X-linked adrenoleukodystrophy (X-ALD) is a common hereditary metabolism disorder characterized by impaired peroxisomal beta-oxidation, subsequent accumulation of very long-chain fatty acids (> 22 carbon atoms), accumulation of saturated very long chain fatty acids and mutations in the ABCD1 gene. It is a progressive metabolic condition that affects the adrenal glands and nervous system of males. Although that condition is variable in the age of onset and presentation in families, X-ALD does present in characteristic phenotypes including a devastating childhood form affecting 35% of boys with this genetic condition.

Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia.

Clinical presentations for adrenoleukodystrophy include inability to manipulate acquired knowledge, important changes of personality such as apathy, inertia, or depression and slowing of thought processes (also known as bradyphrenia). The majority of males with X-ALD will also develop adrenal insufficiency, which may result in crisis. Early detection is desirable in order to prevent morbidity from this condition. Newly developed tandem mass spectroscopy method allows this to be done during newborn screening for other genetic disorder.

References

Grković S, Dordević M, Nikolić R, Zivancević-Simonović S, Puzigaća Z. 2007. Very long chain fatty acids in the pathogenesis, prenatal and postnatal diagnosis of X-linked adrenoleukodystrophy. Med Pregl. 2007 60 (7-8): 401-3

Raymond GV, Jones RO, Moser AB. 2007. Newborn screening for adrenoleukodystrophy: implications for therapy. Mol Diagn Ther. 11(6):381-4

Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I. 2008. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs. 17 (2):169-84

Bonelli RM, Cummings JL. 2008. Frontal-subcortical dementias. Neurologist. 14 (2): 100-7.

Engelen M, Kemp S, van Geel BM. 2008. From gene to disease; X-linked adrenoleukodystrophy. Ned Tijdschr Geneeskd. 152 (14): 804-8

Ferraz-de-Souza B, Achermann JC. 2008. Disorders of adrenal development. Endocr Dev. 13:19-32

Parkinson disease dementia

Depressive pseudodementia

Huntington chorea

Wilson disease

Progressive supranuclear palsy

Thalamic degeneration

Subcortical vascular dementia

Acquired immunodeficiency syndrome dementia complex

Spinocerebellar degenerative syndromes

Hallervorden-Spatz disease

Choreoacanthocytosis

Idiopathic basal ganglia calcification

Guamanian parkinsonism-dementia complex

Corticobasal degeneration multiple system atrophy

Metachromatic leukodystrophy

Hypoparathyroidism

Sarcoidosis

Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia.

Clinical presentations for adrenoleukodystrophy include inability to manipulate acquired knowledge, important changes of personality such as apathy, inertia, or depression and slowing of thought processes (also known as bradyphrenia). The majority of males with X-ALD will also develop adrenal insufficiency, which may result in crisis. Early detection is desirable in order to prevent morbidity from this condition. Newly developed tandem mass spectroscopy method allows this to be done during newborn screening for other genetic disorder.

References

Grković S, Dordević M, Nikolić R, Zivancević-Simonović S, Puzigaća Z. 2007. Very long chain fatty acids in the pathogenesis, prenatal and postnatal diagnosis of X-linked adrenoleukodystrophy. Med Pregl. 2007 60 (7-8): 401-3

Raymond GV, Jones RO, Moser AB. 2007. Newborn screening for adrenoleukodystrophy: implications for therapy. Mol Diagn Ther. 11(6):381-4

Hahnen E, Hauke J, Tränkle C, Eyüpoglu IY, Wirth B, Blümcke I. 2008. Histone deacetylase inhibitors: possible implications for neurodegenerative disorders. Expert Opin Investig Drugs. 17 (2):169-84

Bonelli RM, Cummings JL. 2008. Frontal-subcortical dementias. Neurologist. 14 (2): 100-7.

Engelen M, Kemp S, van Geel BM. 2008. From gene to disease; X-linked adrenoleukodystrophy. Ned Tijdschr Geneeskd. 152 (14): 804-8

Ferraz-de-Souza B, Achermann JC. 2008. Disorders of adrenal development. Endocr Dev. 13:19-32

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 1993, 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.

More recently, all the transporters related to ALD protein have been found in the yeast Saccharomyces cerevisiae, and a mouse model for the human disease has been developed. These and other molecular biology approaches should further our understanding of ALD and hasten our progress toward effective therapies.

Source: National Institute of Health

Symptoms generally begin between the ages of four and ten and include loss of previously developed neurological powers, seizures, dyssynergia, Addison’s syndrome, in addition to as the loss of optic and auditory abilities. It has been considered that babies that have been positively diagnosed by the age of 12 months old have commonly become very disabled by the age of 10 to 12 years of age and decease shortly after. A related condition could likewise occur in teenagers and very seldom in grownups. Hypoadrenalism may be a first symptom of ALD, and numerous paediatric endocrinologists will measure very long chain free fatty acids in new diagnosed males with this condition, as a screening test for ALD.

In a different form of ALD which mainly affects young adult males where the spinal cord dysfunction is more prominent and therefore is called adrenomyeloneuropathy (AMN). The patients normally have to confront with helplessness and numbness of the limbs and urination and/or laxation troubles. Most victims of this disease are males, though some female carriers exhibit symptoms similar to AMN.

Adult and neonatal forms of the disease also manifest itself but they are highly uncommon. (They affect both males and females and are hereditary in an autosomal recessive manner.) A few patients might exhibit adrenal insufficiency (Addisons disease).