Archives: Index of leukodystrophies

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (or LTBL) is an extremely rare genetic disorder in the family of leukodystrophies. Its prevalence is less than one in 1,000,000. It is one of the hypomyelinating leukodystrophies, those white matter pathologies characterised by a permanent deficit of myelin in the brain.

Because the syndrome is so rare, not much is known about the disease and very little information is available.

LTBL syndrome begins in early childhood. It is characterised by abnormalities in certain areas of the brain, including the thalamus and brain stem (the part of the brain that connects to the spinal cord), and by high levels of a substance called lactate in the brain and throughout the body. The syndrome usually leads to motor problems and problems controlling muscle function.

The gene whose mutation is responsible for LTBL syndrome is the EARS2 gene which is located on chromosome 16 (at 16p12.2). This gene codes for a protein, glutamyl-tRNA synthetase , which is involved in the manufacture of proteins in mitochondria.

Protein synthesis: an industry!

In cells, an entire industry is responsible for protein synthesis. These molecules, diverse and numerous in the cell, perform a multitude of roles. Proteins are all synthesised according to the same principle, in the same plants, but each one is made following the instructions specific to that protein which are contained in the genome in the form of a DNA sequence.

The genome is hidden in the cell nucleus, a veritable library storing the recipes for making all proteins. Based on these instructions, a copy of the recipe will be reproduced in RNA form, to be sent to the unit in charge of production. Production units then synthesise the proteins by assembling the building blocks following the instructions reproduced in the RNA.

PRODUCTION SITE

The tRNA gets its name from its function of transferring the blocks (amino acids) necessary for building proteins. It is this conveyor that brings the material into the production area, then allows it to be attached to the bricks already assembled.

The tRNA synthetase is responsible for fixing the right brick to the tRNA. The preparation of this specialised worker and therefore the whole production chain in general depends on it.

Symptoms of the disease

It was in 2012 that a team of researchers was able to put a name to the gene that is mutated in LTBL syndrome. To do this, the researchers analysed the DNA of 12 patients with the same characteristics through next-generation exome sequencing. The disease is so rare that to carry out this work, the young patients came from all over the world: one Italian, two Belgians, two from England, one American, one Israeli, one Swiss, one Portuguese, one German, and two Brazilians.

Forms of the disease

Patients with LTBL syndrome all have symptom onset in infancy and rapid disease progression with severe abnormalities visible in MRI results and increased lactate levels. The disease comes in two forms: a mild form and a severe form.

In its mild form, from 6 months of age, the disease leads to a loss of mental and movement abilities (psychomotor regression). Muscle stiffness (spasticity) and extreme irritability are common, and some people develop seizures. Patients then make a partial recovery. Developmental milestones may be delayed, but children are able to acquire new abilities in the years that follow. MRI results shows striking improvements and lactate levels are dropping.

For patients with the severe form of the disease, symptoms begin soon after birth. These infants generally have delayed development of mental and movement abilities (psychomotor delay), weak muscle tone (hypotonia), involuntary muscle tensing (dystonia), muscle spasticity and seizures. Some have extremely high levels of lactate (lactic acidosis), which can cause serious respiratory and heart problems. Liver failure occurs in some severely affected infants. Subsequently, clinical stagnation, brain atrophy visible on MRI and a persistent increase in lactate levels are noted.

Diagnosis of the disease

A diagnosis can now be suggested by the patient’s clinical picture, and the characteristics of an MRI image. A rise in lactate levels is also measurable and indicative. To confirm the diagnosis, sequencing of the EARS2 gene will show a mutation in each of the two copies of the gene (autosomal recessive disease: parents each carry one copy of the mutated gene, but they usually do not show the signs and symptoms of the disease).

The simplified mechanism leading to the disease

A mitochondrion is a separate structure in the cell, responsible for ensuring the cell’s respiration, and thus producing energy for the cell. Mitochondria use their own protein synthesis system, their own plant, to ensure their own operations. But the principle remains the same (see diagram: Making proteins: an industry!). The tRNA synthetase from the EARS2gene allows glutamate (the brick) to be fixed to its transfer RNA which works in the mitochondria.

Enzymatic binding of amino acids to tRNAs:  glutamyl-tRNA synthetase , derived from the EARS2 gene, is the enzyme (the worker) needed to assemble the amino acid glutamate (the brick) on the tRNA (the transporter).

In LTBL syndrome, researchers have been able to identify the gene that is mutated, and believe that the amount of glutamyl-tRNA synthetase is reduced in patients. The reduced amount of the enzyme probably prevents the normal assembly of new proteins in the mitochondria. It is suggested that this disrupts the mitochondria’s energy production. However, it is not clear today how mutations in the EARS2 gene lead to the clinical features of LTBL syndrome.

Treatments

Day-to-day management of the disease

Treatment is symptomatic and is ideally conducted in a multidisciplinary setting by specialists experienced in treating people with leukodystrophies. Medication is available to manage muscle tone. Intensive physiotherapy can be used to improve mobility and function. The treatment of ataxia, seizures and cognitive problems follows the usual standards, depending on the needs of the individual.

Monitoring should be maintained to assess the child’s growth and nutritional status. Serial physical and/or radiographic examinations of the hips and spine can be used to monitor orthopaedic complications. Past history is made up of the signs and symptoms of seizures.

When a disease is so rare, how can you hope to cope with it and put a name to what affects your child? Mrs Karine Garest, Marion’s mother, tells us how she was finally able to do it by listening to the description of the disease given by Prof. van der Knaap during an ELA family/researcher conference.

“In 2012, during the symposium organised by ELA, I attended the workshop on undetermined leukodystrophies where Prof. van der Knaap presented a new form of leukodystrophy, LTBL. In the description she described a lactate attack in the brain between the ages of 0 and 2 that more or less destroyed the myelin, and that there was a high level of lactate in the blood. Then I remembered a blood test that Marion had taken when she was around 9 months old and she had a high lactate level. This started to send me back to our story. Then she shared the children’s development saying that after this attack there was no more regression and that on the contrary the children were progressing and this was the case for Marion since she sat up at 2 years old, walked at 5 years old etc… so I recognised Marion’s condition in this description and we were able to talk at the end of the workshop and communicate through email afterwards until the blood test which confirmed that Marion was suffering from this form of leukodystrophy……

At the moment, she is the only one who has been diagnosed in France, which, as Prof. Wolf at the symposium, is not possible, there are certainly other people with this form of leukodystrophy, so I hope that my testimony will allow other families to put a name to their child’s disease because if I had not been at the symposium that year, Marion’s condition would still be part of the undetermined leukodystrophies …. ”

CACH syndrome or VWM (Vanishing White Matter)

What’s behind CACH syndrome?

