Types of leukodystrophy



Peroxysomal



Leukodystrophies belonging to the group of peroxisomal diseases are genetic diseases characterized by the impairment of peroxisomal enzymes.

A fatty acids." >peroxisome is a specialized structure within the cell without genome playing a role in the cell detoxification more particularly in the breakdown of very-long-chain fatty acids.

Defective peroxisomal function results in the accumulation of some molecules in the cell that may be the cause of the disease.

This group of disorders includes:

Lysosomal



Leukodystrophies are part of a larger group of lysosomal disorders. These are genetic illnesses characterized by a malfunction of lysosome enzymes.

Lysosomes are a specialised structure (organelle) within the cell containing many enzymes whose function includes the chemical breakdown and recycling of nutrients.

When the lysosome is not functioning correctly, certain nutrient molecules accumulate and this may be the root cause of the disease.

Two leukodystrophies belong to this group of diseases:

Metachromatic leukodystrophy accounts for about 20% of Leukodystrophies registered by ELA.

Metachromatic leukodystrophy (MLD) is a neurodegenerative disease caused by deficiency of a lysosomal enzyme called arylsulfatase A. Onset can occur during childhood, adolescence or in adulthood and is characterized by rapid demyelination of the central and peripheral nervous system associated with sulfatide accumulation in the brain and kidneys.

Metachromatic leukodystrophy is a hereditary disease transmitted as an autosomal-recessive. Which means that for a couple where both individuals are carriers for the defective gene, the risk factor for having a child with the disease (boy or girl) is 25% for each pregnancy. It is estimated that this disease affects 1/45 000 children at birth.

 

The different forms of MLD

The three forms of this disease can be distinguished according to the age of onset of neurological symptoms: late-infantile (60% of cases), juvenile (20-30% of cases) and adult (10-20% of cases).

1. Late-infantile form

In the late infantile form, onset of symptoms can occur between 1½ and 2½ in the form of motor function problems and parents will often seek medical advice about walking difficulties. The disease can progress very rapidly (loss of ability to walk, to sit up, and of cognitive function) over a matter of weeks or months, leading to a bed-ridden state and blindness in a few months and generally to death five years from the onset of symptoms.

2. Juvenile form

The juvenile form arises between the ages of 4 and 12. Usually the first symptoms are behavioral difficulties and a decline in intellectual performance followed later by motor function difficulties, epileptic fits, ataxia and speaking problems. This form progresses less quickly than the infantile form, but is always fatal, most patient dying before they are twenty years old.

3. Adult form

Onset of the adult form can begin from the age of 12 but is often not diagnosed before adulthood. Psychiatric disorders and progressive mental deterioration (personality changes, decline in performance at work, progressing to dementia) or motor function difficulties are all characteristic of this disease. The disease is fatal, and death usually occurs within three years of the onset of symptoms.

 

Metachromatic leukodystrophy

Metachromatic leukodystrophy accounts for about 20% of Leukodystrophies registered by ELA.

Metachromatic leukodystrophy (MLD) is a neurodegenerative disease caused by deficiency of a lysosomal enzyme called arylsulfatase A. Onset can occur during childhood, adolescence or in adulthood and is characterized by rapid demyelination of the central and peripheral nervous system associated with sulfatide accumulation in the brain and kidneys.

Metachromatic leukodystrophy is a hereditary disease transmitted as an autosomal-recessive. Which means that for a couple where both individuals are carriers for the defective gene, the risk factor for having a child with the disease (boy or girl) is 25% for each pregnancy. It is estimated that this disease affects 1/45 000 children at birth.

 

Genetics, Pathophysiology, Diagnosis and Screening for MLD

Genetics and Pathophysiology

Metachromatic leukodystrophy is caused by a mutation of the ARSA gene, mapped to chromosome 22 (22q) which codes for arylsulfatase A, a lysosomal enzyme responsible for the breakdown of sulfatides, a major lipid component of myelin sheaths. To date, more than 115 mutations have been identified in the ARSA gene.

Loss of normal ARSA activity leads to the accumulation of sulfatides in the central and peripheral nervous system resulting in demyelination. The exact mechanism underlying demyelination remains to be clarified. The infantile form is characterized by a severe deficiency of arylsulfatase A activity, or even it's complete absence. In the juvenile form, enzymatic deficiency and excessive sulfatide are still present though less extreme, whereas in the adult form there remains some residual enzyme activity.

In some rare cases, mutations have been observed in the SAP-B gene, mapped to chromosome 10 (10q21-22). SAP-B activates the enzyme for the degradation of sulfatides. Mutations of SAP-B result in sulfatase activator deficiency induced metachromatic leukodystrophy, where the clinical picture is that of classic infantile or juvenile metachromatic leukodystrophy. In this instance, there is no arylsulfatase A deficiency, yet there is excessive presence of sulfatide.

