What is Leukodystrophy?

Leukodystrophy is a term that relates to several progressive diseases that affect the brain, spinal cord and major peripheral nerve network. There are several different diseases that come under this umbrella and every specific disorder is caused by a different genetic defect that contributes to abnormal development or deterioration of the myelin sheath. The myelin sheath is the brain’s white matter. It helps to provide protection for the nerves and without it the nerves are not able to function properly. Each specific disease affects a different part of the myelin sheath and this contributes to a wide range of symptoms.

Types and symptoms of leukodystrophy

Each different type of leukodystrophy affects a different part of the myelin sheath and this can result in a range of symptoms. As this is a progressive group of disorders, symptoms tend to get worse with time.

Leukodystrophy affects movement, vision, balance, eating, hearing, behaviour, memory and cognition. Different forms of leukodystrophy can cause different symptoms and some cases may be more severe than others.

  • Aicardi-Goutieres syndrome: this is an autosomal recessive disorder and affects at least four different genes. It causes high white blood cell count and atrophy (wasting away) of the cerebellar tissue.
  • Alexander disease: this is a very rare form of leukodystrophy, which is most common in infants and children. It occurs when white matter degenerates as a result of a lack of myelin.
  • CADASIL: this rare disorder is caused by defects in the NOTCH3 gene. It causes migraines and recurrent strokes, even in adults with no obvious cardiovascular risk factors. Symptoms are caused by damage to the blood vessels in the brain. CADASIL stands for Cerebral Autosomal Dominant Arteriopathy Subcortical Infarcts Leukodystrophy.
  • Canavan disease: this is another rare disorder that causes degeneration of the brain and the spinal cord and is caused by a defect on the ASPA gene. It most commonly occurs in infancy and causes delayed development, a larger than average head, cognitive decline and a lack of muscle tone and strength.
  • CARASIL: this rare disorder increases the risk of recurrent strokes and it is linked to abnormalities that affect the protein HTRA1, which plays an important role in regulating TGF-B1. The resulting symptoms are caused by damage to the blood vessels. As well as increasing the risk of frequent strokes, CARASIL also causes muscle spasms and rigidity in the muscles. CARASIL stands for Cerebral Autosomal Recessive Arteriopathy Subcortical Infarcts Leukodystrophy.
  • Cerebrotendinous xanthomatosis: this is a recessive disorder that affects the CYP27A1 gene and causes a lack of the enzyme sterol-27 hydroxylase. This enzyme is involved in the processing of cholesterol and it causes fatty deposits to collect in the nerve cells, contributing to cataracts and fatty tumours in the tendons. As it progresses, patients may also experience symptoms similar to dementia, coronary heart disease and paralysis.
  • Childhood ataxia and cerebral hypomyelination (also known as CACH): also known as vanishing white matter disease, this is a recessive form of leukodystrophy, which affects movement and speech. It occurs during the first five years of a child’s life. Seizures are common and decline is fairly rapid. Most people only survive a short period of time after diagnosis.
  • Fabry disease: this is an X-linked form of leukodystrophy, which relates to a lack the enzyme alpha-galactosidase A, which causes a build-up of glycosphingolipids and may result in strokes. In mild cases, no symptoms may be present until adulthood.
  • Fucosidosis: this is a rare autosomal recessive disorder that affects the breakdown of certain compounds, including fucose, a sugar that is essential to carry out certain functions. When fucose is not broken down, it accumulates and fucosidosis results in delayed growth, skin problems and diseases that affect the skeletal system.
  • Glutaric aciduria type I: this autosomal recessive disorder occurs as a result of deficiency in enzyme GCDH (glutaryl-CoA dehydrogenase) and accumulation of glutaric acid in the body.
  • GM1 gangliosidosis: this recessive disorder is caused by mutations on the GLB1 gene, which affects the production and regulation of enzyme ß-galactosidase.
