Alexander disease

The Alexander 's disease ( Alexander) is a rare disease from the group of leukodystrophies. It is a genetic disorder in which a progressive degeneration of the white matter of the brain and spinal cord occurs. Clinically, it makes the Alexander disease often noticeable already in infancy with a delay of psychomotor development and an increase in skull size. Cause of the disease occurring in structural changes in the supporting cells of the brain ( astrocytes) and demyelination are usually spontaneously occurring dominant mutations of the GFAP gene that encodes a structural protein astrozytäres, glial fibrillary acidic protein. A cure of the disease is possible. Diseased young children usually survive six years of age.

Historical Aspects

Was named the disease after the New Zealand pathologist William Alexander Stewart, who had worked as a young doctor in London at the neuropathologist Dorothy Stuart Russell (1895-1983) the section case of a 15- month-old child and the disease first described in 1949.

Epidemiology

The majority of cases occur sporadically, without family history. In the majority of patients, the Alexander disease begins in early childhood, with girls seem to suffer slightly more often than boys. The disease is very rare and has so far been confirmed by molecular genetic in about 150 patients.

Clinical picture

Depending on the age of onset, different forms of Alexander disease delimit.

Occurring in children infantile form is most commonly used. The disease manifests itself at the age of about six months, but can also be used between the first and 24th month of life. Non-specific symptom in affected children is a distinct disorder of motor and mental development. An enlargement of the skull ( macrocephaly ) and brain ( Makroenzephalie ), feeding problems, dysphagia, ataxia, spasticity, and seizures can draw near.

The neonatal form ( in neonates ) shows the most rapidly progressive course with the worst prognosis.

The juvenile form ( in adolescents ) runs a mild, patients do not always have macrocephaly and neurological deficits occur later.

In the adult form, which occurs in adults, the extent of degenerative changes in the white matter is lower and there is often a bulbar symptoms with swallowing and speech disorders in the foreground, because the brainstem is particularly affected. Myoclonus of the soft palate may occur.

Diagnostics

The disease can not be diagnosed clinically, that is, not alone because of a physical examination. Rather technical examination procedures are necessary. Until a few years a bioptic or autoptischer confirmation of the characteristic for Alexander disease pathological changes in brain tissue to confirm the diagnosis was necessary. Since the characterization of the responsible gene DNA analyzes are carried out in suspected cases increasing. Similarly, a magnetic resonance imaging examination of the brain allow differentiation from other diseases. When the child's progressive forms following neuroradiological criteria have been proposed for the diagnosis:

• Extensive frontal matter changes.
• A periventricular hem (signal intensively in the T1-weighted image ).
• A periventricular hem ( in the T2-weighted signal intensity ).
• Changes in basal ganglia, thalamus and brainstem.
• Contrast enhancement in specific brain regions.

In the presence of four of the five criteria, the diagnosis of Alexander disease is considered probable. In the adult form, atrophy and signal changes in the area of the brain stem and spinal cord can be detected.

Pathology

The Alexander 's disease is primarily a disease of astrocytes, support cells of the brain ( glia ), the intermediate filament GFAP is incorrectly formed. Together bearings with other proteins to form astrocytic inclusions known as Rosenthal fibers. Histologically Rosenthal fibers are detectable in the disease throughout the central nervous system (brain and spinal cord), can be found, however, preferred periventricular and in the vicinity of blood vessels. Electron microscopy shows a close connection between the Rosenthal fibers with intermediate filaments.

In addition, can be found in children deficient myelination and demyelination in elderly patients. Both sensory and motor nerve fibers are affected. The Myelinisierungsstörung is especially common in young children sometimes accompanied by a macrocephaly and hydrocephalus.

The distribution pattern of demyelinated areas does not coincide with that of the Rosenthal fibers; Myelinisierungsstörung fiber formation and thus appear to be independent manifestations of the disease. It is assumed that changes in astrocytes secondarily lead to a Myelinisierungsstörung.

Genetics

The autosomal dominant Alexander disease is usually caused by spontaneously occurring mutations in the GFAP gene, which encodes a astrozytäres intermediate filament, glial fibrillary acidic protein. In about 94 % of the cases can prove a GFAP mutation, wherein a plurality of different mutations have been described. These usually involve changes in amino acid residues that are conserved evolutionarily highly and are responsible for the dimerization of the protein and formation of microfilaments. Apparently there is a relationship between the type of genetic modification and the severity of the disease, the phenotype: patients with the codon 79 point mutation in question ( R79H ) are generally less severely ill than patients in whom the codon affected 239.

There are individual families have been described in which several children with healthy parents diseased. In these rare cases probably is either an autosomal recessive mode of inheritance before or Keimbahnmosaizismus with disclosure of the dominant mutation in germ line cells of healthy parents. In fact, the GFAP mutation seems mainly to affect the derived allele from the father, suggesting an origin of the mutation during spermatogenesis. Parents of affected children is therefore at persists, fertility, genetic counseling has been recommended.

Prognosis and therapy

Despite the elucidation of the underlying mutation is no cure possible and the treatment of Alexander disease is so far, therefore, entirely symptomatically and supportively. Children who develop the Alexander disease as infants, not usually survive six years of age.

Veterinary Medicine

Fibrinoid leukodystrophy, which clinically resembles human Alexander disease is described as a single case at two Labrador retrievers and one each Scottish Terrier, a Toy Poodle and Bernese mountain dog. The cases occurred between the ages of 13 weeks and nine months and resulted in progressively worse expectant ataxia. The prognosis is poor to hopeless.