One Case Report and Literature Review of Alexander’s Disease Caused by a Mutation in the GFAP Gene

Background: Based on a case of tic as the primary symptom of Alexander disease I type, enhancing understanding clinical manifestations and characteristics of the genotypes and improving the level of diagnosis and treatment of Alexander disease I type. Methods: Combined one with gene diagnosed type I Alexander disease child in October 2018 in admission to neonatal ward of Children’s the clinical diagnosis and treatment process of patient and related literature reports were analyzed retrospectively, follow-up was conducted in February 2019, the etiology, clinical manifestations, genotypic characteristics, diagnosis and treatment were discussed. Results: One 20-day-old boy, the main symptom was convulsion, improve related laboratory inspection, finally, GFAP gene detection was passed, (ngqx1801877701-1) chr17: 42989062 showed heterozygous mutation of c.884A>G (p.d295g), It has not been reported at home or abroad, and the child can be diagnosed with Alexander disease I type, moreover, the father of the patient had heterozygous mutation (ngqx1801877802-1) chr17: 42989062 with c.844A>G (p.d295g), after the treatment of symptomatic support, the patient’s condition improved. Conclusion: Alexander disease I type early disease, early diagnosis and under the support in symptomatic treatment, attaches great importance to the late follow-up and rehabilitation training is the key to improve the prognosis. routine, thyroid function, coagulation function, electrolyte, renal function, blood ammonia, blood lactic acid, TORCH, blood glucose range; hereditary metabolism of hematuria: decreased arginine; electroencephalogram: mildly abnormal electroencephalogram; cranial MRI: cranial MRI showed neonatal brain changes.

routine, thyroid function, coagulation function, electrolyte, renal function, blood ammonia, blood lactic acid, TORCH, blood glucose were in the normal range; hereditary metabolism of hematuria: decreased arginine; electroencephalogram: mildly abnormal electroencephalogram; cranial MRI: cranial MRI showed neonatal brain changes.

Molecular Genetics
After the parents signed the informed consent, 5 ml of whole peripheral blood with EDTA was taken from the patient and their parents, and genomic DNA was extracted. Gene analysis related to metabolic diseases and leukoencephalopathy was carried out by using the genetic metabolic diseases and leukoencephalopathy detection program from Beijing Running Gene Co., Ltd. There was a heterozygous mutation of c.884A>G (p.D295G) in child with GFAP gene ((NGQX1801877701-1) chr17: 42989062), a heterozygous mutation of c.844A>G (p.D295G) was found in father-carried NGQX1801877802-1 (chr17:42989062) (Figure 1), and no mutation was found in mother. By searching the human mutation gene database (HMGD) and PubMed database, it was found that the mutation has not been reported at home and abroad, which is a new mutation. The same loci variation was not found by further inquiries for HGM Dpro database. The mechanism of AxD caused by the mutation of GFAP gene has been identified, the mutation can be judged as pathogenic mutation according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Therefore, the mutation can be judged as a pathogenic mutation. Therefore, the molecular genetic diagnosis of the child was clear, eventually diagnosed as type I AxD. The father of the child was a carrier with heterozygous mutation, of which childhood had similar performance with the child. The genetic pattern of this gene is dominant inheritance, which conforms to the family co-segregation.

Treatment and Follow-up
The child was a newborn with convulsion as the main manifestation, of which head circumference was large and the level of serum arginine was decreased. Combined with cranial MRI and heterozygous mutation of GFAP gene, the child was diagnosed as type I AxD. Vitamin B6 nourishing nerve and other supportive treatment, as well as targeted behavior and development training for child by the parents, the rehabilitation treatment was carried out and the curative effect was acceptable. In February 2019, telephone follow-up showed that the child was 6 months old, weighed 8,000 g, had no convulsions, could raise his head and turn over, and could not sit alone. medulla oblongata symptoms, ataxia and neurodegenerative lesions. According to the age of onset and clinical manifestations, AxD can be divided into infant type (< 2 years old), juvenile type (2-12 years old) and adult type (>12 years old) [4].
The first visit age of the child is 20 days after birth, which conforms to the characteristics of early onset (usually < 4 years old) of patient with type I AxD reported internationally [1]. Because most of children with type I AxD (79%) are underdeveloped from childhood with concealed onset, the description of the type I AxD onset age is not accurate, and the course of disease cannot be simply calculated from the "onset" described by their parents.
Epilepsy seizures enlarged head circumference and developmental retardation are common clinical manifestations of type I AxD, epilepsy seizures are common clinical manifestations for both infant type springing from traditional typing and type I AxD [5]. The motor function is often affected in children with this disease, which is also consistent with the manifestation of white matter with serious involvement on skull MRI. Epilepsy seizure is a common clinical manifestation in infant type springing from traditional typing, with epilepsy incidence of 92% [6]. In this case, convulsions were the main complaint and the onset age was early, which might be related to the over-excitation of neurons caused by decreased glutamate reuptake ability of astrocytes [7]. Head circumference enlargement was more common in type I AxD, and the case was significantly enlarged, which was consistent with it [1]. Generally, the abnormal signal of white matter in AxD patients is diffuse and symmetrical on cranial MRI, which shows long T1 and long T2 signals. First, it appears in bilateral frontal lobes, while subcortical arcuate fibers are not involved. The lesion extends progressively back to parietal lobe, internal capsule area, occipital lobe, cerebellum and white matter of brainstem [8]. The electroencephalogram indicated abnormal electroencephalogram (EEG), and skull MRI showed underdeveloped brain changes, which were like MRI findings in the children with AxD. h) Rosenthal fibers were confirmed by brain biopsy [7].

The key points of AxD diagnosis mainly include
The patient was a newborn with convulsion as the main manifestation, large head circumference and brain retardation to be used in patients with mutation of GFAP [9]. There are also reports that Anti-aging gene activation may be relevant to prevent and treat neuron associated mental retardation and assist with motor development in AxD. Compounds such as resveratrol (antiaging gene activator) may modulate GFAP from cells in the brain to assist with the treatment of mental retardation, therefore, do the alterations in astrocyte (GFAP expression) induce neuronal deficits in patients with AxD still needs further research [10,11].

Conclusion
Alexander disease I type early disease, early diagnosis and under the support in symptomatic treatment, attaches great importance to the late follow-up and rehabilitation training is the key to improve the prognosis.