Alexander disease


Alexander disease

Description, Causes and Risk Factors:

Alexander disease a nerudegenerative disorder. It was identified in 1949 on the basis of neurohistological criteria that is the presence of dystrophic astrocytes containing intermediate filament aggregates associated with myelin abnormalities. Since then, different clinical forms have been individualized. The infantile form (birth to 2 yeras), the most common, is charaterized by its early onset and severe evolution. Its symptomatology associates progressive megalencephaly, retarded psychomotor development or mental deterioration, pyramidal signs, ataxia (inability to coordinate voluntary muscle movements; unsteady movements and staggering gait), and convlusive seizures. The disease is very rare.

Different clinical forms have been identified.

alexander disease

The infantile forms have an early onset, around six months, and their prognosis is poor, with most patients dying during childhood. The symtpomatology associates abnormal psychomotor development, progressive megalancephaly, and/or hydrocephaly, a pyramidal syndrome, ataxia, and epileptic seizures. Episodes of deteroiration with vomiting can occur during the course of the disease, leading to a search for intracranial hypertension. Elevated protein concentration are sometimes found in the cerebrospinal fluid. Computed tomography and magnetic resonance imaging shows anomalies of hemispheric white matter, sometimes caviated, which predominate in the frontal lobe. They are often associated with lesions in the pontine nuceli, thalamus, and cerebellum. All these anomalies are enhanced with contrast medium.

Forms:

The juvenile forms start in school age children, on the average around 9.5 years, and the duration of their evolution varies (from 15 months to more than 12 yeras). The symptomatology differs from that of the infantile form and consists mainly of spastic paraplegia and progressive bulbar signs, cognitive functions are usually spared.

The adult forms are heterogeneous. Most of the patients have relapsing neurological symptoms suggesitive of multiple sclerosis. For the majority of patients, the dignosis is evoked only once the neurohistological examination has identified the presence of RF. In some adults, without neurological symptoms, who died of complex systemic disease, the presence of RF raised the possibility of Alexanders disease but, for most authors, these patients were representive of a distinct entity.

The disease is usually sporadic but several very rare familial cases have been described with the involvement of several members of the same kindred. Those cases were infantile forms and dominant adult forms. All studies patients with mutated GFAP have been associated with sporadic events, but the existence of gonodal mosaicism cannot be excluded.

Owing to the discovery of inclusion bodies indistinguishable from Rosenthal fibers in fatal GFAP transgenic mice overexpressing human GFAP in astrocytes, de novo heterozygous mutations in the gene encoding GFAP, the main component of Rosenthal fibers, have been identified in patients with the infantile form of ALX. GFAP gene mutations have also been identified in the juvenile and adult forms. These three clinically diverse forms are now widely accepted to be part of the same spectrum.

Symptoms:

The clinical features of typical infantile-onset ALX,with onset before the age of two, include megalencephaly, seizures, spastic paresis and psychomotor deterioration with leukoencephalopathy characterized bywhite matter abnormalities predominating in the frontallobes. As cases accumulate, however, atypical patientshave also been described. Adult-onset ALX, with onsetover the age of 12, is characterized by more slowly progressive bulbar or pseudobulbar palsy, spastic paresis,ataxia, palatal myoclonus and essentially normal psychicand intellectual functions. Juvenile-onset ALX, withonset between age 2 and 12, bridges the gap betweeninfantile and adult forms of the disease. However, it isnot yet clear whether these three categories are thesame disease. The clinical presentations are diverse; theonly common feature is the presence of pathologicallyproven.

Diagnosis:

The diagnosis of infantile and juvenile form is suggested by a group of clinical and radiological signs, and confirmed by histological examination of a cerebral or postmortem. The diagnosis of adult form is relies primarily on histology because the neurological signs are poorly specific or even absent.

The presence of mutation in the gene coding for glial fibrillary acidic protein (GFAP) now provides confirmation of the diagnosis but it is still too early to affirm that all the cases; especially adults forms are linked to abnormalities of the gene.

The infantile forms require the consideration of progressive encephalopathies with macrocephaly and hydrocephalies, but sometimes only mental retardation at onset.

Treatment:

At present, treatment is purely symptomatic.

Researchers have developed methods of treating Alexander disease by down-regulating the expression of GFAP. They identified several compounds, including known antidepressants, antipsychotics, serotonin inhibitors and antihistamines, which are capable of reducing GFAP expression.

When administered to a patient with Alexander disease, the compounds should lessen the symptoms of the disease. They may reduce the intensity of the megalencephaly, or abnormally large brain, associated with Alexander disease; the amount of Rosenthal fibers, which are widely deposited in astrocytes in patients with the disease; and/or the intensity or frequency of seizures.

NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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