Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients.

Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by dominant variants in the Glial Fibrillary Acidic Protein gene. Three main classifications are currently used, the traditional one defined by the age of onset, and two more recent ones based on both clinical features at onset and brain MRI findings. In this study, we retrospectively included patients with genetically confirmed pediatric-onset AxD. Twenty-one Italian patients were enrolled, and we revised all their clinical and radiological data. Participants were divided according to the current classification systems. We qualitatively analyzed data on neurodevelopment and neurologic decline in order to identify the possible trajectories of the evolution of the disease over time. One patient suffered from a Neonatal presentation and showed a rapidly evolving course which led to death within the second year of life (Type Ia). 16 patients suffered from the Infantile presentation: 5 of them (here defined Type Ib) presented developmental delay and began to deteriorate by the age of 5. A second group (Type Ic) included patients who presented a delay in neuromotor development and started deteriorating after 6 years of age. A third group (Type Id) included patients who presented developmental delay and remained clinically stable beyond adolescence. In 4 patients, the age at last evaluation made it not possible to ascertain whether they belonged to Type Ic or Id, as they were too young to evaluate their neurologic decline. 4 patients suffered from the Juvenile presentation: they had normal neuromotor development with no or only mild cognitive impairment; the subsequent clinical evolution was similar to Type Ic AxD in 2 patients, to Id group in the other 2. In conclusion, our results confirm previously described findings about clinical features at onset; based on follow-up data we might classify patients with Type I AxD into four subgroups (Ia, Ib, Ic, Id). Further studies will be needed to confirm our results and to better highlight the existence of clinical and neuroradiological prognostic factors able to predict disease progression.

Alexander disease - astrogliopathy considered as leukodystrophy - experience of an institution.

Alexander Disease (ALXDRD) is an autosomal dominant leukodystrophy caused by mutation in one allele of GFAP gene, encoding glial fibrillary acidic protein (GFAP). Most cases occur due to de novo. There are three clinical subtypes of ALXDRD: infantile, juvenile and adult form, but congenital form is also outlined. The disease's spectrum comprises of macrocephaly, progressive pyramidal signs, and seizures in congenital and infantile subtypes. Neuropathologically are enormous number of Rosenthal fibers (RF) mainly around vessels, in subependymal and subpial regions are found. The diagnosis is based on the typical findings on MRI: diffuse white mater lesions with frontal regions preponderance and possibly on the detection of the gene mutation. Here we present six Polish children affected of Alexander disease with congenital (1), infantile (4) and juvenile (1) form. Five of them were previously misdiagnosed as cerebral palsy or unspecific developmental delay; two patients had MRI because of another suspicion, before specific diagnosis was established. Molecular analysis performed in four cases confirmed mutations of GFAP gene; all mutation were de novo. The role of astroglia in brain is shortly reviewed.

Alexander's disease: reassessment of a neonatal form.

INTRODUCTION: Alexander disease is a disorder caused by a mutation and accumulation of the glial fibrillary acidic protein. Currently, three subtypes are acknowledged: an infantile, a juvenile, and an adult form. However, onset early in infancy or in the prenatal period has been shown to present with a uniform pattern of symptoms-suggesting the presence of a distinct neonatal form of the disease. RESULTS AND DISCUSSION: Though the neonatal form of Alexander disease is not well acknowledged, a uniform and distinct presentation of the disease in neonates has been observed, suggesting the need for a different course of identification and treatment. Clinical presentation of the neonatal form is distinguished by leukodystrophy and generalized, frequent, and intractable seizures. While the infantile form presents with ataxia, hyperreflexia, and other upper motor neuron symptoms, none of these has been observed in the neonatal form. In the diagnosis of neonatal Alexander disease, it is essential to rule out other causes of leukodystrophy and the presence of neoplasms.

GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

OBJECTIVE: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. METHODS: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. RESULTS: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. CONCLUSIONS: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

An infantile-juvenile form of Alexander disease caused by a R79H mutation in GFAP.

Alexander disease is a degenerative white matter disorder due to mutations in the glial fibrillary acidic protein (GFAP) gene. It has been classified into three forms based on the age of onset and severity: an infantile, a juvenile, and an adult form. In a 6-year-old patient with a relatively mild form of Alexander disease, we detected a common R79H mutation in GFAP, previously only described in the infantile form. These results suggest the need for further studies of the genotype-phenotype correlation.

Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease.

Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype-genotype relations.