Follow-up and genetic study of 43 Chinese children with type Ⅰ Alexander disease / 中华儿科杂志

Objective@#To identify the clinical and genetic characteristics in 43 Chinese children diagnosed with type Ⅰ Alexander disease (AxD).@*Method@#Forty-three type Ⅰ AxD cases identified by glial fibrillary acidic protein (GFAP) gene mutations in Peking University First Hospital from 2005 to 2016 were followed up. The data of medical history, physical examination and magnetic resonance imaging (MRI) were collected. All these patients were followed up in December 2010, Febury 2012, June 2014 and January 2016, respectively.@*Result@#Forty-three patients were genetically confirmed as type I AxD and the median age at the last visit was 11.71 years (10.27, 13.15). The characteristic clinical manifestations of these type Ⅰ AxD patients were developmental delay (79%, 34/43), seizures (86%, 37/43), macrocephaly (the median percentile of head circumference is 90%), and paroxysmal deterioration (27%, 13/43). All the 43 patients′ brain MRI satisfied typical MRI features proposed by van der Knaap. According to the analysis of the long-term follow-up, patients with type Ⅰ AxD began to have obvious regression in motor function after 7 years of age, and the social life ability was milally impaired 8(6, 10)scores at the last follow-up. Seventeen heterozygous missense mutations of GFAP were identified in 43 genetically confirmed patients, and 4 mutations were novel. The mutations in 41 patients (95%, 41/43) were de novo. Three hot spots of mutation in Chinese patients were found: p. Arg239(35%, 15/34), p. Arg79 (26%, 11/43) and p. R88 (16%, 7/43).@*Conclusion@#The characteristic clinical manifestations of type Ⅰ AxD patients are developmental delay, seizures, macrocephaly and paroxysmal deterioration. Moreover, a few patients may present with brain stem symptoms, mental abnormalities, scoliosis or kyphosis. Patients with type Ⅰ AxD may show significant regression in motor function after 7 years of age.

Presentación atípica de la enfermedad de Alexander infantil sin macrocefalia / An atypical presentation of Infantile Alexander disease lacking macrocephaly

Resumen: Introducción: La enfermedad de Alexander consiste en una forma de leucodistrofia poco frecuente que afecta principalmente a los astrocitos; tiene un patrón de herencia autosómica recesiva y es causada por mutaciones en el gen GFAP, localizado en el cromosoma 17q21. Puede presentarse a cualquier edad y la forma infantil se caracteriza por macrocefalia, crisis convulsivas, retraso motor y cognitivo grave y espasticidad o ataxia progresivas. Caso clínico: Paciente de sexo femenino de 8 meses evaluada por retraso psicomotor y crisis convulsivas motoras focales no provocadas. En la exploración física, con perímetro cefálico normal, respuesta motora incrementada ante estímulos táctiles y al ruido, signos piramidales y ausencia de visceromegalias. Se observó hipodensidad generalizada de la sustancia blanca en la resonancia magnética y punción lumbar con hiperproteinorraquia. Se descartó enfermedad de Krabbe mediante ensayo enzimático y secuenciación del gen GALC. En la reevaluación del caso, las alteraciones en la neuroimagen hicieron sospechar de enfermedad de Alexander, y la secuenciación del gen GFAP reportó una mutación en el exón 4 c.716G > A, lo que ocasionó un cambio de arginina por histidina en la posición 239 de la proteína (p.Arg239His). Conclusiones: Los signos radiológicos en la resonancia fueron determinantes para el diagnóstico, que posteriormente se confirmó con estudio molecular. Es importante considerar que ciertas mutaciones no se asocian con macrocefalia, lo cual puede ocasionar retraso en el diagnóstico.

