Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation
Introduction
Disorders of complex lipids biosynthesis and remodelling (phospholipids, sphingolipids and fatty acids) are a very recently described group of inborn errors of metabolism (IEM)(Lamari et al., 2013). This field has strongly expanded over the past few years and accounts for more than a hundred different diseases (Lamari et al., 2015). Most of the time, only few cases have been reported so far and the clinical spectrum for each of these IEM remains to be delineated. Clinically, almost all organs and systems can be affected depending on the specific enzymatic defect. Among about eighty genes associated with hereditary spastic paraplegia (HSP), at least thirteen are involved in lipid metabolism. Ophthalmic manifestations appear to be also common among this group of novel diseases, emphasizing the role of complex lipids in the retina, the lens and the optic nerve (Garcia-Cazorla et al., 2015).
Neurodegeneration with brain iron accumulation (NBIA) are autosomal recessive inherited disorders presenting with a progressive extra-pyramidal syndrome and iron deposition in the globus pallidus and/or other basal ganglia (substantia nigra, dentate, caudate, putamen or thalamus depending on specific syndrome). The association of NBIA with ophthalmic manifestations has been reported in patients with PANK2, PLA2G6, FA2H and C19orf12 mutations (Table 1). Intriguingly, only two NBIA-associated genes are clearly implicated in iron metabolism (CP, FTL) whereas the five other known genes encode for enzymes involved in complex lipids metabolism (PANK2, PLA2G6, FA2H, COASY, C19orf12) (Colombelli et al., 2015). Here we report a DDHD1 deficient patient presenting as a complex form of HSP with retinal dystrophy and NBIA.
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Clinical report
A 55-year-old man, born from related parents from South-East Asia, was referred to our hospital for walking disabilities. Family history revealed that his sister also presented with motor symptoms but we were not able to obtain more information about her clinical history. The patient had four healthy children. His clinical course began at age 40 with subtle walking difficulties in cold weather, progressively evolving to spastic paraplegia in 15 years. No significant clinical event was found in
Discussion
This observation highlights that mutations in DDHD1 is a novel cause of complex HSP with retinal dystrophy and NBIA. Mutations in PANK2 are a well-known cause of retinopathy and NBIA (Egan et al., 2005, Han et al., 2016, Hayflick, 2014), whereas the association of optic atrophy and NBIA has been described in patients harbouring mutations in PLA2G6, FA2H and C19orf12 mutations (Table 1). Importantly, all these genes encode for proteins involved in the synthesis and/or remodelling of
Conflict of interest
Authors have no conflict of interest to declare.
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A novel frameshift DDHD1 mutation in a patient with hereditary spastic paraplegia type 28: Case report and review of the literature
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2022, Methods in EnzymologyCitation Excerpt :However, as both potential substrates (PA, phosphatidylinositol (and phosphoinositides)) and products (lysophosphatidic acid (LPA) and LPI) are involved in cell growth and survival (Yamashita et al., 2010), DDHD1 may regulate signaling in focal adhesions. In addition, mutations in human DDHD1 cause the neurodegenerative disorder HSP (SPG28 subtype) (Dard et al., 2017; Liguori et al., 2014; Mignarri et al., 2016; Miura et al., 2016; Tesson et al., 2012); thus, neuronal death may be involved. This study therefore provides scope for future research.
Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization
2021, Journal of Biological ChemistryCitation Excerpt :However, as both potential substrates (PA and phosphatidylinositol (and phosphoinositides)) and products (lysophosphatidic acid (LPA) and LPI) are involved in cell growth and survival (4, 5, 12), DDHD1 may regulate signaling in focal adhesions. In addition, mutation(s) in human DDHD1 cause the neurodegenerative disorder HSP (SPG28 subtype) (16–20), thus neuronal death may be involved. This study presented an important question to be solved in the future.
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2019, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :DDHD1 was identified as the causative gene for a relatively non-complicated form of hereditary spastic paraplegia (HSP), type SPG28 [135–139]. However, a recent study reported that a patient harboring a novel homozygous mutation in DDHD1 presented a complex form of HSP with retinal dystrophy and neurodegeneration with brain iron accumulation (NBIA) [140]. DDHD1 is also implicated in juvenile amyotrophic lateral sclerosis (JALS) [141].