Article reviewed by Prof. Nicole Wolf

CACH syndrome stands for Childhood Ataxia with Central Nervous System Hypomyelination. Today, the name leukoencephalopathy with vanishing white matter (VWM) is preferred. It is a genetic disease of the leukodystrophy family and it is one of the most common leukodystrophies, with a prevalence of about 1 in 80,000. It is one of the hypomyelinating leukodystrophies secondary to astrocyte damage. VWM disease displays a progressive degradation of the white matter in the brain.

VWM disease can occur in early childhood, often before the age of 4 years, but some patients do not show initial symptoms until adulthood. This syndrome is characterised by various neurological features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions visible on brain imaging.

• Progressive cerebellar ataxia is a progressive coordination disorder. Spasticity is a rapid stretching of a muscle that causes a reflex contraction, which results in muscular stiffness, spasms or contractures. Cognitive disorders include memory and perception problems, slowed thinking, and difficulties with problem solving.

Patients generally have normal early development, followed by chronic neurological deterioration and stress-induced episodes of rapid decline. No treatment is currently available.

Five genes have been identified as carrying mutations that can lead to VWM disease. These are the genes for eukaryotic initiation factors or EIF2B1 to 5which are located on different chromosomes. These genes each code for a protein involved in the initiation of translation, i.e. Protein synthesis.

Symptoms of the disease

Although VWM disease was originally recognised as a disorder in young children, it is now known that the onset and severity of the disease varies considerably, from a rapidly progressing prenatal or early childhood disease to a slower progressing adult disease. The syndrome usually leads to ataxia, spasticity, and variable optic atrophy.

Forms of the disease

In children, the disease most often appears before the age of 4 years in the form of motor problems, especially difficulty walking. Prenatal onset may be characterised by intrauterine growth delay, small volume of amniotic fluid, reduced foetal movements and/or contractures at birth. After birth, these children often show signs of encephalopathy, with irritability, drowsiness and seizures. Other organs such as the liver can also be affected in these early forms.

In adolescents and adults, on the other hand, it is common for the disease to begin with the onset of cognitive or psychiatric problems, but loss of acquired motor skills is common.

Diagnosis of the disease

About half of patients have an initial sign of the disease after a triggering event, such as an infection or head injury.

The first 3 cases were described in 1993. Since 1997, 4 diagnostic criteria have been proposed:

1. initial motor and mental development is normal or near normal;
2. neurological deterioration follows a chronic progressive and episodic course, and episodes of deterioration may occur following minor infection and minor head injury, and may result in lethargy or coma;
3. neurological signs consist mainly of cerebellar ataxia and spasticity; optic atrophy may develop later, but not always; epilepsy may occur, but is not the predominant sign of the disease; mental abilities may also be affected, but not to the same degree as motor functions.
4. MRI shows features of VWM leukoencephalopathy that are recognisable by experts.

Magnetic resonance spectroscopy can be used to obtain additional evidence for diagnosis. White matter spectra show a severe decrease, or almost complete disappearance of all normal signals, and a low presence of lactate and glucose.

When clinical suspicion is high, a VWM diagnosis is confirmed by genetically testing the 5 genes encoding the five EIF2B subunits, and homozygous or heterozygous variants are sought.

The simplified mechanism leading to the disease

Identifying the 5 genes responsible for this syndrome has led to a better understanding of what constitutes the clinical phenotype of the disease and to a better understanding of the pathophysiology, i.e. the molecular and cellular disorders responsible for the syndrome.

To put it simply…

Slow and steady wins the race!

In cells, an entire industry is responsible for making proteins. And for VWM disease, as for other leukodystrophies, these are molecules involved in protein synthesis that differ in patients, and more precisely molecules that play an essential role in the initiation of translation, i.e. the first stages of manufacture.

Focus on EIF2B:

EIF2B is itself a collection of several molecules, those made by the five genes whose genetic variants are at the origin of VWM disease.

To enable this first limiting step in protein synthesis, a cascade of events will lead to the assembly of a set of molecules, the initiation complex (corresponding to a production plant). The EIF2B complex is responsible for activating the formation of the Translation Initiation Complex, by activating EIF2:

Translation: making proteins

The EIF2B translation initiation complex is necessary for normal translation of proteins. The genetic variants that cause VWM disease cause a partial reduction in the activity of this complex.

The five genes of the EIF2B complex are involved in the cell’s response to stress. The objective is to restore the cell by focusing on the production of cell repair elements. Patients with VWM disease have an increased susceptibility of white matter to cellular stress.

To put it simply…

When the going gets tough:

The other major function of EIF2B is the regulation of the Integrated Stress Response (ISR). In the event of cellular stress, an alarm signal is pulled by the cell to slow down the protein production chain and allow the cell to put things back in order. The cell will only make the proteins that are needed to put the cell back in order.

The five genes each coding for one of the subunits of the EIF2B complex influence protein synthesis under cellular stress. Their mutation leads to a disturbance in the maturation of astrocytes, the white matter cells associated with neurons, and causes increased susceptibility to cellular stress for the white matter. Doctors are therefore envisaging a way to try to improve the response of these cells to stress by promoting the ISR pathway.

When the ISR pathway is activated, the phosphorylation of EIF2 on its small subunit, called “alpha”, transforms EIF2. Instead of being activated by EIF2B, EIF2 becomes a competitive inhibitor of EIF2B, which means that it prevents the formation of the translation initiation complex and inhibits overall protein synthesis. The objective is to restore the cell by focusing on the production of cell repair elements.

Treatments

Day-to-day management of the disease

Patients’ quality of life and comfort can be improved by managing the symptoms of the disease. Most patients have occasional neurological attacks, which can usually be well controlled with medication. It is important to control these attacks and take preventative measures against head trauma.

Clinical trial

Guanabenz is a long-time antihypertensive treatment known by doctors, which also targets the response to cellular stress.

Treatment of mice with leukoencephalopathy with loss of white matter with guanabenz for 8 months showed an improvement in white matter parameters. This preclinical work has now led to the consideration of the first clinical trial in VWM patients. As guanabenz is an old and safe drug, the first clinical trial is being prepared in partnership with ELA. This trial will include about 15 children in order to establish the optimal dose, establish the safety of the drug in these children, and measure changes in their motor and cognitive abilities over a two-year period.

