Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. X-linked adrenoleukodystrophy X-ALD is a peroxisomal disorder resulting in cerebral demyelination, axonal dysfunction in the spinal cord leading to spastic paraplegia, adrenal insufficiency and in some cases testicular insufficiency. It has been reported throughout the world.
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Alternative titles; symbols. Other entities represented in this entry:. Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids VLCFA in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.
Moser et al. Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. The clinical presentation can vary within the same family.
One male may have the childhood form of the disorder and his brother may have the adult form. It is apparent that neither the genetic mutation nor the level of biochemical abnormality predicts the phenotypic presentation. Davis et al. The patient with adrenomyeloneuropathy was well until age 21 years when he developed spastic paraparesis.
He subsequently fathered 2 daughters and a stillborn child. He was 41 years old at the time of study and showed no clinical manifestations of adrenal insufficiency. A brother of his developed paraparesis at age 13 and progressed to death at age A nephew became ill at age 4 and died at age 7.
Autopsy showed atrophic adrenals although no clinical signs of adrenal insufficiency were observed. O'Neill et al. The latter ratios were not proportional to severity of disease, duration, or character of the neurologic syndrome. In the family reported by O'Neill et al.
Berg et al. They observed clustering of phenotypes within individual sibships of the pedigree. Willems et al. Holmberg et al. Sobue et al. Extensive demyelination in the brain was only prominent in the older twin, while adrenal insufficiency was prominent in the younger twin.
They suggested that nongenetic factors were important determinants of the phenotypic variation of the adrenoleukodystrophy gene. Korenke et al. Wilichowski et al. Di Rocco et al. They suggested that identifying environmental factors could be important for effectively preventing CNS degeneration in this disorder.
By neuropsychologic testing, Cox et al. All of the patients had normal brain MRI studies. However, there was a negative correlation between age and visual perception as well as age and visuomotor skills. Cox et al. The classic presentation of childhood cerebral ALD has been analyzed in several large series Schaumburg et al.
This is the form of the illness that was originally described by Siemerling and Creutzfeldt and, until it was possible to make the biochemical diagnosis, it was the only form of the disease recognized as adrenoleukodystrophy. It is a rapidly progressive demyelinating condition affecting the cerebral white matter. It is by definition confined to boys who develop cerebral involvement before the age of 10 years.
The boys are normal at birth and have unremarkable development. The mean age of onset is approximately 7 years. The disease usually manifests itself early with behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties.
It progresses into visual symptoms, auditory processing difficulties, and motor incoordination. Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years. Budka et al. At the time, a geneticist could raise the possibility of this form being the consequence of an allelic mutation, but phenotypic variability within families has subsequently been demonstrated.
The neurologic picture was dominated by spastic paraplegia. Both clinically and pathologically, absence of diffuse cerebral involvement was noteworthy. The endocrinologic disorder was the particularly striking feature. Griffin et al. Hypogonadism was present in all cases appropriately studied. Adrenal insufficiency began in childhood and progressive spastic paraparesis in the third decade.
Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances. Further study in the family revealed 2 nephews who were also affected as well as asymptomatic carriers in a typical X-linked pedigree pattern.
None had symptoms of adrenal insufficiency. Cotrufo et al. Both were found to have adrenocortical insufficiency as evidenced by compensatory high ACTH release. Uyama et al. The first manifestation was difficulty in recalling where he had placed things. Shortly thereafter, he had problems operating farm machinery and gradually developed difficulty seeing clearly and writing at normal speeds.
He could dress himself but often put garments on backward or inside out. He later developed Balint syndrome and dementia. Balint syndrome is an acquired visuospatial disorder characterized by psychic paralysis of visual fixation, optic ataxia, and disturbance of visual attention with relatively intact vision Hecaen and De Ajuriaguerra, MRI demonstrated demyelinating lesions in the bilateral posterior parietooccipital white matter involving the splenium of the corpus callosum.
The patient could not move his eyes on command or follow a moving object. He had difficulty in maintaining central fixation. Optic ataxia was also shown by frequent errors when he attempted to grasp an object at which he was looking. The patient was bedridden by age 54 and died at age Tests of adrenal function yielded normal results.
