Intra-familial phenotypic heterogeneity in adult onset vanishing white matter disease

Vanishing white matter (VWM) disease, also known as childhood ataxia with central nervous system hypomyelination (CACH) syndrome, is an autosomal recessive transmitted leukodystrophy. Classically characterised by early childhood onset, adult onset formed with slower progression have been recently recognized. The course of neurological impairment is usually progressive with possible occasional episodes of acute deterioration following febrile illnesses or head trauma. Neurological features are dominated by cerebellar ataxia and spasticity with relatively preserved mental abilities. Brain MRI shows diffuse abnormal signal of the cerebral white matter and cystic degeneration. Mutations in one of the genes coding for the five subunits of the translation factor eukaryotic initiation factor 2B (eIF2B) have been identified. We report here on two sisters affected by adult onset VWM with variable phenotypic expression. The proband is remarkable by the very late age of the disease onset (age of 42). A homozygous p.Arg113His mutation in the eIF2Bvarepsilon gene was identified. This mutation had been recurrently associated with adult onset VWM establishing phenotype-genotype correlations. We will show an important intra-familial phenotypic variability and discuss it in the light of recent molecular progresses. External precipitating factors are contributing for some of the differences observed.     

Arg113His mutation of vanishing white matter is not present in multiple sclerosis

Vanishing white matter (VWM) is a childhood leukoencephalopathy with central hypomyelination, white matter rarefaction, and cystic degeneration. Adult onset, variable phenotype, and high frequency characterize Arg113His mutation caused by G338A polymorphism associated with VWM. A patient with trauma-associated onset, and clinical features compatible with multiple sclerosis (MS), was homozygous for G338A mutation of eukaryotic translation initiation factor (eIF2B5). The authors checked a cohort of 101 MS patients, including 19 with head/neck trauma-associated onset, and failed to find the mutation, described above, in MS chromosomes. Our report does not exclude the presence in MS chromosomes of other mutations in the eIF2B gene family.     

Leucoencephalopathy with vanishing white matter may cause progressive myoclonus epilepsy

Leucoencephalopathy with vanishing white matter (VWM) is caused by mutations in the genes encoding for one of the five subunits that constitute the eukaryotic initiation factor 2B (eIF2B), and is characterized by a highly suggestive MRI pattern indicating vanishing of the cerebral white matter. Seizures are well known to occur in VWM disease, but usually do not represent a prominent feature. We report a 40-year-old man who was diagnosed with progressive myoclonus epilepsy in his twenties. All major causes of progressive myoclonus epilepsy (PME) were excluded. Brain MRI showed extensive white matter involvement. Mutation analysis of the EIF2B5 gene revealed a homozygous c.338G>A (p.Arg113His) mutation.     

Acute neurological deterioration in ovarioleukodystrophy related to EIF2B mutations: pregnancy with oocyte donation is a potentially precipitating factor

Mutations in the eukaryotic translation initiation factor 2B (eIF2B) represent a heterogenous group of autosomal recessive leucodystrophy characterized by a diffuse CSF-like aspect of the white matter at MRI designed as vanishing white matter (VWM) and episodes of acute deterioration after stresses. The mild juvenile and adult forms are often associated with primary ovarian failure, a syndrome referred to as ovarioleukodystrophy (OLD). We reported case of a woman with OLD who successfully underwent in vitro fertilization with donated oocytes and embryo transfer. Pregnancy was complicated by a non-convulsive epileptic status leading to the identification of compound heterozygous EIF2B5 mutation (p.Arg113His and p.Arg299His). The patient gave birth to a healthy child by Caesarean section. In conclusion, we report for the first time that in vitro fertilization and embryo transfer can lead to a successful procreation in patients with OLD related to EIF2B mutations. However this procedure must be considered with cautiousness, because of its potential neurological risks.     

