Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia

Zhan, Zi-xiong; Liao, Xinxin; Du, Juan; Luo, Yingying; Hu, Zhongyang; Wang, Junling; Yan, Xinxiang; Zhang, Jianguo; Dai, Meizhi; Zhang, Peng; Xia, Kun; Tang, Beisha; Shen, Lu

doi:10.1016/j.ejmg.2013.04.008

Cited by 17 publications

(13 citation statements)

References 21 publications

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“…Genomic technologies not only provide diagnoses, but similar to the TANGO2 family, there are now many reports describing alteration to patient management. [32][33][34][35] Some diagnoses relate to treatable disorders that can be ameliorated with early therapy, 35 surveillance, or specialist assessment. Therefore the early use of genomic technologies in undiagnosed Mendelian disorders should now be considered best practice.…”

Section: Genomic Diagnoses Enable Optimized Clinical Managementmentioning

confidence: 99%

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Ewans

Schofield

Shrestha

et al. 2018

Genetics in Medicine

160

149

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PurposeWhole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.MethodsWES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).ResultsReanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.ConclusionEarly application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.GENETICS in MEDICINE advance online publication, 29 March 2018; doi:10.1038/gim.2018.39.

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Section: Genomic Diagnoses Enable Optimized Clinical Managementmentioning

confidence: 99%

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Ewans

Schofield

Shrestha

et al. 2018

Genetics in Medicine

160

149

View full text Add to dashboard Cite

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“…Some ALD patients with mutations in a peroxisome membrane protein ABCD1 manifest neurologic symptoms such as spasticity (Balicza et al, 2016;Koutsis et al, 2015;Maris et al, 1995;Shaw-Smith et al, 2004;Zhan et al, 2013), so we tested whether ABCD1 is required for LD-peroxisome contact formation by applying siRNA to knockdown ABCD1 ( Figure S4A). The extent of LD-peroxisome contacts induced by M1 Spastin overexpression was significantly reduced in siABCD1-treated cells as compared to siCtrl-treated cells ( Figures 4A and 4B).…”

Section: Abcd1 Forms a Tethering Complex With M1 Spastin Via The Pxi mentioning

confidence: 99%

“…This coincided with increased cellular lipid peroxidation and reduced energy production, possibly caused by defective FA trafficking to peroxisomes. Intriguingly, some ALD patients with mutations in a peroxisomal FA transporter ATP binding cassette subfamily D member 1 (ABCD1) also manifest neurologic symptoms, such as spasticity (Balicza et al, 2016;Koutsis et al, 2015;Lodhi and Semenkovich, 2014;Maris et al, 1995;Shaw-Smith et al, 2004;Zhan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

Chang

Weigel

Ioannou

et al. 2019

Preprint

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Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two inter-related mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD-peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1 and CHMP1B modifying LD membrane morphology. Furthermore, M1 Spastin, IST1 and CHMP1B are all required to relieve LDs of lipid peroxidation. M1 Spastin's dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD-peroxisome contact sites for FA trafficking may help explain the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.

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“…These considerations should not be limited to male patients. [3][4][5] In conclusion, X-ALD should be biochemically and genetically investigated in patients with progressive spastic paraplegia resembling HSP. We suggest measuring plasma VLCFA levels in all of these patients.…”

mentioning

confidence: 99%

“…3 The HSP-like cases reported show similar baseline characteristics with symptom onset in the third decade of life and normal brain magnetic resonance imaging. [3][4][5] An X-linked inheritance or signs of adrenal dysfunction should guide genetic testing or measurement of VLCFA levels for X-ALD investigation. These considerations should not be limited to male patients.…”

mentioning

confidence: 99%

X‐Linked Adrenoleukodystrophy Mimicking Hereditary Spastic Paraplegia

Ciarlariello

Freitas

Pedroso

et al. 2019

Movement Disord Clin Pract

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Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia

Cited by 17 publications

References 21 publications

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

X‐Linked Adrenoleukodystrophy Mimicking Hereditary Spastic Paraplegia

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