Importance: Many patients undergo a diagnostic odyssey of several years before a diagnosis of late onset hexosaminidase deficiency (Tay-Sachs or Sandhoff disease) is made.  Recognizing the variable presentations of these conditions could allow diagnostic enzyme testing to be performed early in the clinical course.

Objective: To identify the range of clinical presentations for late onset hexosaminidase deficiencies and explore reasons for diagnostic delays.

Design: Clinical information for cases of late onset hexosaminidase deficiencies were gathered as part of routine follow-up of abnormal results in our laboratory.  This information was combined with a literature review to identify previously reported cases in an attempt to clearly define potential presentations, ranging from strictly motor symptoms to severe psychiatric problems.

Participants: Individuals with deficient hexosaminidase enzyme activity suggestive of late onset Tay-Sachs or Sandhoff disease.

Results: Individuals with late onset hexosaminidase deficiencies could be classified as presenting with motor symptoms (gait disturbance, ataxia, and muscle weakness), psychiatric symptoms or a combination.  Long diagnostic delays (mean > 10 years) were common for these patients.

Conclusions and Relevance: Late onset hexosaminidase deficiencies can be diagnosed using an enzyme assay from a routine blood draw.  Despite the ease of testing, many patients wait years before diagnosis.  With the trend towards genome and exome sequencing for diagnostic odyssey cases, many of these individuals may be referred to this type of testing, rather than receiving their diagnosis via the timelier enzyme assay ordered based on clinical suspicion.