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Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

ABSTRACT: BACKGROUND:Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS:Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS:Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS:Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

SUBMITTER: Gantner ML

PROVIDER: S-EPMC7685488 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

Gantner Marin L ML Eade Kevin K Wallace Martina M Handzlik Michal K MK Fallon Regis R Trombley Jennifer J Bonelli Roberto R Giles Sarah S Harkins-Perry Sarah S Heeren Tjebo F C TFC Sauer Lydia L Ideguchi Yoichiro Y Baldini Michelle M Scheppke Lea L Dorrell Michael I MI Kitano Maki M Hart Barbara J BJ Cai Carolyn C Nagasaki Takayuki T Badur Mehmet G MG Okada Mali M Woods Sasha M SM Egan Catherine C Gillies Mark M Guymer Robyn R Eichler Florian F Bahlo Melanie M Fruttiger Marcus M Allikmets Rando R Bernstein Paul S PS Metallo Christian M CM Friedlander Martin M

The New England journal of medicine 20190911 15

<h4>Background</h4>Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously.<h4>Methods</h4>Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in <i>SPTLC1</i> encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT ...[more]

PMID: 31509666

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Project description:Background: Clinically relevant neurological manifestations in children with celiac disease (CD) are unusual, especially when they are considered as signs of the onset of the disease. In this paper, a case of Guillain-Barrè syndrome (GBS) as the first manifestation of CD in a 23-month-old child is reported. Case presentation: We describe a case of CD onset with peripheral neuropathy in a 23-month-old Bulgarian boy presenting with a sudden refusal to walk and absence of deep tendon reflexes in both lower limbs. Neurological symptoms were preceded by two months of gastrointestinal symptoms such as vomiting, abdominal distention, and clear signs of malnutrition and weight loss. When we evaluated the child six months after the onset of the symptoms, clinical and laboratory findings showed clear signs of peripheral neuropathy associated with malnutrition. Serum deamidated gliadin and tissue transglutaminase antibodies were therefore measured. The anti-gliadin levels were more than sixteen times higher than normal and the IgA anti-transglutaminase levels were four times higher than normal. Anti-endomysium antibodies were positive, and human leukocyte antigens (HLA) II typing confirmed a genetic predisposition to CD (DQ2 positive and DQ8 negative). Given the association between the clinical evidence of the disease and the results of the celiac screening tests, a diagnosis of CD was made without biopsy confirmation of the enteropathy. The child began a restricted gluten-free diet that led to complete recovery of the peripheral neuropathy, walking, reflexes, and overall improvement after three months on the diet. Conclusion: Our case underlines the rare but possible associations between CD and peripheral neuropathy in children as an onset symptom, even in the absence of gastrointestinal manifestations, thus suggesting that CD should always be considered in the differential diagnosis of peripheral neuropathy in children. A good knowledge of the extra-intestinal manifestations of CD is essential for the rapid introduction of a gluten-free diet that could be useful for the resolution of the neurological symptoms.

Dataset Information

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

Publications

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

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