Carnitine palmitoyltransferase II deficiency
Nov. 24, 2024
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Vanishing white matter disease is an autosomal recessive, chronic, and progressive leukodystrophy with prominent ataxia and spasticity, cavitary degeneration of the periventricular and subcortical white matter, and exacerbations by infection, head trauma, and other stressors. It is associated with biallelic pathogenic variations in any of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) that encode five subunits of the eukaryotic translation initiation factor 2B (eIF2B). Pathogenic variants in the EIF2B5 gene account for more than half of cases. Patients may develop a wide spectrum of neurologic abnormalities, from prenatal-onset white matter disease to juvenile- or adult-onset ataxia and dementia, sometimes with ovarian insufficiency. The pattern of diffuse white matter abnormalities on brain MRI and diffusion studies is often diagnostic. There is no specific treatment for vanishing white matter disease. Management includes supportive care and avoidance of triggers.
• Vanishing white matter disease is a chronic progressive leukodystrophy with autosomal recessive inheritance that can present antenatally to later in adulthood. | |
• Patients with vanishing white matter disease have an unusual susceptibility to mild head trauma, fever, and other stressors. | |
• The pathognomonic pattern of MRI and diffusion tensor imaging abnormalities are often the earliest clue to diagnosis. | |
• Pathogenic variants in any of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) that encode subunits of the eukaryotic translation initiation factor 2B (eIF2B) are the cause of vanishing white matter disease and its phenotypic variants. | |
• There is no cure or specific treatment, and supportive care along with avoidance of triggers is the mainstay of management for vanishing white matter disease. |
The earliest literature on vanishing white matter disease was in the 1960s in the form of case reports of patients with chronic progressive gait and motor disturbances whose autopsy showed cystic degeneration of the cerebral white matter surrounded by dense networks of oligodendrocytes (08). Subsequent similar but separate neuropathological case descriptions were reported until the 1980s (58; 17; 02; 16).
Three case series were published in the 1990s. All of them described a childhood-onset, progressive leukoencephalopathy with an autosomal recessive mode of inheritance. Schiffmann and colleagues proposed the term “childhood ataxia with central nervous system hypomyelination” (36). Hanefeld and coworkers identified minor head trauma as a provoking factor (19). They also described the unique proton magnetic resonance spectroscopy findings of the disappearance of all white matter signals and replacement with resonances representing lactate and glucose. In late 1990s, Van der Knaap and colleagues described another series of patients and recognized both febrile infections and minor head trauma as provoking factors for the disease (43; 46). They observed that MRI and magnetic resonance spectroscopy findings were indicative of a progressive form of cystic degeneration of the white matter rather than hypomyelination. This interpretation was substantiated by autopsy findings, and the same group proposed the name “vanishing white matter.”
The most common presentation of the classical variant of this disease is of an insidious onset and chronic progressive neurologic syndrome; onset is between 2 and 6 years of age in a previously normal child. Predominant features are ataxia, spasticity, and a relatively mild cognitive decline. Though less common, other features that may be noted during the course of the disease are optic atrophy, dysarthria, tremors, and epilepsy (35). Seizures are often well controlled with medication. Minor head trauma, febrile illnesses, and acute fright are characteristically described as bringing about episodes of major and rapid neurologic deterioration (46; 57). Such episodes may lead to rapid loss of motor abilities, altered sensorium with seizures, and vomiting, which may result in coma and death. If the child recovers from this acute phase, they may not return to their baseline neurologic status. Most children succumb following one such episode over a few years. At any stage of the illness, a child may remain stable for years. Death usually occurs in the first or second decade of life.
Phenotypic variability. Some patients develop symptoms after 5 years of age with a more slowly progressive spastic diplegia, relative sparing of cognitive ability, and a likely long-term survival (36; 46). A rapidly fatal infantile form of this syndrome has been described and has been found to be allelic to the more common form of the disease with the 3q27 locus (15). A subacute variant of childhood ataxia with central nervous system hypomyelination has been reported in the Cree indigenous population of Northern Canada (04; 14). These patients have an onset of neurologic deterioration in the first 6 months of life and die by 2 years of age. Congenital forms of the disease have also been reported, with multisystemic manifestations (51). Adult-onset disease has been reported, particularly with the p.R113H EI2B5 mutation (13; 48). A case series of 16 adult patients demonstrated the common presence of behavioral and psychiatric manifestations, as well as progressive cerebral atrophy, in addition to the more typical white matter findings on MRI (23). Presentation as adult-onset, isolated, bilateral optic neuropathy has also been reported (03).
