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Leukodystrophy refers to a group of rare genetic disorders affecting the central and peripheral nervous systems. They are neurodegenerative diseases characterized by abnormalities in myelin, the fatty substance that surrounds, insulates, and facilitates the function of nerve cells.


Leukodystrophy derives from two Greek words; "leuko" means white, referring to the white matter (myelin) of the nervous system, and "dystrophy" means abnormal growth or development. Myelin insulates, or sheaths, nerve cells, helping them to transmit electrical nerve signals. It is a complex substance composed of a number of fat and protein molecules. Without myelin, nerve cells cease to function and eventually die. It also covers the spinal cord and the long nerve cell projections, known as axons, which innervate all of the peripheral tissues.

More than 15 different types of leukodystrophy have been described, the most common of which will be discussed here. They are all caused by either an abnormality in one of the protein components of myelin, or by a defective or missing enzyme that assists in the production or normal degradation of myelin. As such, leukodystrophies are often referred to as demyelinating or dysmyelinating diseases, as well as leukoencepalopathies.

Based on the part of the nervous system that is most affected, leukodystrophies may be categorized as central (brain and spinal cord), peripheral, or combined. The neurologic symptoms vary widely, both within and between the different types. All types of leukodystrophy are genetic (present at conception), progressive, and never spontaneously resolve. None of the leukodystrophies can be cured, and effective treatments are limited.


Most of the individual leukodystrophies are rare. The most common type is Canavan disease , with an incidence of about one in 8,000, followed by X-linked adrenoleukodystrophy (XL-ALD), which occurs in one in 40,000 male births. Some types of leukodystrophy are more common in certain ethnic groups, such as Canavan disease in Ashkenazi Jews, or globoid cell leukodystrophy (GLD) and metachromatic leukodystrophy (MLD) in Scandinavians.

As indicated, all types of leukodystrophy are genetic, with several patterns of inheritance represented. Genes reside on the chromosomes in the nucleus of each cell; a normal complement is 46 chromosomes arranged in 23 pairs. The first 22 pairs are the autosomes, and the last pair, designated X and Y, are the sex chromosomes. Males have one X and one Y, while females have two X chromosomes. One of each chromosome/gene pair is contributed by each parent at conception.

Autosomal recessive inheritance refers to a disorder that only occurs if both copies of a gene pair are defective. An affected individual is typically born to unaffected parents, who each silently carry one copy of the disease gene. Each time parents who both carry the same recessive gene conceive a pregnancy, there is a 25% chance they will both transmit the disease gene and have an affected child.

Autosomal dominant inheritance requires that only one copy of a gene pair be defective in order to develop the disorder. Each offspring of a parent with an autosomal dominant disorder has a 50% risk of inheriting the gene. In some conditions (e.g., Alexander disease ), most cases are due to a new mutation of the gene in a sperm or egg (unaffected parent).

A male who inherits the gene for an X-linked recessive disorder develops the condition because he has no normal gene on a second X chromosome to compensate for it. Female carriers of an X-linked recessive disorder are usually unaffected, but not always. If they do develop signs/symptoms, they tend to have later onset and milder symptoms. A woman who carries an X-linked recessive gene faces one of four possible outcomes with each pregnancy: affected male, unaffected male, carrier female, and noncarrier female. If an affected male has children, all of his daughters will be carriers, but none of his sons will be affected.

Causes and symptoms

All of the leukodystrophies are caused by either a defective protein component of myelin, or by a malfunctioning enzyme that interacts with one of the protein or lipid constituents. In some cases, defective, deficient, or absent myelin may cause neurons in the central or peripheral nervous system to degenerate. In other cases the neurons remain intact, but transmission of normal signals through the nerves is affected. Brief synopses of the most common leukodystrophies are provided below.

