Disturbed brain ether lipid metabolism and histology in <scp>Sjögren‐Larsson</scp> syndrome

Staps, Pippa; Rizzo, William B.; Vaz, Frédéric M.; Bugiani, Marianna; Giera, Martin; Heijs, Bram; Kampen, Antoine H. C. van; Pras‐Raves, Mia L.; Breur, Marjolein; Groen, Annemieke; Ferdinandusse, Sacha; Goethem, Gert Van; Lammens, Martin; Wevers, Ron A.; Willemsen, M.A.A.P.

doi:10.1002/jimd.12275

Cited by 26 publications

(29 citation statements)

References 39 publications

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“…21 On the other side of the spectrum, three disorders have recently been reported that biochemically show elevated levels of ether lipids: EPT1 deficiency (SELENOI), 22,23 PCYT2 deficiency (PCYT2), 14,24 and Sjögren-Larsson syndrome (SLS, ALDH3A2). 25,26 Like the FAR1 p.Arg480 variant patients, spastic paraparesis and some form of ocular pathology (e.g. cataracts, optic atrophy, macular dystrophy) are frequently observed in these disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Besides ether lipids, fatty alcohols possibly are involved in the pathological mechanism. Fatty alcohols have been shown to accumulate in SLS 25,26 and RCDP types 1-3 27 and may accumulate in PCYT2 and EPT1 deficiency given the disturbed synthesis of ethanolamine ether lipids, 14 but would obviously not accumulate in FAR1 deficiency where they cannot be synthesized. Despite the similarities and differences in symptoms and biochemical abnormalities, the exact pathophysiological mechanism remains enigmatic.…”

Section: Discussionmentioning

confidence: 99%

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An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Ferdinandusse

McWalter²,

Brinke

et al. 2021

Genetics in Medicine

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In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogendependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Ferdinandusse

McWalter²,

Brinke

et al. 2021

Genetics in Medicine

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“…6 Recent lipidomic analysis of autopsied brain from an adult patient with Sjögren-Larsson syndrome demonstrated accumulation of fatty alcohols of unusually long chain length (C18-C24) together with their corresponding ether lipid synthesis products. 16 These lipids were highest in white matter but also accumulated in gray matter. It is likely that the fatty alcohols and ether lipids disrupt myelin membranes and account for the lipid peak seen on MR spectroscopy.…”

Section: Discussionmentioning

confidence: 95%

A Neurodegenerative Phenotype Associated With Sjögren-Larsson Syndrome

2021

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Sjögren-Larsson syndrome (SLS) is a rare neurologic disorder caused by pathogenic sequence variants in ALDH3A2 and characterized by ichthyosis, spasticity, intellectual disability, and a crystalline retinopathy. Neurologic symptoms develop in the first 2 years of life. Except for worsening ambulation due to spastic diplegia and contractures, the neurologic disease has been considered static and a neurodegenerative course is distinctly unusual. We describe a young child with Sjögren-Larsson syndrome who exhibited an early and severely progressive neurologic phenotype that may have been triggered by a febrile rotavirus infection. Together with 7 additional published cases of these atypical patients, we emphasize that a neurodegenerative course can be an extreme outcome for a minority of patients with Sjögren-Larsson syndrome.

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“…In addition, fatty aldehyde dehydrogenase (FALDH) is not solely involved in sphingolipid metabolism but also in ether lipid metabolism. 6 To avoid redundancy, we discuss these enzymes and their associated phenotypes within categories based on clinical context.…”

Section: Traditional Classificationmentioning

confidence: 99%

“…30 There is evidence that ichthyosis in this disorder is caused by abnormal lipid accumulation in keratinocytes that impair adequate delivery of precursor products to the stratum corneum 31 as well as evidence of accumulation of fatty alcohols and ether lipids in the brain. 6 F I G U R E 1 Sphingolipid metabolism. In de novo sphingolipid synthesis, serine palmitoyltransferase produces 3-ketosphinganine from palmitoyl-CoA and serine.…”

Section: Nonlysosomal Sphingolipid Metabolismmentioning

confidence: 99%

Inherited disorders of complex lipid metabolism: A clinical review

Xiao

Rossignol

Vaz

et al. 2021

J of Inher Metab Disea

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Over 80 human diseases have been attributed to defects in complex lipid metabolism. A majority of them have been reported recently in the setting of rapid advances in genomic technology and their increased use in clinical settings. Lipids are ubiquitous in human biology and play roles in many cellular and intercellular processes. While inborn errors in lipid metabolism can affect every organ system with many examples of genetic heterogeneity and pleiotropy, the clinical manifestations of many of these disorders can be explained based on the disruption of the metabolic pathway involved. In this review, we will discuss the physiological function of major pathways in complex lipid metabolism, including nonlysosomal sphingolipid metabolism, acylceramide metabolism, de novo phospholipid synthesis, phospholipid remodeling, phosphatidylinositol metabolism, mitochondrial cardiolipin synthesis and remodeling, and ether lipid metabolism as well as common clinical phenotypes associated with each.

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Disturbed brain ether lipid metabolism and histology in Sjögren‐Larsson syndrome

Cited by 26 publications

References 39 publications

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

A Neurodegenerative Phenotype Associated With Sjögren-Larsson Syndrome

Inherited disorders of complex lipid metabolism: A clinical review

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