Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation

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Abstract

Defects of phospholipids remodelling and synthesis are inborn errors of metabolism responsible for various clinical presentations including spastic paraplegia, retinopathy, optic atrophy, myo- and cardiomyopathies, and osteo-cutaneous manifestations. DDHD1 encodes a phospholipase A1, which is involved in the remodelling of phospholipids. We previously described a relatively pure hereditary spastic paraplegia (HSP) phenotype associated with mutations in DDHD1. Here we report a complex form of HSP associated with retinal dystrophy and a pattern of neurodegeneration with brain iron accumulation (NBIA) on brain MRI, due to a novel homozygous mutation in DDHD1. This observation enlarges the clinical spectrum of DDHD1-associated disorders and sheds light on a new aetiology for syndromes associating retinopathy and NBIA. It also emphasizes the role of complex lipids in the retina.

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.

Section snippets

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.

References (13)

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1

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2

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