ELA supports clinicians and researchers working on leukoencephalopathy with vanishing white matter. Research must continue to improve the understanding of the pathogenesis of the disease, to develop specific treatments and, ideally, to identify a cure. With a first clinical trial today, there is hope that patients’ lives will improve tomorrow.

Aicardi-Goutières syndrome (AGS)

Learn about Pelizaeus-Merzbacher disease (PMD)

Article reviewed by Prof. Nicole Wolf

Pelizaeus-Merzbacher disease (PMD) is a rare genetic disorder in the family of leukodystrophies. Its frequency is 1 per 100,000 births. It is one of the hypomyelinating leukodystrophies, white matter diseases characterised by a permanent deficit of myelin in the brain.

Pelizaeus-Merzbacher disease is named after two German doctors who described it in the early twentieth century. As early as 1885, one family had five boys with involuntary oscillatory eye movement, spasticity in their limbs, very limited head and body control and delayed cognitive development. Twenty-five years later, in 1910, re-examination of the family showed that 14 members of the family had the disease, including two daughters, and that all were descended from the same relative. It was also noted at that time that the disease was never passed from father to son, which has since been known to be a characteristic of genetic diseases in which the responsible gene is carried by the X chromosome.

Pelizaeus-Merzbacher disease presents in different forms depending on the age of onset of the first symptoms: a neonatal form, and a so-called “classic” form which occurs before the age of one. Two other less severe forms have been described: spastic paraplegia type 2 (which includes the recently described form, HEMS – Hypomyelination of Early Myelinating Structures) and the PLP1 null phenotype.

The gene whose mutation is responsible for Pelizaeus-Merzbacher disease is the PLP1 gene which is effectively located on the X sex chromosome (at Xq22.2). For this reason, men and women report the disease differently, and the disease typically affects boys or men. This gene codes for proteolipid protein 1 (PLP1): 188 disease-causing mutations have been described to date.

“PMD-like”

A small percentage of patients with the characteristic phenotype of Pelizaeus-Merzbacher disease do not carry a mutation in the PLP1 gene. These patients are recognised as having a Pelizaeus-Merzbacher-type disease. Mutations in other genes (e.g. GJC2) have been identified. The term Pelizaeus-Merzbacher-like disease (PMLD) is then usually used to signify the similarity of these diseases, hence the use of the word “like” in English.

Genetic mutations

There are different types of genetic mutations, the main ones being: 1) duplications, 2) point mutations and 3) null mutations.

• In the case of duplications, a gene is present in duplicate. And as a result, the protein from the gene can be produced in excess. Duplications can lead to an increase in protein function, a “gain of function”.
• In the case of point mutations, there is a spelling mistake in the gene. The protein being made may be too small, malfunctioning or not functioning at all.
  • coding point mutations: the mutation has a consequence on the composition of the protein
  • nonsensepoint mutations: the mutation results in the production of a truncated protein
  • non-coding point mutations: the mutation has a consequence on the expression of the protein, i.e. the amount of protein produced
  • Null mutations prevent any production of the mutated gene’s protein.

Genetic mutations

Duplications: doubling

Since the 1989 discovery that mutations in the PLP1 gene cause Pelizaeus-Merzbacher disease, it has been established that most cases of Pelizaeus-Merzbacher are due to duplications (or more rarely triplications or even quintuplications) of the entire PLP1 gene. Indeed, duplications are found in about 50-75% of affected families. Duplications result in the classic form of the disease which occurs early and often has severe symptoms.

The size and location of the duplicated fragment varies from one family to another. The PLP1 gene is about 30,000 bases long. The smallest known duplications are around 100,000 bases of DNA, while the largest identified to date is over 5 million bases. The duplicated DNA fragment may therefore be much larger than the PLP1gene alone. It is thought that other genes may also be involved in the neurological differences that may exist between families, genes that are also duplicated and located before or after the PLP1 gene on the X chromosome.

It is currently believed that duplication results in excess protein production. The accumulated proteins are toxic to the cells called oligodendrocytes that make myelin around the axons of neurons.

Point mutations

Point mutations are present in 30-40% of patients with Pelizaeus-Merzbacher disease. Many PLP1 point mutations have been identified. Most of these point mutations are unique to a family. And because they are unique, it is difficult to predict the course of the disease in these patients, especially if there has been no previous case of the disease in the family.

Non-coding mutations

Recently, non-coding mutations have been found in a limited part of the PLP1 gene. These mutations result in a relative under-expression of the PLP1 protein compared to the DM20 protein (a smaller form of the PLP1 protein). It is expressed mainly in the peripheral nervous system and during certain phases of myelination. The brain MRI is characteristic. It shows hypomyelination of normally myelinated structures at an early stage, hence the acronym HEMS (Hypomyelination of Early Myelinating Structures).

Null mutations

Finally, there are patients with Pelizaeus-Merzbacher disease in whom the PLP1 gene is completely absent or with a mutation at the beginning of the gene that results in a complete lack of protein production. Surprisingly, these mutations, called null mutations, lead to a milder syndrome than PLP1duplications or the majority of point mutations. However, the patients’ condition deteriorates, and this form is less benign than initially thought.

Consequences of mutations

The severity of a mutation generally depends on how the structure of the protein is altered by the mutation. Mutations causing major changes in the structure of PLP1 (or misfolding of the protein) result in the unfolded protein response, which leads to oligodendrocyte death (see insert).

The response to unfolded proteins

In cells, proteins are made in a compartment called the endoplasmic reticulum. When the cell needs it, as it does during growth phases, protein production is intensified.

When the production is too high, the cell starts to make mistakes, causing stress to the endoplasmic reticulum. This raises a red flag: a biochemical pathway called the Unfolded Protein Response (UPR) slows down the protein manufacturing chain to allow for improved production quality.
However, when the system is overwhelmed by the amount of malformed proteins, it can lead to the death of the cell to prevent the survival of an unsuitable cell. It is a natural protection system, a system that first tries to repair the damage, even if it means the self-destruction of the cell if the situation becomes too serious.
When a mutated gene causes misfolding of the manufactured protein, the cell can initiate the UPR response leading to its self-destruction.

Mutations that only moderately alter the protein structure do not induce as much protein retention in the cell and cause little or no degeneration of oligodendrocytes. This is the case for null mutations, where the PLP1 protein is completely absent and not misfolded. There is no toxicity related to the misfolding of the protein.

