
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.67050
Neurology
Preventive Medicine
Pediatrics
A Rare Case of Vanishing White Matter Disease
Muacevic Alexander
Adler John R
Thakur Mrinali 1
Pande Vineeta 1
Mane Shailaja V 1
1 Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Center, Dr. D. Y. Patil Vidyapeeth (Deemed to Be University), Pune, IND
Vineeta Pande drvineetapande@gmail.com
17 8 2024
8 2024
16 8 e6705019 7 2024
17 8 2024
Copyright © 2024, Thakur et al.
2024
Thakur et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/279963-a-rare-case-of-vanishing-white-matter-disease
Vanishing white matter disease (VWMD), also known as childhood ataxia with central hypoventilation, is a rare leukodystrophy that is inherited in an autosomal recessive manner. It is triggered by either traumatic brain injury or a febrile episode.

The patient was a three-year-old male child who presented with complaints of fever and diarrhea for three days, along with a paucity of movements of both upper and lower limbs, with decreased tone and diminished reflexes. Previously the child had normal developmental milestones. MRI done showed T2 hyperintensities involving bilateral peri-ventricular white matter, deep white matter, and bilateral sub-cortical U-fibres in bilateral fronto-parietal region and bilateral cerebellar hemispheres. The bilateral external capsule and posterior limb of the internal capsule were also involved. All these findings were likely suggestive of leukodystrophy. Whole exome sequencing was done and a homozygous mutation of the eIF2B5 was noted, which confirmed the diagnosis of VWMD.

The physician must keep in mind this diagnosis in cases of sudden motor abnormalities following any event and proceed for early management such as controlling febrile episodes with liberal use of antibiotics and antipyretics, along with prevention of traumatic brain injury or any stressful event. There is no definitive treatment. Management of these patients includes symptomatic and supportive care. Patients with this disease (VMND) have a poor quality of life as the disease progresses and eventually, death occurs.

rare
sudden onset
leukodystrophy
cach
vwmd
==== Body
pmcIntroduction

Vanishing white matter disease (VWMD), also known as childhood ataxia with central hypoventilation, is a rare form of leukodystrophy inherited in an autosomal recessive pattern. It is mainly caused by a mutation in any of the five genes that encode the subunits of the eukaryotic translation initiation factor (eIF2B) [1]. It can be triggered by a traumatic brain injury or a febrile episode. The age of onset ranges from infancy to adulthood. It is reported to have an incidence of 1.2-3.01 per one lakh population per year [2]. VWMD can present as a congenital or early-to-late childhood-onset form. There are even fewer cases reported in India [3-5]. It has been noted to have triggering factors such as traumatic brain injury, febrile episodes, vaccinations, and stressful and frightening conditions. Recent analysis of cerebrospinal fluid in cases of VWMD has shown a consistent elevation of glycine concentration and a ratio of cerebrospinal fluid to plasma glycine concentrations [6], and asialotransferrin levels can be used as biomarkers in cerebrospinal fluid [7,8]. The patient in this case is a three-year-old male child who presented with complaints of fever and diarrhea for three days, along with paucity of movements of both upper and lower limbs, decreased tone, and diminished reflexes.

Case presentation

The patient was a three-year-old male child, who presented with complaints of fever and diarrhea for three days, along with a paucity of movements of both upper and lower limbs. The child was born out of a second-degree consanguineous marriage with no significant antenatal history or birth history. The child had been immunized till 18 months of age according to the Indian Academy of Pediatrics (IAP) immunization guidelines. The child had attained all milestones till the age of three years in all four domains. On general examination, the child was afebrile and vitally stable. Anthropometric measurements of the child were within normal limits. On neurological examination, the child had an intact sensorium with a Glasgow Coma Scale (GCS) score of 14/15, pupils were reactive to light but decreased tone and diminished reflexes were noted in all four limbs. Power was grade 3 in all 4 limbs. The cranial nerve examination was normal. Other systemic examinations were within normal limits. Diarrhea was treated with antibiotics and laboratory investigations showed the following: whole blood report was suggestive of mild leucopenia along with a normal CRP and no other markers of fever/sepsis were positive. Raised liver enzymes were noted. Dengue and malaria were negative. This is shown in Table 1.