Vanishing white matter disease is usually progressive. In a longitudinal multicenter study among 296 genetically confirmed patients with vanishing white matter disease, earlier disease onset (less than 4 years) was observed to be associated with higher sensitivity to febrile infections, and fever-provoked deterioration was seen in 86% of patients, which led to exacerbations in the disease course (18). Fever-provoked exacerbations were seen in 50% when onset was at 18 years old or older. Earlier onset was also associated with more severe disability and higher mortality. Absence of stress-provoked episodes and absence of seizures were observed to predict a more favorable outcome. In patients with onset after 4 years of age, the disease course was noted to be generally milder, with a wide variation in severity (18).
In the more severe variants, like Cree leukoencephalopathy, brainstem dysfunction leading to breathing difficulties and death was most often the terminal event (36; 46). Some mutations in the homozygous state were observed to be associated with either a mild or a severe form of the disease (13).
Vanishing white matter disease is also known to have multisystemic manifestations. Primary or secondary ovarian failure has been commonly reported across all different disease severities (12). Other features, such as growth failure, cataracts, hepatosplenomegaly, pancreatitis, and kidney hypoplasia, have been reported in the early-onset severe variants of the disease (51).
No statistically significant differences in age of onset and survival have been observed for individuals with pathogenic variants in any of the five genes (18). The only feature noted was better preserved ambulation in five individuals with EIF1B1 pathogenic variants.
A 7.5-year-old boy was admitted for evaluation of a leukodystrophy and an ataxic gait. He was well until 4 years of age, when he developed subacute onset of gait instability and "foot drop." The difficulties became worse, but a few weeks later he progressively improved, recovering an almost normal gait. At the age of 5, he fell and had a mild head trauma and could not stand independently. He had a slow recovery in the subsequent months and required a walker to assist in ambulation. A right ankle foot orthosis was used to facilitate ambulation. Fine motor movements were also affected; he had difficulties opening a door using a key. In the subsequent years, the patient remained mostly stable, showing only mild motor deterioration. His cognitive abilities were normal, and he attended a regular school and performed at grade level.
Family history was unrevealing; the patient was an only child. His examination revealed a head circumference in the 50th percentile, weight at the 80th percentile, and height above the 95th percentile. General examination was unremarkable. His speech was slow. Extraocular movements were normal, as was funduscopic examination. Mild tongue weakness was the only cranial nerve abnormality. He had moderate spastic weakness of the lower extremities in an upper motor neuron pattern. Fine motor movements of the upper extremities were markedly dysmetric. He could not stand unaided but could make a few steps when supported by another person. Tendon reflexes were increased with ankle clonus and Babinski signs bilaterally. Sensory examination was normal to light touch, vibration, and temperature.
A nerve conduction study and electromyography were normal. MRI of the head showed diffuse increase in signal intensity on T2-weighted imaging and correspondingly decreased signal intensity in T1-weighted images.
Magnetic resonance spectroscopic imaging showed reduced choline-containing compounds, N-acetyl aspartate, and creatine in white matter only. An extensive laboratory evaluation consisting of routine hematologic, liver, and renal functions were normal as were tests for known leukodystrophies, lysosomal storage diseases, aminoacidopathies, and organic aciduria. Spinal fluid had normal glucose, lactate, and protein levels. Muscle biopsy was morphologically normal. Mitochondrial enzymes in muscle were normal; nerve biopsy was normal.
At this point, the clinical and neuroradiologic picture coupled with the unremarkable laboratory evaluation was considered consistent with vanishing white matter disease.
Genetic linkage to a region at chromosome 3q27 was found in a Dutch subgroup of children who were then diagnosed with childhood ataxia with central nervous system hypomyelination (24). The gene in this region was subsequently identified as EIF2B5, which codes for the epsilon subunit of the protein translation initiation factor eIF2B (25). It soon became clear, however, that this disorder is genetically heterogeneous and that it can be caused by mutations in any of the five subunits of eIF2B (47; 13; 35). Most patients are compound heterozygotes with a missense mutation in at least one allele (35). A rare submicroscopic deletion of 14q24.3 contributed to the disease in one patient (38). EIF2B-related disorder is panethnic and has been described in a number of Chinese patients (61). Currently more than 120 mutations have been described in patients, with mutations affecting any of the five subunits of eIF2B (27). There are at least two mutations with known founder effect. These are the histidine substitution at arginine 195 of epsilon-eIF2B, R195H, and the A87V mutation in exon 3 of EIF2B3 in Quebec (14; 33).
