Paula and Bobby
Parents of Lillie
What is Alexander Disease?
Alexander Disease is a rare disease.
There are currently no additional known synonyms for this rare genetic disease.
There are at least three types of Alexander's disease, but the classical type has an infantile onset with seizures, neuro-degeneration and spasticity. An important clinical sign is the increasing head size, and most cases die within five years. A case reported by Torisu et al., (2013) had infantile spasms and was without macrocephaly. Clinical diagnosis is difficult, although the CT scan appearance, which shows low attenuation of white matter especially in the frontal areas, is suggestive. Note the MRI criteria outlined by Poloni et al., (2009). 1) Extensive symmetrical white matter abnormalitis (frontal and cystic), 2) a periventricular rim of decreased signal intensity on T2-weighted images, 3) Abnormalities in thalami and basal ganglia (increased signal plus swelling or atrophy, 4) Brain stem abnormalities involving mid brain and medulla, 5) contrast enhancement of optic chiasm, fornix, basal ganglia, hypothalamus, mammillary bodies). The only way in life to confirm the diagnosis is by brain biopsy, which shows Rosenthal fibres in sub-pial regions and around vessels. These are astrocytic processes containing fibrillary aggregates. There is also diffuse demyelination with preservation of neurons. Most cases to date have been single, and the status of this condition as genetically determined is still unresolved. The only possible sibship in the literature, according to Pridmore et al., (1993), was that of Wohlwill et al., (1959) who reported a pathologically proven case who was reported to have three sibs with hydrocephaly. The author of this abstract still counsels a 5-10% figure but this suggests dominant disease and the 10% risk quoted above may be too high (given - see below - that the condition has been proven to be caused by a dominant mutation, 10% is definately too high). Note however that affected sibs have been reported in the juvenile form of the condition (Duckett et al., 1992).
Torreman et al., (1993) reported a 3-year-old boy with a history of macrocephaly due to hydrocephalus and diffuse cerebellar enlargement where Alexander's disease was suggested on biopsy. However Harding (1993) warned of the difficulties in distinguishing the histological features of Alexander's disease from an astrocytic tumour when working with brain biopsies. In a study of unusual cases (they did not meet the MRI criteria of van der Knaap et al., 2001) in which 7 patients had been diagnosed as having Lhermitte-Duclos because of tumour-like lesions, and 1 other was diagnosed as having a brain stem tumour and another with a frontal glioma, GFAP mutations were found in nearly all (van der Knaap et al., 2005). There was only minimal evidence of a leukoencephalopathy.
Brenner et al., (2001) demonstrated mutations in the GFAP gene encoding glial fibrillary acidic protein. Of 11 patients with Alexander Disease, 10 had novel heterozygous mutations of the GFAP gene predicting non-conservative amino acid changes all involving arginines. Five of the mutations affected the same R239 amino acid with four resulting in the same substitution to cysteine. Further mutations were reported by Rodriguez et al., (2001) and Shiroma et al., (2003). Gordon (2003) provides a good review. Nearly all the 41 patients (infantile, juvenile and adult) analysed by Li et al., (2005) had GFAP mutations. In aseriesof 28 cases looked at by Li et al., (2006), 24 of the mutations were inherited from the father.Thirteen Italian patients were analysed by Caroli et al., (2007) and 11 mutations were found.
* This information is courtesy of the L M D.
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What gene changes cause Alexander Disease?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 203450 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
GFAP - 17q21.31
What are the main symptoms of Alexander Disease?
The typical symptoms of the syndrome are:
Muscular hypotonia, Progressive macrocephaly, Neurological speech impairment, Nausea and vomiting, Megalencephaly, Large face, Tremor, Feeding difficulties in infancy, Facial palsy, Encephalitis, EEG abnormality, Constipation, Diabetes mellitus, Developmental regression, Diplopia, Diffuse demyelination of the cerebral white matter, Aqueductal stenosis, Apnea, Aplasia/Hypoplasia of the corpus callosum, Aplasia/Hypoplasia of the cerebellum, Bulbar signs, Bowel incontinence, Self-injurious behavior, Chorea, Ataxia, Cerebral calcification, Abnormal palate morphology, Abnormality of the autonomic nervous system, Abnormal renal physiology, Short neck, Nystagmus, Melanocytic nevus, Autosomal dominant inheritance, Precocious puberty, Seizure, Respiratory failure, Pseudobulbar signs, Recurrent singultus, Frontal bossing, Ptosis, Reduced bone mineral density, Abnormal pyramidal sign, Sudden cardiac death, Spasticity, Infantile onset, Sleep disturbance, Scoliosis, Hypothyroidism, Hypothermia, Hypotension, Increased CSF
How does someone get tested for Alexander Disease?
The initial testing for Alexander Disease can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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