Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

Bachetti, Tiziana; Zanni, Eleonora Di; Adamo, Annalisa; Rosamilia, Francesca; Sechi, Mario; Solla, Paolo; Bozzo, Matteo; Ceccherini, Isabella; Sechi, GianPietro

doi:10.3389/fphar.2021.723218

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…However, long-term use of these drugs can increase the risk of seizures, especially if there is a history of nerve damage ( 69 ), decreasing the potential widespread use of the drug in patients, especially in type I AxD. Bachetti et al ( 70 ) demonstrated for the first time that carbamazepine and phenytoin could inhibit the expression and folding of pathological GFAP cells, thus leading to the reduced formation of mutant GFAP aggregates. Therefore, carbamazepine and phenytoin sodium may have potential therapeutic effects on AxD, especially in patients with partial epilepsy of AxD.…”

Section: Discussionmentioning

confidence: 99%

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Yuan

Huang

et al. 2022

Front. Neurol.

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Alexander's disease (AxD) is a rare autosomal dominant hereditary disorder that is caused by the mutations in the GFAP gene, which encodes the glial fibrillary acidic protein (GFAP). This neurogenerative disease has many clinical manifestations, and the onset of disease spans a wide range of ages, from newborns to children, adults, and even the elderly. An overaccumulation of the expression of GFAP has a close causal relationship with the pathogenesis of Alexander's disease. Usually, the disease has severe morbidity and high mortality, and can be divided into three distinct subgroups that are based on the age of clinical presentation: infantile (0–2 years), juvenile (2–13 years), and adult (>13 years). Children often present with epilepsy, macrocephaly, and psychomotor retardation, while adolescents and adults mainly present with muscle weakness, spasticity, and bulbar symptoms. Atonic seizures are a type of epilepsy that often appears in the Lennox–Gastaut syndrome and myoclonic–astatic epilepsy in early childhood; however, the prognosis is often poor. Atonic episodes are characterized by a sudden or frequent reduction in muscle tone that can be local (such as head, neck, or limb) or generalized. Here, we report a 4-year-old girl whose main symptoms were intermittent head drop movements, which could break the frontal frame and even bleed in severe conditions. A video-encephalography (VEEG) showed that the nodding movements were atonic seizures. A head magnetic resonance imaging (MRI) revealed abnormal signals in the bilateral paraventricular and bilateral subfrontal cortex. The gene detection analyses indicated that the GFAP gene exon 1 c.262 C>T was caused by a heterozygous mutation, as both her parents were of the wild-type. The girl had no other abnormal manifestations except atonic seizures. She could communicate normally and go to kindergarten. After an oral administration of sodium valproate, there were no atonic attacks. Although epilepsy is a common symptom of Alexander's disease, atonic seizures have not been reported to date. Therefore, we report a case of Alexander's disease with atonic seizures as the main symptom and provide a review of the literature.

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Section: Discussionmentioning

confidence: 99%

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Yuan

Huang

et al. 2022

Front. Neurol.

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“…Alexander disease (AxD) is a relatively rare neurodegenerative disease. It a type of leukodystrophy that typically manifests in infancy, although it can occur later in life [ 38 , 39 ].…”

Section: Alexander Diseasementioning

confidence: 99%

“…Disease can be divided into two types depending on the location of the CNS lesions. Type one is characterized by early-onset convulsions, macrocephaly, progressive psychomotor and cognitive delays, and failure to thrive due to lesions in the forebrain [ 39 ]. Type two manifests as posterior brain lesions and associated symptoms such as palatal myoclonus, ataxia, dysphagia, and morphological dysfunction, and it can occur at any age [ 40 , 41 ].…”

Section: Alexander Diseasementioning

confidence: 99%

“…Among the compounds tried, phenytoin (5,5-diphenylhydantoin), carbamazepine (a derivative of iminostilbene with a dibenzazepine nucleus; thus, it has a tricyclic structure similar to clomipramine), and curcumin were utilized in AxD cell models to normalize GFAP expression levels [ 55 ]. It enhanced fiber coiling and organization, while ceftriaxone decreased expression and activated end of mutant GFAP [ 39 , 55 ]. Pexidartinib (a colony-stimulating factor 1 receptor (CSF1R) inhibitor) increased GFAP levels and decreased macrophage numbers in a mouse model of AxD [ 55 ].…”

Section: Alexander Diseasementioning

confidence: 99%

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Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases

Nowak,

Paździor,

Sarna

et al. 2024

CIMB

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Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment.

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Response to amoxicillin and perampanel in infantile Alexander disease

Boronat,

Turon‐Viñas,

Mac Manus

et al. 2024

Epilepsia Open

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Type I Alexander disease (AxD) presents with paroxysmal neurodegeneration, refractory epilepsy, and encephalopathy in the first years of life and is associated with a poor prognosis. Although there is no treatment, mild symptomatic improvement has been reported in one case of adult Alexander treated with ceftriaxone, given its interaction with the mutant glial fibrillary acid protein (GFAP) responsible for the disease's pathogenesis. We describe a patient presenting with irritability starting at 2 months of age, initially attributed to gastroesophageal reflux. A ventriculoperitoneal shunt was placed at 3 months of age due to hydrocephalus secondary to aqueduct stenosis detected through an MRI scan, but the irritability persisted. At 5 months, a new brain MRI was performed due to irritability worsening, onset of abnormal ocular movements and seizures. In addition genetic testing was performed. AxD was diagnosed due to the mutation c.716G>A (p.Arg239His) in GFAP. Since irritability had worsened and had not responded to levomepromazine, treatment with amoxicillin (80 mg/kg/day) was attempted to modulate glutamate levels. The patient showed a striking improvement of irritability in 48 h that persisted over the next months. The patient had frequent daily seizures which did not respond to valproate, clonazepam, or phenobarbital. Perampanel, a postsynaptic AMPA receptor antagonist, was added to phenobarbital and he was seizure free for more than 3 months. Drugs modulating glutamate levels in the central nervous system, including β‐lactam antibiotics and perampanel, may have an important role in the symptomatic treatment of AxD and other neurodegenerative diseases where glutamatergic excitotoxicity is a pathogenic determinant.Plain Language SummaryAlexander disease is a rare and serious condition that affects the brain, often leading to neurodegeneration (brain damage), seizures, and other problems in early childhood. The disease is caused by a mutation in a gene called GFAP. There is no cure, and current treatments mainly focus on relieving symptoms. This article discusses the case of a baby who showed signs of irritability and seizures from a young age. The baby was diagnosed with Alexander disease after brain scans and genetic testing. Despite treatment with various drugs, the baby continued to experience seizures and irritability. The doctors decided to try amoxicillin, a common antibiotic, because of its potential to help control the disease by affecting a brain chemical called glutamate. Surprisingly, the baby's irritability improved within 2 days of starting amoxicillin, and the improvement lasted for several months. However, the seizures persisted until another medication, perampanel, was added. This combination controlled the baby's seizures for over 3 months. Unfortunately, the baby passed away at 13 months due to complications from the disease. However, doctors believe that drugs like amoxicillin and perampanel could be promising treatments for managing symptoms of Alexander disease and other similar brain conditions in the future, especially where excess glutamate plays a role in the damage. This case suggests that these treatments may help control irritability and seizures, offering hope for better management of this challenging disease.

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Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

Cited by 5 publications

References 31 publications

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Case report: Alexander's disease with “head drop” as the main symptom and literature review

Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases

Response to amoxicillin and perampanel in infantile Alexander disease

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