EAJM 2012; 44: 46-50 Case Report

Juvenile Alexander Disease: a Case Report Juvenil Alexander Hastalığı: Vaka sunumu Halit Ozkaya, Abdullah Baris Akcan, Gokhan Aydemir, Mustafa Kul, Secil Aydinoz, Ferhan Karademir, Selami Suleymanoglu Department of Pediatrics, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, Turkey

Abstract Özet Alexander disease is a rare autosomal recessive disorder that is char- Alexander hastalığı, nadir görülen ve santral sinir sisteminde beyaz acterized by degeneration of the in the central nervous cevherin dejenerasyonu ile karakterize otozomal resesif bir rahatsız- system. Alexander disease is a that is usually observed lıktır. Alexander hastalığı, genellikle çocukluk çağında nadir olarakta in early childhood but rarely in adults. It is characterized by megalen- erişkinlerde görülen bir lökodistrofidir. Megalensefali, demyelinizas- cephaly, demyelinization and multiple Rosenthal fibers. Specific mag- yon ve çok sayıda Rosenthal lifleri ile karakterizedir. Hastalığın tanısın- netic resonance imaging (MRI) findings and genetic investigations da spesifik magnetik rezonans (MRI) bulguları ve genetik araştırmalar are necessary to diagnose the disorder. Signs of leukodystrophy were faydalı olabilir. Dört yaşındaki olgunun MRI incelemesinde bilateral found in the bilateral white matter on a brain MRI of our four-year-old frontal beyaz cevherde lökodistrofik değişiklikler gözlenmiştir. İnfant patient. He had since birth. We use this case to discuss döneminden bu yana megalensefali bulguları olguda gözlenmiştir. Alexander disease. Bu olgunun yardımıyla, Alexander hastalığını tartışacağız. Key Words: Alexander disease, Megalencephaly, Leukodystrophy, Anahtar Kelimeler: Alexander hastalığı, Megalensefali, Lökodistrofi, Pediatric Çocuk nörolojisi

Introduction cytes, called Rosenthal fibers, which are composed of glial fibrillary acidic protein (GFAP), the main intermediate fila- Alexander disease is a rare, sporadic leukoencephalopa- ment of , in association with the small heat shock thy that is characterized by white matter abnormalities with a proteins, HSP27 and αB-crystallin [3]. frontal predominance; it is associated with megalencephaly, We report a male, four-year-old patient with leukodys- , and psychomotor deterioration [1]. Four trophic findings in the frontal white matter bilaterally on types can be distinguished based on the age at clinical pre- magnetic resonance imaging. The patient had megalen- sentation: neonatal, infantile, juvenile, and adult [2]. cephaly since the infantile period. We use this case to discuss The clinical features of typical infantile-onset Alexander Alexander disease. disease, with onset before the age of two, include megalen- cephaly, seizures, spastic paresis and psychomotor deteriora- Case Report tion with leukoencephalopathy that is characterized by white matter abnormalities particularly in the frontal lobes. The A four-years-old boy was admitted to our outpatient clinic juvenile type, with an onset in childhood, shows a variable with a history of two seizures and a large head size. His height clinical course: slowly progressive paresis, bulbar signs, and was 102 cm (25-50 percentile), his weight was 16 kg (25-50 brisk reflexes, but often with an intact mental state [2, 3]. percentile), and his head circumference was 55 cm (>95 Adult-onset Alexander disease, with onset after the age of 12, percentile The patient is the first child of unrelated parents is characterized by more slowly progressive bulbar or pseu- without any family history of neurological disorders and was dobulbar palsy, spastic paresis, , palatal myoclonus, and born after a full-term pregnancy with no complications. The essentially normal psychic and intellectual functions. prenatal and natal history was also unremarkable. Postnatally, The pathological hallmark of the disease is the accumu- the boy was able to sit with support when he was 9 months lation of ubiquitinated intracytoplasmic inclusions in astro- old and sat unsupported when he was 11 months. He first

Received: May 16, 2011 / Accepted: November 25, 2011 Correspondence to: A. Baris Akcan, Department of Pediatrics, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Tibbiye Cad., Uskudar, 34668, Istanbul, Turkey Phone: +90 216 542 20 20 Fax: +90 216 348 78 80 e-mail: [email protected] doi:10.5152/eajm.2012.10 EAJM 2012; 44: 46-50 Ozkaya et al. Alexander Disease 47