Adrenoleukodystrophy (ALD), also called Addison disease with cerebral sclerosis, or melanodermic leukodystrophy, is inherited primarily as an X-linked recessive trait, but there is also a rare autosomal recessive form (neonatal ALD). X-linked ALD is caused by defects in the ABCD1 gene, also known as the ALDP (ALD protein) gene. A defective enzyme in the peroxisomes (organelles that assist in degrading substances, including some components of myelin) fails to break down very long chain fatty acids (VLCFA), which then accumulate to harmful levels in the nervous system and adrenal glands. About 35% of affected individuals have the childhood or adolescent cerebral form of ALD, which is the most severe. Age of onset ranges from four to ten years, with initial symptoms of behavioral changes, hyperactivity, and learning problems. The skin takes on a bronzed appearance due to adrenal gland dysfunction. Within several years, significant visual and auditory deficits develop, motor coordination worsens, and nearly all boys with the condition are in a vegetative state by their mid-teens. Adult adrenomyeloneuropathy (AMN) affects 30% of men with ALD, onset of symptoms may occur anywhere from adolescence to late adulthood, and progression of the disorder may occur over several decades. Adrenal dysfunction occurs first, and subsequent neurological impairments may include spastic paraplegia, peripheral neuropathy , impotence, sphincter disturbances, and hypogonadism. Approximately 10% of individuals develop an adult cerebral form, which is similar to the childhood variety, but with milder symptoms and slower progression. Another 15% have adrenal insufficiency only, and 10% of males who are positive for an ALDP gene mutation are presymptomatic at the time of testing. About 15% of carrier females develop some degree of neurologic impairment.

Alexander disease is designated as an autosomal dominant condition, but most reported cases are thought to be due to new mutations in the glial fibrillary acidic protein gene (GFAP). The average age of onset in the infantile form is six months, with death by age five. Signs/symptoms include progressive macrocephaly (large head), psychomotor regression, spasticity , and seizures . The less common juvenile and adult forms have a slower clinical course, present with ataxia and spasticity, but usually have normal intellect. Affected adults may show relapsing-remitting symptoms, similar to multiple sclerosis . The presence of Rosenthal fibers and glial fibrillary acidic proteins (GFAP) around the nerves are classic histological signs.

Canavan disease, also referred to as spongy degeneration of the CNS, is autosomal recessive, secondary to mutations in the aspartoacylase gene (ASPA). Symptoms typically begin two to four months after birth, with death occurring by 10 years of age. Signs/symptoms include increased head circumference, deafness, optic atrophy, nystagmus, blindness, initial hypotonia followed by spasticity, and seizures.

Cerebrotendinous xanthomatosis (CTX) is autosomal recessive, and results from mutations in the CYP27A1 gene. Large deposits of cholesterol and one of its derivatives, cholestanol, are found throughout the body, particularly the Achilles tendons, brain, and lungs. Most individuals with CTX have been diagnosed as juveniles. Signs/symptoms include cataracts and tendon xanthomas (fatty tumors) in the early stages, with ataxia, spasticity, mild mental retardation , dementia , psychiatric symptoms, respiratory insufficiency, and myocardial infarction due to atherosclerosis developing over subsequent decades.

Globoid cell leukodystrophy (GLD), also known as Krabbe disease and galactocerebrosidase deficiency, is autosomal recessively inherited, and caused by defects in the glycosylceramidase (GALC) gene. The four clinical forms of GLD, based on age of onset, are infantile, late infantile, juvenile, and adult. About 90% are diagnosed with infantile GLD, with onset at several months of age, and severe neurologic deterioration progressing to death in early childhood. Signs/symptoms include deafness, blindness, irritability, episodic fever, mental deterioration, hypertonia in early stage, hypotonia later, seizures, motor deterioration, and peripheral neuropathy. The other forms of GLD vary widely in severity of symptoms and rate of progression, but those diagnosed later tend to have a better prognosis.

Leigh syndrome, also called subacute necrotizing encephalopathy (SNE), refers to at least eight distinct disorders inherited as autosomal recessive or X-linked recessive traits. Another six types exhibit an unusual hereditary pattern known as mitochondrial inheritance. Mitochondria are energy producing organelles that contain their own genes. With rare exceptions, all of the mitochondria in the first cell of the embryo come from the egg. Therefore, mitochondrial inheritance resembles X-linked recessive inheritance in that the disease can only be transmitted by women, with the difference, though, that both male and female children are equally affected. Symptoms of Leigh syndrome usually develop in infancy or early childhood (classic form), but later onset with milder symptoms may also occur. Age of onset and symptom severity can be quite variable in families with mitochondrial inheritance. Signs/symptoms include failure to thrive, optic atrophy, nystagmus, pigmentary retinopathy, abnormal respiratory patterns, respiratory failure, hypotonia, psychomotor retardation, ataxia, dystonia , spasticity, brainstem lesions, and mental retardation.