Diagnosis and Screening

Diagnosis is based on evidence of ARSA enzyme deficiency in ARSA, established by way of a simple blood test. This diagnosis is then confirmed through nerve biopsy and by the presence of excessive sulfatides in the urine. An MRI and an electromyogram may also be proposed. In families that are at risk, prenatal diagnosis is an option at the 10th week of pregnancy.

Treatment options for MLD

Allogeneic bone marrow transplant

This is the only treatment available for those affected by the juvenile or adult form of MLD which, if performed right at the onset of symptoms (and before the appearance of signs of neurological degradation), can stabilize or reverse demyelinating cerebral lesions. Bone marrow transplant is only possible if a compatible donor or compatible umbilical cord blood is found. This procedure carries a high mortality rate: 15 to 20%.

Transplant has no affect on any damage to the peripheral nervous system or upon infantile forms of the disease, once the symptoms have already developed.

Symptom-based care

Here treatment aims to improve the quality of life of the children and adults affected: pain, rigidity, epilepsy and spasticity management, treatment of orthopedic complications and the use of a gastric feeding tube to ensure adequate supply of nourishment.

Psychological care

Psychological care should not be only for the patient, but should also be available for siblings, parents, and partners and often for several members of the same family.

Krabbe's disease, also called globoid cell leukodystrophy, is an autosomal recessive condition resulting from galactosylceramidase (or galactocerebrosidase) deficiency, a lysosomal enzyme that catabolizes a major lipid component of myelin.

Incidence in France is an estimated 1:150,000 births.

The disease leads to demyelination of the central and peripheral nervous system.

Onset generally occurs during the first year and the condition is rapidly progressive, but juvenile, adolescent or adult onset forms have also been reported, with a more variable rate of progression.

The classic infantile form accounts for 85 to 90% of cases. Initial symptoms include increasing irritability, hypertonia, hyperesthesia, and signs of peripheral neuropathy. Later on, hypertonic episodes with opisthotonos occur frequently, and convulsions may appear. As the disease progresses, blindness and deafness occur, followed by a vegetative state, and finally by hypotonia.

In the forms with later onset the first signs are often gait disturbancies (spastic paraparesis or ataxia), hemiplegia, visual loss, with or without peripheral neuropathy. Mental deterioration is variable (usually absent in adult forms).

The gene coding for galactosylceramidase is located on 14q31 and has been identified. Two mutations are more frequently observed (65% of alleles in France).

Diagnosis is established from enzyme assay (galactosylceramidase deficiency).

There are several natural animal models (mouse, dog, monkey).

Pathognomonic globoid cells are derived from macrophages and induced by non-hydrolysed galactosylceramides. The early destruction of oligodendrocytes is considered to be due to the accumulation of a cytotoxic metabolite (galactosylsphingosine or 'psychosine').

 

Source: Orphanet

Vacuolating



Vacuolating leukodystrophies represent an heterogeneous group of leukodystrophies characterized by diffuse white matter injuries in the brain associated with a enlargment recognizable by MRI.
They comprise :

Alexander's disease, a neurodegenerative disorder, was identified in 1949 on the basis of neurohistological criteria, i.e., the presence of dystrophic astrocytes containing intermediate filament aggregates (Rosenthal fibers) associated with myelin abnormalities.

 

 

Since then, different clinical forms have been individualized.

The infantile form (birth to 2 years), the most common, is characterized by its early onset and severe evolution. Its symptomatology associates progressive megalencephaly (sometimes hydrocephaly), retarded psychomotor development or mental deterioration, pyramidal signs, ataxia and convulsive seizures. Computed tomography scan and magnetic resonance imaging suggest the diagnosis by revealing white matter anomalies, predominantly in the frontal lobes.

Juvenile forms start in school-aged children and associate spastic paraplegia and progressive bulbar signs.

Adult forms are heterogeneous and difficult to diagnose.

This rare disease, often considered to be a leukodystrophy, is usually sporadic; only a few familial cases have been reported.

The discovery of Rosenthal fibers in transgenic mice overexpressing human glial fibrillary acidic protein (GFAP), which is the main intermediate filament of astrocyte, led to the search for mutations in its encoding gene. More than 20 GFAP mutations have been reported; they are de novo dominant mutations.

However, a prenatal diagnosis seems desirable in light of the risk of germinal/germ-cell mosaicism.

At present, treatment is purely symptomatic.

 

Source: Orphanet

A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria.