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Figure 1. MRI findings in our patient showed white matter degeneration. walked when he was 18 months old. He spoke single words fibrillary astrocytes”. These astrocytic inclusions were later when he was 2 years old, and he currently still cannot form found to be identical to Rosenthal fibers [2]. The presence sentences. When he was 2 years old, he had two generalized of GFAP in Rosenthal fibers led to the identification of muta- tonic clonic seizures. After the second , treatment with tions of the encoding GFAP as the cause of Alexander valproic acid was initiated, and the seizures were controlled. disease [4]. Rosenthal fibers, which are hyaline eosinophilic The patient has a large head and mental retardation. Both rods, are present throughout the gross and fine motor skills were affected, but there was no (CNS) in Alexander disease. These intracytoplasmic astrocytic orolingual involvement or bulbar dysfunction. There was no inclusions are the hallmark of Alexander disease [5]. They diurnal variation in the child’s symptoms. Extensive neuro- are commonly observed in subpial, subependymal, and metabolic investigations involving serum, urine, and cerebro- perivascular regions. The inclusions occur in the perikarya, spinal fluid were non-diagnostic. Cranial MRI was consistent processes, and end-feet of astrocytes and appear round or with Alexander disease, and leukodystrophic frontal white oblong with extensive glial intermediate filaments observed matter degenerations were observed (Figure 1). Genetic test- on electron microscopy. They also contain GFAP. In addition, ing was consistent with Alexander disease. alpha B-crystallin, heat shock protein 27, and ubiquitin are also present in the Rosenthal fibers [6-10]. Discussion In 2001, nonconservative were identified in the regions of chromosome 17q21, which encode the GFAP gene, Alexander disease is a slowly progressing, fatal neurode- from patients with different Alexander disease phenotypes [4]. generative disease. It is a very rare disorder that results from GFAP is an protein that is found in a genetic . It mainly affects infants and children, mature astrocytes and is rapidly synthesized during central causing developmental delays and changes in physical char- nervous system (CNS) injury and reactive [11]. acteristics. The following are some of the observed features Since the initial description of Alexander disease, fewer of Alexander disease: delays in the development of physical, than 450 cases have been reported [12]. Nevertheless, in a psychological and behavioral skills; progressive enlargement series from Germany, Alexander disease accounted for 1.6 of the head (); seizures; spasticity; ; percent of all [13]. Rosenthal fibers are not and in some cases, . found in the astrocytes of healthy people and contain large Alexander disease was first described in 1949, when quantities of the GFAP. Defects in GFAP have been found to W. Stewart Alexander reported a 15-month-old child with be the major cause of Alexander disease. megalencephaly, hydrocephalus, and psychomotor retarda- The neonatal form is associated with increased intra- tion [1]. The child died eight months later, and the brain cranial pressure, elevated cerebrospinal fluid (CSF) protein, pathology revealed “a progressive fibrinoid degeneration of intractable seizures, severe motor retardation (even in the 48 Ozkaya et al. Alexander Disease EAJM 2012; 44: 46-50

