Progressive Leukoencephalopathy Research Articles

Expansion of the clinical spectrum associated with AARS2‐related disorders

Biallelic pathogenic variants in AARS2, a gene encoding the mitochondrial alanyl-tRNA synthetase, result in a spectrum of findings ranging from infantile cardiomyopathy to adult-onset progressive leukoencephalopathy. In this article, we present three unrelated individuals with novel compound heterozygous pathogenic AARS2 variants underlying diverse clinical presentations. Patient 1 is a 51-year-old man with adult-onset progressive cognitive, psychiatric, and motor decline and leukodystrophy. Patient 2 is a 34-year-old man with childhood-onset progressive tremor followed by the development of polyneuropathy, ataxia, and mild cognitive and psychiatric decline without leukodystrophy on imaging. Patient 3 is a 57-year-old woman with childhood-onset tremor and nystagmus which preceded dystonia, chorea, ataxia, depression, and cognitive decline marked by cerebellar atrophy and white matter disease. These cases expand the clinical heterogeneity of AARS2-related disorders, given that the first and third case represent some of the oldest known survivors of this disease, the second is adult-onset AARS2-related neurological decline without leukodystrophy, and the third is biallelic AARS2-related disorder involving a partial gene deletion.

Novel Alanyl-tRNA Synthetase 2 (AARS2) Pathogenic Variants with Progressive Leukoencephalopathy

Novel Alanyl-tRNA Synthetase 2 (AARS2) Pathogenic Variants with Progressive Leukoencephalopathy

KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature

BackgroundKARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed.ResultsHerein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects.ConclusionsWith our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity.Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

Progressive Cavitating Leukoencephalopathy in an Infant Baby: A Case Report

Cavitating leukoencephalopathy is a group of disorders caused by multiple mitochondria dysfunction syndrome (MMDS). Multiple genetic mutations have been identified in its etiology including a mutation in the IBA57 gene on chromosome 1q42. We present the case of a 5-month-old boy who was diagnosed with progressive cavitating leukoencephalopathy at King Faisal specialist Hospital, Riyadh city, Saudi Arabia. The patient presented with frequent excessive crying since birth. He also had a history of abnormal movement described as tonic spasm of the upper limbs for few second, delayed developmental milestones, and regression of the achieved milestones. Neurological examination of the patient was positive for horizontal eye nystagmus and optic nerve atrophy, exaggerated gag response, spastic tone that was more prevalent in the upper limbs, and bilateral clonus. The patient showed abnormal findings on MRI including cavitation and cystic leukodystrophy, and homozygosity mapping showed the IBA57 gene mutation. The patient died at the age of 7 months from progressive respiratory failure. MMDS is a rare condition, and according to available data, this case of MMDS is the first to be reported in Saudi Arabia and in the Gulf region.

Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy.

Autosomal-recessive mutations in TBCK cause intellectual disability of variable severity. Although the physiological function of TBCK remains unclear, loss-of-function mutations are associated with inhibition of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Given that mTORC1 signaling is known to regulate autophagy, we hypothesized that TBCK-encephalopathy patients with a neurodegenerative course have defects in autophagic-lysosomal dysfunction. Children (n = 8) of Puerto Rican (Boricua) descent affected with homozygous TBCK p.R126X mutations underwent extensive neurological phenotyping and neurophysiological studies. We quantified autophagosome content in TBCK-/- patient-derived fibroblasts by immunostaining and assayed autophagic markers by western assay. Free sialylated oligosaccharide profiles were assayed in patient's urine and fibroblasts. The neurological phenotype of children with TBCK p.R126X mutations, which we call TBCK-encephaloneuronopathy (TBCKE), include congenital hypotonia, progressive motor neuronopathy, leukoencephalopathy, and epilepsy. Systemic features include coarse facies, dyslipidemia, and osteoporosis. TBCK-/- fibroblasts in vitro exhibit increased numbers of LC3+ autophagosomes and increased autophagic flux by immunoblots. Free oligosaccharide profiles in fibroblasts and urine of TBCKE patients differ from control fibroblasts and are ameliorated by treatment with the mTORC1 activator leucine. TBCKE is a clinically distinguishable syndrome with progressive central and peripheral nervous system dysfunction, consistently observed in patients with the p.R126X mutation. We provide evidence that inappropriate autophagy in the absence of cellular stressors may play a role in this disorder, and that mTORC1 activation may ameliorate the autophagic-lysosomal system dysfunction. Free oligosaccharide profiles could serve as a novel biomarker for this disorder as well as a tool to evaluate potential therapeutic interventions. Ann Neurol 2018;83:153-165.