Symptoms of the disease

Pelizaeus-Merzbacher disease is characterised by pendular nystagmus, i.e. an involuntary oscillatory movement of the eyes, head tremor and hypotonia, but also developmental delay, spasticity (muscle contraction) and a variable intellectual deficit. The clinical spectrum of the disease is wide, and 2 forms of the disease are described according to the age of onset and severity of symptoms: the classic form of the disease and the neonatal form.

Forms of the disease

• Classic PMD

The classic form of Pelizaeus-Merzbacher disease is the most common form and occurs before the age of one. Early symptoms include muscle weakness, involuntary eye movements (nystagmus) and delayed motor development in the first year of life. These motor and cognitive developmental delays occur to varying degrees. Some patients, for example, develop the ability to walk independently, while others gain head control but are dependent on a wheelchair. In general, motor disability is more severe than cognitive dysfunction.

•  Neonatal PMD

The neonatal form of the disease is the most severe: it involves delayed mental and physical development and severe neurological symptoms. Signs of the disease may be present at birth or appear in the first few weeks of life. These children show developmental arrest at major milestones such as head control and are often bedridden throughout their lives.

• Spastic paraplegia type 2 (SPG2)

These patients represent about 20% of the cases of the disease.

Pure form

Spastic paraplegia type 2 is said to be pure when the only phenotype present is spastic paraplegia, i.e. more or less complete paralysis of both lower limbs associated with spasms, convulsions, due to an exaggeration of the tendon reflex[1]. The least severe form of Pelizaeus-Merzbacher disease, patients with pure spastic paraplegia type 2 have no other neurological manifestations.

[1] Exaggeration of the tendon reflex: involuntary resistance to an imposed movement, which increases with the speed of the movement.

Complicated form

When neurological features are added to the spastic paraplegia, it is called “complicated spastic paraplegia type 2”. These additional neurological features include mild intellectual deficit, optic atrophy, nystagmus and ataxia appearing in the early years of life. The most moderate cases display spastic paraplegia with mild cognitive impairment.

Forms of Pelizaeus-Merzbacher disease: consequences of genetic mutations
Neonatal: neonatal form of Pelizaeus-Merzbacher disease; Classic: classic form of Pelizaeus-Merzbacher disease; SPG2: Spastic paraplegia type 2. PLP1: proteolipid protein 1. Gain of function: increase in the activity normally performed by the protein. Dose effect: the level of activity depends on the dose of protein formed. Loss of function: absence of the activity normally performed by the protein.
Adapted from Inoue Front Mol Biosci. 2017

The diversity of mutations responsible for Pelizaeus-Merzbacher disease illustrates the delicate balance implemented by the genetic program. The proteins produced by each gene, such as PLP1, must be produced by each gene at the right place at the right time, and in quantities that are neither too large nor too small.

Diagnosis of the disease

Pelizaeus-Merzbacher disease is suggested by the clinical picture and white matter abnormalities on the MRI. The MRI will show complete hypomyelination (neonatal form and some transient forms), partial hypomyelination (for the moderate form) or diffuse hypomyelination (Pelizaeus-Merzbacher disease, nonsense mutation of PLP1). The study of “auditory brainstem responses”[1] can be useful to differentiate Pelizaeus-Merzbacher disease (absence of II-V waves) from “PMD-like” disease (recordable II-V waves). A genetic test confirms the diagnosis.

Genetic counselling

When a PLP1 gene mutation is identified in a family, it is possible to screen family members for the mutation and provide prenatal diagnosis for parents at risk of transmitting the disease. The disease is transmitted in an X-linked recessive mode. A boy born to a mother who is a carrier has a 50% chance of having the mutation and developing the disease, while a girl has a 50% chance of being a carrier in turn. All the daughters of an affected man will be carriers, but none of his sons will be affected.

The simplified mechanism leading to the disease

About 75% of myelin is composed of fats and cholesterol, and the remaining 25% is protein. Proteolipid protein 1 (PLP1), also known as lipophilin, makes up about half of the myelin proteins and is the most abundant component of myelin (apart from lipids). The PLP1 protein is made from the PLP1 gene in the endoplasmic reticulum of the cells, the oligodendrocytes, and is then incorporated into the cell membrane which surrounds the axons, the axons where nerve information travels. This is how myelin is formed.

When there is a duplication of the gene, the protein is made in excess. Animal research has shown that excess PLP1 accumulates inside the cell instead of being directed to the cell membrane for incorporation into myelin. Point mutations and other small mutations usually induce the substitution of one amino acid for another, or prevent PLP1 from being made along its entire length. This probably results in a protein that cannot fold properly or a protein that can no longer interact with other myelin components. These mutant proteins are toxic to oligodendrocytes and prevent them from producing normal myelin.

PLP 1 normally represents 50% of the total proteins present in the central nervous system, and only 1% in the peripheral nerves. This explains why the central nervous system is affected by Pelizaeus-Merzbacher disease, and not the peripheral nervous system. However, in exceptional cases (“null” mutations), even the myelin of peripheral nerves is affected.

As with other hypomyelinating leukodystrophies, the low amount of myelin produced in patients with Pelizaeus-Merzbacher disease prevents skill acquisition rather than loss of ability.

Treatments

Day-to-day management of the disease

Currently, treatment of Pelizaeus-Merzbacher disease is symptomatic and supportive. It may include medications for rigidity and spasticity, which are present in most patients after a few years. If seizures or seizure-like episodes occur, anti-epileptic drugs may be required, although epilepsy is not usually a frequent occurrence.

Rehabilitation is useful for maintaining joint flexibility and maximising the patient’s abilities. Crutches or walkers can help with walking. Orthopaedic surgery can also help reduce contractures, locked joints due to spasticity or scoliosis of the spine.

If speech or swallowing is impaired, a speech therapist can provide important advice. When swallowing is severely affected, a feeding tube, inserted directly into the stomach, can help increase food intake. Vitamin D and calcium supplements may be helpful.

The management of patients with Pelizaeus-Merzbacher disease is multidisciplinary and involves many medical specialties. The role of parents and relatives is essential.

Human neural stem cell transplantation

A first clinical trial was conducted to evaluate the safety and efficacy of human neural stem cells in the treatment of Pelizaeus-Merzbacher disease. This is a cell therapy trial using a stem cell bank. The objective of this trial was to inject the patient with normal stem cells that could produce myelin, and to evaluate their safety.