Abstract: Background: Alexander disease is a rare form of leukodystrophy that involves mainly astrocytes; it is inherited in an autosomal recessive manner and occurs by mutations in the GFAP gene, located on chromosome 17q21. It can occur at any age and its infantile form is characterized by macrocephaly, seizures, severe motor and cognitive delay, and progressive spasticity or ataxia. Case report: An 8-month-old female was evaluated with a history of neurodevelopmental delay and unprovoked focal motor seizures. Physical examination showed normal head circumference, increased motor responses to tactile and noise stimuli, pyramidal signs and no visceromegalies. Widespread hypodense white matter was found on magnetic resonance and lumbar puncture showed hyperproteinorrachia. Krabbe disease was ruled out by enzymatic assay and gene sequencing of GALC. In the reassessment of the case, abnormalities in neuroimaging lead to suspicion of Alexander disease, and GFAP gene sequencing reported a pathogenic mutation in exon 4 c.716G > A, which caused a change of arginine to histidine at position 239 of the protein (p.Arg239His). Conclusions: The radiographic signs observed in the resonance were decisive for the diagnosis, later confirmed by molecular study. It is important to consider that certain mutations are not associated with macrocephaly, which may cause delay in diagnosis.

Clinical research of 4 patients with type Ⅱ Alexander disease and literature review / 中华实用儿科临床杂志

Objective To analyze the clinical and MRI features of patients with type Ⅱ Alexander disease (AxD) in order to better understand and diagnose it earlier.Methods Four type Ⅱ AxD patients identified by glial fibrillary acidic protein gene mutations from Peking University First Hospital and 128 type Ⅱ AxD cases from published literatures were collected,and the clinical and MRI features were summarized.Results (1) In 4 type Ⅱ AxD patients,2 adult patients showed abnormal MRI features without clinical manifestation.The other 2 children patients both manifested motor dysfunction of lower limbs,pyramidal signs,paroxysmal deterioration,and seizures during the course of disease,while 1 of them had bulbar paralysis.The MRI of all the cases was abnormal,but only 1 case MRI corresponded with typical MRI features of type Ⅱ AxD.In the other 3 cases MRI showed thc atrophy in the medulla and upper spinal cord,or the brainstem lesions and abnormal signal in the periventricular white matter,and abnormal basal ganglia region.(2) In 128 reported type Ⅱ AxD cases,the age of onset was (32±19) years old.The initial syndromes mainly contained bulbar and/or pseudobulbar paralysis (32.48％,38/117 cases),motor dysfunction of the lower limbs (31.62％,37/117 cases) and autonomic nerve dysfunction (13.67％,16/117 cases).During the course of the disease,the clinical manifestation showed bulbar and/or pseudobulbar paralysis (73.50％,86/117 cases),pyramidal signs (60.68％,71/117 cases) and ataxia (51.28％,60/117 cases).The MRI of all cases was characterized by atrophy or abnormal signals in the brainstem,especially in medulla oblongata,and spinal cord.And abnormal signals in the cerebellar dentate nuclei,white matter,basal ganglia and thalamus were also commonly shown in the MRI.Conclusions The patients with type Ⅱ AxD are late-onsct.The clinical manifestation mainly contains bulbar and/or pseudobulbar paralysis,motor dysfunction of the lower limbs and pyramidal signs.The MRI is characterized by atrophy or abnormal signals in the brainstem (especially in medulla oblongata) and spinal cord.

Alexander Disease

Alexander disease (ALXD) is a rare demyelinating disease of the white matter of the brain that is caused by a mutation in the glial fibrillary acidic protein (GFAP) gene. The overexpression of GFAP in astrocytes induces a failure in the developmental growth of the myelin sheath. The neurodegenerative destruction of the myelin sheath of the white matter is accompanied by an accumulation of abnormal deposits of Rosenthal fibers in astrocytes, which is the hallmark of ALXD. The disease can be divided into four groups based on the onset age of the patients: neonatal, infantile, juvenile, or adult. Early-onset disease is more severe, progresses rapidly, and results in a shorter life span than late-onset cases. Magnetic resonance imaging and genetic tests are mostly used for diagnostic purposes. Pathological tests of brain tissue for Rosenthal fibers are definitive diagnostic methods. Therapeutic strategies are being investigated. Ceftriaxone, which is an enhancer of glial glutamate transporter (GLT-1) expression, is currently in clinical trials for the treatment of patients with ALXD. To date, there are no clinically available treatments. The cause, pathology, pathophysiology, inheritance, clinical features, diagnosis, and treatment of ALXD will be reviewed comprehensively.