Novel Mutation of DARS2 Gene Leading to a Rapidly Progressive Early onset Leukoencephalopathy

Novel Mutation of DARS2 Gene Leading to a Rapidly Progressive Early onset Leukoencephalopathy

IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy.

Objective:To determine the molecular factors contributing to progressive cavitating leukoencephalopathy (PCL) to help resolve the underlying genotype-phenotype associations in the mitochondrial iron-sulfur cluster (ISC) assembly system.Methods:The subjects were 3 patients from 2 families who showed no inconsistencies in either clinical or brain MRI findings as PCL. We used exome sequencing, immunoblotting, and enzyme activity assays to establish a molecular diagnosis and determine the roles of ISC-associated factors in PCL.Results:We performed genetic analyses on these 3 patients and identified compound heterozygosity for the IBA57 gene, which encodes the mitochondrial iron-sulfur protein assembly factor. Protein expression analysis revealed substantial decreases in IBA57 protein expression in myoblasts and fibroblasts. Immunoblotting revealed substantially reduced expression of SDHB, a subunit of complex II, and lipoic acid synthetase (LIAS). Levels of pyruvate dehydrogenase complex-E2 and α-ketoglutarate dehydrogenase-E2, which use lipoic acid as a cofactor, were also reduced. In activity staining, SDH activity was clearly reduced, but it was ameliorated in mitochondrial fractions from rescued myoblasts. In addition, NFU1 protein expression was also decreased, which is required for the assembly of a subset of iron-sulfur proteins to SDH and LIAS in the mitochondrial ISC assembly system.Conclusions:Defects in IBA57 essentially regulate NFU1 expression, and aberrant NFU1 ultimately affects SDH activity and LIAS expression in the ISC biogenesis pathway. This study provides new insights into the role of the iron-sulfur protein assembly system in disorders related to mitochondrial energy metabolism associated with leukoencephalopathy with cavities.

DARS2 protects against neuroinflammation and apoptotic neuronal loss, but is dispensable for myelin producing cells.

Although mitochondria are ubiquitous, each mitochondrial disease has surprisingly distinctly different pattern of tissue and organ involvement. Congruently, mutations in genes encoding for different mitochondrial tRNA synthetases result in the development of a very flamboyant group of diseases. Mutations in some of these genes, including aspartyl-tRNA synthetase (DARS2), lead to the onset of a white matter disease-leukoencephalopathy with brainstem and spinal cord involvement, and lactate elevation (LBSL) characterized by progressive spastic ataxia and characteristic leukoencephalopathy signature with multiple long-tract involvements. Puzzled by the white matter disease phenotypes caused by DARS2 deficiency when numerous other mutations in the genes encoding proteins involved in mitochondrial translation have a detrimental effect predominantly on neurons, we generated transgenic mice in which DARS2 was specifically depleted in forebrain-hippocampal neurons or myelin-producing cells. Our results now provide the first evidence that loss of DARS2 in adult neurons leads to strong mitochondrial dysfunction and progressive loss of cells. In contrast, myelin-producing cells seem to be resistant to cell death induced by DARS2 depletion despite robust respiratory chain deficiency arguing that LBSL might originate from the primary neuronal and axonal defect. Remarkably, our results also suggest a role for early neuroinflammation in the disease progression, highlighting the possibility for therapeutic interventions of this process.

Serial brain MRI findings in a rare survivor of rabies encephalitis.

Rabies is a neurotropic viral illness, almost always fatal, that is equally dreaded by healthcare practitioners and patients due to the dismal prognosis and limited treatment options once symptoms set in. There are hardly any reports on MRI changes in the brain in survivors of rabies encephalitis. We present the clinical course and the imaging findings on serial MRI examinations in a rare patient who survived rabies infection. Initial brain MRI done 8 days after onset of symptoms revealed bilaterally symmetrical non-enhancing areas of T1 and T2 hyperintensity in the basal ganglia, thalami, mid brain, and pons along with T2 hyperintensity and restricted diffusion in fronto-parietal cortical grey matter and left hippocampus. Subsequent MRI scans at 2 months and 5 months revealed progressive brain atrophy, leukoencephalopathy, and gliosis.

