[en] We describe progressive spastic paraparesis in two male siblings and the daughter of one of these individuals. Onset of disease occurred within the first decade, with stiffness and gait difficulties. Brisk deep tendon reflexes and extensor plantar responses were present, in the absence of intellectual disability or dermatological manifestations. Cerebral imaging identified intracranial calcification in all symptomatic family members. A marked upregulation of interferon-stimulated gene transcripts was recorded in all three affected individuals and in two clinically unaffected relatives. A heterozygous IFIH1 c.2544T>G missense variant (p.Asp848Glu) segregated with interferon status. Although not highly conserved (CADD score 10.08 vs. MSC-CADD score of 19.33) and predicted as benign by in silico algorithms, this variant is not present on publically available databases of control alleles, and expression of the D848E construct in HEK293T cells indicated that it confers a gain-of-function. This report illustrates, for the first time, the occurrence of autosomal-dominant spastic paraplegia with intracranial calcifications due to an IFIH1-related type 1 interferonopathy.
Aicardi, J., & Goutières, F. (1984). A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Annals of Neurology, 15, 49–54
Buers, I., Rice, G. I., Crow, Y. J., & Rutsch, F. (2017). MDA5-associated neuroinflammation and the Singleton-Merten Syndrome, two faces of the same type i interferonopathy spectrum. Journal of Interferon and Cytokine Research, 37, 214–219
Bursztejn, A-C., Briggs, T. A., Toro Duany, Y., del, Anderson B. H., O'Sullivan, J., Williams, S. G., … Oojageer, A. (2015). Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1, overlap between Aicardi-Goutières and Singleton-Merten syndromes. British Journal of Dermatology, 173, 1505–1513
Crow, Y. J., Chase, D. S., Schmidt, J. L., Szynkiewicz, M., Forte, G. M. A., Gornall, H. L., … Abdel-Salam, G. M. (2015). Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. American Journal of Medical Genetics. Part A, 0, 296–312
Crow, Y. J., Hayward, B. E., Parmar, R., Robins, P., Leitch, A., Ali, M., … Cowan, F. M., (2006a). Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nature Genetics, 38, 917–920
Crow, Y. J., Leitch, A., Hayward, B. E., Garner, A., Parmar, R., Griffith, E., … Baxter, P., (2006b). Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nature Genetics, 38, 910–916
Crow, Y. J., & Manel, N. (2015). Aicardi-Goutières syndrome and the type I interferonopathies. Nature Reviews Immunology, 15, 429–440
Crow, Y. J., Zaki, M. S., Abdel-Hamid, M. S., Abdel-Salam, G., Boespflug-Tanguy, O., Cordeiro, N. J. V., … Livingston, J. H., (2014). Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia. Neuropediatrics, 45, 386–393
de Carvalho, L. M., Ngoumou, G., Park, J. W., Ehmke, N., Deigendesch, N., Kitabayashi, N., … Louzada-Junior, P. (2017). Musculoskeletal disease in MDA5-related type I interferonopathy - a Mendelian mimic of Jaccoud's arthropathy. Arthritis Rheumatol, 69, 2081–2091
Esteves, T., Durr, A., Mundwiller, E., Loureiro, J. L., Boutry, M., Gonzalez, M. A., … Gaussen, M. (2014). Loss of association of REEP2 with membranes leads to hereditary spastic paraplegia. American Journal of Human Genetics, 94, 268–277
Hacohen, Y., Zuberi, S., Vincent, A., Crow, Y. J., & Cordeiro, N. (2015). Neuromyelitis optica in a child with Aicardi-Goutières syndrome. Neurology, 85, 381–383
Klebe, S., Stevanin, G., & Depienne, C. (2015). Clinical and genetic heterogeneity in hereditary spastic paraplegias, from SPG1 to SPG72 and still counting. Revue Neurologique, 171, 505–530
Marguet, F., Laquerrière, A., Goldenberg, A., Guerrot, A-M., Quenez, O., Flahaut, P., … Tournier, I. (2016). Clinical and pathologic features of Aicardi-Goutières syndrome due to an IFIH1 mutation, A pediatric case report. American Journal of Medical Genetics. Part A, 170A, 1317–1324
Oda, H., Nakagawa, K., Abe, J., Awaya, T., Funabiki, M., Hijikata, A., … Kato, H. (2014). Aicardi-Goutières syndrome is caused by IFIH1 mutations. American Journal of Human Genetics, 95, 121–125
Parodi, L., Fenu, S., Stevanin, G., & Durr, A. (2017). Hereditary spastic paraplegia: More than an upper motor neuron disease. Revue Neurologique, 173, 352–360
Pettersson, M., Bergendal, B., Norderyd, J., Nilsson, D., Anderlid, B-M., Nordgren, A., & Lindstrand, A. (2017). Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity. American Journal of Medical Genetics. Part A, 173, 1396–1399
Rice, G. I., Bond, J., Asipu, A., Brunette, R. L., Manfield, I. W., Carr, I. M., … Gornall, H., (2009). Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nature Genetics, 41, 829–832
Rice, G. I., Del Toro Duany, Y., Jenkinson, E. M., Forte, G. M., Anderson, B. H., Ariaudo, G., … Chouchane, M. (2014). Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nature Genetics, 46, 503–509
Rice, G. I., Forte, G. M. A., Szynkiewicz, M., Chase, D. S., Aeby, A., Abdel-Hamid, M. S., … Bernard, G. (2013). Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR, a case-control study. Lancet Neurology, 12, 1159–1169
Rice, G. I., Kasher, P. R., Forte, G. M. A., Mannion, N. M., Greenwood, S. M., Szynkiewicz, M., … Bacino, C. A. (2012). Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nature Genetics, 44, 1243–1248
Rodero, M. P., Decalf, J., Bondet, V., Hunt, D., Rice, G. I., Werneke, S., … Belot, A., (2017). Detection of interferon alpha protein reveals differential levels and cellular sources in disease. Journal of Experimental Medicine, 214, 1547–1555
Rutsch, F., MacDougall, M., Lu, C., Buers, I., Mamaeva, O., Nitschke, Y., … Höhne, W., (2015). A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. American Journal of Human Genetics, 96, 275–282
Tesson, C., Nawara, M., Salih, M. A. M., Rossignol, R., Zaki, M. S., Al Balwi, M., … Durand, C. M., (2012). Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. American Journal of Human Genetics, 91, 1051–1064