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

Abstract

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 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.

A canine orthologue of the human GFAP c.716G>A (p.Arg239His) variant causes Alexander disease in a Labrador retriever

“…7 The age of onset (3 months) and clinical signs of our dog (eg, spasticity, regurgitation, mild vestibular signs) seem most comparable with the juvenile type of AxD in man. Also, the lack of mental and sensory dysfunction and the absence of megalencephaly points more towards a juvenile type of AxD, 27 although it is not easy to reliably assess the mental and developmental state of such a young dog.…”

“…In this dog, MRI of the brain was declined by the owner, and therefore, it is difficult to apply the more recent classification system. 7 However, the early onset and the severity of the neurological signs point towards a type I AxD. Lesions found in the brain and spinal cord of this dog were typical of AxD.…”

“…7,9 In addition, the variant was not found in 50 unrelated healthy Labrador retrievers. Because the owners of the parents of the case did not want to participate in this study, we could not confirm if the variant was present or not in the parents or littermates.…”

“…7,9 This finding was added as a comment in the ClinVar entry and was supported by the fact that the causal variant was not found in 50 unrelated healthy Labrador retrievers (assay performed with PP8).…”

“…7,9 Because most identified variants generate practically full-length GFAP, GFAP null mice do not display signs of AxD and transgenic mice overexpressing GFAP develop a fatal encephalopathy with accumulations of GFAP in RFs, it is believed that variants cause disease by a dominant gain of function. 6 A similar disorder (OMIA 001208-9615) was already phenotypically described in 12 dogs (5 Bernese mountain dogs, 2 Labrador retrievers, 1 Bernese mountain crossbred dog, 1 Chihuahua, 1 French bulldog, 1 Miniature poodle and 1 Scottish terrier dog) 10-17 and 4 sheep (3 Merino sheep and 1 White alpine sheep), 18,19 but until now no causal variants were described.…”