Clinical Guidance

No obvious genotype-phenotype correlations have been observed in ASAH1-related disorder to date despite a predominance of nonsense and splice-site variants in SMA-PME and a predominance of missense variants in FD. While recurrent pathogenic variants have been observed in the FD phenotype (e.g., ) and the SMA-PME phenotype (e.g., ), to date the only ASAH1 pathogenic variants observed in both phenotypes are those that result in skipping of exon 6 . There is a correlation in FD between age of death, in situ acid ceramidase activity, and the amount of ceramide accumulation .

Source: GeneReviews — "ASAH1-Related Disorders"

Diagnostic Criteria

Suggestive Findings

The following phenotypes of the ASAH1-related disorders should be suspected based on the following age-related clinical and associated findings. Farber disease (FD) should be strongly suspected in a neonate or toddler with the following:

Clinical findings

• Subcutaneous nodules located at pressure points and joints

• Swollen, painful joints with progressive limitation of range of motion resulting in contractures

• Hoarse voice/cry

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)

should be suspected in a previously well child with the following:

Clinical findings

Source: GeneReviews — "ASAH1-Related Disorders"

Differential Diagnosis

Table 2. Inherited Disorders to Consider in the Differential Diagnosis of ASAH1-Related Disorder: Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME)

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an ASAH1-related disorder, the evaluations summarized in and (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 3a. Recommended Evaluations Following Initial Diagnosis of an ASAH1-Related Disorder: Farber Disease

Therapies Under Investigation

Acid ceramidase cDNA introduced into mice in a viral vector has been shown to be expressed over an extended period of time . Further, the expressed acid ceramidase was able to ameliorate the manifestations in a mouse model of Farber disease . Acid ceramidase introduced safely into in non-human, myelo-ablated primates using a lentiviral vector was successfully expressed in hematopoietic cells .

Enzyme replacement therapy

• Human recombinant acid ceramidase reduced ceramide levels in the fibroblasts of an individual with Farber disease .

• Recombinant acid ceramidase treatment of the mouse model resulted in no further accumulation of ceramide and improved survival .

Source: GeneReviews — "ASAH1-Related Disorders"

Surveillance Guidelines

No guidelines have been published for the surveillance of ASAH1-related disorder. Table 5a. Recommended Surveillance for Individuals with ASAH1-Related Disorder: Farber Disease

Source: GeneReviews — "ASAH1-Related Disorders"