Björn M. van Geel

Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy

Our objective was to study the phenotype evolution of X‐linked adrenoleukodystrophy (X‐ALD) and the relation between axonal degeneration and cerebral demyelination. Although different X‐ALD phenotypes are recognized, little is known about their evolution. Neuropathological and electrophysiological studies have shown that X‐ALD is a disease with mixed features of axonal degeneration, leading to myeloneuropathy, and a severe inflammatory reaction in the cerebral white matter, resulting in demyelination. Retrospectively, 129 men with X‐ALD were studied who were 1) at least 20 years presently or at the time of death, and 2) regularly monitored. Phenotype assignments were made at diagnosis and at present, or at death, using medical history and findings of neurological examination. Handicap was studied with the modified Rankin scale, and cerebral abnormalities with the X‐ALD MRI severity (Loes) score. The mean follow‐up interval was 10.1 ± 5.0 years. Among 32 patients neurologically asymptomatic at diagnosis, 16 (50%) developed neurological deficits. Among 68 adrenomyeloneuropathy (AMN) patients initially without clinical brain involvement, 13 (19%) additionally developed cerebral demyelination. In a subset of 60 AMN patients, a moderate handicap evolved over a period of 16.2 ± 8.9 years. Among 13 AMN patients with additional definite or probable cerebral involvement at diagnosis, eight died and one remained in a vegetative state. Most of the 16 patients with the cerebral phenotypes deteriorated. There is a high risk for adult neurologically asymptomatic patients to develop neurological deficits and for AMN patients to develop cerebral demyelination. Axonal degeneration and cerebral demyelination emerge in X‐ALD independently of each other. This may have implications for the phenotype classification, the search for modifying factors, and the development and evaluation of new therapies. Ann Neurol 2001;49:186–194

X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids (VLCFA; ≥C22). A defect in ALDP results in elevated levels of VLCFA in plasma and tissues. The clinical spectrum in males with X-ALD ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. The majority of heterozygous females will develop symptoms by the age of 60 years. In individual patients the disease course remains unpredictable. This review focuses on the diagnosis and management of patients with X-ALD and provides a guideline for clinicians that encounter patients with this highly complex disorder.

X-linked adrenoleukodystrophy in women: a cross-sectional cohort study

X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy.

Lovastatin in X-Linked Adrenoleukodystrophy

To the Editor: As reported previously in the Journal, lovastatin lowers levels of very-long-chain fatty acids in plasma in patients with X-linked adrenoleukodystrophy (X-ALD).1 Further studies did ...

Neonatal paroxysmal trismus and camptodactyly: The Crisponi syndrome

The Crisponi syndrome is an infrequently described syndrome characterized by extensive muscular contractions in the face after even minimal stimuli, hypertonia, camptodactyly, and typical facial features (chubby cheeks, broad nose with anteverted nares, and long philtrum). Most patients have died in the first months of life due to hyperthermia. The syndrome has been described in Italians only; the inheritance pattern is most probably autosomal recessive. Here we describe a 4‐year‐old boy of Portuguese descent with this entity. Polysomnography during a paroxysmal muscle contraction showed severe obstructive breathing pattern. The overall breathing pattern outside the attacks showed a bizarre mix of disorders of control of breathing with central apneas, hypopnea, obstructive apneas, and long periods of expiratory apneas while the boy was awake. The hyperexcitability disappeared in the course of the first year of life. With time it became clear that he was developmentally delayed. A short review is provided, and the resemblance with the Stüve–Wiedemann syndrome is stressed.

Low dehydroepiandrosterone sulphate (DHEAS) levels in X‐linked adrenoleukodystrophy

