Each month, this department features a discussion of an unusual diagnosis in genetics, radiology, or dermatology. A description and images are presented, followed by the diagnosis and an explanation of how the diagnosis was determined. As always, your comments are welcome via email at Pediatrics@Healio.com.
A 15-month-old previously healthy boy arrived at our emergency department (ED) via ambulance after a generalized seizure. The parents reported subjective fever, one episode of emesis, and nasal congestion a few hours prior to the convulsive spell.
Review of systems was negative for irritability or rash. Seizure was preceded by a transient unresponsiveness followed by eye blinking, mouth twitching, and generalized tonic stiffness. Paramedics reported rectal temperature of 102.5°F and persistent seizure activity on their initial assessment. The patient received 0.2 mg of intranasal midazolam and had a rapid clinical response. The seizure lasted less than 10 minutes and was followed by post-ictal drowsiness and sleep. The child returned to normal mental status within the next 2 hours.
The child’s medical history was remarkable for borderline delay in developmental milestones, manifested by inability to walk independently and a limited vocabulary of only four words. There was no history of epilepsy in the family.
Initial physical assessment showed a well-nourished child with vital signs revealing rectal temperature up to 101.5°F. The head circumference showed relative microcephaly with head circumference between 80th and 90th percentile. There were no signs of trauma. Head, eyes, ear, nose, and throat (HEENT) examination was normal except for mucoid rhinorrhea. Cardiovascular and pulmonary examinations were unremarkable. Abdomen examination did not show hepatosplenomegaly or masses. There were no rashes or peripheral edema. Initial neurologic evaluation revealed an irritable young child without neck stiffness or focal motor deficit. He was able to crawl and stand on his own (no instability). There was no dysmetria or nystagmus.
While under observation in the ED, he had a second generalized tonic convulsive seizure that lasted for 30 seconds followed by post-ictal drowsiness. This prompted the medical staff to obtain neuroimaging. Subsequent computerized tomography (CT) imaging of the head demonstrated an abnormal low density throughout the frontal white matter and basal ganglia. Additional ED diagnostic workup included evaluation of cerebrospinal fluid indexes and complete liver and renal chemistries (which were normal). An electroencephalogram demonstrated bifrontal intermittent rhythmic delta activity.
The patient was admitted to our hospital for further management. A brain magnetic resonance imaging (MRI) scan was obtained that demonstrated symmetric area of increased T2 signals involving the supratentorial white matter (predominately anterior distribution) and central gray nuclei suggestive of Alexander disease (see Figure).
Figure. Brain magnetic resonance imaging scan shows a symmetric area of increased T2 signals involving the supratentorial white matter (most notable over frontal lobe) and central gray nuclei. Image courtesy of Luis Seguias, MD.
He was discharged on levetiracetam because of a high risk for recurrent seizures.
Alexander disease (AxD) is a rare neurodegenerative disorder characterized by progressive failure of central myelination.
Mutations in the glial fibrillary acidic protein (GFAP) gene lead to abnormal protein aggregation, which is thought to be the main cytotoxic mechanism in AxD.1,2 Abnormal polymerization of GFAP causes cytoskeleton instability as well.3
GFAP mutations that affect the pediatric population are de novo. All of these are heterozygous (ie, only one allele) and act in a dominant fashion.4 In our case, genetic testing reported abnormal DNA sequence variant in the GFAP gene, supporting a diagnosis of AxD. Inheritance in the adult-onset familial variant is autosomal dominant.5 A total of 72 distinct mutations have been identified to date.6
Currently, there is no genetically engineered animal model that mimics all features of AxD in humans.
Typical histopathological findings reveal the presence of cytoplasmatic inclusions within the astrocytes, termed “Rosenthal fibers.”7 These filament-like protein aggregates are composed mainly of GFAP and heat shock proteins.8,9 Widespread distribution of Rosenthal fibers is unique to AxD, but the focal pattern is present in other neurological conditions such as astrocytomas and multiple sclerosis.2
AxD is very rare, but the actual incidence and prevalence rates are unknown; only 189 cases of AxD with GFAP mutations have been reported in the literature.6
This leukodystrophic disorder usually has its onset in infancy or early childhood and is associated with macrocephaly, psychomotor retardation, seizures, and death in the first decade of life. Late-onset forms of AxD show a wide clinical variability.
