was decerebrate and unresponsive. In personally observed cases, the first abnormalities appeared at 9 to 10 years and took the form of episodic vomiting, decline in scholastic performance and change in personality with inappropriate giggling and crying. After a time, severe vomiting and an episode of circulatory collapse occurred, following which the gait became unsteady and arms ataxic with an intention tremor. Only then did the addisonian increase of pigmentation of the oral mucosa and the skin around nipples and over elbows, knees, and scrotum become evident. Cortical blindness follows in some instances. The late stages are marked by bilateral hemiplegia (at first asymmetrical), pseudobulbar paralysis, blindness, deafness, and impairment of all higher cerebral functions.
The severity of the disease varies. We have cared for adult men in whom the cerebral symptoms have been mild, allowing for high-level cognitive achievement, albeit with peculiarities of personality, and with mild spastic gait, urinary difficulty, testicular insufficiency, and baldness. In each family there was a male sibling who died in childhood, ostensibly of adrenal insufficiency.
neuropathic form of the disease (adrenomyeloneuropathy [AMN]). In their patients, evidence of adrenal insufficiency had been present since early childhood, but only in the third decade of life did a progressive spastic paraparesis and a relatively mild polyneuropathy develop. It should be noted that the spasticity is occasionally asymmetrical, and the gait may have an ataxic component. This neurologic picture, in mild form and without adrenal insufficiency, is also the manner in which the disease may present in female carriers of the gene abnormality (see below). Like adrenoleukodystrophy, adrenomyeloneuropathy is typically inherited as an X-linked, male-specific trait. However, we have encountered a large family with adrenomyeloneuropathy in which males and females are both affected in a pattern that suggests dominant inheritance. The VLCFAs are modestly elevated in affected individuals, and there is no evidence of cerebral involvement.
Moser and colleagues (1980), using clinical and biochemical criteria, identified the following clinical subtypes of ALD, all derived from similar mutations: 1. A progressive degeneration of cerebral white matter in young males, often with cortical blindness—the classic type, accounting for half of all cases (Fig. 36-10) 2. An intermediate form in juvenile or young adult males with cerebral and spinal involvement (5 percent of cases) 3. A progressive spinal cord tract degeneration in adult males (25 percent of cases) 4. A chronic mild, nonprogressive spastic paraparesis in heterozygous female carriers (10 percent of cases) 5. Familial instances of Addison disease without neurologic involvement in males (10 percent of cases) 6. Possibly, in male infants, a form originating at birth (e.g., Zellweger disease)