OVARIOLEUKODYSTROPHY, INCLUDED
CHILDHOOD ATAXIA WITH CENTRAL NERVOUS SYSTEM HYPOMYELINIZATION
VANISHING WHITE MATTER LEUKODYSTROPHY
CREE LEUKOENCEPHALOPATHY
CLE VANISHING WHITE MATTER LEUKODYSTROPHY WITH OVARIAN FAILURE, INCLUDED
VWM
CACH
Vanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from ... Vanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by Van der Knaap et al., 1998 and Schiffmann et al., 1997).
Van der Knaap et al. (1998) proposed the following diagnostic criteria for vanishing white matter: (1) initial motor and mental development is normal or mildly delayed; (2) neurologic deterioration has a chronic progressive and episodic course, and episodes ... Van der Knaap et al. (1998) proposed the following diagnostic criteria for vanishing white matter: (1) initial motor and mental development is normal or mildly delayed; (2) neurologic deterioration has a chronic progressive and episodic course, and episodes of deterioration may follow minor infection and minor head trauma and may lead to lethargy or coma; (3) neurologic signs consist mainly of cerebellar ataxia and spasticity; optic atrophy may develop, but is not obligatory; epilepsy may occur, but is not the predominant sign of the disease; mental abilities may also be affected, but not to the same degree as the motor functions; and (4) MRI may indicate symmetric involvement of the cerebral hemispheric white matter, and part or all of the white matter has a signal intensity close to or the same as CSF on proton-density, T2-weighted, T1-weighted, and FLAIR images, and cerebellar atrophy varies from mild to severe and primarily involves the vermis. Magnetic resonance spectroscopy can be used to obtain additional evidence for the diagnosis. White matter spectra show a serious decrease or almost complete disappearance of all normal signals and presence of some lactate and glucose. The initial report of vanishing white matter leukoencephalopathy was a report by Hanefeld et al. (1993) of 3 cases with unique features on MRI and proton MRS.
Van der Knaap et al. (1997) identified 9 children with a 'new' leukoencephalopathy with vanishing white matter. The 9 patients included 3 affected sib pairs; the age range was 3 to 19 years. The onset of the disease ... Van der Knaap et al. (1997) identified 9 children with a 'new' leukoencephalopathy with vanishing white matter. The 9 patients included 3 affected sib pairs; the age range was 3 to 19 years. The onset of the disease was in childhood and the course was chronic, progressive, and episodic. Episodes of deterioration followed infections and minor head traumas, and these could result in unexplained coma. In 8 patients with advanced disease, magnetic resonance imaging (MRI) revealed a diffuse cerebral hemispheric leukoencephalopathy in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In 1 patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate compatible with the presence of mainly CSF and little brain tissue. Autopsy in 1 patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. The disease has an autosomal recessive mode of inheritance. One of the 9 patients who was not part of an affected sib pair had consanguineous parents. Van der Knaap et al. (1998) reported on phenotypic variation in leukoencephalopathy with vanishing white matter in 5 additional patients who met the diagnostic criteria for the disorder except for the age at onset. Four of the patients had onset in late childhood or adolescence, and one was presymptomatic in his early twenties. The course of the disease tended to be milder than in the patients with early childhood onset. Van der Knaap et al. (1998) concluded that later onset does occur in the disease of vanishing white matter and that both MRS and histopathology are compatible with a primary axonopathy rather than primary demyelination. Extensive metabolic investigation in these 5 patients and the 9 previously reported patients failed to determine an underlying cause. Schiffmann et al. (1994) described 4 unrelated girls with progressive ataxic diplegia who had normal development until the ages of 1.5 to 5 years. A diffuse confluent abnormality of the white matter of the central nervous system was present on computed tomography and magnetic resonance scans obtained early in the course of the illness. Light and electron microscopy of open-brain biopsy specimens from 2 girls showed selective white matter abnormalities including hypomyelination, demyelination, and gliosis. Myelin-specific proteins in the subcortical white matter were of normal molecular size but were markedly reduced in quantity in both patients compared to control subjects. Lipid analysis revealed decreased levels of characteristic myelin lipids. When examined by magnetic resonance