Atypical Presentation of Alexander Disease in a 4-Month-Old Infant: Emphasizing the Importance of Integrated Genetic and Biochemical Testing
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Alexander disease (AxD) is a rare and often fatal neurodegenerative disorder that primarily affects the white matter of the brain, a condition known as leukoencephalopathy. This disease is caused by mutations in the GFAP gene, responsible for encoding the glial fibrillary acidic protein, a crucial component of astrocytes. Astrocytes play a critical role in supporting and protecting neurons in the central nervous system, and their dysfunction, resulting from GFAP mutations, leads to the white matter abnormalities and neurological impairments characteristic of AxD.
AxD typically presents in infancy or early childhood, and its recognition can be challenging due to the broad spectrum of symptoms and its similarity to other neurological disorders. As a result, diagnosis is often difficult and usually requires genetic testing. Variants of uncertain significance in the GFAP gene can further complicate the diagnosis, necessitating biochemical testing for confirmation. Here, we present a case that illustrates the difficulties in determining whether a variant of uncertain significance (VUS) is pathogenic.
Case Presentation
This report describes a 4-month-old male who presented with explosive onset seizures, hypotonia, and microcephaly. Initial assessments suggested post-infectious encephalitis, but extensive investigations for infectious, metabolic, mitochondrial, and autoimmune etiologies were inconclusive.
Diagnostic Workup
Initial brain MRI revealed multifocal areas of T2 hyperintensity with varying degrees of enhancement affecting the cortex, basal ganglia, brainstem, and cerebellum. CSF analysis showed elevated protein levels. Subsequent MRIs showed progressive, bilateral T2/FLAIR hyperintensity and ventricular dilation. Whole genome sequencing identified a variant of uncertain significance (VUS) in the GFAP gene. Parental testing was not possible as the patient originated from a donor embryo.
Treatment and Management
The patient initially received Acyclovir, Ceftriaxone, and Vancomycin for suspected encephalitis. Seizures were managed with Keppra, Vimpat, and clonazepam. After a second admission for breakthrough seizures and poor feeding, he received methylprednisolone, leading to improved feeding and growth. IVIG was added due to the positive response to steroids.
Outcome and Follow-Up
Subsequent attempts to taper steroids resulted in worsening seizures. The patient remained on a low dose of prednisolone, lacosamide, and clobazam. Parents deferred attempts to initiate a ketogenic diet.
Discussion
The case highlights the importance of considering AxD in neonatal leukoencephalopathy, even with atypical presentations like microcephaly. The significance of combining genetic and biochemical testing is emphasized, especially when genetic findings are inconclusive. Biochemical testing confirmed the diagnosis of AxD by revealing elevated serum and CSF GFAP levels, solidifying the VUS as a pathogenic variant.
Conclusion
This case underscores the need for integrated genetic and biochemical testing in diagnosing leukoencephalopathies. It emphasizes the value of a comprehensive approach for timely diagnosis, particularly given AxD's potential for rapid progression and high mortality rate in infancy. The ethical considerations surrounding VUS interpretation and their impact on management decisions and prognostic information are also highlighted.
Alexander disease (AxD) is a rare and often fatal neurodegenerative disorder that primarily affects the white matter of the brain, a condition known as leukoencephalopathy. This disease is caused by mutations in the GFAP gene, responsible for encoding the glial fibrillary acidic protein, a crucial component of astrocytes. Astrocytes play a critical role in supporting and protecting neurons in the central nervous system, and their dysfunction, resulting from GFAP mutations, leads to the white matter abnormalities and neurological impairments characteristic of AxD.
AxD typically presents in infancy or early childhood, and its recognition can be challenging due to the broad spectrum of symptoms and its similarity to other neurological disorders. As a result, diagnosis is often difficult and usually requires genetic testing. Variants of uncertain significance in the GFAP gene can further complicate the diagnosis, necessitating biochemical testing for confirmation. Here, we present a case that illustrates the difficulties in determining whether a variant of uncertain significance (VUS) is pathogenic.
Case Presentation
This report describes a 4-month-old male who presented with explosive onset seizures, hypotonia, and microcephaly. Initial assessments suggested post-infectious encephalitis, but extensive investigations for infectious, metabolic, mitochondrial, and autoimmune etiologies were inconclusive.
Diagnostic Workup
Initial brain MRI revealed multifocal areas of T2 hyperintensity with varying degrees of enhancement affecting the cortex, basal ganglia, brainstem, and cerebellum. CSF analysis showed elevated protein levels. Subsequent MRIs showed progressive, bilateral T2/FLAIR hyperintensity and ventricular dilation. Whole genome sequencing identified a variant of uncertain significance (VUS) in the GFAP gene. Parental testing was not possible as the patient originated from a donor embryo.
Treatment and Management
The patient initially received Acyclovir, Ceftriaxone, and Vancomycin for suspected encephalitis. Seizures were managed with Keppra, Vimpat, and clonazepam. After a second admission for breakthrough seizures and poor feeding, he received methylprednisolone, leading to improved feeding and growth. IVIG was added due to the positive response to steroids.
Outcome and Follow-Up
Subsequent attempts to taper steroids resulted in worsening seizures. The patient remained on a low dose of prednisolone, lacosamide, and clobazam. Parents deferred attempts to initiate a ketogenic diet.
Discussion
The case highlights the importance of considering AxD in neonatal leukoencephalopathy, even with atypical presentations like microcephaly. The significance of combining genetic and biochemical testing is emphasized, especially when genetic findings are inconclusive. Biochemical testing confirmed the diagnosis of AxD by revealing elevated serum and CSF GFAP levels, solidifying the VUS as a pathogenic variant.
Conclusion
This case underscores the need for integrated genetic and biochemical testing in diagnosing leukoencephalopathies. It emphasizes the value of a comprehensive approach for timely diagnosis, particularly given AxD's potential for rapid progression and high mortality rate in infancy. The ethical considerations surrounding VUS interpretation and their impact on management decisions and prognostic information are also highlighted.