Adult-onset vanishing white matter disease presenting as dementia

Vanishing White Matter Disease (VWMD), also known as Childhood Ataxia with Central Hypomyelination (CACH) is a leukoencephalopathy with an autosomal recessive inheritance. It is caused by mutations in any of the fi ve genes encoding the fi ve subunits of the eukaryotic translational initiation factor 2B (eIF2B). Although VWMD was initially described in young children, it is now well known that it has a wide phenotypic spectrum, affecting people of all ages. VWMD is typically characterized by normal or mildly delayed initial psychomotor development, followed by episodic or chronic neurological deterioration, often provoked by infections or minor head trauma. Neurological signs consist mainly of cerebellar ataxia and spasticity. There is no specifi c treatment beside the “prevention” of cellular stress. Therefore, early recognition of the diagnosis is important to avoid triggering factors and allow genetic counseling. The reported case describes the clinical and radiological characteristics of a patient with adulthood onset of VWMD, revealed by subcortical dementia. Case Report Adult-onset vanishing white matter disease presenting as dementia Soreya Belarbi*, Selma Dounia Bensemmane, Imene Bouguerra, Meriem Ouali and Samira Makri Mokrane Department of Neurology, Ali Ait Idir Hospital, Algiers, Algeria Received: 08 March, 2021 Accepted: 18 March, 2021 Published: 20 March, 2021 *Corresponding author: Soreya Belarbi, Department of Neurology, Ali Ait Idir Hospital, Algiers, Algeria, E-mail:


Introduction
Vanishing White Matter Disease (VWMD), also known as Childhood Ataxia with Central nervous system Hypomyelination (CACH), is an autosomal recessive leukoencephalopathy caused by mutations in one of fi ve genes: EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, located respectively on chromosomes 12q24.3, 14q24, 1p34.1,2p23.3 and 3q27 [1][2][3]. Eukaryotic translation initiation factor 2B (EIF2B) is a key for the initiation of translation and the regulation of protein synthesis in response to cellular stresses [4]. Until now, more than 150 mutations in the 5 EIF2B genes have been reported [5,6]. The most common mutation in both children and adults is the p.Arg113His mutation of the EIF2B5 gene, generally associated with a relatively benign phenotype and slower course of the disease [7,8].
Although VWMD was initially recognized as a disease of young children, it has now become clear that there is an extreme variation in the phenotype and severity of the disease depending on the age of onset [9]. Severe forms of VWMD begin in the prenatal or infantile period and manifest as cerebellar ataxia and spasticity and then lead to early death [14]. The milder variants start in adolescence or adulthood and are characterized by slow disease progression [15].
The progression of leukoencephalopathy with vanishing white matter is generally variable with periods of relative stability interrupted by episodes of rapid decline. Stress, infection and head injury are known as stressors which could trigger a clinical / radiological decline.
These stresses can trigger the fi rst symptoms of the disease or make existing symptoms worse.
The diagnosis of VWMD is primarily made by MRI due to Citation: Belarbi  pathognomonic imaging, which is very specifi c to the disease. Brain MRI shows diffuse, bilateral and symmetric abnormalities of the cerebral white matter with signal similar to that of the Cerebrospinal Fluid (CSF): Hyposignal on T1, hypersignal on T2, without any contrast enhancement after injection of the contrast medium. Substantial impairment is predominant with respect for the U fi bers and in subtentorial of the corticospinal bundles, cerebellum and spinal cord. On the FLAIR (fl uid attenuated inversion recovery) sequences (or proton density), within white matter hypersignal abnormalities, there are extensive hypointense zones attesting to the cavity character of this leukodystrophy [16] in which the white matter is replaced by fl uid [17]. Cavitary areas are preferentially found in the periventricular white matter mainly in frontal or sometimes occipital regions. The extensive character of white matter cavitation in infantile forms explains the term Vanishing White Matter, given to this syndrome. In juvenile / adult forms, cavitations can be absent or appear later [18][19][20].
In this paper, we are reporting a case of late-onset VWMD presenting slowly progressive cognitive defect with a neuropsychological profi le of subcortical dementia.

