SSIEM 2014 Annual Symposium: Abstracts

doi:10.1007/s10545-014-9740-5

Cited by 5 publications

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“…While there are some common clinical features that all LBSL and HBSL patients share, clinical presentation and progression seem to differ between different age groups. Infantile-onset LBSL patients typically present with hypotonia, areflexia and developmental delay or regression of achieved developmental milestones (Miyake et al, 2011;Steenweg et al, 2012;Grechanina and Zdubskaya, 2014;Tylki-Szymanska et al, 2014;Kohler et al, 2015;Navarro Vázquez et al, 2016;Yahia et al, 2018). Progression of the disease is also more rapid and typically followed by development of upper motor neuron (UMN) signs such as spasticity, hyperreflexia, and a positive Babinski sign.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…Ultimately, the most common sign in LBSL is cerebellar ataxia and unsteady gait. Motor impairment is mainly caused by UMN dysfunction, however lower motor neuron (LMN) signs have also been described (Miyake et al, 2011;Steenweg et al, 2012;Grechanina and Zdubskaya, 2014;Yelam et al, 2019). Some other less frequent symptoms that have been observed in LBSL patients include unspecified tremor (Isohanni et al, 2010;Galluzzi et al, 2011;Sharma et al, 2011;Yamashita et al, 2013;Werner et al, 2018) and peripheral neuropathy (Linnankivi et al, 2004;Uluc et al, 2008), among others.…”

Section: Clinical Featuresmentioning

confidence: 99%

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The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

Muthiah

Housley

Klugmann

et al. 2021

Front. Cell. Neurosci.

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Aminoacyl-tRNA synthetases (ARSs) accurately charge tRNAs with their respective amino acids. As such, they are vital for the initiation of cytosolic and mitochondrial protein translation. These enzymes have become increasingly scrutinized in recent years for their role in neurodegenerative disorders caused by the mutations of ARS-encoding genes. This review focuses on two such genes—DARS1 and DARS2—which encode cytosolic and mitochondrial aspartyl-tRNA synthetases, and the clinical conditions associated with mutations of these genes. We also describe attempts made at modeling these conditions in mice, which have both yielded important mechanistic insights. Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a disease caused by a range of mutations in the DARS2 gene, initially identified in 2003. Ten years later, hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL), caused by mutations of cytosolic DARS1, was discovered. Multiple parallels have been drawn between the two conditions. The Magnetic Resonance Imaging (MRI) patterns are strikingly similar, but still set these two conditions apart from other leukodystrophies. Clinically, both conditions are characterized by lower limb spasticity, often associated with other pyramidal signs. However, perhaps due to earlier detection, a wider range of symptoms, including peripheral neuropathy, as well as visual and hearing changes have been described in LBSL patients. Both HBSL and LBSL are spectrum disorders lacking genotype to phenotype correlation. While the fatal phenotype of Dars1 or Dars2 single gene deletion mouse mutants revealed that the two enzymes lack functional redundancy, further pursuit of disease modeling are required to shed light onto the underlying disease mechanism, and enable examination of experimental treatments, including gene therapies.

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Section: Clinical Featuresmentioning

confidence: 99%

Section: Clinical Featuresmentioning

confidence: 99%

The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

Muthiah

Housley

Klugmann

et al. 2021

Front. Cell. Neurosci.

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Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

et al. 2015

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Introduction: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1.Methods: Plasma cholestane-3b,5a,6b-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining.Results: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3b,5a,6b-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3b,5a,6b-triol concentration markedly above the reference range was found.Conclusions: Measurement of plasma cholestane3b,5a,6b-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

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SSIEM 2014 Annual Symposium: Abstracts

Cited by 5 publications

References 0 publications

The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

The Leukodystrophies HBSL and LBSL—Correlates and Distinctions

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3β,5α,6β-Triol and Further Insight into the Clinical Phenotype

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