Sirs, X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, characterized by deficient degradation of saturated very long-chain fatty acids (VLCFAs). The CNS white matter, adrenal cortex and testis are predominantly affected by the accumulation of VLCFAs (Van Geelet al., 1997). The most frequent phenotypes are childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN). The onset of CCALD is between the age of 5 and 10 years; rapidly progressive cerebral demyelination results in a vegetative state and death within 3 years in most patients. The onset of AMN occurs in the second or third decade; mainly the spinal cord and peripheral nerves are affected. Primary adrenocortical insufficiency is present in most CCALD and AMN patients. Some patients manifest only adrenocortical insufficiency (the ‘Addison-only’ phenotype). We recently found some signs of clinical hypogonadism in 20/26 men with X-ALD (Assieset al., 1997). A few patients have neither neurological nor endocrinological deficits (asymptomatic X-ALD).The immune system is involved in the CNS demyelination, in CCALD particularly. Cortico-steroids and sex steroids modulate the immune response (Grossman, 1994; Chrousos, 1995; Van Geel et al., 1997). A distinct role is emerging for DHEA and its sulphate ester DHEAS – man’s most abundantly produced adrenal steroid (Rook et al., 1994). We therefore retrospectively studied plasma levels in 26 men with X-ALD (21 with AMN, 4 with asymptomatic X-ALD, 1 with primary thyroidal, adrenocortical and testicular failure). In 26 of the 26 patients (100%) DHEAS-levels were below the lower limits of the normal range. This was to be expected in the 13 of 26 patients who were already treated for adrenocortical insufficiency. In 5 of 26 patients who were not yet treated with corticosteroids elevated ACTH levels indicated incipient adrenocortical failure, thereby explaining their lowered DHEAS levels. However, in the remaining 8 men very low DHEAS levels were also found in the presence of normal

Pathogenicity of novel ABCD1 variants: The need for biochemical testing in the era of advanced genetics.

X-linked adrenoleukodystrophy (ALD), a progressive neurodegenerative disease, is caused by mutations in ABCD1 and characterized by very-long-chain fatty acids (VLCFA) accumulation. In male patients, an increased plasma VLCFA levels in combination with a pathogenic mutation in ABCD1 confirms the diagnosis. Recent studies have shown that many women with ALD also develop myelopathy. Correct diagnosis is important for management including genetic counseling. Diagnosis in women can only be confirmed when VLCFA levels are elevated or when a known pathogenic ABCD1 mutation is identified. However, in 15-20% of women with ALD VLCFA plasma levels are not elevated. Demonstration that a novel sequence variant is pathogenic can be a challenge when VLCFA levels are in the normal range. Here we report two women with a clinical presentation compatible with ALD, an ABCD1 variation (p.Arg17His and p.Ser358Pro) of unknown significance, but with normal VLCFA levels. We developed a diagnostic test that is based on generating clonal cell lines that express only one of the two alleles. Subsequent biochemical studies enabled us to show that the two sequence variants were not pathogenic, thereby excluding the diagnosis ALD in these women. We conclude that the clonal approach is an important addition to the existing diagnostic array.

X-linked adrenomyeloneuropathy due to a novel missense mutation in the ABCD1 start codon presenting as demyelinating neuropathy

Dear Editor, X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene which encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal transmembrane protein (Mosser et al., 1993; Moser et al., 2001). Several often overlapping phenotypes can be distinguished. Approximately, half of all patients develop adrenomyeloneuropathy (AMN), characterized by slowly progressive spastic paraparesis, peripheral neuropathy, sphincter dysfunction, and adrenocortical insufficiency (Moser et al., 2001). We present a patient with an unusual neuropathy who was shown to have X-ALD caused by a mutation in the ABCD1 gene. A 27-year-old man presented with exercise-related weakness and fatigue in the legs which progressed slowly over the last 2 years. Three years prior to presentation he shortly used testosterone replacement therapy for decreased libido. Family history was negative for neuromuscular and endocrinological disorders. Physical examination revealed slight generalized wasting and weakness of the legs and decreased sensation for light touch at the dorsum of both feet with decreased position sense of the toes. Pes cavus was not present. Deep tendon reflexes were normal, and plantar reflexes were flexor. Electrophysiologic findings were compatible with a mild, symmetric demyelinating neuropathy confined to the lower limbs (Table 1). Serum creatine kinase activity was elevated (270 U/l, normal <193 U/l). Normal or negative results were obtained for thyroid stimulating hormone, sodium and potassium, and vasculitis parameters (Anti-neutrophil cytoplasmic antibody, antinuclear antibody and complement levels). Cerebrospinal fluid examination showed elevated protein (0.66 g/l, upper limit of normal 0.49). DNA analysis revealed no mutations in the PMP22 gene. Refsum’s