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Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement.

ABSTRACT: To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings.The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed.Clinical and laboratory data were retrospectively collected.University hospital.Seven patients (3 male) shared similar MRI abnormalities and clinical features.Pattern of MRI abnormalities and clinical and laboratory findings.The MRIs showed signal abnormalities of the deep cerebral white matter, corpus callosum, thalamus, basal ganglia,brainstem, and cerebellar white matter between the ages of 9 months and 2 years. On follow-up, abnormalities gradually improved. Clinical regression occurred in the second half-year of life with spasticity and loss of milestones.From the second year on, clinical improvement occurred.So far, no second episode of regression has happened.Lactate levels were elevated during clinical regression.These patients represent a single novel leukoencephalopathy,probably caused by a mitochondrial defect.

SUBMITTER: Steenweg ME

PROVIDER: S-EPMC4154514 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement.

Steenweg Marjan E ME Vanderver Adeline A Ceulemans Berten B Prabhakar Prab P Régal Luc L Fattal-Valevski Aviva A Richer Lawrence L Simonetti Barbara Goeggel BG Barkhof Frederik F Rodenburg Richard J T RJ Pouwels Petra J W PJ van der Knaap Marjo S MS

Archives of neurology 20120601 6

<h4>Objective</h4>To describe a novel pattern of magnetic resonance imaging (MRI) abnormalities as well as the associated clinical and laboratory findings.<h4>Design</h4>The MRIs of more than 3000 patients with an unclassified leukoencephalopathy were systematically reviewed.Clinical and laboratory data were retrospectively collected.<h4>Setting</h4>University hospital.<h4>Patients</h4>Seven patients (3 male) shared similar MRI abnormalities and clinical features.<h4>Main outcome measures</h4>Pa ...[more]

PMID: 22312165

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Project description:ObjectiveSuccinate dehydrogenase-deficient leukoencephalopathy is a complex II-related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern, and genetic findings have not been comprehensively reviewed.MethodsNineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, clinical, and genetic findings as part of institutional review board-approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, the Netherlands).ResultsAll individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles, and cerebellar white matter, and elevated succinate on magnetic resonance spectroscopy (MRS). The thalamus was involved in most studies, with a predilection for the anterior nucleus, pulvinar, and geniculate bodies. Clinically, infantile onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB, or SDHAF1, or proven biochemical defect.InterpretationSuccinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami, and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate.

Project description:BackgroundSandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene.MethodThis study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019.ResultsFive unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604.ConclusionThe study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.

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Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement.

Publications

Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement.

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