Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease
| Autor: | Belinda Campos-Xavier, Shokouholsadat Mahdavi, Luisa Bonafé, Andrea Superti-Furga, Ralph L. Lachman, Beryl Royer-Bertrand, Sheila Unger, Thierry Levade, Bita Bozorgmehr, Carlo Rivolta, Lauréane Mittaz-Crettol, Jia Li, Virginie Garcia, Ariana Kariminejad, Sheela Nampoothiri |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proband Sanger sequencing Pathology medicine.medical_specialty Osteolysis business.industry Immunology medicine.disease Compound heterozygosity Metacarpal bones Acid Ceramidase 03 medical and health sciences symbols.namesake 030104 developmental biology 0302 clinical medicine Rheumatology ASAH1 symbols Immunology and Allergy Medicine business 030217 neurology & neurosurgery Exome sequencing |
| Zdroj: | Arthritis & Rheumatology. 68:2323-2327 |
| ISSN: | 2326-5191 |
| Popis: | Objective To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis. Methods Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed. Results The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease. Conclusion Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far. |
| Databáze: | OpenAIRE |
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