Leukodystrophies are a group of around a hundred rare genetic diseases characterised by damage to the white matter of the central nervous system (brain and spinal cord) with or without damage to the myelin of the peripheral nervous system.
It is estimated that between 150 and 300 children a year are born with leukodystrophy in France.
The causes and biological mechanisms of leukodystrophies
The majority of leukodystrophies are genetic, and to date more than 200 genes have been identified as being involved in these diseases. The mode of transmission of the causative mutations in the family and the function of the mutated gene lead to different clinical pictures.
Leukodystrophies are caused by genetic anomalies called mutations in genes that code for proteins playing a key role in the synthesis or maintenance of myelin (a substance that serves to insulate and protect the axons of neurons like an insulating sheath around electrical wires, and which plays an important role in the rapid propagation of nerve messages from one neuron to another).
Myelin is a highly specialised membrane made up of proteins and lipids that must be produced and renewed throughout life. Mutations in a gene involved in one of these stages within the glial cells compromise the myelin synthesis and/or maintenance cycles, and consequently lead to a reduction in the quantity of myelin or an impairment of myelin functions. Any degradation of myelin causes the neuron to suffer, which can then degenerate, leading to a loss of communication between the brain and the periphery and the appearance of motor and sensory symptoms.
There are so-called “hypomyelinating” leukodystrophies, in which insufficient myelin is produced from birth, and “demyelinating” leukodystrophies, in which the existing myelin is degraded. The latter are generally more severe and progress more rapidly.
Leukodystrophies are generally progressive neurodegenerative diseases, and can appear in early childhood, adolescence or adulthood.
Symptoms and diagnosis of leukodystrophies
Leukodystrophies compromise the function of the myelin sheath. This causes a loss of communication between neurons and the appearance of motor, cognitive, psychiatric and/or sensory symptoms.
The symptoms presented by patients differ according to the type of leukodystrophy and degree of severity of the damage. However, the common and most frequent clinical signs are, from a motor point of view, spasticity (stiffness of the muscles), ataxia (lack of fine coordination of voluntary movements), speech disorders and abnormal movements such as dystonia (involuntary contraction of the muscles) or tremors. These motor disorders are often associated with bladder control difficulties.
Depending on the age, cognitive symptoms can lead to psychomotor development delays, difficulties at school or work, and even dementia.
Behavioural and mood disorders are also common.Vision and/or hearing problems may also occur, particularly in children.
Diagnosis of leukodystrophies is based primarily on analysis of brain imaging (MRI), which will reveal myelin abnormalities and classify leukodystrophies as hypomyelinating or demyelinating. A more precise diagnosis of the type of leukodystrophy is based on biochemical assays for certain leukodystrophies and genetic analyses in all cases. Once the diagnosis has been made, a family investigation (genetic counselling) is offered to identify relatives at risk of developing or passing on the disease to their offspring.There are often delays in diagnosing leukodystrophies in adults because they are confused with multiple sclerosis, the most common acquired myelin disease and the best known to neurologists.
In France, there are expert centres called Centres de Référence de Leucodystrophies Rares (Reference Centres for Rare Leukodystrophies), and one of their missions is to help improve diagnosis of leukodystrophies and offer appropriate treatment.
Treatments for leukodystrophies
Dedicated treatments exist for certain leukodystrophies, in particular bone marrow transplants for X-linked adrenoleukodystrophy (X-ALD), leukodystrophies with spheroid axons and ALSP pigmented glial cells and certain forms of metachromatic leukodystrophy.
To be effective, transplants must be carried out at an early stage of the disease. Medicinal treatments are sometimes possible, as in the case of cerebrotendinous xanthomatosis.Several gene therapies are also being developed for leukodystrophies.
In addition, in all leukodystrophies, symptomatic treatments are possible, involving medication and/or rehabilitation, to improve certain symptoms such as spasticity or pain.