  • Krabbe disease: this recessive disorder affects the storage of lipids and is caused by a lack of the enzyme galactocerebrosidase, which is needed to break down lipids. The failure to break down specific types of lipids causes damage to the myelin sheath. Common side effects include progressive neurological degeneration, going backwards in terms of development, irritability and seizures.
  • L-2-hydroxyglutaric aciduria: this rare recessive disorder is caused by mutations that affect both copies of the L2HDGH gene and compromise the activity of the enzyme L-2 hydroxyglutarate dehydrogenase. Commonly, those affected have delayed speech development and progressive decline in cognition.
  • Megalencephalic leukoencephalopathy with subcortical cysts: MLC is a rare recessive disorder which is usually characterised by a larger than average head. Delayed motor skill acquisition is accompanied by deteriorating mobility, spasticity and seizures.
  • Metachromatic leukodystrophy: this form of autosomal recessive leukodystrophy is caused by a deficiency of A (ASA), also known as arylsulphatase. As a result, lipids collect around the body and the myelin is damaged. Symptoms include seizures, changes in behaviour and personality and symptoms associated with dementia.
  • Multiple sulfatase deficiency: this very rare disorder is linked to mutations on the SUMF1 gene and symptoms include abnormal facial features, hearing problems and deafness and a larger than average spleen.
  • Pelizaeus-Merzbacher disease: this is a rare X-linked form, which occurs when the myelin sheath is deficient. Symptoms include delayed development, stiffness, poor coordination and muscle spasms.
  • Refsum disease: this recessive form of leukodystrophy is related to delayed or impaired development of the myelin sheath. It is caused by a build-up of fatty acids in the blood plasma and causes a loss of vision, lack of coordination and itchy, dry skin.
  • Salma disease (free sialic acid storage disease):  this recessive disorder is caused by a deficiency of SLC17A5, which is responsible for transporting sialic acid. It is most common in infants and can affect growth and development.
  • Sjogren-Larsson syndrome: this syndrome is linked to defects in the ALDH3A2 gene, which contains the instructions for aldehyde hydrogenase. There are many different types of mutation and symptoms include both cognitive and motor delay. Most babies with this syndrome are born prematurely.
  • X-linked adrenoleukodystrophy: this is the most common form of leukodystrophy and it is associated with more than 1,000 different mutations that affect the ABCD1 gene. Life expectancy is short after diagnosis.
  • Zellweger syndrome spectrum disorders: this group of disorders is characterised by a lack of peroxisomes in the liver, kidney and brain cells. Peroxisomes are involved in the body’s waste disposal system. Symptoms are varied and include delayed development, hearing loss, problems with vision and impaired liver function.


What causes leukodystrophy?

Leukodystrophy is caused by genetic abnormalities, also known as mutations. These mutations can be passed down by one or both parents depending on the inheritance pattern for the specific type of leukodystrophy. With dominant patterns, only 1 faulty pair of genes needs to be passed on for the individual to develop the syndrome. With recessive, both parents mush pass a defective copy to the child. In the case of X-linked disorders, this relates to passing on genes on the X chromosome. Males have 1 X and 1 Y chromosome, while females have 2 X chromosomes. This means that if a female only inherits 1 faulty gene on the X chromosome, they will only be a carrier, while a male will be a sufferer because they only have one X chromosome.

Who is affected?

Leukodystrophy affects people of all ages, but it is most commonly found in infants and children. Leukodystrophy may sometimes be confused with multiple sclerosis (MS) before a diagnosis is made. MS also affects the myelin sheath and it causes deposits to form along the sheath, which prevent normal nerve activity. Symptoms are progressive and wide-ranging and include incontinence, loss of sensation, lack of balance and coordination, loss of vision and speech problems.

Treatment for leukodystrophy

There is no cure for these disorders and treatment aims to ease symptoms and try and support the individual in the best way possible. Treatments that may be recommended include medication and physiotherapy.



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