Infantile Alexander disease: A rare leukodystrophy.

Infantile Alexander disease (AD) is a rare leukodystrophy characterized by its early onset within 2 years of life and clinically presents with macrocephaly, seizures, and retarded psychomotor development. Magnetic resonance imaging (MRI) shows characteristic symmetric white matter abnormalities with frontal predominance. We present a case of infantile AD with typical clinical characteristics and MRI features.

Introduction

Alexander disease (AD) is a rare, progressive non familial leukodystrophy affecting the central nervous system (CNS) white matter with frontal lobe preponderance.[1-3] The most distinctive pathological feature is widespread deposition of cytoplasmic inclusions, termed “Rosenthal fibers,” throughout CNS, mainly in perivascular, subpial, and subependymal astrocytes.[1245] The genetic basis is presence of mutations in the glial fibrillary acidic protein (GFAP) gene.[5] There are three clinical subgroups: Infantile, juvenile, and adult forms. The infantile form comprises about 51% of affected individuals, the juvenile form about 23%, and the adult form about 24%.[6] The infantile form usually presents within first 2 years of life and is characterized clinically by megalencephaly, developmental delay, psychomotor retardation, seizures, and a lethal progressive course.[2] Magnetic resonance imaging (MRI) is useful for diagnosis and shows extensive cerebral white matter changes with a frontal predominance and relative sparing of occipital and temporal white matter and in some patients abnormalities of the basal ganglia and the thalamus.[16] We present a case of infantile form of AD with typical clinical characteristics and MRI features.

Case Report

A one and half year old boy was brought with status epilepticus to emergency ward and treated with Lorazepam and Phenytoin. The child was the first issue of a non-consanguineous marriage, who was born after full term uneventful pregnancy. He had global developmental delay in the milestones. His fine and gross motor skills were consistent with 8-month level; and language and social skills were consistent with a 6-month level. There was no family history of seizures or neurological illness. At the age of 5 months, he developed generalized tonic–clonic seizures without fever for the first time and till the present admission he had three episodes of seizures (not on anticonvulsants). On examination, his head circumference was 48.2 cm (>95th centile) with frontal bossing [Figure 1], weight 9 kg and height 72 cm. He did not have any neurocutaneous markers. On neurologic examination, cranial nerves were normal, muscle strength and tone were normal, and deep tendon reflexes were brisk with bilateral plantar extensors. His fundus examination did not show any abnormality. Examination of other systems was unremarkable. His blood counts, serum electrolytes, renal and liver functions, blood glucose, serum calcium, phosphorous, magnesium, serum lactate, serum ammonia, cerebrospinal fluid (CSF) analysis, Electroencephalogram (EEG), and arterial blood gases were normal. His computed tomography (CT) scan of brain and urine chromatography was also normal. MRI brain with contrast: Diffuse white matter paucity and signal alteration predominantly involving bilateral frontal cortex also involving caudate nuclei, genu of internal capsule on T2-weighted with relative sparing of the temporo-occipital lobes. Magnetic resonance (MR) spectroscopy study of bilateral fronto-parietal cortex white matter shows decreased N-acetyl aspartic acid ratio values [Figure 1].

Figure 1

Diffuse white matter paucity and signal alteration predominantly involving bilateral frontal cortex also involving caudate nuclei, genu of internal capsule on T2-weighted with relative sparing of the temporo-occipital lobes. Spectroscopy showing decreased N-acetyl aspartic acid levels. There is macrocephaly with frontal bossing

Discussion

AD is a rare progressive neurodegenerative disorder occurring primarily in infants and children.[6] A characteristic histological feature of infantile AD is a nearly complete absence of myelin sheaths, which is most pronounced in the frontal white matter.[35]

The majority of patients present with macrocephaly with frontal bossing, developmental retardation, seizures, and spasticity before the age of 2 years, leading to rapid lethal course.[3] Our child also had macrocephaly with classical frontal bossing and presented to us with status epilepticus. Similar presentation with status epilepticus is reported by others also.[7] Cerebral white matter abnormalities, predominating in the frontal lobes, are typical of the infantile form of AD whereas nodular brainstem lesions and a kind of “garland” along the ventricular wall are seen, with contrast enhancement, in the juvenile form.[1] The diagnostic MRI imaging features established by Van der Knaap, et al. consisted of extensive white matter increased signal intensity on T2-weighted images, mainly in the frontal regions; a rim of periventricular T2 hypointensity; involvement of the basal ganglia, thalami, and brain stem; and post-contrast enhancement in the periventricular regions and scattered areas of the brain stem. In juvenile or adult forms MRI imaging pattern is remarkably different from that observed in infantile form, with predominant focal involvement of the lower brain stem.[1] MR spectroscopy shows decreased total N-acetyl-aspartate and N-acetyl-aspartyl-glutamate levels in the abnormal white matter in a study by Van der Voorn, et al.[3] Similar observation was made in our case also. None of the clinical or neurological findings is pathognomonic and the radiological picture is not diagnostic in all cases. The diagnosis of AD is strongly suggested by MRI and confirmed by GFAP gene analysis.[6] The diagnosis of AD is made on the basis of a combination of macrocephaly, clinical findings, and imaging findings, but definite diagnosis requires brain biopsy.[8] Our child was diagnosed as AD in view of macrocephaly, seizures, developmental delay in a young child with MRI findings. Brain biopsy was not done on humanitarian grounds and GFAP was not available. AD is usually considered in the differential diagnosis of infants who present with megalencephaly, developmental delay, and seizures.[6] The clinical picture mimics that of other neurological disorders like leukodystrophies, Canavan disease, mitochondrial myopathy, encephalopathy, lactic acidosis and stroke (MELAS), Leigh disease, glutaric aciduria, organic acidurias, and Zellweger syndrome.[6] In glutaric acidurias, early accelerated head growth with normal intellectual function can precede neurological deterioration and MRI shows selective frontotemporal atrophy especially involving subcortical white matter with prominent extra axial CSF collections.[69] In X-linked adrenoleukodystrophy, the white matter involvement is most severe in the parietal and occipital lobes.[6] In metachromatic leukodystrophy, MRI reveals a hyperintense signal in the periventricular and central white matter on T2-weighed images, which may initially be limited to parieto-occipital region and contrast enhancement is not a feature of this disease.[689] Canavan disease is characterized by a combination of macroencephaly, extensive cerebral white matter changes (without frontal preponderance), and basal ganglia abnormalities.[1] MR Spectroscopy may be diagnostic revealing an elevated N-acetyl aspartate to creatinine ratio.[9] In Krabbe disease, MRI demonstrates symmetric high-signal intensity areas in the deep white matter and abnormal signal intensity in the thalami.[8] In adrenoleukodystrophy, MRI shows symmetric confluent demyelination in the peritrigonal white matter and the corpus callosum and no abnormality of the periventricular white matter.[8] In Leigh disease, T2-weighted MRI image shows bilateral high-signal intensity areas in the putamen and globus pallidus.[8] The parietal and occipital lobes along with basal ganglia are frequently involved and follow-up MRI images may show resolution and subsequent reappearance of the abnormal areas in MELAS.[8] MRI shows diffuse cerebral white matter swelling with appearance of subcortical cysts, particularly in the frontotemporal regions in vacuolating megalencephalic leukoencephalopathy with subcortical cysts.[1] To conclude, AD should be kept in mind in a young macrocephalic child with developmental delay and MRI throws the light for the diagnosis.