In 2019, Prof. Fanny MOCHEL, neurologist (Pitié-Salpêtrière Hospital, APHP) and researcher in the MOV’IT team led by Prof. Stéphane LEHERICY and Prof. Marie VIDAILHET at the Institut du Cerveau performed a haematopoietic stem cell transplant in a patient with rapidly progressing ALSP.Follow-up of this patient over 30 months showed a regression of the symptoms and cerebral lesions associated with the disease.
Lien vers cette publication : DOI: 10.1111/ene.14694
3 types of leukodystrophy studied at the Paris Brain Institute
At the Institut du Cerveau, research is focusing on 3 of the most common types of leukodystrophy:
- X-linked adrenoleukodystrophies (ALD)
- Metachromatic leukodystrophies (MLD)
- Leukodystrophies with spheroid axons and pigmented glial cells (ALSP)
Violetta ZUJOVIC’s team is working on the mechanisms of demyelination and remyelination in multiple sclerosis using cells from the immune system.
As shown by the success of bone marrow transplants, the immune system plays a key role in certain leukodystrophies. In collaboration with Prof. Fanny MOCHEL and Dr Caroline SEVIN, Violetta ZUJOVIC is now studying the role of the immune system in leukodystrophies in order to identify new therapeutic avenues.
Prof. MOCHEL’s team is interested in the metabolic regulation of glial cells and how metabolic treatments can slow or even halt certain neurodegenerative processes.His team recently took part in an international therapeutic trial which showed that a molecule targeting energy metabolism and inflammation in X-ALD could reduce the risk of cerebral forms of the disease. Work is currently underway to determine whether this treatment could be an alternative to marrow transplantation in X-ALD.
Dr SEVIN’s team is using gene therapy to correct the genetic anomaly in question at presymptomatic stages (before the onset of symptoms) in children with X-ALD, metachromatic leukodystrophy and Krabbe disease.
X-linked adrenoleukodystrophies (ALD)
These diseases affect 1 in 17,000 newborn babies worldwide. It is the most common leukodystrophy. ALD combines demyelination of the central and peripheral nervous system with dysfunction of the adrenal glands (adrenal insufficiency), glands located above the kidneys which secrete certain hormones such as adrenaline.
ALD is caused by mutations in the ABCD1 gene located on the X chromosome. The role of the ATP-binding cassette protein (ABCD1) is to break down very long-chain fatty acids (VLCFAs) inside cells. When this protein is no longer functional due to a mutation, VLCFAs accumulate in tissues and become toxic. The level of VLCFAs in the blood is a marker of the disease and aids diagnosis.
Men with XALD pass the disease on to their daughters but never to their sons. Affected women have a 50% risk of transmitting the disease to their children.
There are 3 clinical pictures described for ALD, which differ in terms of symptoms and patient population.
| Form | Age of onset | Symptoms | Treatments |
| CALD. ALD of the brain in children, adolescents and adults. The most serious form of ALD. It is characterised by rapid neurological deterioration. The majority of men with ALD are at risk of developing cerebral damage, compared with less than 1% of women. | C-CALD 3-10 years
Ado-CALD 11-21 years A-CALD > 18 years |
Attentional, visual, auditory and psychiatric disorders associated with walking and coordination problems | Treatment of symptoms.
In the early stages of the disease, a stem cell transplant may be offered. |
| AMN. adrenomyeloneuropathy. Chronic and progressive damage to central and peripheral myelin. Common in women with leukodystrophy and in 100% of men with the disease. | AMN between 20 and 40 for men
Between 40 and 60 for women |
Problems with walking, balance and bladder and bowel function. Mild paralysis of the lower limbs associated with muscle contractures. | Treatment of symptoms, spasticity, urinary and sphincter disorders and neuropathic pain. |
| ISRN. Lower adrenal insufficiency. This condition is characterised by progressive destruction of the adrenal glands. It is found in less than 1% of women with leukodystrophy and in almost 100% of men. | Between 3 and 10 years old
All ages |
The first visible sign of this condition is a spontaneous tanning of the patient, known as melanoderma. | Treatment by hormone supplementation |
Metachromatic leukodystrophies (MLD)
Metachromatic leukodystrophies are rare autosomal recessive genetic diseases that affect 1 in 45,000 newborns and can develop in childhood, adolescence or adulthood.