Table 1 Hematological investigations on admission

Parameters	Results	Normal range	
Hemoglobin	11.3 gm/dl	11-14.5 gm/dl	
Total leucocytes count	3400/µL	4000-12000/µL	
Platelets	253000/µL	150000-410000/µL	
Neutrophils	54%	-	
Lymphocytes	40%	-	
Monocytes	6%	-	
C-reactive protein	3.2 mg/Lt	<3 mg/Lt	
Aspartate aminotransferase	353 U/Lt	8-60 U/Lt	
Alanine aminotransferase	186 U/Lt	7-55 U/Lt	
Ammonia	35 /µL	2-120 /µL	
Lactate	3.6 mg/dl	3.6-18 mg/dl	
Malaria	Plasmodium vivax: negative; Plasmodium falciparum: negative	-	
Dengue	IgM: negative; IgG: negative; NS1: negative	-	

MRI brain was done, because of the acute onset of symptoms, with the central nervous system involved. It revealed a reduction in the volume of white matter in bilateral centrum semiovale and in the deep periventricular location with associated altered signal intensity appearing hyperintense on T2-weighted fluid-attenuated inversion recovery (T2 W/FLAIR) images, which was suggestive of leukodystrophy. Differential diagnosis included all leukodystrophies such as Alexander disease, VWMD, Canavan disease, Krabbe disease, and metachromatic leukodystrophy.

Whole exome sequencing was done for a confirmatory diagnosis which showed a homozygous variant of EIF2B5 on exon 7, known to cause leukoencephalopathy with VWMD (Table 2).

Table 2 Whole Exome Sequencing

Gene and transcript	Exon/intron number	Variant nomenclature	Zygosity	Classification	Disease	Inheritance	
EIF2B5	Exon 7	c.1135A>T p.lle379Phe	Homozygous	Uncertain significance	Leuko-encephalopathy with vanishing white matter	Autosomal recessive	

A nerve conduction test was done for all four limbs which turned out to be normal.

The child was managed conservatively as there is no definitive treatment available and was discharged on supplements and physiotherapy exercises. Parents were counseled about the condition and its genetic implications. The importance of control of febrile episodes and the use of antipyretics to prevent progression was explained.

After eight months of diagnosis, the child presented to the hospital with an episode of febrile illness lasting three days, following which the child had further deterioration of the sensorium and shallow breathing. On examination, the child had a GCS of 7/15 with decreased breathing efforts. Vitally, the child had a high-grade fever with bradypnea. On neurological examination, bilateral pupils were reactive to light, and the cranial nerve examination was normal. Upper and lower limbs were hypertonic, and spasticity was noted along with exaggerated reflexes. Other systematic examinations were not significant. The child was intubated and mechanically ventilated, started on antibiotics to treat the infection, and started on antipyretics to control the fever. During the course of admission, the child had an episode of generalized tonic-clonic seizure, for which an antiepileptic was given to the child.

A repeat MRI was done that was suggestive of multiple Ill-defined confluent T2 hyperintensities involving bilateral peri-ventricular white matter, deep white matter, and bilateral sub-cortical U-fibres in the bilateral fronto-parietal region and bilateral cerebellar hemispheres involving white matter and bilateral brachium pontis. The tigroid appearance was noted due to sparing of periventricular white matter, bilateral external capsule and posterior limb of internal capsule are involved, and subtle diffusion restriction in the splenium of corpus callosum and along lateral margins of white matter hyperintensity in both cerebral hemispheres (Figure 1).