absence of spasticity), mental retardation, and ataxia. These ease may also be so mild that symptoms are not even noticed features reflect involvement of the frontal white matter, until an autopsy reveals the presence of the Rosenthal fibers. basal ganglia, and [14, 15]. In the neonatal form, Adult-onset forms of Alexander disease are rare but have death usually occurs within the first few weeks to years of life, been reported. The symptoms sometimes mimic those of although some affected infants survive until the end of the Parkinson’s disease, or brain tumors. first decade [12, 14, 15]. Ninety-four percent of the Alexander disease cases are The infantile form is the most common, accounting for associated with mutations in the coding region of the GFAP 63 percent of all cases [12]. The onset occurs before the age gene [3, 12, 17]. Approximately 50 GFAP mutations have of two [15]. Infantile Alexander disease leads to symptoms in been reported in the literature, and a genetic diagnosis of the first two years of life; while some children die in the first Alexander disease has been confirmed in 137 patients [11]. year of life, a larger number live to be 5-10 years old. Infants An updated list of GFAP mutations associated with Alexander and young children have spasticity, feeding difficulties, and disease is available online from the Waisman Center [17]. psychomotor retardation with loss of developmental mile- GFAP mutations usually arise de novo. At present, there stones. Affected infants may have head enlargement (macro- is no precise animal model for Alexander disease; however, cephaly) secondary to brain enlargement (megalencephaly), mice have been engineered to produce the same mutant frontal bossing, seizures, and hydrocephalus. Most children forms of GFAP found in individuals with the disease. These with the infantile form do not survive past the age of 6. The mice form Rosenthal fibers and have a predisposition for sei- usual course of the disease is progressive, leading to eventual zures, but they do not yet mimic all features of human disease severe mental retardation and spastic quadriparesis. Feeding (such as the leukodystrophies). often becomes a problem, and assisted feeding (with a naso- Most affected individuals with infantile and juvenile onset gastric tube) may become necessary. Generally, the earlier do not live until child-bearing age and do not reproduce, indi- the age of onset of Alexander disease, the more severe and cating that the majority of cases are sporadic [18]. Molecular rapid the course. The clinical findings include megalenceph- in those cases was consistent with Alexander aly, hydrocephaly, failure to thrive, seizures, spasticity/spastic disease. quadriparesis, progressive psychomotor retardation, difficul- ties with walking, speech difficulties, and mental regression. The diagnosis of Alexander disease can be established The juvenile phenotype, observed in approximately 24 based on clinical and radiographic (MRI) features. Van der percent of affected patients, typically presents between ages Knaap et al. [19] suggested that the presence of four of the 4 and 14 [12, 16]. It is associated with pseudobulbar and five following criteria establish an MRI-based diagnosis of bulbar signs, including swallowing and speech difficulties. Alexander disease: Patients may have vomiting, ataxia, spasticity (principally 1. Extensive cerebral white matter abnormalities with a affecting the lower extremities), and kyphoscoliosis. Juvenile frontal predominance; Alexander disease is characterized by difficulty with talking 2. A periventricular rim of decreased signal intensity on and swallowing and the inability to cough. There can also be T2-weighted images; weakness and spasticity of the extremities, particularly the 3. Elevated signal intensity on T1-weighted images; legs. Unlike the infantile form of the disease, mental ability 4. Abnormalities of the basal ganglia and thalami that and head size may be normal. Survival can extend several may include any of the following: elevated signal inten- years following the onset of symptoms, with occasional lon- sity and swelling; atrophy; elevated or decreased sig- ger survival into middle age. Mental function often slowly nal intensity on T2-weighted images; and brain stem declines, although in some cases, the intellectual skills remain abnormalities particularly involving the medulla and intact. The juvenile form generally leads to changes in the ; brain stem rather than in the brain. There are many Rosen- 5. Contrast enhancement of one or more of the follow- thal fibers (as in infantile Alexander Disease), but the lack ing: ventricular lining, periventricular rim, frontal white of is less prominent in the juvenile form than in the matter, optic chiasm, fornix, basal ganglia, thalamus, infantile form. dentate nucleus, and brain stem. Adult-onset Alexander disease is the rarest of the disease The availability of molecular genetic testing practically forms and is generally the most mild. Onset can occur any- eliminates the need for immunohistochemical staining of where from the late teens to very late in life. In older patients, brain biopsy material as a diagnostic tool even in very young ataxia often occurs and difficulties in speech articulation, infants. In addition, the diagnosis is confirmed by demon- swallowing, and sleep disturbances may occur. Symptoms strating a GFAP gene mutation. Although genetic testing is can be similar to those in juvenile disease, although the dis- not necessarily required for the diagnosis, genetic confirma- EAJM 2012; 44: 46-50 Ozkaya et al. Alexander Disease 49 tion should always be attempted due to the heterogeneity References of the disease and its presentation [20]. Prenatal testing for pregnancies that are at increased risk is possible if the 1. Alexander WS. Progressive fibrinoid degeneration of fibrillary disease-causing mutation has been identified in an affected astrocytes associated with mental retardation in a hydrocephal- family member. Increased levels of αβ-crystallin and heat ic infant. Brain 1949; 72: 373-81. [CrossRef] shock protein 27 have been observed in cerebrospinal fluid 2. Springer S, Erlewein R, Naegele T, et al. Alexander disease clas- sification revisited and isolation of neonatal form. Neuropediat- (CSF) of individuals with Alexander disease. Increased levels rics 2000; 31: 86-92. 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