Eukaryotic initiation factors (eIFs) are involved in the initiation of translation of mRNAs into polypeptides (31). eIF2B is the guanine nucleotide-exchange factor for eIF2 and plays a key role in protein synthesis. Vanishing white matter disease mutations have functional consequences on eIF2B activity, preferentially in the glial cells. Impaired activity of eIF2B leads to an impairment of the cellular stress response, potentially leading to deposition of denatured and misfolded proteins in the endoplasmic reticulum of the glial cells under conditions of stress, especially fever (25). The exact reason for the preferential involvement of glial cells is unknown. Earlier studies hypothesized that overall eIF2B activity might be relatively low in glia, and further reduction in eIF2B activity caused by vanishing white matter disease mutations could make these cells more vulnerable (32). Additional studies on eIF2B mutations have described a more complex phenomenon and have hypothesized that the unbalanced stoichiometry of subunits within large protein complexes were found to be dysfunctional in astrocytes and oligodendrocytes, hence, causing their preferential affection (09; 20)/
In autopsies of patients with vanishing white matter disease, white matter is noted to be gelatinous or cystic or, frankly, cavitary. A predilection for frontoparietal white matter, particularly deep and periventricular, is commonly observed, with relative sparing of the temporal lobe, optic system, corpus callosum, anterior commissure, and internal capsule. There is also a relative sparing of the subcortical U fibers, though this is not a consistent finding (36; 43). Microscopic changes in the affected white matter are noted as pallor of myelin, thin myelin sheaths, vacuolation, myelin loss, cystic change, and, rarely, active demyelination. Myelin sheaths are abnormal and vary from pale to thin to vacuolated. Inflammatory response is not significantly noted. There is also a relative preservation of grey matter. Axons are usually spared, but sometimes axonal loss may be as severe as myelin loss, which is specially noted in areas of cavitation (34; 59). The presence of “foamy” oligodendrocytes is typical of this disease and distinguishes it from the other leukodystrophies. Marked loss of oligodendrocytes is noted around the cavitary areas. In the relatively preserved areas, there is an increase in apparently mature oligodendrocytes (34). The astrocytes are observed to be reduced in number, coarse, and dysmorphic with blunt broad processes rather than their typical delicate arborizations (59; 15).
Major pathologic features | |
• Foamy oligodendroglial cell and possibly increase in the number of oligodendrocytes | |
• Rarefaction of the white matter (hematoxylin and eosin, Luxol fast blue) | |
• Relative axonal preservation compared to white matter loss | |
• Relative sparing of the white matter U-fibers | |
• Atypical perivascular astrogliosis with blunted processes and, in some cases, decrease in the number of astrocytes that are immature | |
Minor pathologic features | |
• Microgliosis, focal, absent to moderate in severity | |
• Macrophages, focal, absent to moderate in severity |
The exact incidence of vanishing white matter disease is unknown. In a study of 349 children with diagnosed leukodystrophies in the UK, 17 (5%) children had vanishing white matter disease (39).
Prenatal diagnosis when the mutations affecting an EIF2B subunit are known is currently possible.
The differential diagnosis of vanishing white matter disease includes both acquired and inherited conditions with progressive neurologic deterioration and leukoencephalopathy on MRI. The acquired conditions need to be excluded based on the age of presentation and include common demyelinating disorders, such as multiple sclerosis and related neuro-autoimmune conditions, acute disseminated encephalomyelitis (ADEM), and encephalitis. The majority of these conditions can be differentiated based on the typical MRI changes (with specific MRI criteria for some of these conditions) (10). A detailed review of these conditions is presented under the appropriate topics.
The other group of differentials include inherited disorders presenting in infancy and childhood, such as mitochondrial respiratory chain disorders, which may present with leukoencephalopathy with diffuse rarefaction and cystic degeneration of white matter (11; 07), Alexander disease with variable phenotypic features akin to vanishing white matter disease but a distinctive MRI pattern; megalencephalic leukoencephalopathy with subcortical cysts, which presents with cystic brain lesions in the frontoparietal border zone region and anterior-temporal subcortical white matter (45); and AARS2-associated disorders with leukoencephalopathy and premature ovarian failure (29). Other common leukodystrophies in children, such as X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe disease, have different clinical or MRI features and are not commonly associated with diffuse cystic cerebral white matter degeneration as seen in vanishing white matter disease.