Four young children with a severe early form of Pelizaeus-Merzbacher disease each received 300 million cells injected into each cerebral hemisphere. To avoid immune rejection of the transplanted cells, immunosuppression was administered during the 9 months around the transplant. Patients were monitored for 12 months after transplantation. Published at the end of 2012, the results indicated a good safety profile, the objective of this first study. However, clinical evaluation also revealed small motor and cognitive improvements in three of the four patients; the fourth patient remained clinically stable. In addition, MRIs suggested minimal myelin production in the transplant area, persisting or even increasing over time. These four patients are now in long-term follow-up.

Cell therapy using the patient’s own cells

A new approach to cell therapy is now being developed. The idea is to use the patient’s own cells, rather than foreign cells from a donor. This approach uses induced pluripotent stem cell technology, iPSC.

From a skin or blood sample, the patient’s cells are transformed (induced) back into stem cells by stimulating certain genes. They are then corrected in the laboratory to no longer carry the mutation responsible for Pelizaeus-Merzbacher disease. These corrected cells could then be re-injected into the patient to produce normal myelin. The first very encouraging trials were conducted in mice and give hope that clinical trials and a treatment for this orphan disease will be set up.

ELA supports clinicians and researchers working on Pelizaeus-Merzbacher disease. Research must continue to improve the understanding of the pathogenesis of the disease, and the development of specific treatments and, ideally, a cure. Today, hope is focused on cell therapy and induced pluripotent stem cells (iPSCs) as a source of neural progenitors[3]in the treatment of Pelizaeus-Merzbacher disease.

[3] Neural progenitors: cells capable of multiplying and transforming into all types of neural cells, i.e. neurons, astrocytes or oligodendrocytes that produce myelin.

Better understanding of Metachromatic Leukodystrophy (MLD)

Metachromatic Leukodystrophy (MLD) is a member of the lysosomal leukodystrophy family. It’s a rare autosomal recessive genetic disorder. Its frequency is 1 per 45,000 births. It can begin in childhood, adolescence or adulthood and leads to severe neurological dysfunction affecting motor and cognitive functions that can lead to death.

The gene whose mutation is responsible for Metachromatic Leukodystrophy is the ARSA gene which is located on chromosome 22 (at 22q13.31). This gene codes for arylsulfatase A, an enzyme located in the lysosome of cells. This enzyme causes damage to sulfatides, an important lipid component of the myelin of the brain and peripheral nerves, but also of the neurons of the brain. To date, more than 160 mutations in the ARSA gene have been identified (167 on HGMD).

Alternatively, a very small number of patients carry a mutation in the PSAP gene for Saposin B, a co-activator of the ARSA enzyme.

Mutations

Patients with Metachromatic Leukodystrophy are classified into two main groups according to the mutation they carry: The “O” alleles are associated with extremely low enzyme activity while the “R” alleles are associated with residual enzyme activity.
Carriers of one “O” and one “R” allele account for 50% of Caucasian patients. Other mutations are unique or much rarer.

There is some correlation between patient genotype and the onset of  symptoms.

• When patients have both an “O” and an “R” allele, they are most often in the juvenile group.
• Homozygous patients for the “O” allele (who have two copies of the “O” type), with a very low level of ARSA enzyme activity, are found most often in the group of patients with the late infantile form.
• Those with two “R” alleles are found in the adult form group.

So the longer the enzyme remains “active”, the later the disease develops.

Metachromatic Leukodystrophy: from gene to symptoms. Depending on the genes (“O” and “R” alleles), the ARSA enzyme is more or less active. The less active the enzyme is (“O” + “O”), the more sulfatides that accumulate. The less active the enzyme is, the younger and faster the symptoms appear.

Symptoms of the disease

Metachromatic Leukodystrophy is characterised by progressive motor and cognitive deficits.

Late infantile and early juvenile forms

Late infantile and early juvenile metachromatic leukodystrophies appear before the age of 6 years old. These are the most frequent (60%). They are characterised by motor and cognitive deficits that worsen very rapidly and inexorably. The prognosis is very severe and treatment must be considered very quickly to improve the child’s quality of life.

Late juvenile form

In the late juvenile forms, which appear on average between 6 and 16 years of age, cognitive difficulties may precede motor disorders. The progression of the disease tends to be slower.

Adult form

The adult forms of the disease, declared after puberty, are accompanied by cognitive difficulties and abnormal behaviours that are at the forefront, with isolated peripheral neuropathy in rare cases. In other cases, the symptoms combine motor and cognitive deficits as in the late juvenile form, but with a slower progression.

Diagnosis of the disease

Metachromatic Leukodystrophy is evoked in front of the clinical picture and an evocative aspect on cerebral MRI. It is diagnosed by the detection of a deficiency of the ARSA enzyme in blood cells and abnormal excretion of sulfatides in the urine. These 2 tests are essential for the diagnosis. When the disease is due to a mutation in the PSAP gene, the activity of the ARSA enzyme measured in blood cells or fibroblasts is normal but abnormal excretion of sulfatides is observed in the urine. The diagnosis must be confirmed by sequencing the ARSA or PSAP gene and identifying pathogenic mutations in the gene.

Genetic counselling

When a mutation in both copies of the ARSA or PSAP gene is identified in a patient (an affected patient always has a mutation in both copies of the gene), it is also necessary to look for a mutation in one of the copies of the gene in both parents who are “obligatory heterozygotes”*[1]. In a future pregnancy, there is a 25% risk that the unborn child will be affected. It is possible to offer a reliable prenatal diagnosis of the disease. It is also essential to screen brothers and sisters, especially if they are younger. Indeed, if they have the disease but are still asymptomatic or at the very beginning of their illness with a diagnosis yet to be made, experimental treatment may eventually be offered to them. Each of the siblings of an affected patient has a 25% risk of being affected, a 50% risk of being heterozygous like their parents and a 25% risk of not having any pathogenic mutation in the ARSA or PSAPgene. Other family members (siblings of both parents) may also be heterozygous. Heterozygous people never develop the disease. It is quite common to see subjects with decreased ARSA activity but with no abnormal excretion of sulfatides. These so-called “pseudo-deficient” subjects do not develop any symptoms.

[1] *Compulsory heterozygotes: parents of children with autosomal recessive disease are called “compulsory heterozygotes” because they must carry a mutation.