Leukoencephalopathy with Vanishing White Matter (LVWM) includes childhood ataxia with central nervous system hypomyelinization (CACH), Cree leukoencephalopathy (CLE), and ovarioleukodystrophy. All forms show autosomal recessive inheritance, and are caused by mutations in the EIF2B class of genes. Individuals with LVWM are typically diagnosed in childhood, but later diagnoses have been described. Symptoms mainly include ataxia, spasticity, and seizures. Optic atrophy may also be present, along with mild intellectual decline. Neurologic symptoms are progressive, and episodes of dramatic deterioration may follow infection or minor head trauma. Average age of onset of CLE is six months, followed by a rapid progression and death by two years of age. Symptoms include hypotonia, seizures, spasticity, vomiting, and diarrhea. Ovarioleukodystrophy presents with neurologic symptoms similar to those of LVWM, with the added finding in women of ovarian dysgenesis.

Metachromatic leukodystrophy (MLD), also called sulfatide lipidosis and arylsulfatase A (ARSA) deficiency, is inherited as an autosomal recessive trait, due to mutations in the arylsulfatase A (ARSA) gene. The late infantile form has onset at six to 24 months, and the primary early symptoms are speech difficulties, gait disturbance, behavioral problems, and intellectual decline. The disease progresses rapidly; seizures, blindness, and severe muscle contractions may occur, and most children are bedridden by early childhood. Juvenile and adult forms of MLD typically first present with psychological symptoms and decreasing intellectual performance. Disease progression is similar to the late infantile form, but may occur over several years to several decades.

Pelizaeus-Merzbacher disease (PMD), which includes spastic paraplegia 2 (SPG2), is X-linked recessive, and caused by mutations in the PLP1 gene. Signs/symptoms in the classical form (type 1) develop in infancy and progress slowly, with death occurring in late adolescence or early adulthood. The connatal form (type 2) also develops in infancy, but progresses more rapidly. Initial, stereotypical symptoms involve rotary movements of the head and eyes, which may later disappear. Other symptoms include hypotonia, choreoathetosis (slow or jerky involuntary movements), spasticity, cerebellar ataxia, dementia, and parkinsonian symptoms. Spastic paraplegia is the primary, initial symptom in SPG2. Depending on the type of gene mutation in the family, occasional carrier females may develop some neurologic symptoms.

Refsum disease , also called hereditary motor and sensory neuropathy (HMSN) IV, shows autosomal recessive inheritance, and is caused by mutations in the PAHX/PHYH or PEX7 genes. Individuals with Refsum disease are unable to metabolize phytanic acid, which then accumulates in tissues to harmful levels. Onset of symptoms occurs anywhere from childhood to late adulthood, but most individuals are diagnosed by age 20. Signs/symptoms include retinitis pigmentosa (vision loss), polyneuropathy, ataxia, anosmia (no sense of smell), nerve deafness, and ichthyosis (scaly skin).

Zellweger syndrome (ZS), also known as cerebrohepatorenal (CHR) syndrome, is autosomal recessively inherited, and caused by mutations in seven different genes affecting peroxisome function. They are especially numerous in the brain, liver, and kidneys. A set of distinctive facial/physical signs, anomalies, and neurologic symptoms are present at birth. The primary neurologic symptoms are failure to thrive (poor weight gain and lack of development of normal motor skills), mental retardation, hypotonia, and seizures. Most babies with ZS do not survive past 12 months.


A wide variety of tests and procedures to diagnose leukodystrophy are available. The methods employed depend upon a clinician's suspected diagnosis, and this is based on physical and neurological findings, along with the presence or absence of a positive family history. Testing falls into several categories:

  • Imaging studies, such as specialized magnetic resonance imaging (MRI) , to visualize any abnormalities of the white matter of the brain
  • Histological (microscopic) studies on small samples of neural tissue to look for abnormal myelin and/or nerve cell structure
  • Testing of peripheral nerve function using a procedure such as nerve conduction velocity (NCV), which measures how quickly electrical signals pass through nerves
  • Biochemical studies to look for excess/diminished components or breakdown products of myelin, or defective/absent myelin-related enzymes
  • Genetic testing to screen for mutations in one or more genes associated with the suspected leukodystrophy

Different types of leukodystrophy may mimic each other, as well as other neurodegenerative diseases (e.g., multiple sclerosis), so multiple tests could be attempted before a diagnosis is reached. A few individuals with a neurodegenerative disorder may never receive a diagnosis. A board-certified geneticist is most likely to make the correct diagnosis, using the fewest tests in the least amount of time.

