A cross-sectional quantitative analysis of the natural history of Farber disease: an ultra-orphan condition with rheumatologic and neurological cardinal disease features

Abstract

PurposeFarber disease (OMIM 22800) is an ultrarare progressive multisystemic neurodevelopmental storage disorder caused by a deficiency of the lysosomal enzyme acid ceramidase (AC). Hard clinical end points for future clinical trials remain to be defined.MethodsWe quantitatively analyzed published cases with Farber disease (N = 96). The main outcome variables were survival and diagnostic delay. As a potential predictor of survival, the influence of residual AC enzyme activity was investigated. The analysis was performed in compliance with STROBE criteria.ResultsThe median survival period of the study population was 3 years. The median age at disease onset was 3 months, and the median age at diagnosis was 17 months. The median diagnostic delay was 13.75 months. Patients with residual AC activity in fibroblasts at more than 5.1% of the normal level survived significantly longer than patients with residual AC activity below this threshold. In addition, higher residual AC activity was associated with a later onset of symptoms.ConclusionFarber disease onset is in infancy. Diagnostic delay is typically substantial. Our data suggest a phenotype-biomarker association with implications for future clinical and therapeutic trials. In the absence of a prospective multicenter natural-history study protocol, we believe that our modeling approach, based on published case descriptions, is the best and most timely approximation for generalizability.

Ultra‐orphan lysosomal storage diseases: A cross‐sectional quantitative analysis of the natural history of alpha‐mannosidosis

“…Year of publication did not affect survival rates, indicating that possibly changing supportive/symptomatic standard of care over time may only have had a small effect size. As in other orphan lysosomal storage diseases, the diagnostic delay in alpha‐mannosidosis is substantial, as shown by our results (Figure ). Early diagnosis is important to minimize uncertainty for affected families and might help to make informed decision in family planning.…”

“…In our study, reported clinical features in alpha‐mannosidosis were developmental delay or cognitive impairment, bone anomalies, coarse facies, hearing loss, recurrent airway infections, dysmorphism, organomegaly, hernias, ataxia, short stature, and spasticity in descending order of frequency, which corroborates and expands the data presented by Beck et al Cluster analysis enabled the mathematical distinction of five statistically similar subgroups, which clinically exhibited overlapping neurological as well as generalized disease features suggesting that pattern of clinical features and manifestations are heterogeneous and a continuous spectrum rather than well‐delineated clinical subtypes. This observation is in accordance with other lysosomal storage disorders such as free sialic acid storage disease, Farber disease or Gaucher disease …”

Quantitative natural history characterization in a cohort of 142 published cases of patients with galactosialidosis—A cross‐sectional study

“…Diagnostic delay and underdiagnosing of the disease are a substantial issue of GS patients and patients with other rare diseases as well. [14][15][16] A median diagnostic delay of 8 years highlights this problem. The diagnostic delay increases from EI to J/A patients, that is, with age of patients.…”

“…Raising disease awareness as well as screening of high-risk populations may be of substantial help to reduce time to diagnosis, in addition, time-to-diagnosis may decrease once a specific therapy becomes available. 15,16 GS is a progressive and multisystemic LSD. The phenotypical spectrum is broad and outlines the typical features of LSDs with its specifics depending on subtype.…”

“…Nonetheless, this method has been successfully applied in the quantitative natural history documentation of other rare inborn metabolic disorders such as molybdenum cofactor deficiency, MPS VII, or Farber disease. [14][15][16] For this reason, we would like to encourage our international colleagues to publish their cases of patients with rare diseases. Analyzing these data with quantitative retrospective natural history modeling will set important bases for future orphan drug development.…”