Adult‐onset cerebello‐brainstem dominant form of X‐linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review

X‐linked adrenoleukodystrophy (X‐ALD) is the most common peroxisomal disorder and is caused by ABCD1 mutations. A cerebello‐brainstem dominant form that mainly involves the cerebellum and brainstem is summarized in a review of the literature, with autopsy‐confirmed cases exceedingly rare. We report a 69‐year‐old White man who was diagnosed with this rare disorder and describe neuropathologic, ultrastructural and genetic analyses. He did not have adrenal insufficiency or a family history of X‐ALD or Addison's disease. His initial symptom was temporary loss of eyesight at age 34 years. His major symptoms were chronic and progressive gait disorder, weakness in his lower extremities and spasticity, as well as autonomic failure and cerebellar ataxia suggesting possible multiple system atrophy (MSA). He also had seizures, hearing loss and sensory disturbances. His brain MRI showed no obvious atrophy or significant white matter pathology in cerebrum, brainstem or cerebellum. He died at age 69 years with a diagnosis of MSA. Microscopic analysis showed mild, patchy myelin rarefaction with perivascular clusters of PAS‐positive, CD68‐positive macrophages in the white matter most prominent in the cerebellum and occipital lobe, but also affecting the optic tract and internal capsule. Electron microscopy of cerebellar white matter showed cleft‐like trilamellar cytoplasmic inclusions in macrophages typical of X‐ALD, which prompted genetic analysis that revealed a novel ABCD1 mutation, p.R163G. Given the relatively mild pathological findings and long disease duration, it is likely that the observed pathology was the result of a slow and indolent disease process. We described a patient who had sporadic cerebello‐brainstem dominant form of X‐ALD with long clinical course, mild pathological findings, and an ABCD1 p.R163G substitution. We also review a total of 34 cases of adult‐onset cerebello‐brainstem dominant form of X‐ALD. Although rare, X‐ALD should be considered in the differential diagnosis of MSA.     

The ovarioleukodystrophy

The “ovarioleukodystrophies” comprise a group of rare leukodystrophies associated with primary or premature ovarian failure. Some of the patients have a variant of “vanishing white matter disease” with mutations in subunits of eukaryotic initiation factor 2B (EIF2B). A 32-year-old woman who developed neurological signs related to an extensive leukoencephalopathy on magnetic resonance imaging (MRI) in the context of amenorrhea since the age of 18 years was found to be homozygous for a mutation in the EIF2B5 gene: c.338G>A/p.Arg113His. She had a progressive disease with development of tetraparesia in less than 6 years. Our observation confirms that ovarian failure in the context of a leukodystrophy warrants mutational analysis of the genes encoding the subunits of EIF2B.     

An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene

We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin.     

Patterns of Magnetic Resonance Imaging Abnormalities in Symptomatic Patients With Krabbe Disease Correspond to Phenotype

BackgroundInitial magnetic resonance imaging studies of individuals with Krabbe disease were analyzed to determine whether the pattern of abnormalities corresponded to the phenotype.MethodsThis was a retrospective, nonblinded study. Families/patients diagnosed with Krabbe disease submitted medical records and magnetic resonance imaging discs for central review. Institutional review board approval/informed consents were obtained. Sixty-four magnetic resonance imaging scans were reviewed by two neuroradiologists and a child neurologist according to phenotype: early infantile (onset 0-6 months) = 39 patients; late infantile (onset 7-12 months) = 10 patients; later onset (onset 13 months-10 years) = 11 patients; adolescent (onset 11-20 years) = one patient; and adult (21 years or greater) = three patients. Local interpretations were compared with central review.ResultsMagnetic resonance imaging abnormalities differed among phenotypes. Early infantile patients had a predominance of increased intensity in the dentate/cerebellar white matter as well as changes in the deep cerebral white matter. Later onset patients did not demonstrate involvement in the dentate/cerebellar white matter but had extensive involvement of the deep cerebral white matter, parieto-occipital region, and posterior corpus callosum. Late infantile patients exhibited a mixed pattern; 40% had dentate/cerebellar white matter involvement while all had involvement of the deep cerebral white matter. Adolescent/adult patients demonstrated isolated corticospinal tract involvement. Local and central reviews primarily differed in interpretation of the early infantile phenotype.ConclusionAnalysis of magnetic resonance imaging in a large cohort of symptomatic patients with Krabbe disease demonstrated imaging abnormalities correspond to specific phenotypes. Knowledge of these patterns along with typical clinical signs/symptoms should promote earlier diagnosis and facilitate treatment.     

Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions

We evaluated the characteristic clinical features of one family of familial amyotrophic sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase (SOD1). Codon 46 encodes the binding site for copper and the His46Arg mutation may result in decreased copper binding and copper toxicity. The disease duration of this family was 17.8+/-13.2 years (mean+/-S.D.) with the age at onset being 42.9+/-4.7 years old (mean+/-S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the other lower limb. An autopsy was performed on a 62-year-old female member of the family who had the mutation. Her disease duration was 23 years, and she died of tonsillar herniation caused by metastasis of colon cancer in the cerebellum. Neuropathological findings showed marked loss of large anterior horn cells and very mild degeneration of corticospinal tracts as well as posterior columns. The number of nuclei of Clark's column was reduced. Lewy body-like hyaline inclusion bodies (LBHIs) were frequently seen in the remaining anterior horn cells. Astrocytic hyaline inclusions (Ast-HIs) were also seen. This is the first autopsy report of FALS with a His46Arg mutation presenting neuronal LBHIs and Ast-HIs. The formation of LBHIs and Ast-HIs may be dependent on the phenotype of the preferential lower motor neuron involvement in FALS with a SOD mutation and long disease duration.     

X-linked adrenoleukodystrophy: spinocerebellar variant.

The phenotypic variability in X-linked adrenoleukodystrophy (X-ALD) can be wide and varied. Rarely, it can present with clinical signs of spinocerebellar degeneration. There are very few reported cases of selective predominant white matter disease of the cerebellum in these patients. We report a patient with a rare variant of adult onset ALD who was previously diagnosed as spinocerebellar ataxia. He was a 24-year-old male who had delayed developmental milestones, developed signs of spinocerebellar degeneration (SCD) after 10 years of Addison's disease. Serial Magnetic Resonance Imaging (MRI), revealed cerebellar and pontine white matter disease but sparing the cerebral cortex and supratentorial white matter. His diagnosis of X-ALD was subsequently confirmed by the elevated serum very long chain fatty acids. This patient illustrates the unusual clinical presentation and imaging features of X-ALD and the importance of considering X-ALD in the clinical context of spinocerebellar degeneration. Early recognition of this rare variant would allow proper genetic counselling and institution of dietary therapy and/or bone marrow transplantation.     

A novel NDRG1 mutation in a non‐Romani patient with CMT4D/HMSN‐Lom

Charcot‐Marie‐Tooth disease type 4D (CMT4D), also known as hereditary motor and sensory neuropathy Lom type (HMSNL), is an autosomal recessive, early onset, severe demyelinating neuropathy with hearing loss, caused by N‐Myc downstream‐regulated gene 1 (NDRG1) mutations. CMT4D is rare with only three known mutations, one of which (p.Arg148Ter) is found in patients of Romani ancestry and accounts for the vast majority of cases. We report a 38‐year‐old Italian female with motor development delay, progressive neuropathy, and sensorineural deafness. Magnetic resonance imaging showed slight atrophy of cerebellum, medulla oblongata, and upper cervical spinal cord. She had a novel homozygous NDRG1 frameshift mutation (c.739delC; p.His247ThrfsTer74). The identification of this NDRG1 mutation confirms that CMT4D is not a private Romani disease and should be considered in the differential diagnosis of recessive demyelinating CMT.     

An unusual presentation of juvenile Alexander disease

Alexander disease is a rare leukodystrophy that most often presents in infancy but also includes neonatal, juvenile, and adult variants. Juvenile Alexander disease presents primarily with bulbar symptoms between 2 and 12 years of age. The diagnosis is often suggested by the clinical course and brain magnetic resonance image pattern and then confirmed by the presence of a mutation in the glial fibrillary acidic protein gene. A young girl presented with globus sensation and magnetic resonance imaging of the brain revealed abnormalities mainly involving white matter tracts of the medulla oblongata and cerebellum. The presence of a mutation in the glial fibrillary acidic protein gene confirmed the diagnosis of juvenile Alexander disease. A high index of clinical suspicion is necessary for the diagnosis of late-onset presentations of Alexander disease.     