Figure 1 MRI showing (a) multiple ill-defined confluent T2 hyperintensities involving bilateral peri-ventricular white matter, deep white matter, and the bilateral fronto-parietal region. Tigroid appearance noted due to sparing of periventricular white matter; the bilateral external capsule and posterior limb of the internal capsule are involved; and subtle diffusion restriction in the splenium of the corpus callosum and along the lateral margins of white matter hyperintensity in both cerebral hemispheres; (b) bilateral cerebellar hemispheres involving white matter. All these findings support the diagnosis of vanishing white matter disease

The presence of fever with acute neurological symptoms and specific neurological findings point toward VWMD.

The child was on mechanical ventilation for five days. He was weaned of ventilation and managed with supportive care and supplements. The child was discharged on day 20 of hospitalization.

Discussion

The incidence of VWMD ranges from 1.2 to 3.01 per 100,000 people per year [2]. The disease is known to affect children and adults. This fatal disease has been associated with various comorbidities. The range of presentation of the disease includes 1) prenatal/congenital form, 2) subacute infantile form where age is <1 year, 3) early childhood onset form with age between 1 and <4 years, 4) a juvenile-onset form with age between >4 and 18 years, and 5) an adult-onset form where age is ≥18 years. Severe encephalopathy has been noted in the congenital/prenatal form. Patients who present with later-onset forms have an initial normal motor and intellectual development, followed by a sudden neurologic deterioration that has a chronically progressive or subacute course. Motor deterioration is more prominent in the early childhood onset form of cognitive decline, and personality changes are dominant in the adult onset form. The rapid deterioration in the clinical condition is noted during febrile illnesses, following head trauma or major surgical procedures, or by acute and extreme fright [9]. The case presented had similar findings, where initial deterioration started following a febrile episode.

A diagnostic criterion has been proposed where four important features have been noticed: first, a normal or near-normal initial psychomotor development; second, the onset of neurologic deterioration following any event such as traumatic brain injury or febrile episodes that occur in childhood; third, neurologic signs include cerebellar ataxia, spasticity, epilepsy (not always), optic atrophy (not always), and motor functions disproportionately affected; and fourth, an MRI showing bilateral and symmetric cerebral hemispheric white matter signal intensity similar to cerebrospinal fluid. All four criteria should be identified for diagnosis [10]. Findings in the patient were crucial in ruling out other potential diagnoses and confirming VWMD.

The histology of VWMD reveals several key features: rarefaction of deep white matter, microcystic changes in periventricular white matter, spongiform changes in arcuate fibers and the corpus callosum, and the absence of neuronal loss. These pathological changes are characterized by astrocytic dysfunction [11].

There is no definitive cure for VWMD. Only comprehensive medical care helps the child have a better life in terms of quality, which includes avoiding unnecessary suffering and complications. With each febrile episode or traumatic episode, there is further injury to the brain, and mortality is seen within months to years. Hence, it is important to use antipyretics liberally. Targeted therapy has been researched, which targets eIF2B enzymes, and guanabenz has shown promising results that help in motor performance and brain pathology in animal studies [12,13]. Genetic counseling should be provided to the parents. Ongoing studies that analyze cerebrospinal fluid in cases of VWMD have shown a consistent elevation of glycine concentration with an elevated ratio of cerebrospinal fluid to plasma glycine concentrations [6] and biomarkers such as a decreased level of asialotransferrin levels in cerebrospinal fluid [7,8].

Outcome and follow-up

The disease usually starts at a median age of three to four years; 60% of the cases are symptomatic [14]. Motor symptoms are more common in childhood-onset forms, while cognitive problems are more common in adolescent and adult-onset forms. An analysis revealed that mortality is around 13% in cases where the onset is <2 years of age, which is usually after an acute event [14].

