Clinical, biochemical, and genetic aspects of Sjögren‐Larsson syndrome

Cho, Kye Hee; Shim, Sung Han; Kim, MinYoung

doi:10.1111/cge.13058

Cited by 20 publications

(17 citation statements)

References 55 publications

(110 reference statements)

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“…2–4 In 95% of patients it is caused by mutations of the ALDH3A2 gene which encodes for the fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that oxidizes long-chain aldehydes to fatty acids. 2,5,6 SLS patients without mutations in the ALDH3A2 gene have also been identified, leaving the cause of the symptoms unknown. 7 Here, we report a patient with a congenital neuro-ichthyotic syndrome but atypical phenotype displaying dysmorphic features, and abnormalities on MRI and MR ( 1 H-MRS) spectroscopy in the absence of ALDH3A2 gene mutations and no spastic paraplegia to suggest classic SLS.…”

Section: Introductionmentioning

confidence: 99%

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

et al. 2019

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Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the ALDH1L2 (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.

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Section: Introductionmentioning

confidence: 99%

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

et al. 2019

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“…Mutation in the ALDH3A2 gene encoding fatty aldehyde dehydrogenase (FALDH), a microsomal nicotinamide-adenine-dinucleotide-dependent enzyme, is the pathognomic basis for SLS [ 1 ]. As oxidation of long-chain aliphatic aldehydes to fatty acids requires FALDH, the symptoms of FALDH-deficient SLS patients are caused by defective clearance of aldehydes [ 5 ]. Neurological disturbances may stem from the accumulation of defective eicosanoid metabolite lipids and aldehyde Schiff base in the brain [ 6 ]; reversal of reactive aldehydes produced by oxidative stress-induced lipid peroxidation is also defective without FALDH in SLS [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration in an adolescent with Sjogren-Larsson syndrome: a decade-long follow-up case report

et al. 2018

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BackgroundSjogren-Larsson syndrome is a hereditary neurocutaneous syndrome that is non-progressive in nature. Although neuroregression has been reported in seizure-prone preschool children requiring anti-epileptic treatment, teenage-onset dystonia precipitating neurodegeneration without any immediate causal events has yet to be reported.Case presentationWe describe a young woman with spastic diplegia and intellectual disability who began to show progressive neurological deterioration from 12 years of age, with the onset of dystonia and tremor. She was initially diagnosed with spastic cerebral palsy and periventricular leukomalacia based on brain magnetic resonance imaging. Follow-up brain imaging from 13 years of age did not reveal apparent changes, though abnormal electroencephalographic findings occurred in parallel with her decline in motor function. By 19 years of age, she had developed dysphagia and became completely dependent on others for most activities of daily living. Ultimately, whole-exome sequencing revealed a heterozygous compound mutation in the ALDH3A2 gene that corresponds to Sjogren-Larsson syndrome: an exon 9 deletion (1291-1292delAA) from the mother and an exon 5 splicing mutation (798 + 1delG) from the father. Neuroregression has been reported in preschool children after seizures requiring treatment, though our patient did not experience any immediate causal events. This report summarizes the clinical, radiologic, and electrophysiological findings observed over a decade concurrent with neurological deterioration after the onset of dystonia and tremor at the age of developmental ceiling in Sjogren-Larsson syndrome.ConclusionsIn addition to the influence of additive variants or other environmental factors, accumulation of metabolites due to defective fatty aldehyde dehydrogenase is a potential pathomechanism of neurodegeneration in this patient. Neurological deterioration may be a presentation that is unnoticed in Sjogren-Larsson syndrome due to the rarity of the disease. This report highlights a unique clinical feature of Sjogren-Larsson syndrome with progressive neurodegeneration associated with dystonia and tremor.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0663-0) contains supplementary material, which is available to authorized users.

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“…Eventually, yellowish lichenification and hyperkeratosis develops which is most pronounced in flexural regions and the neck area (Figure E). Infants with SLS also suffer from refractory pruritus partially due to an elevation of proinflammatory leukotriene B4 that can be detected in urine samples of SLS patients . A definitive diagnosis of SLS is established by targeted sequencing of the ALDH3A2 gene.…”

Section: Differential Diagnoses Of the Red Scaly Babymentioning

confidence: 99%

“…Infants with SLS also suffer from refractory pruritus partially due to an elevation of proinflammatory leukotriene B4 that can be detected in urine samples of SLS patients. 16,17 A definitive diagnosis of SLS is established by targeted sequencing of the ALDH3A2 gene.…”

Section: Eventually Yellowish Lichenification and Hyperkeratosis Devmentioning

confidence: 99%

Guidance for assessment of erythroderma in neonates and infants for the pediatric immunologist

Ott

2019

Pediatric Allergy Immunology

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Neonatal and infantile erythroderma (NIE) represents the common clinical phenotype of heterogeneous diseases ranging from benign and transient skin conditions to fatal multiorgan disorders. NIE regularly demands a comprehensive diagnostic workup in a multiprofessional setting, especially if newborns and young infants with the disease develop a failure to thrive and concomitant infectious, neurologic, or metabolic complications. By obtaining a detailed medical history and performing a thorough clinical examination, targeted diagnostic steps can be scheduled for most affected children. If NIE occurs in the early neonatal period, lesional skin biopsy and histology are often indicated. Likewise, if monogenic skin or immunologic diseases are suspected, genetic testing with customized panels of potentially underlying genes is mandatory. Of note, if acute symptoms such as severe infections, metabolic acidosis, or seizures occur, rapid microbiologic and metabolic investigations are warranted to rule out immunodeficiency and inborn errors of metabolism.

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Clinical, biochemical, and genetic aspects of Sjögren‐Larsson syndrome

Cited by 20 publications

References 55 publications

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

Deleterious mutations in ALDH1L2 suggest a novel cause for neuro-ichthyotic syndrome

Neurodegeneration in an adolescent with Sjogren-Larsson syndrome: a decade-long follow-up case report

Guidance for assessment of erythroderma in neonates and infants for the pediatric immunologist

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