A recently revised clinical classification of AxD proposed two distinct patterns of phenotypic expression (Type I and II) based on analysis of statistically defined patient groups.10 Type I AxD is characterized by early onset, seizures, macrocephaly, paroxysmal deterioration, failure to thrive, developmental delay, and typical neuroimaging features. Type II AxD occurs across the lifespan and is distinguished by autonomic dysfunction, bulbar symptoms, eye movement abnormalities, and atypical neuroimaging elements.10
After a comprehensive analysis, van der Knaap et al11 proposed a set of neuroimaging diagnostic criteria for AxD. The presence of any 4 of the 5 criteria establishes an MRI-based diagnosis of AxD (see Sidebar). Larger case series with genetic assessments are needed to further clarify genotype-phenotype correlations.
AxD diagnosis is established based on clinical and radiological (MRI) criteria. GFAP gene analysis is not necessary but can be used to confirm the presumptive diagnosis. In one case report, elevated GFAP levels in cerebrospinal fluid were detected in three genetically confirmed cases of AxD.12
Currently, only supportive treatment is available for AxD. The goal of treatment is to prevent, control, or relieve complications and to improve the patient’s quality of life. Genomic therapy seems to be a promising therapeutic intervention in the disease. Prenatal genetic counseling for families with increased risk may become possible if the disease-causing mutation is identified.
This case illustrates that diagnostic MRI abnormalities of AxD may be present at a very young age, long before the appearance of characteristic clinical signs. Early diagnosis allows prompt counseling of families.
- Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001;27(1):117–120 doi:10.1038/83679 [CrossRef] .
- Johnson AB, Brenner M. Alexander’s disease: clinical, pathologic, and genetic features. J Child Neurol. 2003;18(9):625–632 doi:10.1177/08830738030180090901 [CrossRef] .
- Nielsen AL, Jorgensen P, Jorgensen AL. Mutations associated with a childhood leukodystrophy, Alexander disease, cause deficiency in dimerization of the cytoskeletal protein GFAP. J Neurogenet. 2002;16(3):175–179 doi:10.1080/01677060215305 [CrossRef] .
- Li R, Messing A, Goldman J, Brenner M. GFAP mutations in Alexander disease. Int J Dev Neurosci. 2002;20(3–5):259–268 doi:10.1016/S0736-5748(02)00019-9 [CrossRef] .
- Stumpf E, Masson H, Duquette A, et al. Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol. 2003;60(9):1307–1312 doi:10.1001/archneur.60.9.1307 [CrossRef] .
- Gorospe JR. Alexander disease. Available at: www.ncbi.nlm.nih.gov/books/NBK1172. Accessed April 16, 2013.
- Alexander WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain. 1949;72(3):373–381 doi:10.1093/brain/72.3.373 [CrossRef] .
- Iwaki A, Iwaki T, Goldman JE, Ogomori K, Tateishi K, Sakaki Y. Accumulation of alpha B-crystallin in brains of patients with Alexander’s disease is not due to an abnormality of the 5′-flanking and coding sequence of the genomic DNA. Neurosci Lett. 1992;140(1):89–92 doi:10.1016/0304-3940(92)90689-5 [CrossRef] .
- Head MW, Goldman JE. Small heat shock proteins, the cytoskeleton, and inclusion body formation. Neuropathol Appl Neurobiol. 2000;26(4):304–312 doi:10.1046/j.1365-2990.2000.00269.x [CrossRef] .
- Prust M, Wang J, Morizono H, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology. 2011;77(13):1287–1294 doi:10.1212/WNL.0b013e3182309f72 [CrossRef] .
- van der Knaap MS, Naidu S, Breiter SN, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol. 2001;22(3):541–552.
- Kyllerman M, Rosengren L, Wiklund LM, Holmberg E. Increased levels of GFAP in the cerebrospinal fluid in three subtypes of genetically confirmed Alexander disease. Neuropediatrics. 2005;36(5):319–323 doi:10.1055/s-2005-872876 [CrossRef].