Conclusions

The VWMD, though rare, should be kept in mind while examining cases of sudden motor difficulty following head trauma or other events. The specific MRI characteristics (such as T2 hyperintensities and the involvement of specific brain regions) and the EIF2B5 mutation are hallmark features that confirmed the diagnosis. Avoiding stressful events such as vaccination, absenteeism from contact sports, and liberal use of antipyretics and antibiotics along with anti-seizure medication is advised, which would prevent the progression of the disease. It has no definitive treatment. Only symptomatic and preventive measures can be given; hence, it is essential to diagnose the disease the disease early and counsel parents regarding its progression. Hence, the early recognition of symptoms (such as the acute onset of neurological issues following a febrile episode) helps with better outcomes, even though the disease is progressive and ultimately fatal. Physicians should also help parents improve the quality of life of their children by providing a comprehensive management plan.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Mrinali Thakur, Vineeta Pande, Shailaja V. Mane

Acquisition, analysis, or interpretation of data:  Mrinali Thakur, Vineeta Pande, Shailaja V. Mane

Drafting of the manuscript:  Mrinali Thakur, Vineeta Pande, Shailaja V. Mane

Critical review of the manuscript for important intellectual content:  Mrinali Thakur, Vineeta Pande, Shailaja V. Mane
==== Refs
References

1 Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter Ann Neurol van der Knaap MS Leegwater PA Könst AA 264 270 51 2002 11835386
2 Vanishing white matter disease Lancet Neurol van der Knaap MS Pronk JC Scheper GC 413 423 5(5) 2006 16632312
3 Profile of Indian children with childhood ataxia and central nervous system hypomyelination/vanishing white matter disease: a single center experience from southern India J Pediatr Genet Gowda VK Srinivasan VM Nagarajan B Bhat M Shivappa SK Benakappa N 205 212 10 2021 34504724
4 The spectrum of leukodystrophies in children: experience at a tertiary care centre from North India Ann Indian Acad Neurol Gulati S Jain P Chakrabarty B Kumar A Gupta N Kabra M 332 338 19 2016 27570384
5 Vanishing white matter disease: phenotypic, MR imaging and 1H spectroscopic observations Ann Indian Acad Neurol Ravishankar S Sinha S Taly AB 172 174 9(3) Jul-Sep 2006
6 Increased cerebrospinal fluid glycine: a biochemical marker for a leukoencephalopathy with vanishing white matter J Child Neurol van der Knaap MS Wevers RA Kure S Gabreëls FJ Verhoeven NM van Raaij-Selten B Jaeken J 728 731 14 1999 10593550
7 Decreased asialotransferrin in cerebrospinal fluid of patients with childhood-onset ataxia and central nervous system hypomyelination/vanishing white matter disease Clin Chem Vanderver A Schiffmann R Timmons M 2031 2042 51 2005 16155092
8 Determination of asialotransferrin in the cerebrospinal fluid with the HPLC method Scand J Clin Lab Invest Dastych M Gottwaldova J Pohludka M Prikryl P Benovska M 87 91 70 2010 20073671
9 Childhood ataxia with central nervous system hypomyelination/vanishing white matter GeneReviews® [Internet] van der Knaap MS Fogli A Boespflug-Tanguy O Abbink EM Truus Schiffmann R Seattle University of Washington 2003 https://www.ncbi.nlm.nih.gov/books/NBK1258/
10 A new leukoencephalopathy with vanishing white matter Neurology van der Knaap MS Barth PG Gabreëls FJ 845 855 48 1997 9109866
11 MR imaging of vanishing white matter AJR Am J Roentgenol Senol U Haspolat S Karaali K Lüleci E 826 828 175 2000 10954652
12 eIF2B activator prevents neurological defects caused by a chronic integrated stress response Elife Wong YL LeBon L Basso AM 0 8 2019
13 Guanabenz ameliorates disease in vanishing white matter mice in contrast to sephin1 Ann Clin Transl Neurol Witkamp D Oudejans E Hu-A-Ng GV 1147 1162 9 2022 35778832
14 Natural history of vanishing white matter Ann Neurol Hamilton EM van der Lei HD Vermeulen G 274 288 84 2018 30014503