Childhood onset tubular aggregate myopathy associated with de novo STIM1 mutations

We investigated three unrelated patients with tubular-aggregate myopathy and slowly progressive muscle weakness manifesting in the first years of life. All patients showed type 1 muscle fiber predominance and hypotrophy of type 2 fibers. Tubular aggregates were abundant. In all three patients mutations were identified in the gene STIM1, and the mutations were found to be de novo in all patients. In one of the patients the mutation was identified by exome sequencing. Two patients harbored the previously described mutation c.326A>G p.(His109Arg), while the third patient had a novel mutation c.343A>T p.(Ile115Phe). Taking our series together with previously published cases, the c.326A>G p.(His109Arg) seems to be a hotspot mutation that is characteristically related to early onset muscle weakness.     

POLG mutations presenting as Charcot‐Marie‐Tooth disease

We report on two patients, with different POLG mutations, in whom axonal neuropathy dominated the clinical picture. One patient presented with late onset sensory axonal neuropathy caused by a homozygous c.2243G>C (p.Trp748Ser) mutation that resulted from uniparental disomy of the long arm of chromosome 15. The other patient had a complex phenotype that included early onset axonal Charcot‐Marie‐Tooth disease (CMT) caused by compound heterozygous c.926G>A (p.Arg309His) and c.2209G>C (p.Gly737Arg) mutations.     

Spectroscopic data following stroke reveal tissue abnormality beyond the region of T2-weighted hyperintensity

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1 +/- 13.2 (mean +/- S.D.) years, with the age at onset being 39.7 +/- 10.5 years old (mean +/- S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8 +/- 3.2 years after the onset. Upper limb weakness started at 15.5 +/- 8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke's columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme.     

A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1

A novel mutation (Arg381Cys) in the second zinc-finger domain of early growth response 2 (EGR2) was identified in a late-onset Charcot--Marie--Tooth disease type 1 (CMT1) patient. This patient had initial symptoms of numbness and weakness in the leg at age 59, and a median nerve motor conduction velocity of 27 m/s. A sural nerve biopsy showed a severe loss of myelinated fibers with numerous onion bulbs. This is the first report of the EGR2 mutation presenting a late onset of CMT1 phenotype. Its mutation was a different amino acid substitution at codon 381 (Arg381His) which demonstrated congenital hypomyelinating neuropathy or early-onset CMT1. This report suggests that the EGR2 mutation represents divergent phenotypes at codon 381, which may be a mutation hotspot.     

Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation

Familial hypokalemic periodic paralysis is an autosomal-dominant disorder with features of both genetic and phenotypic heterogeneity. Mutation screening was performed on Korean hypokalemic periodic paralysis patients to locate the corresponding mutations and to specify the clinical features associated with the mutations. Target-exon PCR, direct sequencing, and restriction fragment length polymorphism analysis were used. A novel SCN4A Arg672Cys mutation and a known CACNL1A3 Arg528His mutation were identified. Incomplete penetrance in women with Arg672Cys mutation was evident. A comparison of the present study with previous studies raises the possibility that hypokalemic periodic paralysis is an allelic-specific or mulfactorial, rather than a gene-specific, disorder. Reported herein are two Korean hypokalemic periodic paralysis families, one carrying a novel SCN4A Arg672Cys mutation with incomplete penetrance in women, and the other carrying a CACNL1A3 Arg528His mutation, with the onset of characteristics of hypoPP developing at an earlier age, as well as a higher penetrance rate in women.     

Serial MRI changes in a patient with infantile Alexander disease and prolonged survival

Alexander disease is a major entity of leukodystrophy; magnetic resonance imaging (MRI) studies of the brain typically show extensive changes in the cerebral white matter with frontal predominance. Heterozygous missense mutations of GFAP are thought to be sufficient for the molecular diagnosis, which has widened the Alexander disease entity beyond the classical one. We report the patient, a 16-year-old Japanese boy, with infantile-onset Alexander disease, showing striking MRI findings; extreme white matter loss of cerebrum through cerebellum, severe atrophy of basal ganglia, cerebellum, brain stem, and cervical spinal cord. Molecular analysis showed a heterozygous mutation R239L (c.730G > T) in GFAP. A relative long disease course, over 15 years, with the help of mechanical ventilation revealed the striking MRI progression.