Adrenoleukodystrophy overview: Difference between revisions
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==Diagnosis== | ==Diagnosis== | ||
===History and Symptoms=== | ===History and Symptoms=== | ||
The clinical manifestations of the disease are highly variable, with at least six different types ranging from childhood cerebral to asymptomatic.The most severe type is the childhood cerebral form, which normally occurs in males between the ages of 5 and 10 and is characterized by failure to develop, [[Seizure|seizures]], [[ataxia]], [[adrenal insufficiency]], as well as degeneration of visual and auditory function. Frequent initial symptoms include [[emotional lability]], hyperactive behaviour, school failure, impaired auditory discrimination and difficulties in vision. The adolescent type usually starts between age 11 and 21 years. Adrenomyeloneuropathy usually presents with weakness and numbness of the limbs and problems with [[urination]] or [[defecation]]. Some patients may present with sole findings of primary adrenal insufficiency. | |||
===Physical Examination=== | ===Physical Examination=== | ||
Most males in childhood have adrenal insufficiency that can show orthostatic hypotension, hyperpigmentation and confusion. Females who are heterozygous and symptomatic can have sphincter disturbances, incoordination and paraparesis.The most aggressive one is Childhood cerebral type which can show behavioural changes, school failure, dementia, speech impairment, bulbar palsy, paralysis and audiovisual changes on examination. Some of the general examination findings which can occur in all phenotypes includes [[Strabismus]], [[Swallowing difficulties]], [[Aphasia]], Deterioration of handwriting, Difficulty at school, Difficulty understanding spoken material, [[Hyperactivity]][[Coma|,Coma,]] Decreased fine motor control[[Paralysis|,Paralysis,]] [[Seizures]], Possible worsening [[muscle weakness]] or [[leg]] [[stiffness]], Problems with thinking speed and [[visual memory]]. | |||
===Laboratory Findings=== | ===Laboratory Findings=== | ||
An elevated concentration of plasma levels of VLCFA suggests the presence of Adrenoleukodystrophy. DNA-based diagnosis can be obtained to look for mutations in the ABCD1 gene in the case of carriers and is particularly important in the diagnosis of the disease in women. Assessment of physical capabilities and measurements of walking speed, hip strength, vibration sense and nerve conductions studies has been used in assessing disease severity in AMN. | |||
===Imaging Findings=== | ===Imaging Findings=== | ||
==== '''MRI''' ==== | |||
Brain MRI may be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Abnormal bright signal intensities on the T2-weighted MRI images, Involvement of Corticospinal tracts is the most common finding in male patients whereas in females there is mild diffuse increase of signal intensity in the parieto occipital or frontal lobe white matter. Spine MRI may also be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Magnetization transfer-weighted (MTw) images showing signal hyperintensities in the lateral and dorsal columns and Diffuse spinal cord atrophy, mainly in the thoracic and cervical regions. | |||
==== '''CT''' Scan ==== | |||
Brain CT scan may be helpful in the diagnosis of Adrenoleukodystrophy but not used as it is less sensitive than MRI. Findings on CT scan suggestive of Adrenoleukodystrophy can include Contrast enhancement within or adjacent to the abnormally hypodense deep white matter of the parietal, occipital lobes and at the interface between this active demyelinating area and uninvolved normal brain, Asymmetric areas of diminished attenuation in occipital horns of the lateral ventricles and the splenium of the corpus callosum. | |||
==== '''Proton Magnetic Resonance Spectroscopic (MRS)''' imaging ==== | |||
This imaging technique show changes in metabolic rates. MRS imaging was able to demonstrate low NAA and high choline levels in white matter as a first indicator of metabolic dysfunction, prior to MRI changes in ALD. | |||
==== '''Diffusion Tensor Imaging (DTI)''' ==== | |||
This imaging technique show changes in water diffusion parameters. High directionality and structure of white matter, resulting from the directional morphology of myelinated axons, is quantified by a higher relative Fractional anisotropic (FA) with DTI. A decreased FA can be seen in central cALD lesion areas. | |||
===Other Diagnostic Studies=== | ===Other Diagnostic Studies=== | ||
<br /> | |||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===Medical Therapy=== | ||
The mainstay of treatment for adrenoleukodystrophy is Hematopoietic stem cell transplantation. Supportive therapy includes Lorenzo's oil and Lovastatin therapy. Antioxidant therapy has also shown some persuasive results demanding a larger study whereas treatment with Gene therapy including Ex vivo lentiviral gene correction and in vivo adeno-associated virus 9 (AAV9) based gene therapy is being pursued. | |||
===Surgery=== | ===Surgery=== | ||
Surgical intervention is not recommended for the management of adrenoleukodystrophy. | |||
==Prevention== | |||
===Prevention=== | === Primary Prevention === | ||
There are no established measures for the primary prevention of adrenoleukodystrophy. | |||
==References== | ==References== | ||
Revision as of 12:46, 29 June 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
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Overview
Adrenoleukodystrophy (ALD) is a degenerative disorder of myelin, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without myelin, nerves are unable to conduct an impulse, leading to increasing disability as myelin destruction increases and intensifies. The victims of ALD are always male, and the disease begins its expression around the ages 5 to 10. The disease is due to an X-linked inheritance of peroxisomes that cannot properly process long chain fatty acids in the brain.
