Second edition

08.qxd 3/10/08 9:38 AM Page 376
376 Neurodegenerative and movement disorders
Treatment
Bone marrow transplantation may retard or halt the progression
of the disease (Kidd et al. 1998; Krivit et al. 1987;
Navarro et al. 1996). The general treatment of psychosis is
discussed in Section 7.1, of personality change in Section
7.2, and of dementia in Section 5.1.
8.30 ADRENOLEUKODYSTROPHY
Adrenoleukodystrophy is a rare, X-linked disorder characterized
pathologically by the accumulation of very-longchain
fatty acids in the brain, spinal cord, peripheral
nerves, and adrenal glands, and clinically by a variable
combination of dementia, spasticity, and adrenal failure.
Clinical features
Clinically (Moser et al. 1984), adrenoleukodystrophy may
be characterized according to either the age of onset or the
primary site of pathology. Thus, onset may be in childhood
(at an average age of 8 years), adolescence, or adult years,
and the primary site may be cerebral, spinal, or adrenal.
Childhood-onset adrenoleukodystrophy usually presents
with cerebral symptomatology, often with a personality
change and visual symptoms. These patients may
become withdrawn and irritable, and school performance
declines. Varying degrees of hemianopia or cortical blindness
may occur, followed by a dementia accompanied by
spasticity (Moser et al. 1984; Schaumburg et al. 1975).
Adolescent-onset adrenoleukodystrophy tends to present
in a fashion similar to that of the childhood-onset form.
Adult-onset adrenoleukodystrophy tends to present
with spinal cord involvement, adrenal failure or, less commonly,
with cerebral involvement; in cases that present
with cord involvement or adrenal failure, long-term follow-up
reveals the development of cerebral involvement in
a significant minority (van Geel et al. 2001). Cord involvement
yields a syndrome known as adrenomyeloneuropathy
(Griffin et al. 1977), wherein gait becomes clumsy and
stiff, and a spastic paraplegia eventually appears. Cerebral
involvement produces a dementia that may be nonspecific
in character, or which may be marked by manic
symptoms (Weller et al. 1992) or a Kluver–Bucy syndrome
(Powers et al. 1980).
Peripheral nerve involvement tends to be mild and may
in some cases only be apparent with nerve conduction
velocity studies.
Seizures occur in about one-fifth of all patients, usually
late in the course of the disease.
Adrenal involvement may occur at any age and may
indeed be the sole presentation of adrenoleukodystrophy
(O’Neill et al. 1982). In some cases, the only evidence of
adrenal cortical involvement may be a decreased cortisol
level or an increased adrenocorticotrophic hormone level,
whereas in others there may be melanoderma, nausea,
vomiting, abdominal pain, diarrhea, and hyperkalemia. It
must be kept in mind that, in some cases with cerebral or
cord involvement, adrenal function may be normal.
Phenotypic variability is the rule in adrenoleukodystrophy,
and even members of the same family may have different
presentations (Erlington et al. 1989). Indeed, even
monozygotic twins may exhibit phenotypic heterogeneity
(Sobue et al. 1994), to the point of one twin being affected
while the other is not (Korenke et al. 1996).
Female heterozygotes may occasionally have mild
symptoms.
Computed tomography scanning in patients with cerebral
involvement may reveal areas of radiolucency in the
white matter: typically these first appear in the occipital
lobes and then spread anteriorly into the parietal and temporal
lobes. With contrast administration, enhancement is
seen at the boundary between the areas of radiolucency
and normal tissue. T2-weighted MR scanning reveals
increased signal intensity in the white matter, following the
same pattern as seen on CT scans, with the same pattern of
enhancement upon administration of gadolinium.
Cerebrospinal fluid analysis may reveal a mild lymphocytic
pleocytosis and an elevated total protein. In patients with
adrenal involvement, there may be hyperkalemia and
decreased cortisol and increased adrenocorticotropic hormone
(ACTH) levels. The diagnosis is confirmed by finding
elevated levels of very-long-chain fatty acids in plasma
or cultured skin fibroblasts. Given the very large number of
mutations, genetic testing is not practical.
Course
Childhood-onset cases generally progress fairly rapidly,
death supervening within 3–5 years; adolescent- and adultonset
cases, especially those with the adrenomyeloneuropathy
syndrome, may progress very slowly. There may
rarely be periods of partial remission, only to be followed
eventually by relapse (Walsh 1980).
Etiology
Adrenoleukodystrophy is an X-linked disorder (Mosser
et al. 1994) that occurs secondary to any of a large number
of different mutations in the ALD gene on the X chromosome.
These mutations cause defective functioning of a
peroxisome membrane-associated protein, which in turn
leads to an accumulation of very-long-chain fatty acids in
the white matter of the brain or spinal cord, in the peripheral
nerves, and in the adrenal cortex.
Within the brain (Schaumburg et al. 1975), one typically
finds an advancing wave of demyelinization that
begins in the occipital lobe and then moves forward into
the parietal and temporal lobes; the frontal lobes are
broached in only a minority. An inflammatory response is