Genetic Diseases Mimicking Multiple Sclerosis: Unraveling the Diagnostic Challenge

Multiple sclerosis (MS) is a complex inflammatory neurodegenerative disorder that primarily affects the central nervous system (CNS). The characteristic demyelination of neurons in MS leads to symptoms such as muscle weakness, sensory disturbances, and vision problems. However, diagnosing MS can be a challenging task, especially when genetic disorders present with overlapping clinical features. This blog post explores key genetic diseases that mimic MS, as discussed in the comprehensive review by Chueh Lin Hsu et al. (2021).

Understanding Multiple Sclerosis
MS is associated with environmental, genetic, and infectious risk factors. The Epstein-Barr virus (EBV) and vitamin D levels are among the commonly cited contributors to MS. The autoimmune theory of MS remains widely accepted, where T cells, upon activation, infiltrate the CNS and attack oligodendrocytes, the cells responsible for maintaining myelin sheaths around neurons. As a result, symptoms of demyelination appear, including muscle weakness, sensory dysfunction, and cognitive impairment.

The diagnosis of MS is often made based on the McDonald criteria, which emphasize lesion dissemination in space and time, as well as the presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF). Nevertheless, several genetic diseases share clinical and imaging features with MS, leading to misdiagnoses. Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
CADASIL is a hereditary stroke disorder caused by mutations in the NOTCH3 gene. Clinically, CADASIL manifests with migraines, transient ischemic attacks, and cognitive decline—symptoms that may resemble MS. Magnetic resonance imaging (MRI) often shows confluent deep white matter hyperintensities, which can be confused with MS lesions. However, the absence of Dawson’s fingers, a hallmark of MS, and the presence of O’Sullivan signs in CADASIL serve as distinguishing features. The definitive diagnosis of CADASIL requires NOTCH3 gene sequencing or a skin biopsy.

Adult-Onset Krabbe Disease (AOKD)
Krabbe disease, or globoid cell leukodystrophy, is another genetic disorder that can mimic MS. Adult-onset Krabbe disease presents with spasticity, vision problems, and weakness, which are common in MS. However, MRI patterns differ, with Krabbe disease showing hyperintensities in the corticospinal tracts and sparing of subcortical U-fibers, unlike typical MS lesions. Additionally, CSF analysis in Krabbe disease patients reveals elevated protein levels but no oligoclonal bands, unlike MS.

X-Linked Adrenoleukodystrophy (X-ALD)
X-ALD is caused by mutations in the ABCD1 gene, which leads to the buildup of very long-chain fatty acids that damage myelin. Males are more commonly affected, and clinical presentations may include spastic paraparesis and voiding disturbances, which can be mistaken for MS. While cerebral demyelination in X-ALD may resemble MS, adrenal insufficiency and early baldness in male patients often point to an X-ALD diagnosis. Genetic testing for ABCD1 mutations is essential for confirmation.

Fabry Disease
Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene. Neurological manifestations such as pain attacks, ataxia, and hearing loss can mimic MS. MRI findings may show white matter hyperintensities similar to MS, but the absence of infratentorial lesions in Fabry disease serves as a clue for differentiation. Additionally, genetic testing for GLA mutations is critical in establishing the diagnosis, especially in female patients with normal or low alpha-galactosidase A enzyme activity.

Vanishing White Matter Disease (VWD)
VWD, a genetic disorder caused by mutations in the EIF2B genes, leads to the progressive loss of white matter in the brain. While it shares symptoms with MS, including ataxia, spasticity, and seizures, MRI findings in VWD reveal anterior brain cavitary lesions, which are not seen in MS. Furthermore, VWD does not typically present with oligoclonal bands, helping to distinguish it from MS.

Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS)
HDLS is an autosomal-dominant disorder resulting from mutations in the CSF1R gene. The clinical symptoms of HDLS, such as cognitive decline, spasticity, and seizures, can mimic MS. However, MRI findings in HDLS typically show frontoparietal hyperintensities and corpus callosum atrophy, which can differentiate it from MS, where occipitotemporal lesions are more common. Genetic testing for CSF1R mutations confirms the diagnosis.

Conclusion
The overlap in clinical and imaging features between MS and certain genetic disorders highlights the importance of thorough diagnostic evaluations. Utilizing genetic testing, MRI, and CSF analysis is crucial in distinguishing between MS and its genetic mimics. Early and accurate diagnosis ensures appropriate management and prevents the potentially severe consequences of delayed or incorrect treatment.

References:
Hsu, C. L., Iwanowski, P., Hsu, C. H., & Kozubski, W. (2021). Genetic diseases mimicking multiple sclerosis. Postgraduate Medicine.