 

Classically, this disease is characterized by

(1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution,

(2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation),

(3) a recessive autosomal mode of inheritance,

(4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes ``foamy'' aspect.

A total of 148 cases have been reported so far.

This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stress.

Clinical symptoms are variable, from fatal infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behavioural dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies.

Prevalence of this disease remains unknown.

Diagnosis relies on the detection of eIF2B mutations, predominantly affecting the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value.

The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress.

No specific treatment exists besides the ``prevention'' of cellular stress. Corticosteroids sometimes proved to be useful in acute phases.

Prognosis seems to be correlated with the age of onset, the earliest forms being more severe.

 

Source: Orphanet

Canavan's disease or spongy degeneration of the central nervous system or aspartoacylase deficiency is an autosomal recessive neurological degeneration that usually causes early death.

 

 

Patients appear to be normal at birth and during their first month. Axial hypotonia and macrocephaly appear between the 2nd and 4th months in infantile forms, later on in the juvenile form.

Neurological degeneration continues with spasticity, opisthotonos, loss of contact with the outer world, sleep disorders, blindness, and convulsions.

Imaging of the brain evidences leukodystrophy. Increased urinary output of N-acetylaspartate (x50) is diagnostic. Histopathology shows spongy degeneration of the brain.

The disease is due to aspartoacylase deficiency. The enzyme is localised in the oligodendrocytes- the myelin synthesizing cells- its gene is on the short arm of chromosome 17. Aspartoacylase converts N-acetylaspartate to aspartate and acetic acid. It can be found in white substance and can be dosed in cultured fibroblasts.

The enzyme is coded by 6 exons and the gene spans 29kb of the genome. The protein is a 55kDa monomere with 313 aminoacids. Two mutations have been identified in Ashkenasi Jews (A854G and C692A) and account for 97% of cases in this particular population. Other mutations that are not related to a foundation effect have been found among other populations.

Prenatal diagnosis is easily made by measuring N-acetylaspartate in amniotic fluid or, when the mutation has been pinpointed, by identifying it in the chorionic villi.

Physiopathology of the disease is still unclear: N-acetylaspartate that accumulates in the white substance because of enzyme deficiency is specifically synthesized in the neurons of grey matter, where aspartoacylase has very little activity. The role of N-acetylaspartate in the brain is related either as a molecular water pump in myelinated neurons or as acetyl groups donor for synthesis of myelin lipids.

 

Source: Orphanet

Vacuolating megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare form of leukodystrophy.

The phenotype consists of early onset ataxia followed by progressive signs of pyramidal tract involvement and mental deterioration.

Prevalence is unknown, but the disease occurs more frequently in populations with high degree of consanguinity.

Megalencephaly, appearing in the first year of life, is a characteristic feature of this syndrome.

Magnetic resonance imaging (MRI) of MLC patients shows early and severe cerebral white matter involvement, despite relatively mild neurological findings during the early stages of the disease. In addition to a widespread T2 hyperintensity of the white matter, MRI shows T1 weighted and fluid attenuated inversion recovery (FLAIR) hypointense subcortical cysts in the temporal lobes and in the fronto-parietal subcortical areas.

Overall, these severe neuroradiological abnormalities are concomitant with the clinical features, which are milder than those of other childhood leukodystrophie's forms. In the later stages of this disorder, cognitive impairment appears slowly, contributing significantly to the overall disability. Some patients show early onset learning disability starting during the first years of scholarship.

MLC is an autosomal recessive inherited disease. Mutations in the MLC1 gene (22q13.33), coding for a protein whose function is unknown, were identified in MLC families of different ethnic background. Some patients do not harbor mutations in MLC1 and there is evidence of genetic heterogeneity in some sibships.

No specific therapy is available for MLC. Management is based on physiotherapy procedures, psychomotor stimulation and treatment of seizures.

 

Source: Orphanet

Hypomyelinating



Hypomyelinating leukodystrophies are diseases of the white matter characterized by a permanent myelin deficit in the brain.
In this category are found :

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive inherited leukodystrophy.

An array of clinical, electrophysiologic, and neuroradiological signs lead to the diagnosis.

Prevalence is estimated at 1/400 000.

The disease occurs as an early motor development impairment marked by hypotonia associated with nystagmus, ataxochoreic movements of the axis and limbs, especially during the first 2 years of life. Symptoms often progress slowly until adolescence.

The diagnosis of primitive disorder of CNS myelin development is made when 2 criteria are met:

a) major disturbances in the intracerebral conduction of auditory, somesthesic and visual evoked potentials, contrasting with normal peripheral conduction, and

b) a diffuse hypersignal of the white mater on the MRI T2-weighted image contrasting with a normal image on the T1-weighted image.