spectroscopic imaging, all patients showed a marked decrease of N-acetylaspartic acid, choline, and creatine in white matter only. The authors concluded that the magnetic resonance spectroscopic imaging profile was a unique diagnostic feature of this group of patients. Rodriguez et al. (1999) reported neuropathologic, biochemical, and molecular studies of 2 patients, ages 6 and 10 years, who had died of complications of childhood ataxia with diffuse central nervous system hypomyelination. At autopsy, both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter. The severity of white matter lesions contrasted with the paucity of myelin breakdown products and astroglial and microglial reactions. Within the white matter, there was an increase in oligodendrocytes. Myelin protein and lipid content were reduced. In 1 case, there was a decreased amount of proteolipid protein (PLP1; 300401) demonstrated by Western blot, but Southern blot analysis of the PLP1 gene, as well as sequencing of the coding region of the PLP1 gene, were unremarkable. Cree leukoencephalopathy, or CLE, is a rapidly fatal leukodystrophy described first by Black et al. (1988) in the native Cree and Chippewayan indigenous population of northern Quebec and Manitoba. The onset of CLE is between 3 and 9 months of age, with death in 100% by 21 months of age. Hypotonia often is noted in early infancy followed by relatively sudden onset of seizures, spasticity, hyperventilation, vomiting, and diarrhea, often in a setting of a febrile illness. Onset is followed by developmental regression, lethargy, blindness, and cessation of head growth seen as flattening of the head circumference curve. Computerized tomography of the head shows symmetrically hypodense white matter. Gross neuropathologic examination has shown that white matter is grayish white with translucent zones and subcortical cavitation. Microscopic examination has shown diffuse white matter vacuolation in some cases and astrogliosis with presence of oligodendrocytes and cells described as lipid-laden macrophages (Alorainy et al., 1999). Parents of affected children are normal, and because of a high level of consanguinity in this population, CLE is considered autosomal recessive. Fogli et al. (2002) investigated microscopically 3 brains of CLE patients and found the same typical foamy oligodendrocytes observed in patients with childhood ataxia with diffuse central hypomyelination (CACH), also called myelinopathia centralis diffusa or vanishing white matter disease (VWM). Black et al. (1988) described an early-onset, progressive encephalopathy in an inbred Canadian Aboriginal community. They termed this disorder Cree encephalitis (225750) and distinguished it clinically from Cree leukoencephalopathy. Vermeulen et al. (2005) reported 2 unrelated patients with VWM disease, confirmed by genetic analysis, who experienced episodes of rapid neurologic decline after being frightened. At age 4 years, the first patient witnessed his mother falling down the stairs. He lost consciousness immediately after that and remained in a coma for 10 days. He showed partial recovery afterwards, but permanently lost the ability to walk. At age 18 years, he was severely handicapped, wheelchair-bound, and unable to speak. The second patient was frightened by a dog at age 4 years. He had instantaneous neurologic decline with stupor and spastic hemiparesis. Vermeulen et al. (2005) emphasized the rapid onset of neurologic deterioration in these 2 cases compared to the neurologic decline after infection, which usually occurs over the course of a few days. Federico et al. (2006) reported a Romanian boy who developed VWM disease at age 3 years. He had spasticity, hypotonia, and distal muscle weakness. In addition, he had a peripheral demyelinating neuropathy with decreased sensory and motor nerve conduction velocities. Sural nerve biopsy showed a moderate decrease in the myelinated fibers. Passemard et al. (2007) reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (603945.0009-603945.0011). In the first family, 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 of 2 sisters who survived beyond age 3 years developed macrocephaly. Passemard et al. (2007) suggested that altered brain water balance may result in swelling of the diseased white matter and macrocephaly in some patients with VWM disease. - Adult-Onset Biancheri et al. (2003) reported adult onset of VWM in a 27-year-old woman, confirmed by mutation in the EIF2B5 gene (603945.0004). At the age of 25 years, an MRI study was performed to evaluate the pituitary gland because of elevated prolactin levels. A diffuse leukoencephalopathy was depicted in the absence of any clinical neurologic signs. Two years later, she developed progressive gait