A Neonatal Form of Alexander Disease Presented with Intractable Seizures and Obstructive Hydrocephalus

Alexander disease is a rare degenerative leukodystrophy caused by dominant mutations in glial fibrillary acidic protein (GFAP). The neonatal form of Alexander disease may manifest as frequent and intractable seizures or obstructive hydrocephalus, with rapid progression leading to severe disability or death within two years. We report a case of a 50-day-old male who presented with intractable seizures and obstructive hydrocephalus. His initial magnetic resonance imaging (MRI) suggested a tumor-like lesion in the tectal area causing obstructive hydrocephalus. Despite endoscopic third ventriculostomy and multiple administrations of antiepileptic drugs, the patient experienced intractable seizures with rapid deterioration of his clinical status. After reviewing serial brain MRI scans, Alexander disease was suspected. Subsequently, we confirmed the de novo missense mutation in GFAP (c.1096T>C, Y366H). Although the onset was slightly delayed from the neonatal period (50 days old), we concluded that the overall clinical features were consistent with the neonatal form of Alexander disease. Furthermore, we also suspected that a Y366 residue might be closely linked to the neonatal form of Alexander disease based on a literature review.

Anesthetic Management of a Patient with Alexander's Disease: Case Report / 영남의대학술지

We present here the case of a 13-year-old male patient with Alexander's disease who underwent surgical correction of a femur fracture. Alexander's disease is a rare and fatal disorder that affects the white matter in the brain and it causes developmental delay, psychomotor regression, spasticity, megaloencephaly and seizure. The patient had the possibility of a seizure attack during the perioperative period. We discuss the anesthetic management of a patient with Alexander's disease and we review the relevant literature.

A Case of Infantile Alexander Disease / 대한소아신경학회지

Alexander disease(AD) is a rare fatal demyelinating disorder, caused by the mutation of glial fibrillary acidic protein(GFAP) gene. It is characterized by progressive demyelination of central nervous system, and the accumulation of Rosenthal fibers within astrocytes. It is divided into three group: infantile, juvenile, and adult. The infantile type is most common, has onset during the first 2 years of life. It shows macrocephaly and psychomotor delay, spastic paraparesis, seizure, and feeding problems, and usually dies within the first decade. The severity of the pathological changes depend on the age of onset. Radiological study revealed white matter loss, usually with frontal predominance. It is diagnosed by DNA analysis. We present case of a 10-month-old male patient with AD. He had focal seizures, demyelination in the frontal lobe in MRI, and the presence of a K86E mutaion in the GFAP gene, involving the replacement of adenosine with guanine.

A Case of Infantile Alexander Disease Accompanied by Infantile Spasms Diagnosed by DNA Analysis

Alexander disease (AD) is a rare leukodystrophy of the central nervous system of unknown etiology. AD is characterized by progressive failure of central myelination and the accumulation of Rosenthal fibers in astrocytes, and is inevitably lethal in nature. Symptomatically, AD is associated with leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation in infants, and usually leads to death within the first decade. Its characteristic magnetic resonance imaging (MRI) findings have been described as demyelination predominantly in the frontal lobe. Moreover, dominant mutations in the GFAP gene, coding for glial fibrillary acidic protein (GFAP), a principal astrocytic intermediate filament protein, have been shown to lead to AD. The disease can now be detected by genetic diagnosis. We report the Korean case of an 8-month-old male patient with AD. He was clinically characterized due to the presence of psychomotor retardation, megalencephaly, spasticity, and recurrent seizures including infantile spasms which is a remarkable presentation. Demyelination in the frontal lobe and in a portion of the temporal lobe was demonstrated by brain MRI. Moreover, DNA analysis of peripheral blood showed the presence of a R239L mutation in the GFAP gene, involving the replacement of guanine with thymine.