A Rare Case of Adult-Onset Vanishing White Matter Leukoencephalopathy With Movement Disorder

doi:10.21203/rs.3.rs-5241534/v1

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Case Report

A Rare Case of Adult-Onset Vanishing White Matter Leukoencephalopathy With Movement Disorder

https://doi.org/10.21203/rs.3.rs-5241534/v1

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Background:

Vanishing white matter disease (VWMD) is a rare autosomal recessive leukoencephalopathy. It is typified by a gradual loss of white matter in the brain and spinal cord, which results in impairments in vision and hearing, cerebellar ataxia, muscular weakness, stiffness, seizures, and dysarthria cogitative decline. The majority of reports involve minors. Very few instances worldwide have been reported, with adult onset of vanishing white matter considered to account for 15% of cases. Clinical evaluation, MRI results, and confirmatory genetic testing are used to diagnose VWMD.

Case presentation:

A 39-year-old male from Hebron, Palestine, presented with a 7-month history of postural instability, imbalanced gait, and progressive deterioration of his lower extremities. Additionally, the patient suffered from ocular abnormalities and sphincteric issues. The patient's sibling showed comparable symptoms but was never diagnosed, as he passed away as a result of colon cancer, as per his family history. Reduced cognitive function, spastic quadriparesis, hyperreflexia, bradykinesia, and shuffling gait were found during a neurological examination. Normal results were obtained from routine laboratory tests, including cerebrospinal fluid (CSF), blood, and urine. Periventricular white matter hyperintensities, which are indicative of vanishing white matter leukoencephalopathy (VWML), were identified during an MRI. The diagnosis of adult-onset VWML with movement disability was substantiated by genetic testing, which named a homozygous pathogenic missense mutation, EIF2B3, and a deletion in PRKN/PARK2. The patient's motor symptoms were temporarily alleviated following the administration of Levodopa/Carbidopa. Nevertheless, the long-term consequences are uncertain due to the illness's ongoing progression and the absence of a cure at this time.

Conclusion:

This instance of vanishing white matter leukoencephalopathy (VWML) is particularly remarkable in adults because of its rarity and complexity. The diagnosis is further complicated by the coexistence of Parkinsonism and VWML. Although a cure is not currently known. Early discovery is crucial to effectively manage symptoms. This example underscores the importance of more VWML research, particularly in Palestine, where studies on neurological disorders are limited. These findings underscore the importance of enhancing the region's diagnostic and therapeutic capabilities.

Vanishing white matter leukoencephalopathy (VWML)

Vanishing white matter disease (VWMD)

Movement disorder.

Vanishing white matter disease (VWMD) is a rare autosomal recessive leukoencephalopathy. It is characterized by the progressive loss of white matter in the brain and spinal cord, which leads to cerebellar ataxia, muscle weakness, spasticity, seizures, dysarthria, cogitative decline, and vision and hearing impairments. It is mostly reported in children as a congenital form or early to late childhood-onset type, with an incidence ranging from 1.2 to 3 per 100,000 people per year or 1 in 80,000 live births.(1, 2)

The adult onset of vanishing white matter is thought to account for 15% of cases, so only a few cases have been documented around the world.(1)However, cognitive decline and behavioral symptoms are more prominent in adults, and motor impairment is less severe. In addition, disease progression is slower, and acute episodes are less common but still possible.(3)

Mutations in one of the five eukaryotic translation initiation factor 2B (eIF2B) genes, with eIF2B5 mutations being the most common, follow an autosomal recessive pattern. eIF2 starts the translation of mRNAs into polypeptides by forming a ternary complex with GTP and methionyl-transfer RNA (MettRNAi). One crucial stage in the regulation of protein synthesis under a range of stress conditions is the translation start point. The cellular stress response, a defensive mechanism that helps cells survive by limiting the accumulation of denatured proteins and preserving energy, involves the inhibition of protein synthesis. When eIF2B genes are altered, this mechanism is dysregulated, particularly impairing myelination and damaging oligodendrocytes and astrocytes while protecting neurons. (1, 4)

Stressful situations such as head trauma, sudden frightness, acute psychological stress, or infection provoke severe and rapid neurological deterioration (1). VWMD is a combination of clinical assessment, MRI findings, and confirmatory genetic testing. MRI changes in white matter are key to suspecting VWMD, and genetic testing provides a definitive diagnosis.(2)

In light of its rarity, we report a case of a 39-year-old male who presented to our clinic with lower limb weakness, postural instability, cognitive decline, and other symptoms. Imaging and genetic studies were performed on the patient, which they have confirmed the diagnosis of adult-onset vanishing white matter leukoencephalopathy with movement disorders. This case is believed to be the first case reported in Palestine.