The simplified mechanism leading to the disease

The ARSA enzyme is at work in the lysosome. It transforms its substrate, 3-O-sulfogalactosylceramide (sulfatide), into another lipid. Sulfatides are important lipid components of myelin, but also of neurons.

The Lysosome: where ARSA works

Lysosome comes from the prefix “lysis” (releasing action) and the Greek suffix “some” meaning “body” ( = soma ). So a lysosome is a eukaryotic cellular organelle[2] which allows the degradation of molecules, mostly lipids. It is a small spherical structure (a vesicle) delimited by a lipid membrane located in the cytoplasm of eukaryotic cells. The membrane contains ion channels (proton pumps and others specific to Cl-chloride ions) that allow the active entry of H+ ions, in order to maintain an acidic pH (between pH 3.5 and 5) within the lysosomal vesicle.

The lysosome has a waste destruction function, where molecules are eliminated by digestion, thanks to enzymes called hydrolases, which are active at acidic pH.

The majority of lysosomal diseases are severe, disabling and degenerative, often leading to premature death.

[2]  *Eukaryote: A set of organisms (single or multi-cellular) having a nucleus.

In Metachromatic Leukodystrophy, sulfatides, which are not destroyed by ARSA, accumulate in excess in the white matter cells (oligodendrocytes, microglia) of the brain, brain neurons and Schwann cells that make the myelin of peripheral nerves. This accumulation is toxic to cells, leads to cell death and is responsible for demyelination and destruction of neurons.

Depending on the mutation, the enzyme will be made a little or not at all and therefore be less active (residual) or practically inactive (“O”).

Treatments

• Allogeneic bone marrow transplantation : A hematopoietic stem cell transplant from the bone marrow of a matching donor may be offered to patients with late juvenile or adult forms of the disease. Alternatively, cells from cord blood can be used as a source of stem cells for transplantation. The transplant requires 12 to 24 months to be effective, which does not allow treatment of patients with the late infantile and early juvenile forms, whose development is very rapid. The results are encouraging in the medium term in patients whose disease progresses slowly. Long-term effectiveness is less certain.

• Gene therapy : A clinical study is underway to evaluate the safety and efficacy of gene therapy in children with MLD at different stages, late infantile pre-symptomatic or early juvenile pre-symptomatic, or even early juvenile at the onset of their disease. This trial involves taking hematopoietic stem cells from patients, injecting the normal enzyme gene into these cells in the laboratory with a lentiviral gene therapy vector, and re-infusing the cells (after myeloablative conditioning as in an allogeneic bone marrow transplant). It is ex vivo gene therapy. A first evaluation was carried out in Milan on 9 children who had been undergoing gene therapy for a minimum of 18 months (Sessa et al., 2016). They are all alive and the activity of the ARSA enzyme was gradually restored in the circulating hematopoietic cells and in the cerebrospinal fluid. This study, although early, is very encouraging on the safety and efficacy of gene therapy for children treated at an asymptomatic stage (before the appearance of any abnormal neurological signs). Evaluation of the effectiveness of this approach on early juvenile symptomatic forms is still ongoing. However, other questions are emerging: the use of a lentiviral vector allows the insertion of the drug gene into the genome and therefore runs the risk of disrupting the proper functioning of the genome. The long-term risks, including cancerous mutagenesis that may result in the development of Leukemia of this form of ex vivo gene therapy are unknown.
  At the same time, a clinical study is being carried out at the Bicêtre hospital and consists of injecting the normal gene for the enzyme (inserted in a viral vector) directly into the brain of the patients (NCT01801709). It is in vivo gene therapy. With this method, a sample is not required and the drug gene enters the patient’s brain cells. If it proves effective, this technique would make it possible to circumvent the risks associated with ex vivo gene therapy. Indeed, the viral vector used allows the therapeutic gene to be inserted into the brain cells but not into the genome of the cells. This approach also has its own risks: the risk of haematoma at the intracerebral injection sites of the vector.

• Enzyme replacement : An alternative approach is to inject the enzyme protein directly into the cerebrospinal fluid from where it could integrate the brain cells and join the lysosomes of these cells to become active. In this therapeutic approach, it is not the gene but the enzyme that is injected, which allows a rapid but temporary action. Indeed, the protein is eliminated quickly and lost over time, hence the need for repeated injections. A clinical study is underway to evaluate the safety and efficacy of this procedure (NCT01510028). The injections are given every two weeks for 38 weeks using a catheter implanted in the lumbar region of the subdural space around the spinal cord where the cerebrospinal fluid is located. The first results are not expected before 2018.

Day-to-day management of the disease

Currently, the treatment of MLD is a supportive symptomatic treatment. It is always possible to offer a comfort solution and all those involved in the care, the medical profession and family members, must work together to identify obstacles and propose solutions.

Metachromatic Leukodystrophy remains an extremely serious disease, except in rare cases where an early marrow transplant can be performed in the late juvenile or adult forms. Gene therapy may offer a long-term alternative for patients with Metachromatic Leukodystrophy who cannot receive a bone marrow transplant. In this battle against time, a combination of effective short-term (enzyme replacement) and long-term (gene therapy) treatments could be considered to treat even the youngest children developing the disease. In all cases, however, these treatments only have a chance of being effective in the early stages of the disease or better when patients are still asymptomatic.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC)

Article reviewed by Prof. Raul Estevez

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a member of the family of leukodystrophies. It is an extremely rare genetic disease. Its frequency is less than 1 per 1,000,000 births, but the disease is more common in certain populations with high consanguinity. It is an orphan disease, which means that there is currently no treatment.

Megalencephalic leukoencephalopathy with subcortical cysts occurs mainly before the age of three and leads to severe neurological dysfunction affecting motor and cognitive functions, which may lead to death. The disease is characterised by infant macrocephaly[1], often associated with initially mild neurological signs (such as mild motor retardation), which worsen over time, leading to difficulty walking, falls, ataxia[2], spasticity[3], progressive seizures and cognitive decline.

[1] Macrocephaly: abnormal increase in the size of the head.
[2] Ataxia: fine coordination disorder affecting voluntary movements
[3] Spasticity: intermittent or sustained involuntary activation of muscles, manifested by muscle stiffness.

Genetic mutation

The genes whose mutation is responsible for Megalencephalic Leukoencephalopathy with subcortical cysts are the MLC1 gene which is located on chromosome 22 (at 22q13.33) and the MLC2 gene on chromosome 11 (at 11q24.2). Mutations in the MLC1 gene are recessive and are present in 75% of patients. Mutations in the MLC2 gene are recessive or dominant and represent 20% of cases. More than 20 different mutations have been identified in this second gene and doctors distinguish between two forms, 2A and 2B, in these patients. In the MLC2B form, signs and symptoms improve over time, but the reasons for this are not yet understood.