Ratios of C to C in plasma and in erythrocyte membranes established the diagnosis of ALD in the proband and demonstrated that his mother was a heterozygote. Van Geel et al. They studied men retrospectively, with a mean follow-up period of There was a high risk for adult neurologically asymptomatic patients to develop neurologic deficits and for AMN patients to develop cerebral demyelination.
This had implications for the phenotype classification, search for modifying factors, and the development and evaluation of new therapies. Eichler et al. Disease progression was slower in adults compared to that previously observed in affected children.
Only 3 adult patients showed isolated lesions in the genu or the splenium, all of which developed in childhood or adolescence. The findings suggested that progressive inflammatory demyelination can occur along with the known axonopathy of adulthood. Addison disease in young males should prompt consideration of ALD as the underlying abnormality.
See also Sadeghi-Nejad and Senior Laureti et al. In 5 of the 14 patients, elevated levels of very long chain fatty acids VLCFA were found in plasma; none had adrenocortical antibodies.
By electrophysiologic tests and magnetic resonance imaging, it was determined that 2 had cerebral ALD, 1 had adrenomyeloneuropathy with cerebral involvement, and 2 had preclinical AMN. Since the adrenal insufficiency may long precede neurologic manifestations and perhaps may occur alone, caution must be exercised in the interpretation of isolated X-linked Addison disease as a separate entity.
Of course, autopsy-confirmed adrenal hypoplasia is a well-established entity. The achalasia-Addisonian syndrome , which appears to be autosomal recessive, is another example of combined adrenal and neurologic autonomic involvement. The postperfusion syndrome is an uncommon event following open-heart surgery with extracorporeal circulation.
It is associated with a young age at surgery less than 1 year and bypass lasting longer than 60 minutes. Luciani et al. Preoperatively, the patient exhibited a slight gait disorder and unremarkable EEG and laboratory findings.
Twelve hours after surgery he developed hypotension and circulatory collapse. This was treated successfully, but 10 days after discharge the patient was admitted with findings suggesting Addison disease. He showed a worsening disturbance of gait, with ataxia and EEG abnormalities. The diagnosis of adrenoleukodystrophy was supported by MRI of the head and confirmed by increased plasma levels of very long chain saturated fatty acids. Thus, Luciani et al. Women who are carriers for the condition may develop spastic paraparesis with bowel and bladder difficulties.
This appears to be partially a function of age. Heffungs et al. They suggested that this was the first documented example of adrenoleukodystrophy in a heterozygote.
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X-linked adrenoleukodystrophy ALD is a genetically determined metabolic disorder that manifests clinically as dysfunctions of the central nervous system CNS , adrenal glands and testicles. These dysfunctions are related to excessive accumulation of very long chain fatty acid VLCFA in tissues and plasma, which is caused by the failure of oxidative degradation of VLCFA that normally takes place in peroxisomes. There is widespread demyelination of white matter particularly bilateral parieto-occipital region with inflammatory reaction and atrophy of adrenal cortex.. Support Radiopaedia and see fewer ads. Updating… Please wait.
[X-linked Adrenoleukodystrophy With an Atypical Radiological Pattern]
NCBI Bookshelf. Genes and Disease [Internet]. Adrenoleukodystrophy ALD is a rare, inherited metabolic disorder that afflicts the young boy Lorenzo Odone, whose story is told in the film "Lorenzo's oil. People with ALD accumulate high levels of saturated, very long chain fatty acids in their brain and adrenal cortex because the fatty acids are not broken down by an enzyme in the normal manner. So, when the ALD gene was discovered in , it was a surprise that the corresponding protein was in fact a member of a family of transporter proteins, not an enzyme. It is still a mystery as to how the transporter affects the function the fatty acid enzyme and, for that matter, how high levels of very long chain fatty acids cause the loss of myelin on nerve fibers.
It is due to a mutation in the ABCD1 gene. The loss of functioning of ABCD1 triggers ineffective beta oxidation of very long-chain fatty acids, which gives rise to an accumulation of these fatty acids. The typical alteration revealed in neuroimaging scans in the cerebral form is symmetrical periventricular demyelination with posterior location. Case report: We report the case of a year-old boy with right spastic hemiparesis and subacute cognitive impairment.
Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil. Carmen R. Barschak 1 , Daniella M. Coelho 1 , Vivian Furlanetto 1 , Carolina F.