abnormalities consistent with spastic paraparesis and speech difficulties. A second MRI showed worsening of the white matter abnormalities with some cystic degeneration. Biancheri et al. (2003) emphasized the clinical variability of the disorder and the importance of a high level of suspicion for VWM even in cases of adult onset. Ohtake et al. (2004) reported a Japanese woman, born of consanguineous parents, with adult-onset VWM caused by a homozygous mutation in the EIF2B5 gene (603945.0008). The patient had been well until a traffic accident at age 40 years, after which she became progressively disorganized, forgetful, delusional, and emotionally unstable. By age 52 years, she had developed spastic gait, hyperreflexia, and frank dementia with defective planning and confabulation. T2-weighted MRI showed diffuse hyperintense lesions in the cerebral white matter, most prominent in the frontal lobe. Other findings indicated focal rarefaction and cystic degeneration of the white matter, consistent with VWM. Ohtake et al. (2004) suggested that patients with adult-onset VWM may present with presenile dementia or psychiatric symptoms. Labauge et al. (2009) reviewed the phenotypes of 16 patients from 14 families with adult-onset VWM, defined as onset after age 16 years. The mean age of onset was 31.1 years (range, 16 to 62 years), and there was a decreased male:female ratio (3:13). Initial symptoms were neurologic in 11 patients, psychiatric in 2, and ovarian failure in 2, and 1 patient was initially asymptomatic but diagnosed on brain MRI. Onset of the symptoms was linked to a precipitating factor in 13% of cases, including minor head trauma and delivery. Two (12.5%) patients died during a mean follow-up period of 11.2 years after a stress-induced deterioration. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One individual remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. MRI findings included cerebral atrophy (75%), extensive cystic cavitating leukoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. Thirteen of the families had mutations in the EIF2B5 gene, including the common R113H mutation (603945.0004), which was found in 11 (79%) of the 14 families. The last family had a mutation in the EIF2B2 gene (E213G; 606454.0001). Labauge et al. (2009) concluded that VWM may be underestimated as an adult-onset inherited leukoencephalopathy. - Ovarioleukodystrophy Ovarian failure can be expressed as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years. Schiffmann et al. (1997) described 4 patients with the unusual association of ovarian failure with white matter abnormalities observed on cerebral magnetic resonance imaging (MRI), a condition they termed ovarioleukodystrophy. Fogli et al. (2003) reported 8 patients from 7 families with ovarioleukodystrophy. The cerebral abnormalities in patients with ovarioleukodystrophy were similar to those in patients with vanishing white matter leukodystrophy. The diagnosis of ovarian failure was confirmed by findings of high basal gonadotropin levels and low estrogen and progesterone levels. All the patients had a normal karyotype, and only 1 patient had consanguineous parents. In 3 patients with primary amenorrhea, school difficulties, together with poor fine motor performance, were present prior to the development of a slowly progressive neurologic disease in adolescence. Only 1 patient presented with rapid cognitive decline, including a frontal lobe syndrome. The age at menarche was normal in the 5 patients with secondary amenorrhea. The age at onset of neurologic deterioration correlated positively with the severity of ovarian dysfunction. In at least 1 case ovarian failure preceded neurologic decline. Fogli et al. (2003) noted that 2 indigenous North American populations, the Cree and the Chippewa, have a particularly severe form of leukodystrophy and are homozygous for an arg195-to-his (R195H; 603945.0005) mutation in the EIF2B5 gene. Patients with this severe EIF2B mutation, as well as patients with the classical form of VWM, do not survive to puberty and therefore do not express ovarian failure. However, Fogli et al. (2003) pointed out that several reports had suggested that ovarian dysgenesis may be present in these patients. Two children with neuropathologic abnormalities suggestive of VWM were also found at autopsy to have 'ovarian dysgenesis' (Boltshauser et al., 2002) or 'bilateral streak ovaries' (van der Knaap et al., 1997). Furthermore, Verghese et al. (2002) reported 2 sisters who presented with primary amenorrhea and behavior problems at ages greater than 30 years, with subsequent neurologic deterioration, white matter abnormalities detected during cerebral MRI, and pigmentary orthochromatic leukodystrophy observed at autopsy.