A 39-year-old male from Palestine lived in Hebron. The patient presented to our clinic with a 7-month history of progressive worsening of lower limb weakness, gait imbalance, and postural instability. The patient had no significant medical or surgical history. In terms of family history, the patient reported that he had a brother who died recently due to colon cancer, for which he had the same presenting symptoms as our patient but had never been diagnosed. The symptoms of our patient started subtly and started to progressively worsen slowly over time. The patient also complained of visual disturbances that occurred over time; in addition, the patient complained of sphincteric disorders that occurred during the period of disease progression.

On neurological examination, the patient had a stooped posture, bradykinesia, a shuffling gait, and rigidity. In addition, the patient also had spastic weakness in both the upper and lower limbs (spastic quadriparesis) with hyperreflexia and a positive Babinski sign. On a mental examination, the patient had decreased mental ability and cognition. Cranial nerve examination and sensation were normal.

Owing to worsening symptoms, the patient was admitted to our hospital, and an extensive range of tests was performed. Routine laboratory tests, including blood, urine, and cerebrospinal fluid (CSF) tests, were performed, and the results were within normal limits. The screening results for endocrine and immunologic disorders were negative. Neuroimaging was performed with magnetic resonance imaging (MRI), which revealed confluent areas of periventricular white matter hyperintensities in T2 and fluid-attenuated inversion recovery (FLAIR) sequence (Fig. 1). These findings were consistent with vanishing white matter leukoencephalopathy (VWML). Genetic testing revealed an EIF2B3 gene mutation and a PRKN/PARK2 gene mutation (Table 1).

Figure 1: uploaded in a separate file

Table 1

Primary Findings
Gene	Nomenclature	Consequence	Genotype	Classification
EIF2B3	c.687T > G, p.(Ile229Met)	Missense variant	Homozygous	Likely pathogenic
PRKN	c.(412 + 1_413-1)_(534 + 1_535-1)del	Deletion	Homozygous	pathogenic
This table represents the primary findings that are seen in the whole exome test, which consists of a sequence analysis of all protein-coding genes in the genome for the proband, coupled with whole exome deletion/duplication analysis.

On the basis of the patient's history, physical examination, neurological imaging, and genetic testing, a diagnosis of vanishing white matter leukoencephalopathy (VWML) with a movement disorder was confirmed. The patient was discharged only on Levodopa/Carbidopa since there is no cure for vanishing white matter leukoencephalopathy (VWML). The patient's motor symptoms improved in the short term, but we cannot suspect long-term outcomes as the patient's disease is progressive and there is no available curative treatment for his condition.

Our case report involves a 39-year-old gentleman from Palestine who was diagnosed with adult-onset vanishing white matter disease (VWMD) with movement disorders. Over seven months, he experienced a gradual decline in weakness in his lower limbs, difficulties with balance, visual disturbances, and issues related to sphincter control.

Owing to their relative rarity, varied presentations, and perceived diagnostic challenges, the adult leukodystrophy spectrum is less understood than the child spectrum is because of the greater proportion of confounding mimics such as multiple sclerosis and small vessel disease. The epidemiology of adult leukodystrophies also differs. In a cohort study performed in Europe in 2015 with 154 patients, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was the most common diagnosis (33%), followed by vanishing white matter disease (VWMD), X-linked adrenoleukodystrophy (X-ALD), and Collagen type IV alpha 1 chain(COL4A1) related disorders. (5)Currently, VWMD is increasingly recognized in adulthood, manifesting large phenotypical and severe variability, with the latest known onset of disease being 55 years. Late-

onset VWMD corresponds to 15% of all described cases. (6) In the context of Palestine, this case is exceptionally rare, as studies addressing VWMD and its manifestations in the adult population are scarce. The limited research on neurological disorders in Palestine underscores the need for more comprehensive studies to understand the prevalence and characteristics of such conditions within the region.