Leukodystrophies are mainly caused by mutations in the ARSA gene, which codes for a protein responsible for the breakdown of lipids called sulphatides that are essential for the formation and maintenance of central and peripheral myelin.
Infantile forms of the disease develop before the age of 30 months and cause symptoms such as muscular weakness (hypotonia), language difficulties and motor deficits. As the disease progresses, spasticity, convulsive seizures and visual and hearing problems appear.
Juvenile forms appear between 30 months and 16 years of age and cause behavioural and balance problems.
Adult forms, which appear after the age of 16, lead to personality changes, increased emotionality and motor disorders.
Treatment must be comprehensive, and in some cases a stem cell transplant may be considered in the early stages of the disease.
Leukodystrophies with axonal spheroids and pigmented glial cells (ALSP).
These leukodystrophies, also known as leukoencephalopathies, are due to a mutation in the CSF1-R gene, which codes for a receptor present on the surface of microglial cells, the resident immune cells of the central nervous system. These are autosomal dominant diseases, meaning that the children of an affected person have a 50% risk of being affected. They affect between 10% and 25% of adults with leukodystrophies.
The average age of onset of these leukodystrophies is 40.
It affects both men and women, and presents mainly as rapidly progressive spasticity and/or cognitive and psychiatric disorders. The first signs of the disease generally appear after the age of 30, but the disease has incomplete penetrance.
It is characterised by a progressive loss of memory, personality changes, motor disorders sometimes associated with a loss of judgement and social disinhibition.
To date, there is no specific treatment for ALSP. Secondary risks associated with this disease need to be monitored, such as recurrent pneumonia or urinary tract infections.
Pelizaeus Merzbacher disease
Pelizaeus Merzbacher disease is caused by mutations in the PLP1 gene, which codes for a protein present in oligodendrocytes and involved in the synthesis of myelin. This disease mainly affects children, with significant developmental delays affecting both motor and cognitive functions. Women carrying mutations in the PLP1 gene may also develop symptoms in adulthood, in particular spasticity and urinary disorders.
Projects at the Paris Brain Institute:
2 collaborative projects involving 2 research teams are underway:
Myelin plasticity and regeneration” team – Brain Institute.Project leader Violetta ZUJOVIC, INSERM researcher
Mov’It team – Brain and Spinal Cord Institute. Project leader Pr Fanny MOCHEL, neurologist APHP
The Matrix project
The MATTRIX project concerns the study of macrophage activation profiles in X-ALD.
In this disease, acute and chronic inflammation is observed due to the activation of macrophage immune cells.
Macrophages are blood cells (white blood cells) whose role is to defend the body against pathogens such as viruses and bacteria. Along with other immune cells such as lymphocytes, they participate in the inflammatory response.
The aim of the MATTRIX project is to understand how mutations in the ABCD1 gene influence the intrinsic capacity of macrophages to become activated and orient themselves towards inflammatory or anti-inflammatory profiles. The results of this project could lead to individualised management of patients, with better prediction of disease progression to guide 1st-line treatments.
Inspire project
The INSPIRE project focuses on 3 types of leukodystrophies (ALSP, MLD and ALD) and aims to :
- Gain a better understanding of the inflammation observed in these diseases in order to identify new therapeutic targets.
- Contribute to the development of reliable biological criteria to guide patients as early as possible towards stem cell transplantation, currently the only effective therapy for the progression of leukodystrophies.
- Validate a new non-invasive treatment for cerebral leukodystrophy (CALD)
- Finding new biomarkers for the early detection of neuroinflammation and gaining a better understanding of the biological mechanisms of leukodystrophies by targeting the anti-inflammatory response.
Last updated Mai 2024.