Both these signs are systematically found early on and throughout the disease. Their presence is required to ascertain the diagnosis, and they should be sought for repeatedly, every 1 or 2 years.

The severity of the disease is not correlated with the MRI aspect or electrophysiological results, but with the level of motor ability acquired between the ages of 5 and 10.

In severe forms, no motor skills are acquired and patients usually die of decubitus complications during adolescence. In the most moderate forms, patients learn to walk with assistance and their speech is understandable. Their life span is quite long, even though the disease progresses slowly after adolescence.

The expression of the disease is usually homogenous among members of a same family.

Autosomal recessive and some dominant forms with late onset have been described as having the same neuropathological characteristics as Pelizaeus-Merzbacher disease (e.g., sudanophilic leukodystrophy with persisting islets of perivascular myeline, but no destruction of axons or inflammation). Their nosology has not yet been clearly defined, nor has their relationship with the X-linked forms as described by Pelizaeus and Merzbacher.

A phase I clinical trial will soon begin at the University of California, San Francisco (UCSF), United States, in collaboration with the biotechnology company StemCells, Inc. to test the safety and preliminary efficacy of using neural stem cells to treat children with Pelizaeus-Merzbacher disease (PMD).

Source: Orphanet

Atypical



This group brings together atypical leukodystrophies that could not be classified in the different existing categories such as:

OVERVIEW

In 1984, Jean Aicardi and Françoise Goutières, two French paediatric neurologists, described a childhood onset genetic brain disorder mimicking the features of viral infections affecting children in the womb. Clinical indicators of this disease now known as Aicardi-Goutieres syndrome (AGS) include:

• The accumulation of calcium (calcification) in the brain, best seen on CT scan

• Changes in the white nerve tissue of the brain and spinal cord brain best seen on MRI scan

• Raised levels of white cells, interferon-alpha and pterins (proteins produced by the body to fight viral infection) in the cerebrospinal fluid (tested by lumbar puncture)

• Distinctive ‘chilblain-like’ lesions on the hands and feet which are usually worse in the cold
GENETICS

Six different genes (see table) have so far been described that, when damaged by a genetic change/mutation, can cause AGS. As far as we know, only one gene is involved in any one family.

Gene        Chromosome Position        Other names             Percentage of families with mutations

AGS1                  3                                          TREX1                                                22%

AGS2                13                                     RNASEH2B                                           38%

AGS3                11                                     RNASEH2C                                           14%

AGS4                19                                     RNASEH2A                                            6%

AGS5                20                                   SAMHD1/DCIP                                     12,5%

AGS6                1                                            ADAR1                                               7,5%

CLINICAL PRESENTATION

Broadly speaking there are two types of presentation in AGS. Some babies, especially those with AGS1 mutations, experience problems at or very soon after birth. Features include feeding difficulties, abnormal neurological signs, low platelets (blood cells involved in clotting) and liver abnormalities. In contrast, other children, often those with AGS2 mutations, develop normally for the first few weeks or months of life. They then experience the sudden onset of a period of intense irritability, cry a lot for hours at a time, sleep poorly and develop fevers without infection. During this period there is a loss of skills. After a few months the disease process seems to ‘stop’. Many individuals with AGS are still stable in their late teens and early twenties. Typical neurological features of AGS include learning problems, stiffness of the limbs with poor trunk and head control and impairment of muscle tone (dystonia) of the limbs. Although the neurological problems seen in AGS are often severe, a small number of children, usually those with AGS2 mutations, show good communication skills and other neurological function.

 

INHERITANCE PATTERNS

Aicardi-Goutières syndrome is usually inherited as an autosomal recessive genetic disorder. This means that for a couple with one affected child there is a 1 in 4 risk of having a further affected child in any future pregnancy. Three cases are known to us where AGS has been inherited as a ‘new dominant’. In these rare cases the risk of recurrence is very low.
PRENATAL DIAGNOSIS

The availability of genetic testing allows us to confirm the diagnosis of AGS in most, but not all, families. This is important in view of the associated 1 in 4 risk of recurrence. For some couples, if both mutations can be identified in their child it is now possible to offer testing during a subsequent pregnancy or even using a new technique called preimplantation genetic diagnosis (PGD which is becoming more readily available.

 

 

HOW DO CHANGES IN THE TREX1, RNASEH2A/B/C AND SAMHD1 GENES CAUSE AGS?