The diagnosis of vanishing white matter disease is considered based on the typical clinical features and MRI pattern recognition and then confirmed by genetic testing. The presence of family history of disease and association of various stressors with clinical deterioration provide additional clues.
Neuroimaging features. Cranial CT scan is of limited use and usually shows diffuse and symmetric hypodensity of the cerebral hemispheric white matter with no calcifications. Strict diagnostic MRI criteria for vanishing white matter disease have not been established. The typical MRI features described for vanishing white matter disease are shown in Table 2 (37). These are more relevant to the classic early-childhood type but may variably be found in atypical presentations, such as the antenatal or adult-onset forms of vanishing white matter disease, and in presymptomatic patients in whom secondary cavitation may be absent (49).
• There is extensive abnormal signal from the periventricular and deep cerebral white matter; the subcortical white matter is relatively spared. The cerebral white matter is symmetrically and diffusely abnormal (49). | |
• Progressive white matter degeneration leads to diffuse cystic changes in place of the “vanishing” white matter, which becomes isointense to the CSF, surrounded by a rim of hyperintensity demonstrating the cavitated breakdown of the white matter. | |
• Cerebellar white matter and cerebral temporal lobes are spared from the cystic changes. Over time, mild to severe cerebellar atrophy is seen, primarily in the vermis. | |
• There is no contrast enhancement of the lesions and abnormal areas. | |
• There is involvement of the inner rim of the corpus callosum, with sparing of the outer rim. | |
• A dot-like pattern in the centrum semiovale and fine meshwork of radiating stripes within the abnormal white matter may be seen on T1 or FLAIR images. | |
• Symmetric signal change may be seen in the central tegmental tracts in the pons. | |
• Spinal cord atrophy and post-contrast enhancement with enlargement of cranial nerves has been described (10). | |
• Severe cerebral atrophy can be observed in adult-onset forms with slow progression. | |
• MR spectroscopic imaging shows a marked decrease in all metabolites over the white matter only (36). However, other leukodystrophies may show a similar pattern. |
MRI abnormalities are present in all affected individuals, regardless of age of onset, and are even present in asymptomatic affected siblings of a proband; however, the cerebral white matter may be abnormal on MRI, but not yet CSF-like, in presymptomatic and early symptomatic individuals. Over time, increasing amounts of white matter vanish and are replaced with CSF; cystic breakdown of the white matter is seen on proton density or FLAIR images (49). Patients with classic variants of the disease usually have relatively preserved white matter volume despite severe cystic degeneration. However, juvenile and adult forms of the disease may show ex vacuo dilatation of the ventricles (35; 12). Early in life, there may be a component of delayed myelination in the subcortical areas (52). These areas are more cellular and were found to have relatively restricted diffusion on diffusion-weighted imaging studies (06; 53). Similar MRI images may be seen in mitochondrial diseases, pyruvate carboxylase deficiency, and pyruvate dehydrogenase deficiency as well as in merosin-deficient muscular dystrophy. However, extensive cavitation of the white matter as observed in vanishing white matter disease is not seen in those conditions (05; 21; 41; 50).
Genetic testing. Once suspected, the diagnosis can be confirmed by the identification of pathogenic variants affecting any of the five genes, EIF2B1 to EIF2B5, encoding the five subunits of eIF2B. Exome sequencing is most commonly used; genome sequencing is also possible. Of the five genes, EIF2B5 contributes to almost 66% of the cases identifiable on sequence analysis, followed by EIF2B2 (16% of the cases). To date, all individuals with eIF2B-related disease have a leukodystrophy; no other phenotypes have been observed. A contiguous gene deletion that included EIF2B2 and an additional heterozygous EIF2B2 pathogenic variant were reported in a child with features of vanishing white matter disease plus dysmorphic facial features (38).
Genotype-phenotype correlation. There are no specific genotype-phenotype correlations, but some observations have been made based on limited natural history studies (13; 54; 18).
