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X Linked Adrenoleukodystrophy: Clinical Presentation, Diagnosis, and Therapy 4 Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:4–14 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from REVIEW X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy Björn M van Geel, Johanna Assies, RonaldJAWanders, Peter G Barth Abstract that has its onset in adulthood, was first X linked adrenoleukodystrophy (X-ALD) reported in 1976.4 Now, at least six diVerent is an inherited disorder of peroxisomal phenotypes are recognised.5 Not only men are metabolism, biochemically characterised aVected: in the early 1980s it was shown that by accumulation of saturated very long female carriers are at risk for developing chain fatty acids. Accumulation of these neurological deficits as well.6 fatty acids is associated with cerebral In 1976 the accumulation of saturated very demyelination, peripheral nerve abnor- long chain fatty acids (VLCFAs) in brain lipids malities, and adrenocortical and testicu- and adrenal cortex of patients with X-ALD was lar insuYciency. The lowest estimated reported.78 In 1980 raised concentrations of birth incidence is one per 100 000. At least VLCFAs were shown in cultured skin 9 10 six phenotypes can be distinguished, of fibroblasts and in 1981 in plasma, thus Department of which the two most frequent are child- providing a reliable biochemical diagnostic Neurology, Academic hood cerebral ALD and adrenomyelo- test. In 1984 a defect in peroxisomal metabo- Medical Center, 11 neuropathy. The X-ALD gene has been lism was suggested, and shortly thereafter the University of defective enzyme activity in peroxisomal Amsterdam, PO Box identified, but thus far no relation between â-oxidation of VLCFAs was discovered.12 13 In 22700, 1100 DE genotype and phenotype has been found. 14 Amsterdam, the Diagnosis is relatively easy and can be 1981 the X-ALD locus was mapped to Xq28, Netherlands confirmed reliably, and prenatal testing is and in 1993 the gene predisposing for X-ALD B M van Geel 15 possible in aVected families. Several was identified. therapeutic options, some with promising Nevertheless, many physicians are still unfa- Departments of miliar with X-ALD and its many facets. Psychiatry and perspectives, are available. Neurologists Although the disease is rare, the estimated http://jnnp.bmj.com/ Internal Medicine and other physicians seem not to be 51617 J Assies familiar with the many facets of X-ALD. birth incidence is at least one per 100 000. Early identification is mandatory, as untreated In this review, the clinical presentation, Department of Clinical patients with adrenocortical insu ciency need the relative frequencies of the diVerent Y Biochemistry, steroid hormone substitution therapy. Genetic phenotypes, and the diagnostic and thera- Academic Medical counselling should be performed, and prenatal Center, University of peutic options are presented. diagnosis is possible and desired in aVected Amsterdam, PO Box 18 22700, 1100 DE families. Dietary treatment with “Lorenzo’s (J Neurol Neurosurg Psychiatry 1997;63:4–14) 19 Amsterdam, the oil” can be considered, particularly in male on September 28, 2021 by guest. Protected copyright. Netherlands patients without neurological symptoms, and RJAWanders Keywords: adrenoleukodystrophy; adrenomyeloneu- ropathy; very long chain fatty acids; peroxisome cerebral demyelination in boys may be halted or reversed by bone marrow transplantation.20 Departments of Furthermore, gene therapy may become a seri- Neurology and 21 22 Pediatrics, Academic More than seven decades have passed since ous therapeutic option in the near future. Medical Center, Siemerling and Creutzfeldt reported a seven The aim of this review is to familiarise University of year old previously healthy boy with a bronzed neurologists and other physicians with the Amsterdam, PO Box skin, behavioural abnormalities, dysphagia, clinical presentation of X-ALD and the diag- 22700, 1100 DE 1 nostic and therapeutic options. Amsterdam, the and spasticity of the lower limbs. Within Netherlands months he became tetraplegic, developed dys- P G Barth arthria and seizures, and died six months after presentation. Postmortem examination dis- Clinical manifestations Correspondence to: Dr B M van Geel, closed atrophy of the adrenal cortex and diffuse HEMIZYGOTES Department of Neurology, cerebral sclerosis. In 1963 an X linked mode The classification of the diVerent phenotypes Academic Medical Center, of inheritance was suggested,2 and in the of X-ALD is somewhat arbitrary, and based on University of Amsterdam, mid-1970s the term adrenoleukodystrophy the age of onset and the organs principally PO Box 22700, 1100 DE 3 Amsterdam, the Netherlands. was coined for this mysterious