These genes make chemicals called nucleases which break down DNA and RNA. During the normal life-cycle of our cells, nucleases clean up naturally produced waste DNA and RNA. A failure of this process can induce the body to mount an immune reaction against its own DNA and RNA. A similar immune reaction is seen in response to viral DNA and RNA following an infection. This would explain why the clinical features of AGS and viral infection overlap and why we see high levels of the anti-viral agent interferon-alpha in children with AGS. Very importantly, interferon-alpha and the removal of self nucleic acids also seem to be crucial in preventing the body developing an immune-response against its own tissues in so-called autoimmune diseases such as systemic lupus erythematosus (SLE/lupus).

 

TREATMENTS

At the moment, once the child has incurred significant brain damage there is no treatment that has been shown to reverse this damage. However, if treatments could be instigated at an early stage of the disease, therapies might prove extremely useful. These might be medicines relevant to other leukodystrophies and inflamatory disorders, or compounds specific to the disease process involved in AGS.

 

RESEARCH

We have been working on AGS for the last 10 years and our lab is currently dedicated to the development of treatments for the disease. Of great importance, understanding of the genetic basis and cellular pathology of AGS is providing remarkable new insights into key pathways of the innate immune response. Consequently, many laboratories interested in autoimmune diseases are taking note of what AGS can teach them about the diseases they study (such as lupus). The involvement of these groups in such ‘allied research’ means that major advances in our understanding of AGS can realistically be expected in the next few years. We are confident that such understanding will allow us to provide effective treatments for this devastating illness.

 

Pr. Yanick Crow, University of Manchester, United Kingdom.

Undetermined



Undetermined leukodystrophies constitute a group of diseases for which the responsible gene has not yet been identified or is in the process of being identified. Together, these account for 30% of leukodystrophies.

Undetermined leukodystrophies are extremely rare diseases that are difficult to identify and diagnose.

These include:

  • Pigmented orthochromatic leukodystrophy
  • Leukodystrophy with progressive ataxia, deafness and cardiomyopathy
  • Leukodystrophy with oligodontia and hypomyelination

In the majority of cases, the disease is so rare that it is difficult to even give it a name.

Magnetic resonance imaging (MRI) makes it possible to explore the brain and shows up any white matter anomalies. The diagnosis of undetermined leukodystrophy is only made when possible diagnosis of other similar disease has been eliminated.

It is important not to confuse undetermined leukodystrophies with other diseases such as:

- white-matter anomalies of non-genetic origin ; which may have circulatory , infectious, toxic or inflammatory causes,

- white-matter signal modifications observed in many genetic diseases, especially metabolic disorders, but without primitive myelin deficiency.

While the clinical context, the MRI and certain specific tests will generally enable us to eliminate these causes, it is important to be aware that doubts may remain. Indeed, leukodystrophies caused by hereditary problems concerning the myelin formation of the central nervous system often appear, in childhood, as non-progressive illness, although sometimes cerebral lesions acquired during the prenatal, or perinatal period can appear to be evolve because of changes in how they manifest as the brain matures.

It is also important not to confuse them with the identified leukodystrophies. Some leukodystrophies have biological markers that make it possible to identify them by a blood or urine test, or even a cerebrospinal fluid test. These possibilities must be systematically explored before arriving at a diagnosis of undetrmined leukodystrophy, even though their manifestations vary hugely, especially according to the patient's age.

Other leukodystrophies can be recognized by a set of indicators gleaned from the clinical presentation, the mode of genetic transmission and the results of medical examinations, particularly radiological (scanner and MRI) and electrophysiological examinations. A biopsy of nerve tissue may also prove revelatory.

Rigorous assessment, careful observation of the evolution of the disease and the repetition of key medical examinations must all be accomplished before a diagnosis of leukodystrophy of unknown etiology can be made.

The vast heterogeneity of undetermined leukodystrophies makes them particularly difficult to study.

To make progress, we need to:

  • identify homogenous subgroups of patients so as to be able to apply molecular genetic methods. Research needs to be undertaken on a European or even international scale and the establishment of a network organization would help speed up the identification of homogenous subgroups of patients and optimize molecular research that can lead to identification of the responsible gene;
  • use new investigative techniques: magnetic resonance spectroscopy can help us find new biological markers; new techniques for cellular analysis (immunofluorescence, in situ hybridization) will help inform gene therapy and genetic counseling;
  • identify the causal genes, and with this in view, we need to conserve and immortalize all blood samples, taken from patients and their families, in liquid nitrogen, so as to have a store of quantities of DNA for when that becomes useful.

In conclusion, the role played by the families of patients affected by undetermined leukodystrophy is of utmost importance: the more information is shared, and the more families group together and make contact with the research laboratories, the better we will understand these very rare diseases.