• There may be intra-familial variability with the same pathogenic variation. | |
• The EIF2B5 homozygous p.Thr91Ala pathogenic variant has been associated with variable phenotypes from childhood onset to adults with no symptoms. | |
• Another EIF2B5 homozygous pathogenic variant, p.Arg113His, has often been associated with a mild disease form that has never given rise to the infantile type. | |
• EIF2B5 pathogenic variants p.Arg339 (p.Arg339Trp, p.Arg339Gln, or p.Arg339Pro) and p.Val309Leu have been predictably associated with severe disease. |
Brain biopsy. Although characteristic pathologic findings have been seen in virtually all vanishing white matter disease brains examined thus far, a brain biopsy is not required to diagnose this leukodystrophy. An important development is the discovery of a significant decrease in the percent asialotransferrin of total transferrin in the CSF of EIF2B-mutated patients (56; 55). This finding may be particularly important in identifying patients with rather typical clinical and MRI abnormalities; however, the advent of genetic testing has circumvented the need for other corroborative tests. Blood or CSF-based biomarkers may have a role in newborn screening for this rare disorder.
Laboratory testing. Routine laboratory tests are generally normal in patients with vanishing white matter disease. Lumbar puncture is not routinely needed for the diagnosis. CSF analysis is typically normal, although CSF glycine may be elevated. The sensitivity and specificity of the latter test is not known.
Brainstem auditory evoked potentials remain normal, even in severely affected patients (40).
Determination of the CSF asialotransferrin/total transferrin ratio has been utilized as a research tool but is not routinely done clinically (55). This ratio has been found to be low in people with genetically confirmed vanishing white matter disease.
Eukaryotic translation initiation factor 2B (eIF2B) guanine exchange factor (GEF) activity was found to be low in lymphoblastoid cell lines from patients with vanishing white matter disease (13). The assay showed 100% specificity and 89% sensitivity when the activity threshold was set at 77.5% of normal (22). However, a similar pattern was not found in late-onset cases, and no correlation between eIF2B GEF activity and disease severity was found (26). It was concluded that if decreased activity is found, vanishing white matter disease is the most likely diagnosis; however, if normal or increased activity is found, vanishing white matter disease cannot be ruled out.
No specific treatment is available for vanishing white matter disease. Improving quality of life with physical assistive devices for motor disabilities, along with avoidance of trigger deteriorations, is the mainstay of management and may prolong the lifespan. Aggressive management of infections, fever management following vaccinations, and avoidance of contact sports risking impact trauma are essential. One case of deep brain stimulation successfully reducing cerebellar tremor in a child with vanishing white matter disease was reported in 2012 (42). Integrated stress response inhibitor (ISRIB), a molecule that stabilizes the eIF2B complex and normalizes its activity, is being studied but has not yet found its place in human studies (60; 01). An in-vitro study suggests that edaravone and mitochondrial transfer are potential therapeutic strategies for consideration in vanishing white matter disease that can impact pathogenic pathways in astrocytes (28). In 2022, an expert consortium came together to formulate therapeutic trial designs for patients with vanishing white matter disease, recognizing the urgent need to offer therapies in this fatal disease (44). Recommendations were drafted based on evaluation of the current clinical, laboratory, and molecular data in each age group. However, low disease burden, heterogenous phenotypes, and unpredictability in the disease course were recognized as major limitations for formulating robust therapeutic trial designs. From a clinical perspective, neurologic decline is inevitable in children with vanishing white matter disease. Prenatal diagnosis can be offered to families with affected children, which emphasizes the need for a confirmatory genetic diagnosis in all index cases.
Pregnancy may be a risk factor as it was in a patient when it was associated with oocyte donation (30).
Anesthesia can be performed in the usual manner in these children; however, in rare cases the neurologic status may deteriorate after general anesthesia.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
A S Jyotsna MBBS DNB DM
Dr. Jyotsna of Apollo BGS Hospital has no relevant financial relationships to disclose.
See ProfileArushi Gahlot Saini MD DM MNAMS
Dr. Saini of Postgraduate Institute of Medical Education and Research, Chandigarh, India, has no relevant financial relationships to disclose.
See ProfileK P Vinayan MD DM
Dr. Vinayan of the Amrita Institute of Medical Sciences has no relevant financial relationships to disclose.
See ProfileSolomon L Moshé MD
Dr. Moshé of Albert Einstein College of Medicine has no relevant financial relationships to disclose.
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