Carrier testing, as well as prenatal diagnosis, depends upon the availability of an established biochemical or genetic marker. The availability and accuracy of these tests are constantly changing for all genetic disorders, and the interpretation of results may be complicated. For rare disorders such as the leukodystrophies, it is especially critical to seek a consultation with a genetics counselor or geneticist to obtain the most complete and current information available.

Treatment team

A neurologist manages the basic care of an individual with a neurodegenerative disorder. Given their special training and greater familiarity with these rare diseases, a geneticist would likely be consulted to make or confirm the diagnosis. The geneticist and/or genetics counselor also provides support for the family, along with the most current information on the natural history and inheritance of the disorder, options for diagnostic and prenatal testing, availability of specialized reproductive procedures, and referrals to other specialists and support groups. A diagnosis of leukodystrophy might also require involvement of neonatal intensive care unit (NICU) staff, a developmental pediatrician, occupational and physical therapists, and health professionals associated with institutional or specialized home care.


In the majority of cases, there is no effective treatment for an individual diagnosed with a leukodystrophy. However, several of the conditions do respond to specific treatments.

Bone marrow transplantation has been shown to be successful in treating XL-ALD (and MLD), but only in very specific situations. The use of "Lorenzo's oil," a food product consisting of oleic acid, to treat XL-ALD has not been shown in multiple studies to provide any consistent benefit. Adrenal insufficiency in ALD can be successfully managed with the use of glucocorticosteroids.

Effective treatment of Refsum disease is possible with a diet low in phytanic acid. Improvements in ataxia, neuropathy and ichthyosis are seen, but the diet cannot restore any vision or hearing loss that has occurred.

The use of chenodeoxycholic acid and cholic acid (CDCA), in combination with a cholesterol lowering drug, for the treatment of CTX has been successful in stopping the progression of the disease.

In general, all that can be offered to most individuals with a leukodystrophy is supportive care and therapy to address their neurologic symptoms.

Clinical trials

As of 2004, a primary focus for research on the treatment of leukodystrophies is on the use of stem cells from umbilical cord blood for transplantation, known as allogeneic hematopoietic stem cell transplantation. The cells are easily obtained, and are less likely than bone marrow to elicit immune system reactions in the patient. There has been some success in treating GLD, and there is hope that both XL-ALD and MLD will respond favorably as well. Both the United Leukodystrophy Foundation (ULF) and the National Institute of Neurological Disorders and Stroke (NINDS) (see below) are excellent sources of information for research being conducted on the various forms of leukodystrophy.


The prognosis for leukodystrophy depends on the specific diagnosis. In general, a younger age of symptom onset implies a worse prognosis. With few effective treatments, and the progressive nature of hereditary, myelin-related disorders, the overall prognosis for individuals with leukodystrophy is poor.



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Association for Neuro-Metabolic Disorders. 5223 Brookfield Lane, Sylvania, OH 43560-1809. 419-885-1497.

Kennedy Krieger Institute. 707 North Broadway, Baltimore, MD 21205. 888-554-2080. <http://www.kennedykrieger.org>.

MLD Foundation. 21345 Miles Drive, West Linn, OR 97068-2878. 800-617-8387; Fax: 503-212-0159. <http://www.MLDfoundation.org>.

National Tay-Sachs and Allied Diseases Association, Inc. 2001 Beacon Street, Boston, MA 02135. 800-906-8723. <http://www.NTSAD.org>.

NIH/NINDS Brain Resources and Information Network. PO Box 5801, Bethesda, MD 20824. 800-352-9424. <http://www.ninds.nih.gov/>.

United Leukodystrophy Foundation. 2304 Highland Drive, Sycamore, IL 60178. 800-728-5483. <http://www.ulf.org/>.

Scott J. Polzin, MS, CGC

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