Molecular analyses of novel <i><scp>ASAH1</scp></i> mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Bashyam, Murali D.; Chaudhary, Ajay Kumar; Kiran, Manjari; Reddy, Vijay Anand P.; Nagarajaram, Hampapathalu A.; Dalal, Ashwin; Bashyam, Leena; Suri, Deepti; Gupta, Anju; Gupta, Neerja; Kabra, Madhulika; Puri, Ratna Dua; Ramadevi, R.; Kapoor, Seema; Danda, Sumita

doi:10.1111/cge.12316

Cited by 21 publications

(9 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, the other mutation, p.R333C, has not been reported, but mutations in the same position (p.R333G, p.R333H) have been reported earlier [Bashyam et al, ]. The patient with the homozygous mutation of p.R333H exhibited a severe phenotype, whereas the heterozygous mutations p.R333G and p.F136L are associated with a milder phenotype [Bashyam et al, ]. These findings suggest that p.R333C is associated with the severity of FD in our patient, although more molecular analyses and clinical studies are required to confirm the relationship between phenotype and genotype.…”

Section: Discussionsupporting

confidence: 70%

“…The mutation p.G235R has been reported as one type of compound heterozygote mutation in a Japanese patient with the mild phenotype of contracted joints, subcutaneous nodules, and mild cognitive disability at the age of 5 years [Muramatsu et al, ]. To our knowledge, the other mutation, p.R333C, has not been reported, but mutations in the same position (p.R333G, p.R333H) have been reported earlier [Bashyam et al, ]. The patient with the homozygous mutation of p.R333H exhibited a severe phenotype, whereas the heterozygous mutations p.R333G and p.F136L are associated with a milder phenotype [Bashyam et al, ].…”

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Atypical presentation of infantile‐onset farber disease with novel ASAH1 mutations

Kim

Choi

Lee

et al. 2016

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Farber disease is a very rare autosomal recessive disease caused by mutation of ASAH1 that results in the accumulation of ceramide in various tissues. Clinical symptoms of classic Farber disease comprise painful joint deformity, hoarseness of voice, and subcutaneous nodules. Here, we describe a patient with Farber disease with atypical presentation of early onset hypotonia, sacral mass, congenital heart disease, and dysmorphic face since birth. Severe cognitive disability, failure to gain motor skills, failure to thrive, and joint contractures developed. Using whole-exome sequencing, we identified the compound heterozygote missense mutations of ASAH1 (p.R333C and p.G235R). Because of the diagnostic delay, she underwent sacral mass excision, which revealed enlarged lysosomes and zebra bodies. We report an atypical presentation of Farber disease with her pathology and associated genetic defect. This case expands the phenotypic spectrum of Farber disease to include novel mutations of ASAH1, which pose a diagnostic challenge. We also discuss the clinical utility of whole-exome sequencing for diagnosis of ultra-rare diseases. © 2016 Wiley Periodicals, Inc.

show abstract

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 93%

Atypical presentation of infantile‐onset farber disease with novel ASAH1 mutations

Kim

Choi

Lee

et al. 2016

American J of Med Genetics Pt A

View full text Add to dashboard Cite

show abstract

“…31 Increased ASAH1 expression has been reported in the aging kidney, 32 while lack of ceramidase activity in the kidney was observed in Farber disease or lipogranulomatosis. 33 Farber lipogranulomatosis (MIM 228000) is a lysosomal storage disorder due to autosomal recessive ASAH1 variants 34,35 that leads to accumulation of ceramide in tissues due to enzymatic deficiency, and is primarily characterized by subcutaneous nodules, joint deformities and hoarseness, although severe and atypical forms such as hydrops fetalis, failure to thrive and congenital heart disease have also been reported. 36,37 Autosomal recessive ASAH1 variants can also cause spinal muscular atrophy with progressive myoclonic epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Identification of ASAH1 as a susceptibility gene for familial keloids

Santos‐Cortez

Sun

et al. 2017

Eur J Hum Genet

View full text Add to dashboard Cite

Keloids result from abnormal proliferative scar formation with scar tissue expanding beyond the margin of the original wound and are mostly found in individuals of sub-Saharan African descent. The etiology of keloids has not been resolved but previous studies suggest that keloids are a genetically heterogeneous disorder. Although possible candidate genes have been suggested by genome-wide association studies using common variants, by upregulation in keloids or their involvement in syndromes that include keloid formation, rare coding variants that contribute to susceptibility in non-syndromic keloid formation have not been previously identified. Through analysis of whole-genome data we mapped a locus to chromosome 8p23.3-p21.3 with a statistically significant maximum multipoint LOD score of 4.48. This finding was followed up using exome sequencing and led to the identification of a c.1202T>C (p.(Leu401Pro)) variant in the N-acylsphingosine amidohydrolase (ASAH1) gene that co-segregates with the keloid phenotype in a large Yoruba family. ASAH1 is an acid ceramidase known to be involved in tumor formation by controlling the ratio of ceramide and sphingosine. ASAH1 is also involved in cell proliferation and inflammation, and may affect the development of keloids via multiple mechanisms. Functional studies need to clarify the role of the ASAH1 variant in wound healing.

show abstract

“…Other findings related to the eyes have included the presence of xanthoma-like growths in the conjunctiva, poor visual fixation, and nystagmus [ 102 , 120 , 127 ]. Post-mortem analyses of the eyes showed no abnormalities in the anterior segment, but the posterior segment contained birefringent lipids within the ganglion cell layer and displayed significant storage pathology in other cell types in the eye [ 128 , 131 ].…”

Section: The Diverse Signs and Symptoms In Acdase Deficiencymentioning

confidence: 99%

Acid ceramidase deficiency: Farber disease and SMA-PME

Yu¹,

Amintas²,

Levade

et al. 2018

Orphanet J Rare Dis

108

104

View full text Add to dashboard Cite

Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0845-z) contains supplementary material, which is available to authorized users.

show abstract

Molecular analyses of novel ASAH1 mutations causing Farber lipogranulomatosis: analyses of exonic splicing enhancer inactivating mutation

Cited by 21 publications

References 15 publications

Atypical presentation of infantile‐onset farber disease with novel ASAH1 mutations

Atypical presentation of infantile‐onset farber disease with novel ASAH1 mutations

Identification of ASAH1 as a susceptibility gene for familial keloids

Acid ceramidase deficiency: Farber disease and SMA-PME

Contact Info

Product

Resources

About