The MLC1 gene codes for a membrane protein of the same name, which resembles an ion channel[1]. The exact function of this protein has not yet been established. MLC2, also known as HEPACAM, codes for an adhesion molecule called GlialCAM. GlialCAM is a better known protein than MLC1. It regulates the localisation of the ClC-2 chloride channel with which it is associated, the localisation of connexin 43, and the maintenance at cell-cell junctions.

Together, the MLC1 and GlialCAM proteins form a complex the function of which is still unknown, but which is mainly produced in the white matter cells that surround the blood vessels, the astrocytes.

[1] Ion channel: a structure in the cell that allows ions to pass in and out. Calcium, potassium or sodium, for example, enter and leave the cells via this type of channel.

Symptoms of the disease

Megalencephalic leukoencephalopathy with subcortical cysts is characterised by progressive motor and cognitive deficits. It is an inherited childhood disease characterised by early onset macrocephaly.

Clinically, patients show deterioration of motor functions with ataxia and spasticity, seizures and mental decline. Unlike other leukodystrophies, megalencephalic leukoencephalopathy with subcortical cysts progresses very slowly, but minor head trauma and common infections can exacerbate the clinical condition of patients.

Many factors seem to be involved in the severity of the disease. Indeed, siblings with the same mutation may have different phenotypes, i.e., express the disease differently. Thus, patients with a clinical picture similar to others at the outset show improvement or even normalisation on subsequent MRIs. This course of the disease corresponds to the so-called MLC2B phenotype. These patients may also have different phenotypes, ranging from a benign transient form of megalencephalic leukoencephalopathy with subcortical cysts, to a form with macrocephaly and mental retardation, with or without autism.

Diagnosis of the disease

When suspected, magnetic resonance imaging (MRI) is used to diagnose the disease in children. Diffuse white matter abnormalities of the brain with mild oedema are visible, as well as subcortical cysts in the frontoparietal and anterior temporal regions.

On a brain MRI, brain white matter swelling with the presence of subcortical cysts and myelin vacuoles, mainly in the anterior temporal regions, are indicative of megalencephalic leukoencephalopathy with subcortical cysts. The diagnosis can often be confirmed by genetic testing of a blood sample. But these tests may also be inconclusive because other genes that have not been associated with the disease are probably involved.

Genetic counselling

In the majority of cases, this genetic disease is transmitted in an autosomal recessive manner, i.e., both parents are carriers of a mutation. The presence of two mutated copies of the gene is necessary for the disease to manifest itself as an MLC1 or MLC2A form. For MLC2B forms, unlike the other two forms, the transmission of the disease is dominant. A genetic counsellor can be consulted to determine the risk of transmission to children. For recessive forms, each pregnancy carries a 25% chance that the child will be affected, and a 75% chance that the child will not be affected.

The simplified mechanism leading to the disease

Megalencephalic leukoencephalopathy with subcortical cysts is an astrocyte disease.

The astrocyte: a key player in white matter

Astrocytes are the most numerous cells in the central nervous system. Thanks to their extensions, they form a complex network of cells. The astrocytes are connected to each other and to the cells of blood vessels (at the blood-brain barrier). Cells exchange ions, small molecules and metabolites via tight junctions. Tight junctions allow for coordinated action by all actors in the network, who then act in unison.

The complex formed by the MLC1 and GlialCAM proteins in astrocytes could modify the functional properties of certain channels responsible for the passage of ions and other molecules, notably across the blood-brain barrier, the border between the brain and the blood. The deregulation of the channels could explain the formation of the vesicles, visible as cysts on MRI, and classifies megalencephalic leukoencephalopathy with subcortical cysts among the so-called cavitary leukodystrophies.

The fact that patients with megalencephalic leukoencephalopathy with subcortical cysts can present with epilepsy is not typical for leukodystrophies, but it is typical for diseases caused by mutations in ion channel proteins. MLC1 could be an ion sensor or a tetraspanin involved in regulating the activity of different proteins through changes in signal transduction. It is envisaged by experts that intracellular calcium dynamics are defective in patients and that this contributes to the pathogenesis.

Day-to-day management of the disease

The treatment of megalencephalic leukoencephalopathy with subcortical cysts is currently supportive symptomatic treatment. Management is based on physiotherapy, psychomotor stimulation and treatment of seizures. It is always possible to offer a comfort solution and all those involved in care, the medical profession and relatives, must work together to identify obstacles and propose solutions.

Treatment research

To date, there is no definitive therapy for megalencephalic leukoencephalopathy with subcortical cysts. A lack of in-depth understanding of the molecular mechanisms of the disease is hampering therapeutic development for this leukodystrophy.

The two main proteins involved in the disease are known, but the function of the MLC1/GlialCAM complex and the associated pathological mechanisms are still unknown. It has been hypothesised that in megalencephalic leukoencephalopathy with subcortical cysts, the role of glial cells in brain ion homeostasis is altered under physiological and inflammatory conditions, explaining the progression of the disease during minor head trauma or common infections.

However, as patients with the MLC2B form have a reversible phenotype, experts envisage that the phenotype of MLC1 and MLC2A patients could also be alleviated by reintroducing the corrected gene, even at later stages. Pre-clinical work supported by ELA is underway to assess the feasibility of gene therapy. Progress is being made in the search for a treatment for megalencephalic leukoencephalopathy with subcortical cysts but there is still a long way to go.

Undefined leukodystrophies (LDI)

Canavan disease

Canavan’s disease or aspartoacylase deficiency is an autosomal recessive neurodegenerative disease that is often fatal in childhood.

Krabbe disease or globoid cell leukodystrophy

Krabbe disease is a rare hereditary disease that affects the white matter of the central (brain and spinal cord) and peripheral (nerves of the lower and upper limbs) nervous systems.