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration.

l-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the l-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of l-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.

Rapidly progressive psychotic symptoms triggered by infection in a patient with methylenetetrahydrofolate reductase deficiency: a case report

BackgroundMethylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn error of metabolism inherited in autosomal recessive pattern and is associated with a wide spectrum of neurological abnormalities.Case presentationWe herein describe a 15-year-old boy with MTHFR deficiency who presented with a slowly progressive decline of school performance and a spastic gait. Rapidly deteriorating psychosis and repetitive seizures triggered by a febrile infection prompted neurological investigation. He had significantly elevated total plasma homocysteine and urinary homocystine levels, as well as a decreased plasma methionine level. Brain magnetic resonance imaging (MRI) revealed leukoencephalopathy. DNA gene sequencing showed c.446_447 del GC ins TT and c.137G > A, and c.665C > T heterozygous mutations in the MTHFR gene of the patient. Oral administration of betaine drastically improved his clinical symptoms within a few months. After 8 months of treatment, his total plasma homocysteine level moderately decreased; and the plasma methionine concentration became normalized. Furthermore, the white matter lesions on MRI had disappeared.ConclusionThis patient demonstrates the possibility that MTHFR deficiency should be considered in mentally retarded adolescents who display an abnormally elevated plasma level of homocysteine in association with progressive neurological dysfunction and leukoencephalopathy. Febrile infections may be an aggravating factor in patients with MTHFR deficiency.

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders.

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Clinical and morphological analysis of the case of lethal outcome in a patient with Binswanger’s disease

Progressive subcortical vascular leukoencephalopathy caused by chronic hypertension was singled out as a separate disease by Alois Alzheimer and named “Binswanger’s Disease”(BD). Before the introduction of neuroimaging techniques in clinical practice BD was considered as a rare disease and in most cases it was diagnosed during autopsy. More than 80% of BD’s debuts occur on the sixth or seventh decade of life and are characterized by a mild but inexorably progressive course with episodes of exacerbation. At the last stage of the disease, clinical picture is presented by dementia, disorders of the self-service and the pelvic organs functions. The article presents a 42 years-old patient with the terminal stage of the BD’s type vascular dementia verified by postmortem histological examination. It is known that age is an unmodified risk factor for cardiovascular disease. However, in recent decades there has been “vascular risk rejuvenation” of the world, which calls for the development and improvement of approaches to screening and clinical examination of these contingents. The presented case report demonstrates the difficulty in the diagnosis of this pathology of the brain and demonstrates the need for inclusion of the BD in a number of differential diagnostic in patients with cerebrovascular diseases. In addition, we believe that dementia screening should include medical and psychological counseling of patients at risk.

Mitochondrial Neurogastrointestinal Encephalomyopathy Presenting as Anorexia Nervosa

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare multisystemic autosomal recessive disorder mainly caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase. It generally appears in childhood and is clinically characterized by severe gastrointestinal dysmotility, cachexia, ptosis, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy on brain magnetic resonance imaging. The disease is clinically heterogeneous with the main symptoms being gastrointestinal, with an important weight loss. Symptoms might worsen rapidly, and a timely diagnosis is vital. However, patients report retrospectively their first symptoms before the age of 12 years, but the delay in diagnosis varies from 5 to 10 years. In the present study, we report a case of an adolescent with MNGIE, which was initially, and erroneously, diagnosed as anorexia nervosa. To make a timely and accurate differential diagnosis, we will discuss the clinical differences and similarities between MNGIE and anorexia nervosa and the importance of a multidisciplinary evaluation.

Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

EIF2B-related multisystem disorder in two sisters with atypical presentations

Vanishing white matter disease (VWM) is a chronic progressive leukoencephalopathy that is characterized by cerebellar ataxia and spasticity, together with cystic degeneration of the cerebral white matter as evidenced by brain magnetic resonance imaging (MRI). Here, we report two sisters with EIF2B2 variants, who presented with delayed development and failure to thrive before 1 year of age, developed cataracts, and showed diffuse leukoencephalopathy. The index case had a history of hepatomegaly and intermittent vomiting after upper respiratory infection at 11 months of age. Her older brothers had died at an early age, one with similar symptoms and the other because of septic shock. Her older sister had similar presenting symptoms; she later suffered from both cataracts and primary amenorrhea, but showed neurological improvement. Her follow-up MRIs (at 21 years of age) revealed progressive diffuse brain atrophy with leukoencephalopathy, without cystic rarefaction. Whole-exome sequencing of the index case revealed the presence of the compound heterozygous variants, Val85Glu and Met226Lys in EIF2B2. The affected sister had the same compound heterozygous variants, and their unaffected parents were heterozygous carriers of each variant. This study expanded the clinical and genetic spectrum of VWM with EIF2B2 variants. It would be better to consider VWM as an eIF2B-related multisystem disorder, not just as a neurological disorder, on the basis that this is a family of housekeeping genes that affect multiple organs.

Dimethyl fumarate in the management of multiple sclerosis: appropriate patient selection and special considerations.

Delayed-release dimethyl fumarate (DMF), also known as gastroresistant DMF, is the most recently approved oral disease-modifying treatment (DMT) for relapsing multiple sclerosis. Two randomized clinical trials (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing–Remitting MS [DEFINE] and Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis [CONFIRM]) demonstrated significant efficacy in reducing relapse rate and radiological signs of disease activity, as seen on magnetic resonance imaging. The DEFINE study also indicated a significant effect of DMF on disability worsening, while the low incidence of confirmed disability worsening in the CONFIRM trial rendered an insignificant reduction among the DMF-treated groups when compared to placebo. DMF also demonstrated a good safety profile and acceptable tolerability, since the most common side effects (gastrointestinal events and flushing reactions) are usually transient and mild to moderate in severity. Here, we discuss the place in therapy of DMF for individuals with relapsing multiple sclerosis, providing a tentative therapeutic algorithm to manage newly diagnosed patients and those who do not adequately respond to self-injectable DMTs. Literature data supporting the potential role of DMF as a first-line therapy are presented. The possibility of using DMF as switching treatment or even as an add-on strategy in patients with breakthrough disease despite self-injectable DMTs will also be discussed. Lastly, we argue about the role of DMF as an exit strategy from natalizumab-treated patients who are considered at risk for developing multifocal progressive leukoencephalopathy.

Mitochondrial Neuro-Gastrointestinal Encephalopathy (MNGIE), Index of Suspicion

Mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE), is an autosomal recessive disease, is one of the mitochondrial disorders, and is a multisystem disease clinically defined by progressive ophthalmoplegia, peripheral neuropathy, leukoencephalopathy, mitochondrial abnormalities and severe gastrointestinal involvement. Mitochondrial disorders have clinical manifestations reflecting the fact that nearly all organ systems utilize oxidative metabolism. Clinical features often involve tissues with high energy requirements such as central and peripheral nervous systems, and eye, muscle, kidney and endocrine organs.. To the best of our knowledge there is no case report of this syndrome from Middle East and since this presents with diagnostic difficulties so is being reported.

Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: A potential role for glutamatergic-induced excitotoxicity in GA I neuropathology

Glutaric aciduria type I (GA I) is biochemically characterized by accumulation of glutaric and 3-hydroxyglutaric acids in body fluids and tissues, particularly in the brain. Affected patients show progressive cortical leukoencephalopathy and chronic degeneration of the basal ganglia whose pathogenesis is still unclear. In the present work we investigated parameters of bioenergetics and redox homeostasis in various cerebral structures (cerebral cortex, striatum and hippocampus) and heart of adult wild type (Gcdh+/+) and glutaryl-CoA dehydrogenase deficient knockout (Gcdh−/−) mice fed a baseline chow. Oxidative stress parameters were also measured after acute lysine overload. Finally, mRNA expression of NMDA subunits and GLT1 transporter was determined in cerebral cortex and striatum of these animals fed a baseline or high lysine (4.7%) chow. No significant alterations of bioenergetics or redox status were observed in these mice. In contrast, mRNA expression of the NR2B glutamate receptor subunit and of the GLT1 glutamate transporter was higher in cerebral cortex of Gcdh−/− mice. Furthermore, NR2B expression was markedly elevated in striatum of Gcdh−/− animals receiving chronic Lys overload. These data indicate higher susceptibility of Gcdh−/− mice to excitotoxic damage, implying that this pathomechanism may contribute to the cortical and striatum alterations observed in GA I patients.