A novel frameshift DDHD1 mutation in a patient with hereditary spastic paraplegia type 28: Case report and review of the literature.

Hereditary spastic paraplegias (HSP) encompass a heterogeneous group of inherited neurological disorders, characterized by progressive lower limb weakness, spasticity, and hyperreflexia. HSP type 28 (HSP28) is a particularly rare autosomal recessive neurodegenerative disorder with a variable clinical phenotype. The main associated phenotype is characterized by an early onset pure form of HSP, with first symptoms emerging during the second decade of life. However clinical heterogeneity is evident, as complex forms of HSP with axonal neuropathy, cerebellar dysfunction, neuropsychiatric manifestations (depression), or musculoskeletal abnormalities (scoliosis, bilateral hallux valgus) have also been described [ 1 Mignarri A. Rubegni A. Tessa A. et al. Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28. J. Neurol. Sci. 2016; 15: 287-291 Abstract Full Text Full Text PDF Scopus (18) Google Scholar , 2 Liguori R. Giannoccaro M. Arnoldi A. et al. Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations. J. Neurol. 2014; 2611789:93 Crossref Scopus (21) Google Scholar , 3 Meyyazhagan A. Orlacchio A. Hereditary spastic paraplegia: an update. Int. J. Mol. Sci. 2022; 23: 1697 Crossref PubMed Scopus (28) Google Scholar , 4 Miura S. Morikawa T. Fujioka R. et al. A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia. Eur. J. Med. Genet. 2016; : 1-4 Google Scholar , 5 Tesson C. Nawara M. Salih M. et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am. J. Hum. Genet. 2012; 91: 1051-1064 Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar , 6 Bouslam N. Benomar A. Azzedine H. et al. Mapping of a new form of pure autosomal recessive spastic paraplegia (SPG28). Ann. Neurol. 2005; 57: 567-571 Crossref PubMed Scopus (55) Google Scholar , 7 Dard R. Meyniel C. Touitou V. et al. Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation. Eur. J. Med. Genet. 2017; : 1-4 Google Scholar ]. HSP28 is caused by biallelic pathogenic variants in DDHD1 gene, responsible for encoding phospholipase A1, an enzyme essential for the hydrolysis of the fatty acids of glycerophospholipids, structural components of the cellular membrane [ [8] Matsumoto N. Nemoto-Sasaki Y. Oka S. et al. Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization. J. Biol. Chem. 2021; 297100851 Abstract Full Text Full Text PDF Scopus (6) Google Scholar ]. Pathogenic variants in DDHD1 gene impact mitochondrial architecture and bioenergetics, thereby triggering cellular dysfunction [ [5] Tesson C. Nawara M. Salih M. et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am. J. Hum. Genet. 2012; 91: 1051-1064 Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar , [8] Matsumoto N. Nemoto-Sasaki Y. Oka S. et al. Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization. J. Biol. Chem. 2021; 297100851 Abstract Full Text Full Text PDF Scopus (6) Google Scholar ]. The maintenance of membrane composition, particularly of the mitochondrial membrane, is crucial for the proper functioning of long axons of the corticospinal tracts [ [5] Tesson C. Nawara M. Salih M. et al. Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am. J. Hum. Genet. 2012; 91: 1051-1064 Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar ]. The impairment of this neurons can be attributed to the underlying disruption in cellular energy metabolism. The distinct variants in DDHD1, further contribute to the variable clinical presentation. Herein, we review existing literature on HSP28 and describe a patient with a novel DDHD1 gene mutation.