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Alexander disease type I
An astrogliopathy and the most severe and common form of Alexander disease (AxD), presenting before the age of 4 and characterized by seizures, megalencephaly and developmental delay with progressive deterioration.
ORPHA:363717Classification level: Subtype of disorder
- AxD type I
- Prevalence: Unknown
- Inheritance: Not applicable
- Age of onset: Infancy, Neonatal
- ICD-10: E75.2
- OMIM: 203450
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
The prevalence is unknown. This form accounts for approximately 60% of AxD cases.
AxD type I typically presents between birth and the age of 4. Those with a neonatal onset (within the first 30 days) usually have a more severe disease course presenting with symptoms of generalized, frequent, and often intractable seizures, aqueductal stenosis (leading to hydrocephalus with raised intracranial pressure) and severe motor and intellectual disability. In infantile-onset cases, ataxia, hyperreflexia and pyramidal signs are seen along with seizures. Megalencephaly and frontal bossing are further manifestations of the disease. In all infants there is a loss of developmental milestones with progressive psychomotor retardation. The disease course is severe with death usually, but not always, occurring in the first two decades after diagnosis. In the neonatal form the disease progresses even faster with severe disability or death occurring within the first years of life.
AxD is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). This gene encodes GFAP, the major intermediate filament protein found in astrocytes. The over-expression and accumulation of this mutant protein leads to the formation of astrocytic inclusion bodies (Rosenthal fibers) throughout the CNS. It is currently unknown how Rosenthal fibers are involved in disease pathogenesis.
MRI shows characteristic leukodystrophy with frontal, basal ganglia signal abnormality, brainstem signal abnormality and contrast enhancement. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. The presence of Rosenthal fibers in astrocytes can also be seen in other diseases and is therefore not diagnostic.
Differential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, Aicardi-Goutières syndrome, the frontal variant of adrenoleukodystrophy and megalencephalic leukoencephalopathy with subcortical cysts (see these terms).
Although most cases of AxD type I are sporadic, antenatal diagnosis is possible if a disease causing mutation has been identified in an affected family member.
AxD type I typically occurs sporadically and is associated with the occurrence of de novo mutations. Most patients do not reproduce. Gonadal mosaicism should be considered in advising families of the risk of recurrence when a de novo mutation is identified. Genetic counseling can be proposed to families with a history of the disease and family members can be tested for the disease-causing mutation. Penetrance is complete.
Management and treatment
There is no cure for AxD type I. Treatment is symptomatic and focuses on seizure control, maintenance of pulmonary function and nutrition. Those with severe feeding difficulties and recurrent vomiting may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Antibiotics can be given to treat intercurrent infections and antiepileptic drugs are given to control seizures. Orthopedic complications should be prevented, in particular scoliosis, and the management of spasticity by a multidisciplinary team is an important component of care. Psychological counseling can also be proposed to families of infants with the disease.
The prognosis is poor but with supportive therapies some patients have lived into adolescence and adulthood.