Leukodystrophies are a group of different genetic diseases characterized by progressive damage to the central nervous system (brain and spinal cord) and rarely to peripheral nerves caused by alterations in the structure and functioning of its main component. myelin.

In the central nervous system myelin is produced by cells called oligodendrocytes and is mainly made up of fats and proteins; envelops the axons of neurons like an insulating sheath, thus allowing the rapid transmission of nerve impulses.

In leukodystrophies, inherited mutations in genes that produce myelin proteins, or are essential for the functioning of oligodendrocytes, result in primary degeneration of the white matter (demyelinating leukodystrophies) or reduced myelin production (hypomyelinating leukodystrophies), resulting in impaired function of neurons. In some leukodystrophies, myelin is damaged by mutations that cause the malfunctioning of cells, called astrocytes, which participate in the development and maintenance of oligodendrocyte function.

Leukodystrophies are rare diseases, occurring in less than 5 cases per 10,000 people; for many of them it is not possible to have even an estimate of their diffusion.

Among the best known leukodystrophies we find: metachromatic leukodystrophy, X-associated adrenoleukodystrophy, Krabbe disease, vanishing white matter disease (in English Vanishing White Matter, also called CACH syndrome), Pelizaeus-Merzbacher disease, Canavan's disease, Alexander's disease, vacuolized megalencephalic leukodystrophy (MLC).

Most leukodystrophies occur shortly after birth and have a progressive degenerative course. There are, however, variants that appear in adolescence or adulthood (late-infantile / juvenile and adult forms). Generally, these forms have a less severe evolution.

Despite the considerable diversity of mutations and genes involved, the alterations of the white matter that characterize leukodystrophies determine in all cases the reduction of the ability to move which initially manifests itself as hypotonia (loss of muscle tone), which then progresses over time, causing severe movement limitations and spasticity.


The most common disorder (symptom) of leukodystrophies is a gradual decrease in movement skills (or a delay in motor development) starting in the early stages of childhood.

"The initial loss of muscle tone is generally followed by changes in body position, movements and gait, with ataxia (loss of muscle coordination), dyskinesia (appearance of involuntary movements) e dystonia (twitching and muscle spasms).

Over time, some vital functions may be compromised, such as swallowing, chewing and, in severe cases, breathing.

Damage to the motor system may also be associated with a decrease in mental abilities and alterations in language, vision, hearing and behavior (attention deficit hyperactivity disorder, sleep disturbances).

Often, there is a general slowdown in the physical and mental development of affected children.

Among the disorders (symptoms) typical of some leukodystrophies are episodes of epilepsy and sudden worsening of clinical conditions after head trauma, even mild, or fevers.

In addition, some orthopedic complications (scoliosis, hip dislocation) and bladder problems may occur.

The disorders (symptoms) can vary depending on the type of leukodystrophy and for this reason it is not always possible to recognize them in the early stages of the disease.


Leukodystrophies are genetic diseases, that is, caused by permanent alterations (mutations) of the DNA, ie of one's own genetic heritage.

These mutations result in the production of proteins that do not perform their function correctly in the formation and / or maintenance of myelin, resulting in damage to the white matter of the central nervous system.

Mutations are inherited from parents in different ways depending on the type of leukodystrophy:

  • autosomal dominant (only one sick parent transmits the disease)
  • autosomal recessive (the two parents are both healthy carriers of the mutated gene)
  • recessive associated with the X chromosome (the mutated gene is passed from the healthy carrier mother to the sons).

The genes affected by the mutations of many leukodystrophies have not yet been identified; some of the genes involved are known but not the molecular mechanisms that cause damage to the nervous system; of others, however, both the mutated genes and the pathological mechanisms are known.

The leukodystrophies of which the genetic and molecular causes are known include:

  • metachromatic leukodystrophy, caused by the accumulation, mainly in the brain tissue, of sulfatides, substances necessary for the development of myelin. Gene mutations that alter the functionality of the protein responsible for their degradation (arisulfatase A) are the most common cause of this disease which is transmitted as autosomal recessive trait
  • X-associated adrenoleukodystrophy, caused by mutations in the ABCD1 protein that render cells unable to degrade very long chain fatty acids (VLCFA) within organelles called peroxisomes. Non-degraded fatty acids are toxic, in particular for the brain and adrenal glands. Adrenoleukodystrophy is transmitted in a recessive mode linked to the X chromosome; for this reason, generally, only males have the disorders (symptoms), while females, with some exceptions, are healthy carriers
  • Krabbe disease (also called globoid cell leukodystrophy), caused mainly by gene changes GALC which intervenes in the production of the galactocerebrosidase enzyme. This enzyme is responsible for the disposal of particular sugars (galactocerebrosides) present in the membranes of nerve cells which, if not correctly transformed, accumulate causing damage to myelin and to the cells that produce myelin (oligodendrocytes). The disease is transmitted in an autosomal recessive manner
  • Pelizaeus-Merzbacher disease (PMD), leukodystrophy linked to the sex chromosome X (see adrenoleukodystrophy) which therefore mainly affects males. The disease is due to mutations in the gene that encodes the PLP protein, the most abundant protein component of the myelin sheath. The consequence of these genetic anomalies is always a decrease in myelin production (hypomyelinating leukodystrophy)
  • Vanishing White Matter (CACH syndrome), due to mutations affecting one of the five genes that regulate the activity of structures, the subunit of the eIF2B complex, involved in the production of proteins (protein synthesis). The disease impairs the maturation and functioning of astrocytes, cells that are important for maintaining the normal conditions of balance of brain tissue and myelin. The disease has an autosomal recessive mode of inheritance
  • Canavan disease, due to mutations in the gene that intervenes in the production of the aspartoacylase enzyme causing the excessive accumulation of a substance, N-acetyl aspartic acid, in the cells of the central nervous system, in particular in astrocytes. The malfunctioning of astrocytes causes structural damage and functional to myelin.It is transmitted in an autosomal recessive manner
  • Alexander's disease, due to mutations in the gene involved in the production of an astrocyte protein called GFAP. Due to the mutations, the GFAP protein accumulates in astrocytes and damages them. The degeneration of the white matter observed in Alexander's disease is, therefore, due to the lack of support of these cells to the formation and functionality of myelin. Autosomal dominant inheritance has been observed in several familial cases
  • vacuolized megalencephalic leukodystrophy (MLC), caused by mutations in the gene involved in the production of the MLC1 protein by astrocytes. Also in this leukodystrophy the malfunction of the astrocytes causes secondary damage to the myelin. The disease is transmitted in an autosomal recessive manner


It is not always possible to quickly ascertain (diagnose) these rare genetic diseases because the disorders they cause, especially in the early stages, can be similar and overlap between different types of leukodystrophies.

For this reason it is necessary to carry out careful investigations that include:

  • neurological visit
  • nuclear magnetic resonance
  • genetic counseling, to analyze the trend over time of the state of health of the members of a family and verify the presence of other cases of illness
  • laboratory tests, specific for the different types of leukodystrophies, such as: biochemical and histological analyzes, enzymatic assays, molecular genetic analysis

For some types of leukodystrophies, prenatal testing can be done if the genetic mutations present in at-risk families are known.


There is still no cure for leukodystrophies and, in almost all cases, no treatments are available to slow its course. However, careful management of both physical and psychological disorders (symptoms) that characterize these diseases can greatly improve the comfort and living conditions of sick children and adults.

For this reason, specialist checkups and specific therapies are needed to alleviate the various symptoms, such as:

  • spasticity, drug treatments may be used to manage muscle problems (loss of tone, involuntary contractions). Intense exercise is recommended to increase mobility and slow motor degeneration
  • extrapyramidal manifestations, muscle twitching and spasms and involuntary movements can cause high levels of disability; specific drug therapies can promote significant improvements
  • ataxia, specific rehabilitation techniques allow you to manage it
  • epileptic fits, can be treated with anticonvulsant drugs
  • delay in motor / cognitive development, for children / young people with motor disabilities and cognitive retardation, adequate technological and psychological supports are required to favor their correct school integration. So-called techniques of augmentative and alternative communication they can be applied to address language problems
  • orthopedic problems, it is necessary to pay particular attention to the prevention and treatment of orthopedic problems, such as scoliosis or hip dislocation
  • power problemsSwallowing dysfunctions that worsen as the disease progresses are some of the more serious and common consequences of leukodystrophies. Generally, there is a progressive decrease in the ability to ingest food which can, in turn, lead to significant delays in growth. The decision to insert a gastric tube for artificial feeding is based on the assessment of the person's general state of health, on the evolution of the disease and on the wishes of family members

For any type of leukodystrophy it is advisable:

  • carry out regular monitoring of the patient's clinical condition, neurological examinations, magnetic resonance examinations, periodic assessments of growth and nutrition status, specialist examinations to check for orthopedic and urinary complications
  • avoid situations that can exacerbate the disease, even minor trauma and fevers (or infections) must be avoided, which in many cases cause a worsening of the clinical conditions of patients, accelerating the degeneration associated with the disease
  • carry out genetic testing in families at risk (families in which cases of leukodystrophies have occurred) in order to identify any healthy carriers of mutated genes

In a small number of leukodystrophies (adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy) it is possible to slow down the initial disturbances (symptoms) of the disease by transplanting stem cells or bone marrow cells from a healthy donor.Autologous hematopoietic cell transplants genetically engineered to produce mutation-free proteins, capable of compensating for mutated proteins, have been performed with good results in patients with adrenoleukodystrophy and metachromatic leukodystrophy.

These interventions can be beneficial if carried out early, in optimal conditions before the onset of the first symptoms.

Genetic evaluation and / or biochemical tests to discover people at genetic risk can be of great help in carrying out the treatment in the shortest possible time.

Further links

Orphanet. Leukodystrophy

NIH. Genetic and Rare Diseases Information Center (GARD). Leukodystrophy (English)

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