Case report
A 41-year-old man was admitted to our neurology department due to the presence of memory impairment. He was the third child of consanguineous parents, originally from Bordj Menail, a city located in east of Algiers. In terms of development, the patient had normal psychomotor and language acquisitions. He worked as a farmer and then as a worker in a chocolate factory until 1 year ago, which corresponds to the beginning of the memory problems. There were no neurological or psychiatric disorder in the family.
The onset of the disorders dates back to the age of 40, marked by the progressive appearance of memory disorders relating to recent events "anterograde amnesia", with inability to perform his work, as well as concentrating and decision making diffi culties.
His family noticed a lack of personal hygiene as well as memory problems. He forgets what to buy and repeats the same things to himself. Subsequently, behavioral disorders appeared with a tendency to withdraw into oneself, a fl at progressive affect and an amotivational state with lack of initiative. These disorders affected the basic activities of daily living. He had to stop all professional activity.
The evolution of the disorders was gradually worsening, with the appearance 6 months later of muscular weakness and stiffness of the lower limbs, markedly of the left with diffi culty in walking.
He has no history of head trauma or episodic worsening after febrile illness.
Neurologic examination revealed brisk and exaggerated tendon refl exes, bilateral Babinski sign, and mild spastic gait.
We performed a neuropsychological workup, neuroimaging of brain and spine, a lumbar puncture with cytochemical and immunological study of the CSF, an autoimmunity workup, an Eye exam (Slit lamp exam and fundus examination (to look for optic neuropathy and an Electroencephalogram (EEG).
We also performed thyroid hormones and Thyroid Peroxidase antibodies (TPO) assay, vitamin B12, folic acid and homocysteine assay, as well as leukocyte enzyme assay. As for the language, it was evaluated by Verbal fl uency (Categorical and Lexical).
The Bells Test, a cancellation task, allowed a quantitative and qualitative evaluation of visual neglect.

Result of neuropsychological assessment
The global cognitive assessment by MMSE revealed a score of 26/30 for a socio-cultural level NSC5 "11 years of studies", with delayed recall failure that improved with clues. Language and praxis were preserved.
In addition, the neuropsychological assessment was in favor of subcortical dementia (Table 1), with a dysexecutive syndrome, including programming and planning disorders and loss of inhibitory control, a lack of access to the lexical Table1: Neuropsychological assessment.

Standby EEG
The trace is slowed down as a whole, without epileptic abnormalities.
Eye Exam was without anomalies.

Comment
VWMD is a rare disease that typically occurs in children presenting progressive and chronic cerebellar ataxia, spasticity, epilepsy, and relatively mild intellectual decline [17]. Adulthood onset VWMD is even rarer. It is estimated that it represents 15% of cases [21,22] and that it is characterized by a large phenotypic variability compared to early VWMD.
Women can rarely suffer from ovarioleukodystrophy syndrome [25], Pauci-symptomatic forms, or asymptomatic, or even revealed by non-neurological symptoms, have also been described.
With the great phenotypic variability of late-onset VWMD, it can be diffi cult to make a clinical diagnosis.
It is now well established that the severity of the disease is inversely proportional to the age of onset [2]. Indeed, a late onset age is generally associated with a milder course of the disease [26]. Episodes of rapid deterioration are less frequent.
The last case of late-onset VWMD was reported in a 43-year-old patient with depressed mood, irritability, personality change with uncontrollable anger and disinhibition with coprolalia and cognitive decline. These were memory disorders relating to short-term memory and working memory, attention disorders and a reduced capacity for organization.
These disorders were associated with progressive dystonia [27] and ataxia with postural instability and frequent falls.
In our patient, the disease began late at the age of 41 with mental decline and a slight pyramidal syndrome. The neuropsychological evaluation was in favor of a subcortical dementia marked by a dysexecutive syndrome. To our knowledge, this is the fi rst case described in Algeria of VWMD beginning in adulthood with a dementia syndrome.
An observation of presenile subcortical dementia beginning at age 55, without other clinical abnormalities apart from a frustrated pyramidal syndrome has also been reported by Gascon-Bayarri J, et al. [28]. As reported in our patient, VWMD onset in adulthood presents earlier and more severe cognitive impairment than early onset disease [29].
The main diagnostic feature in our patient with subcortical dementia is an extensive leukoencephalopathy on cerebral