ALD is a type of leukodystrophy, disorders affecting the growth and/or development of myelin. Leukodystrophies are different from demyelinating disorders such as multiple sclerosis where myelin is formed normally but is lost by immunologic dysfunction or for other reasons.
Historical Perspective
Adrenoleukodystrophy was first described by Siemerling and Creutzfeld in 1923. The X-linked recessive inheritance pattern was explained by Fanconi et al in 1963. Previously It was known as Schilder's disease but Michael Blaw changed it to "Adrenoleukodystrophy" in 1970.
Classification
Pathophysiology
Causes
Differentiating Adrenoleukodystrophy from Other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications, and Prognosis
Diagnosis
History and Symptoms
The clinical manifestations of the disease are highly variable, with at least six different types ranging from childhood cerebral to asymptomatic.The most severe type is the childhood cerebral form, which normally occurs in males between the ages of 5 and 10 and is characterized by failure to develop, seizures, ataxia, adrenal insufficiency, as well as degeneration of visual and auditory function. Frequent initial symptoms include emotional lability, hyperactive behaviour, school failure, impaired auditory discrimination and difficulties in vision. The adolescent type usually starts between age 11 and 21 years. Adrenomyeloneuropathy usually presents with weakness and numbness of the limbs and problems with urination or defecation. Some patients may present with sole findings of primary adrenal insufficiency.
Physical Examination
Most males in childhood have adrenal insufficiency that can show orthostatic hypotension, hyperpigmentation and confusion. Females who are heterozygous and symptomatic can have sphincter disturbances, incoordination and paraparesis.The most aggressive one is Childhood cerebral type which can show behavioural changes, school failure, dementia, speech impairment, bulbar palsy, paralysis and audiovisual changes on examination. Some of the general examination findings which can occur in all phenotypes includes Strabismus, Swallowing difficulties, Aphasia, Deterioration of handwriting, Difficulty at school, Difficulty understanding spoken material, Hyperactivity,Coma, Decreased fine motor control,Paralysis, Seizures, Possible worsening muscle weakness or leg stiffness, Problems with thinking speed and visual memory.
Laboratory Findings
An elevated concentration of plasma levels of VLCFA suggests the presence of Adrenoleukodystrophy. DNA-based diagnosis can be obtained to look for mutations in the ABCD1 gene in the case of carriers and is particularly important in the diagnosis of the disease in women. Assessment of physical capabilities and measurements of walking speed, hip strength, vibration sense and nerve conductions studies has been used in assessing disease severity in AMN.
Imaging Findings
MRI
Brain MRI may be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Abnormal bright signal intensities on the T2-weighted MRI images, Involvement of Corticospinal tracts is the most common finding in male patients whereas in females there is mild diffuse increase of signal intensity in the parieto occipital or frontal lobe white matter. Spine MRI may also be helpful in the diagnosis of Adrenoleukodystrophy. Findings on MRI suggestive of Adrenoleukodystrophy include Magnetization transfer-weighted (MTw) images showing signal hyperintensities in the lateral and dorsal columns and Diffuse spinal cord atrophy, mainly in the thoracic and cervical regions.
CT Scan
Brain CT scan may be helpful in the diagnosis of Adrenoleukodystrophy but not used as it is less sensitive than MRI. Findings on CT scan suggestive of Adrenoleukodystrophy can include Contrast enhancement within or adjacent to the abnormally hypodense deep white matter of the parietal, occipital lobes and at the interface between this active demyelinating area and uninvolved normal brain, Asymmetric areas of diminished attenuation in occipital horns of the lateral ventricles and the splenium of the corpus callosum.
Proton Magnetic Resonance Spectroscopic (MRS) imaging
This imaging technique show changes in metabolic rates. MRS imaging was able to demonstrate low NAA and high choline levels in white matter as a first indicator of metabolic dysfunction, prior to MRI changes in ALD.
Diffusion Tensor Imaging (DTI)
This imaging technique show changes in water diffusion parameters. High directionality and structure of white matter, resulting from the directional morphology of myelinated axons, is quantified by a higher relative Fractional anisotropic (FA) with DTI. A decreased FA can be seen in central cALD lesion areas.
Other Diagnostic Studies
Treatment
Medical Therapy
The mainstay of treatment for adrenoleukodystrophy is Hematopoietic stem cell transplantation. Supportive therapy includes Lorenzo's oil and Lovastatin therapy. Antioxidant therapy has also shown some persuasive results demanding a larger study whereas treatment with Gene therapy including Ex vivo lentiviral gene correction and in vivo adeno-associated virus 9 (AAV9) based gene therapy is being pursued.
Surgery
Surgical intervention is not recommended for the management of adrenoleukodystrophy.
Prevention
Primary Prevention
There are no established measures for the primary prevention of adrenoleukodystrophy.