Adrenoleukodystrophy

Alternative Names:  Adrenoleukodystrophy; Adrenomyeloneuropathy; Childhood cerebral adrenoleukodystrophy; ALD; Schilder-Addison Complex


Definition:

Adrenoleukodystrophy (ALD),  is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies. Adrenoleukodystrophy progressively damages the myelin sheath, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without functional myelin, nerves are unable to aid in the conduction of an impulse, which leads to increasing disability.

click & see the pictures

Patients with X-linked ALD have defects in the ATP-binding cassette, sub-family D (ALD), member 1 transporter protein, which is encoded by the ABCD1 gene. The ABCD1 (aka ALDP) protein is indirectly involved in the break down of very long-chain fatty acids (VLCFAs) found in the normal diet. Lack of this protein can give rise to an over-accumulation of VLCFAs which can lead to damage to the brain, adrenal gland, and peripheral nervous system.

There are several different types of the disease which can be inherited, but the most common form is an X-linked condition. X-linked ALD primarily affects males, but about one in five women with the disease gene develop some symptoms. Adrenomyeloneuropathy is a less-severe form of ALD, with onset of symptoms occurring in adolescence or adulthood. This form does not include cerebral involvement, and should be included in the differential diagnosis of all males with adrenal insufficiency. Although they share a similar name, X-linked ALD and neonatal adrenoleukodystrophy (NALD), a peroxisome biogenesis disorder, are completely different diseases.

Although this disorder affects 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.

Causes:

There are several types of ALD, which may be inherited in two different ways, and which can cause different patterns of disease even among people in the same families.

ALD is most commonly inherited as an X-linked condition. This means the abnormal gene is found on the X chromosome.

Because women have two X chromosomes, they have a spare normal gene as well as the abnormal one, so generally only carry the condition (although they may have a mild form of the disease). Men have only one X, so they are affected by the condition.

X-linked ALD may occur in three forms, with onset of symptoms in either childhood or adulthood.

Neonatal ALD is much less common. In this type of ALD the faulty gene isn’t X-linked but is found on one of the other chromosomes. This means both boys and girls can be affected.

Symptoms:
Childhood cerebral type:

•Changes in muscle tone, especially muscle spasms and spasticity
•Crossed eyes (strabismus)
•Decreased understanding of verbal communication (aphasia)
•Deterioration of handwriting
•Difficulty at school
•Difficulty understanding spoken material
•Hearing loss
•Hyperactivity
•Worsening nervous system deterioration
*Coma
*Decreased fine motor control
*Paralysis
•Seizures
•Swallowing difficulties
•Visual impairment or blindness

Adrenomyelopathy:
•Difficulty controlling urination
•Possible worsening muscle weakness or leg stiffness
•Problems with thinking speed and visual memory

.
Adrenal gland failure (Addison type):

•Coma
•Decreased appetite
•Increased skin color (pigmentation)
•Loss of weight, muscle mass (wasting)
•Muscle weakness
•Vomiting

Diagnosis:

The diagnosis is established by clinical findings and the detection of serum very long-chain free fatty acid levels. MRI examination reveals white matter abnormalities, and neuro-imaging findings of this disease are somewhat reminiscent of the findings of multiple sclerosis. Genetic testing for the analysis of the defective gene is available in some centers.

Your ads will be inserted here by

Easy Plugin for AdSense.

Please go to the plugin admin page to
Paste your ad code OR
Suppress this ad slot.

Neonatal screening may become available in the future, which may permit early diagnosis and treatment.

Genetics:

X-linkedX-linked ALD (X-ALD) is the most common form of ALD. In X-ALD, the defective ABCD1 gene resides on the X chromosome (Xq28). The incidence of X-ALD is at least 1 in 20,000 male births.[6] The ABCD1 (“ATP-binding cassette, subfamily D, member 1”) gene was discovered in 1993 and codes for a peroxisome membrane protein necessary for the ?-oxidation of VLCFAs.

X-ALD is characterized by excessive accumulation of very long-chain fatty acids (VLCFA), which are fatty acids with chains of 25–30 carbon atoms. The most common is hexacosanoate, with a 26 carbon skeleton. The elevation in (VLCFA) was originally described by Moser et al. in 1981.[8] The precise mechanisms through which high VLCFA concentrations in affected organs cause the disease is still unknown.

Autosomal
Neonatal adrenoleukodystrophy (NALD) is one of three autosomal dominant disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).The other two disorders are Zellweger syndrome (ZS), and infantile Refsum disease (IRD). NALD is most frequently caused by mutations in the PEX1, PEX5, PEX10, PEX13, and PEX26 genes.

Treatment:

There’s no cure for ALD, and the nervous system progressively deteriorates, with death usually occurring between one and ten years after the start of symptoms.

Research suggests that a mixture of oleic acid and euric acid, known as Lorenzo’s oil, may delay or reduce symptoms in boys with X-linked ALD by lowering levels of VLCFAs. The most benefit is seen when the treatment is used before symptoms develop, before irreversible damage has occurred.

Bone marrow transplants have also been used with some success in boys in the early stages of X-linked ALD but are not without considerable risk. Newer treatments that may lower brain levels of VLCFA are being tested. Treatment with docosahexanoic acid (DHA) may help young children with neonatal ALD.

Genetic research has identified the transporter proteins and their faulty genes, starting the path towards gene therapy.

Research directions:
Active clinical trials are currently in progress to determine if the proposed treatments are effective:

*Glyceryl Trioleate (Lorenzo’s oil) for Adrenomyelneuropathy.
*Beta Interferon and Thalidomide  This study is closed.
*Combination of Glyceryl Trierucate and Glyceryl Trioleate (Lorenzo’s Oil) in assymptomatic patients.[26]
*Hematopoietic stem cell transplantation.

Prognosis:
Treatment is symptomatic. Progressive neurological degeneration makes the prognosis generally poor. Death occurs within one to ten years of presentation of symptoms. The use of Lorenzo’s Oil, bone marrow transplant, and gene therapy is currently under investigation.

Possible Complications:
•Adrenal crisis
•Vegetative state (long-term coma)

Prevention:
Genetic counseling is recommended for prospective parents with a family history of X-linked adrenoleukodystrophy. Female carriers can be diagnosed 85% of the time using a very-long-chain fatty acid test and a DNA probe study done by specialized laboratories.

Prenatal diagnosis of X-linked adrenoleukodystrophy is also available. It is done by evaluating cells from chorionic villus sampling or amniocentesis.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://www.bbc.co.uk/health/physical_health/conditions/adrenoleukodystrophy1.shtml
http://en.wikipedia.org/wiki/Adrenoleukodystrophy
http://www.nlm.nih.gov/medlineplus/ency/article/001182.htm

http://health.bwmc.umms.org/imagepages/17277.htm

Enhanced by Zemanta

Leave a Reply

Your email address will not be published. Required fields are marked *