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