disorder. aVected. At present, at least six variants can be Apparently only boys were aVected by the distinguished (table).5 The two most frequent Received 9 December 1996 disease, now known as X linked adrenoleuko- phenotypes, that account for about 80% of all and in revised form 11 February 1997 dystrophy (X-ALD). Adrenomyeloneuropathy cases, are childhood cerebral ALD and Accepted 14 February 1997 (AMN), a more indolent phenotypic variant adrenomyeloneuropathy.5162324 The delay X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy 5 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from Clinical characteristics of the diVerent phenotypes of X-ALD in hemizygotes Pre- or asymptomatic Addison ALD CCALD AdolCALD ACALD AMN only Relative frequencies (%) 4-10 31-57 1-3 25-46 8-14 Age at onset of − < 10 10-21 > 21 > 18; frequent >2 neurological 3rd-4th decade symptoms Behavioural disturbances − + + + − − Impaired cognition − + + Frequent − − Pyramidal tract − Eventually, not Eventually, not Frequent Present by − involvement initially initially definition Cerebral MRI Absent or Extensive in Extensive in Extensive in Internal capsule Absent or abnormalities mild* occipital or occipital or occipital or basal ganglia, mild* frontal myelin frontal myelin frontal myelin mesencephalon, pons Polyneuropathy − − Rare Possible Sensorimotor, − mostly axonal Abnormal evoked − VEP, BAEP VEP, BAEP VEP (not BAEP, SEP Sometimes potentials (not initially) (not initially) initially), BAEP BAEP sometimes SEP sometimes SEP Impaired endocrine − ADinmost ADinmost ADinmost ADand AD by function hypogonadism in definition most Abnormal neuropsychological examination − + + Frequent − − Progression − Rapidly, rarely Rapidly, rarely Rapidly, Slowly, sometimes − slowly slowly sometimes rapidly slowly − = Absent; + = present; * = depending on definition; CCALD = childhood cerebral ALD; AdolCALD = adolescent cerebral ALD; ACALD = adult cerebral ALD; AMN = adrenomyeloneuropathy; VEP = visual evoked potential; BAEP = brainstem auditory evoked potential; SEP = somatosensory evoked potential; AD = adrenocortical insuYciency (Addison’s disease). between onset and diagnosis may be long, par- and impaired auditory discrimination. The ticularly in probands.25 course is relentlessly progressive, and seizures, About two thirds of the male patients with spastic tetraplegia, and dementia become neurological dysfunction also have overt or manifest within months. Figure 2 shows a typi- subclinical adrenocortical insuYciency (Addi- cal patient with CCALD. Most patients die son’s disease).26 This may precede, accompany, within two to three years after the onset of or follow the onset of neurological symptoms. neurological symptoms.5 However, some pa- Virtually all aVected men have manifest or tients survive longer, albeit in a persistent veg- subclinical testicular insuYciency (Assies et al, etative state. In 80% of patients with CCALD, unpublished data), and many have typical, cerebral MRI typically shows extensive demy- scanty scalp hair (fig 1). elination in the occipital periventricular white http://jnnp.bmj.com/ matter (fig 3).29 The early symptoms of Childhood cerebral ALD CCALD are often attributed to an attention Childhood cerebral ALD (CCALD) is charac- deficit disorder or hyperactivity. Before the terised by rapidly progressive cerebral advent of reliable diagnostic tests and MRI, demyelination.27 28 The onset is between 3 and metachromatic leukodystrophy, ceroid lipofus- 10 years of age. Frequent early neurological cinosis, globoid cell leukodystrophy (Krabbe’s symptoms are behavioural disturbances, poor disease), and subacute sclerosing panencepha- school performance, deterioration of vision, litis were sometimes diagnosed instead of on September 28, 2021 by guest. Protected copyright. CCALD.5 Adolescent cerebral ALD Adolescent cerebral ALD (AdolCALD) occurs much less often. The symptoms and progression are similar to those of CCALD, but the onset is between 10 and 21 years of age (fig 4). Adult cerebral ALD (ACALD) Very rarely, cerebral demyelination occurs in adult hemizygotes and causes symptoms as seen in CCALD.30–35 These patients may be misdiagnosed as having paranoid psychosis, schizophrenia, or other psychiatric disorders. The illness may progress rapidly. Adrenomyeloneuropathy (AMN) At least in The Netherlands, AMN (fig 5) is the most common phenotype of X-ALD.16 The Figure 1 The typical scanty scalp hair that can be seen in all phenotypes. This patient onset of neurological symptoms in this pheno- with AMN developed the hair pattern during adolescence. type usually occurs in the third and fourth 6 van Geel, Assies, Wanders, Barth J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from Figure
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