Fogli et al. (2004) found that 68 (87%) of 78 families with MRI criteria of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two families (62%) had a mutation in the EIF2B5 gene, and 71% had ... Fogli et al. (2004) found that 68 (87%) of 78 families with MRI criteria of leukodystrophy had a mutation in 4 of the EIF2B genes. Forty-two families (62%) had a mutation in the EIF2B5 gene, and 71% had the arg113-to-his mutation (R113H; 603945.0004). Thirteen families (19%), 10 families (15%), and 3 families (4%) had mutations in the EIF2B2, EIF2B4, and EIF2B3 genes, respectively. No mutations were identified in the EIF2B1 gene. Disease onset ranged from 4 months to 30 years of age, with a mean of 3.9 years, and disease severity ranged from no neurologic signs in 2 to death in 24 individuals; there was no correlation between type of mutated gene and the age at onset or disease severity. However, the EIF2B5 R113H mutation and the EIF2B2 glu213-to-gly mutation (E213G; 606454.0001) were significantly associated with milder phenotypes. Van der Lei et al. (2010) identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (603945.0004), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (603945.0001), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. Van der Lei et al. (2010) concluded that the clinical phenotype in VWM is influenced by the combination of both mutations. Matsukawa et al. (2011) reported 3 unrelated Japanese patients, each born of consanguineous parents, with adult-onset VWM. Each carried a homozygous mutation in the EIF2B2 (V85E; 606454.0006), EIF2B5 (D270H; 603945.0012), or EIF2B3 (L27Q; 606273.0005) gene, respectively. The 2 affected women also had evidence of ovarian failure. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing the mutant subunits was significantly decreased (20-40% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset.
By a genealogic study and haplotyping, Leegwater et al. (2001) showed that single founder was involved for 12 people with VWM in 9 families. This permitted narrowing of the location of the gene to a critical region containing ... By a genealogic study and haplotyping, Leegwater et al. (2001) showed that single founder was involved for 12 people with VWM in 9 families. This permitted narrowing of the location of the gene to a critical region containing a total of 25 genes and STSs. One of these genes, EIF2B5 (603945), contained 16 different mutations in 29 patients from 23 families. In addition, they found 2 distantly related individuals who were homozygous for a missense mutation in EIF2B2 (606454), affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration in persons with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. Leegwater et al. (2001) and van der Knaap et al. (2002) showed that leukoencephalopathy with vanishing white matter may be caused by mutation in any of the 5 subunits of translation initiation factor eIF2B. Fogli et al. (2002) identified a homozygous missense mutation in the EIF2B5 gene (R195H; 603945.0005) in 3 patients with CLE from 2 Cree families. They speculated on the phenotypic differences between CLE and CACH/VWM. A long presymptomatic phase, despite the presence of severe white matter abnormalities on MRI, has been observed in CACH/VWM, in contrast to the early onset and death by 21 months of age in all cases of CLE. Basal ganglia and thalamic abnormalities described in CLE have not been observed in CACH/VWM. Fogli et al. (2002) suggested that the indigenous population of northern Quebec may have evolved an adaptation to an extremely cold environment, rendering them particularly susceptible to dysregulation of protective mechanisms that respond to temperature elevation, such as eIF2B. They concluded that CLE may represent the most severe observed form of eIF2-related disorders, possibly because of an exaggerated response to heat stress induced by a common infectious illness. van der Knaap et al. (2003) analyzed the eIF2B genes in 9 patients with an antenatal- or early infantile-onset encephalopathy and an early demise. Mutations were found in 8 of the patients, with a total count of 7 different mutations: 2 in EIF2B2, 2 in EIF2B4, and 3 in EIF2B5. In addition to signs of serious encephalopathy, they found oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, hypoplasia of the kidneys, and ovarian dysgenesis. Three of the patients were sisters; 2 other patients were brother and sister. The consistently severe phenotype in affected sibs and in Cree encephalopathy patients suggested an influence of the genotype on the phenotype. Among 11 unrelated Chinese patients with VWM disease, Wu et al. (2009) found that 6 had mutations in the EIF2B5 gene and 5 had mutations in the EIF2B3 gene. Four of the patients had the same novel mutation in EIF2B3 (I346T; 606273.0004). The phenotype was similar to that reported in other populations. - Ovarioleukodystrophy Because of the similarity of cerebral abnormalities in patients with ovarioleukodystrophy to those in patients with VWM, Fogli et al. (2003) tested 8 patients with ovarioleukodystrophy for mutations in the 5 EIF2B genes. In 7 of the patients, they identified mutations in the EIF2B2, EIF2B4, and EIF2B5 genes, including 5 novel mutations. The only patient without identified EIF2B mutations had a distinctive neurologic presentation.