VWMD in adults is defined as rare progressive leukodystrophy that affects only the white matter of the brain via autosomal recessive mutations in one of the five eukaryotic translation initiation factor 2B (EIF2B) genes, particularly EIF2B5, that are responsible for this condition, leading to defects in protein translation initiation and the regulation of protein synthesis. Myelination is impaired as a result of disruption of the cellular stress response, which affects astrocytes and oligodendrocytes but not neurons. This frequently leads to a rapid and severe neurological decline that is induced by stressors such as infection, minor head trauma, acute psychological stress, or sudden fright.(7, 8) Adult-onset VWM typically presents with milder symptoms and a slower decline in neurological function, with a focus on cognitive impairments rather than the motor disabilities prevalent in early-onset cases. Seizures and episodic exacerbations are crucial to disease progression in all patients, underscoring the need for effective seizure management and prevention strategies, including infection control, head injury prevention, and keeping emotional stability.(9)

The symptoms presented by our patient resonate with findings from recent studies that have documented similar motor and cognitive challenges. What makes this case particularly intriguing is the identification of both EIF2B3 and PRKN/PARK2 mutations, which have not often been reported together in adults. While previous studies have noted isolated instances of VWMD linked to EIF2B mutations, the combination of VWMD with PRKN mutations adds a fresh perspective to our understanding of this complex disease. The PRKN mutation, which is commonly associated with Parkinson's disease, may explain some of the motor symptoms seen in this patient, suggesting a potential overlap in the underlying mechanisms of these disorders.(10) Understanding these pathophysiological links is crucial for developing targeted therapies in the future.

Diagnosing VWMD can be quite challenging because its symptoms overlap with those of various neurological disorders. In this particular case, we had to consider differential diagnoses such as multiple sclerosis and other leukodystrophies. Advanced neuroimaging techniques, particularly MRI, play a pivotal role in revealing the characteristic periventricular white matter hyperintensities associated with VWMD.(11) confirmation through genetic testing further emphasizes the necessity of a thorough diagnostic approach, especially for atypical presentations.

To manage this case, we opted for symptomatic treatment with Levodopa/Carbidopa, which led to noticeable improvements in the patient's motor symptoms. This choice aligns with literature suggesting that dopaminergic treatment can be beneficial for patients with movement disorders linked to PRKN mutations.(12), While we did not explore alternative treatments targeting the integrated stress response, such avenues are still promising for future management strategies. Following treatment, the patient showed short-term improvements in motor function. However, long-term outcomes stay uncertain, as VWMD is a progressive disorder with a highly variable prognosis. The literature writes down that early intervention and a multidisciplinary approach can significantly enhance quality of life and functional independence. Factors such as the extent of neurological involvement and the presence of genetic mutations are likely to influence patient's prognosis.(13)

Our case report contributes valuable insights into the recognition of adult-onset VWMD and the implications of genetic mutations in its clinical presentation. This underscores the importance of considering genetic testing for patients showing atypical neurological symptoms, particularly when there is a family history of similar conditions. Furthermore, this case highlights the necessity of a multidisciplinary approach to improve patient care and management.

This case is particularly noteworthy because of the rarity and complexity of vanishing white matter leukoencephalopathy (VWML), particularly in adult populations. vanishing white matter leukoencephalopathy (VWML) is often associated with children; however, when it occurs in adults and is characterized by added symptoms such as parkinsonism, it becomes even rarer and more challenging to diagnose. Although there is currently no treatment, early discovery is imperative to manage symptoms and prevent the occurrence of more issues. The importance of giving information about vanishing white matter leukoencephalopathy (VWML) is underscored by this narrative, particularly in regions such as Palestine where there is a chronic shortage of neurological disease research. The need for more comprehensive investigations in this field is underscored by the scarcity of research on vanishing white matter leukoencephalopathy (VWML) in adult Palestinians. This paper advances knowledge about vanishing white matter leukoencephalopathy (VWML) and encourages the development of more medical resources and research in Palestine to improve the capacity for diagnosis and treatment of neurological disorders in patients by focusing on this unique occurrence.

VWMD

Vanishing white matter disease

VWML

Vanishing white matter leukoencephalopathy

eIF2B

Eukaryotic translation initiation factor 2B

MRI

Magnetic resonance imaging

CSF

Cerebrospinal Fluid

FLAIR

Fluid-attenuated inversion recovery

Acknowledgments

We thank the patient for giving consent for publication. The authors would like to thank Al-Quds University for proof-reading and revising our manuscript.

Authors’ contributions

BD contributed to handling manuscript formation and data collection. YA, NA & MA contributed to the study design and analyzing data. IA contributed to the supervision of the case report. All authors read and approved the final manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and materials

The data generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Ethics approval and consent to participate

Ethics approval for this study was obtained from the ethics committee of Al-Quds University, and informed consent was provided by the patient involved.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report.

Competing interests

The authors declare that they have no competing interests.

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No competing interests reported.

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You are reading this latest preprint version

A Rare Case of Adult-Onset Vanishing White Matter Leukoencephalopathy With Movement Disorder

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Abstract

Background:

Case presentation:

Conclusion:

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Background

Case presentation

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