A very rare genetic disease (about 1 per 100,000 births)

Like all genetic diseases, you cannot “catch” Krabbe disease in the same way that you contract an infectious disease, such as the flu. A child is born with a genetic mutation, the equivalent of a computer bug in the genetic make-up of the cells. The cells then produce abnormal proteins, unable to catalyse the chemical reactions essential for the cell’s functioning.
Krabbe disease is caused by mutations in the GALC gene (14q31) encoding the lysosomal enzyme galactocerebrosidase which splits the galactose residue of galactocerebroside and galactosylsphingosine, two complex lipids found in myelin. Much more rarely, the disease is caused by a mutation in the prosaposin PSAP gene (10q21-q22) encoding saposin-A, a protein required for GALC activity. These mutations lead to an accumulation of galactosylsphingosine, leading to apoptosis of oligodendrocytes (death of cells that produce myelin), followed by demyelination of the central and peripheral nervous systems. This biological abnormality results in the presence of cells (macrophages) with a characteristic globoid appearance in the white matter (myelin-rich region of the brain).
The clinical consequences are variable. They are very severe in children but are milder when the disease occurs later on.
The disease is transmitted in an autosomal recessive way, i.e. the gene involved is carried on a non-sex chromosome (neither X nor Y) and both copies of the gene must be mutated (one from the father and one from the mother) for the trait to express itself.
The European Union defines a rare disease as a disease whose prevalence (i.e. the number of living patients with the disease) is less than 1/2000. Krabbe disease, which has a worldwide impact at birth of between 1/100,000 and 1/250,000 births, is fortunately extremely rare. Prevalence is much lower, with the majority of patients dying before they reach 1 year old.

Symptoms of the disease

Described for the first time in 1916, Krabbe disease is expressed in several forms: an infantile form, a late onset form (late infantile/juvenile) and an adult form.

The infantile form, by far the most common, appears in infants between the age of two and six months old and develops in three characteristic stages. Early symptoms include severe irritability, muscle spasms, inability to hold the head upright (axial hypotonia), loss of acquired intellectual functions, growth retardation, feeding difficulties and febrile episodes. Then hypertonic episodes and seizures appear. The last stage is calmer, the child becomes hypotonic and swallowing problems appear, which can lead to respiratory infections. The outcome is often fatal before the age of 2 to 3 years old.

Much more rarely, the disease starts later (after the age of 2 years, or even in adulthood). The progression of the disease is slower with motor disorders and intellectual regression, but it remains highly variable, even within the same family. The first signs that occur in adults are muscular weakness, walking disorders corresponding to spastic paraparesis, ataxia (balance disorders), peripheral neuropathy, associated with sensory disorders such as burns, often an impairment of visual acuity. Cognitive functions remain preserved for a long time in adult forms.

Diagnosis of the disease

The diagnosis evoked before the clinical picture and white matter abnormalities on MRI is made on the basis of enzymatic tests on leukocytes or in cultured fibroblasts, revealing a deficiency of GALC protein activity in almost all cases. Detection of the mutation confirms the diagnosis.

Prenatal diagnosis, enzyme screening or mutation analysis, is possible for families at risk. This screening of newborns at birth is only routinely performed in the State of New York. Genetic counselling should be offered to couples at risk (both individuals are carriers of the mutation), informing them of the 25% risk of giving birth to a sick child. Prenatal genetic screening at 11 weeks of pregnancy is then possible.

The simplified mechanism leading to the disease

The brain controls many body functions such as posture, movement, senses, speech, thinking and memory. The flow of this information is essential. In the brain, oligodendrocytes are the specialised cells separate from neurons that make the myelin needed for the proper flow of information between neurons along the “links” that connect them, called axons.

Krabbe disease is a disorder of the lysosome functions affecting the white matter of the central and peripheral nervous systems. In cells, lysosomes are responsible for “recycling” cellular waste. But in patients with Krabbe disease, the lysosomes do not function properly and waste accumulates. The accumulation of toxic products in the oligodendrocytes (notably a compound called psychosine) leads to their disappearance (death by apoptosis), leading to the demyelination of the central and peripheral nervous systems, which prevents the proper circulation of nerve signals.

The treatment

Because of the speed and severity of the disease in its infantile form, the brain damage is already too great at the time of diagnosis for treatment to be effective before irreversible brain damage leading to a bedridden state occurs. Only rare patients with either a pre-symptomatic infantile form (most often detected among siblings) or a later onset form are sometimes receptive to therapy. However, this treatment is currently limited to bone marrow transplantation, also known as hematopoietic stem cell transplantation or cord blood stem cell transplantation.  Bone marrow transplantation requires finding an immunologically compatible donor and either slows the progression of the disease or stops it from progressing, but always within 6 to 12 months after the transplant is done. This treatment is not without risks: failure to take the graft, severe reaction of the graft against the host (the donor cells “attack” the recipient’s cells), severe infections, particularly viral infections due to the temporary drop in immune defences in connection with the preparation for the graft, any complication that may lead to death.

Other treatment options are currently being investigated, but only in animal forms of the disease, such as gene therapy, which involves transferring a normal version of the gene coding for the GALC enzyme to the animal cells, or enzyme replacement, which involves injecting the normal enzyme into the cells. However, this last method comes up against a physical limit: the brain is surrounded by a barrier that not only protects it, but also limits its access.

Finally, the study of chaperone proteins that allow the modification of conformational abnormalities of a mutated protein could be an interesting lead, if it could increase the enzymatic activity of the mutated GALC enzyme.

Day-to-day management of the disease

It is not at all specific to Krabbe disease: treatment of bouts of stiffness and the pain that accompanies them, motor rehabilitation, prevention of swallowing disorders and lung infections, sufficient calorie intake which may require tube feeding or gastrostomy (a tube placed directly into the stomach), prevention and treatment of scoliosis if it occurs, psychological care for siblings and parents.

It is particularly difficult in the infantile forms of Krabbe disease where bouts of hypertonia causing pain for the young patient and episodes of unexplained fever occur very frequently for a few months. In order to relieve children’s pain, which remains a priority, we are often led to propose an escalation of analgesic treatment (painkillers), which also has its downside: children are more sleepier and react much less to those around them. These bouts of pain and fever disappear spontaneously. The children then appear much better and it is not uncommon to see the reappearance of real contact and even a small motor improvement. At this stage, nutritional, motor (physiotherapy, prevention of the consequences of swallowing disorders) and relational care with those around them is fundamental to optimizing the children’s comfort.

Thus, Krabbe disease is a very rare leukodystrophy, but particularly severe in its infantile form for which we are relatively deprived from a therapeutic point of view. Treatment leads are still in the pre-clinical stage.

Refsum disease

Refsum’s disease is a member of the leukodystrophies group and is characterised biochemically by an accumulation of phytanic acid. The prevalence of the disease is 1 case per 1,000,000; both sexes are affected.