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Alexander disease type II
An astrogliopathy and a form of Alexander disease (AxD) characterized by ataxia, bulbar symptoms, spastic paraparesis, palatal myoclonus, and autonomic symptoms.
ORPHA:363722Classification level: Subtype of disorder
- AxD type II
- Prevalence: Unknown
- Inheritance: Autosomal dominant
- Age of onset: Adolescent, Childhood, Adult
- ICD-10: E75.2
- OMIM: 203450
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Prevalence is unknown. It accounts for approximately 40% of AxD cases.
AxD type II can present throughout life, most commonly in late adolescence or adulthood (over the age of 12) and more rarely in childhood, with the age of onset ranging from 4-62 in published cases. It presents most commonly with bulbar symptoms (dysarthria, dysphonia, dysphagia), pyramidal signs and gait difficulties due to ataxia and/or spastic paraparesis. Unlike AxD type I (see this term), seizures are rarely seen and cognitive impairment is sometimes absent. Abnormalities of ocular movements are common and include saccadic pursuit, nystagmus, mild upper lid ptosis or diplopia. Sleep disorders (apneas and snoring) due to brainstem involvement are common as are urinary disturbances. Palatal myoclonus is also common. Other manifestations may include hypothermia episodes, sweating disturbances, constipation, pupillary abnormalities, impotence, kyphosis and scoliosis. Progression is slow and disease course is less severe than AxD type I but eventually muscle wasting and weakness often lead to motor impairment and dysphagia. Death is often due to aspiration pneumonia and respiratory insufficiency.
AxD type II is caused by gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene (17q21). Both sporadic cases with de novo mutations and familial cases have been reported. 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 is the most useful diagnostic tool as AxD type II characteristically shows a predominance of hindbrain lesions with mild to severe atrophy of the medulla oblongata and upper spinal cord. Molecular genetic testing for a mutation in the GFAP gene confirms diagnosis. Pathological findings of Rosenthal fibers do not determine diagnosis as they are present in other conditions.
Differential diagnoses include: peroxisomal biogenesis disorders, Zellweger syndrome spectrum, glutaric aciduria type I, megalencephalic leukoencephalopathy with subcortical cysts as well as other leukodystrophies such as Canavan disease, X-linked adrenoleukodystrophy and Krabbe disease (see these terms). AxD type II can also be misdiagnosed as primary lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and amyotrophic lateral sclerosis (see these terms) or one of numerous types of neoplasms (ex. spinal cord lesions, focal brain stem glioma, focal posterior fossa lesions).
Antenatal diagnosis is possible if a disease causing mutation has been identified in a family member.
The disease is transmitted autosomal dominantly. Both de novo and familial cases have been reported. Genetic counseling can be offered to those with a family member with a mutation in the GFAP gene but is difficult as penetrance is sometimes incomplete.
Management and treatment
There is no cure for AxD type II. Treatment is symptomatic and supportive. Monitoring and assessment of speech and swallowing difficulties is necessary. Evaluation and management of sleep apnea can greatly improve quality of life. Early recognition of scoliosis can prevent long term complications. As the disease progresses most patients require walking aids and/or wheelchairs. Patients with dysphagia may require a percutaneous gastrostomy tube or the placement of a nasogastric tube. Psychological assessment of patients along with counseling for patients and their families can be offered.
The prognosis is quite poor with median survival time after disease onset being 25 years.