Balkan Journal of Medical Genetics

INFANTILE ALEXANDER DISEASE WITH LATE ONSET INFANTILE SPASMS AND HYPSARRHYTHMIA
Paprocka J1,*, Rzepka-Migut B2, Rzepka N2, Jezela-Stanek A3, Morava E4
*Corresponding Author: Dr. Justyna Paprocka, Department of Paediatric Neurology, School of Medicine in Katowice, Medical University of Silesia, Medyków 16, 40-752 Katowice, Poland. Tel: +48-606- 415-888. Fax: +48-322-071-615. E-mail: justyna.paprocka@interia.pl
page: 77

DISCUSSION

Pathomechanism of the disease is connected with a toxic gain of function mechanism, in which the mutated GFAP gene accumulates within astrocytes and aggregates with several other proteins to form inclusion bodies, known as Rosenthal fibers. Based on experimental studies there is a suspicion that accumulation of GFAP may lead to microglia activation and T-cell infiltration [6]. Van der Knaap et al. [7] proposed specific MRI criteria for the diagnosis of AxD including extensive, symmetric white matter abnormalities with frontal preponderance, periventricular signal changes, basal ganglia and thalamic signal changes, brainstem lesions, and contrast enhancement of multiple areas throughout the brain. The diagnosis required fulfilling at least four of five criteria. The presented boy fulfilled four of the five criteria. The most commonly used criteria were: extensive, symmetrical, cerebral white matter abnormalities with frontal preponderance, either in the extent of white matter abnormalities, the degree of swelling, the degree of signal change, or the degree of tissue loss (white matter atrophy or cystic degeneration) in 14/15 of the cases described [1-5]. One of the main goals of this study was to describe a patient with an AxD involving hydrocephalus without macrocephaly as well as to compare all stages of the disease with other cases in the literature. Another exceptional feature seen in our patient is late-onset epileptic spasms with hypsarrythmia. Characteristic symptoms for the infantile form are seizures, retarded psychomotor development and macrocephaly. Muscle tone abnormalities are also common symptoms. Generalized hypotonia appears in the presented case. Literature data show 15 cases of infantile form: six children had spasticity and four had hypotonia. Pyramidal symptoms, which are more common in juvenile forms, were found in the presented boy and in two other cases [2]. Hydrocephaly, which was one of the first alarming symptoms, was described only in one analyzed case [5]. Gorospe et al. [8] reported 12 genetically confirmed cases of AxD including seven with infantile onset. All had megalencephaly at presentation [1-5]. Li et al. [9] studied 26 subjects with infantile AxD and found macrocephaly in 62.0% of cases. In their study seizures (92.0%) were the most common feature followed by cognitive defects (82.0%). Bulbar signs (62.0%), ataxia (58.0%) and spasticity (52.0%), were observed less often. Wilson et al. [10] described the longest survivor with AxD, who was diagnosed with this disease at the age of 5 years and is still alive at the age of 38. The final AxD diagnosis was possible through results of genetic testing. Despite the fact that R79H amino acid substitution is the most common AxD variant, we did not find any case of another child with the c.236G>A mutation and similar clinical outcome, improvement after treatment of seizures, in the literature [11-15]. There is also lack of reliable phenotype-genotype correlation in other GFAP gene variants. Of these, the p.Arg239His mutation was described twice [3,4], and in one case macrocephaly was not found [4]. The p.Arg79His mutation was seen twice [3] and in one case, the disease proceeded with normal head circumference [4]. The mutation p.Arg79Cys was also recorded twice [5]. Both cases were associated with hypo-tension and epileptic seizures. The R239L mutation was described twice [1,2]. Despite some description of epileptic spasms in the infancy period [16,17], the onset of this form of seizure in our patient was surprisingly late. The study was limited by the small number of publications that were compared with the gathered results. This demonstrates the importance of our work, because with more publications it would be possible to associate the type of mutation with the clinical image and the changes visible in brain MRI. Conclusions. Alexander disease leads to severe disability and a child’s death. Sometimes, with atypical presentations or course, such as in our patient. The disease is incurable and rehabilitation is the only chance to improve functioning of a child. It is essential to limit seizures and infections occurrence which may accelerate progression of the disease.

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