PracticeUpdate Conference Series_WORLDSymposium 2019

Tripeptidyl Peptidase 1 Assay for Dried Blood Specimens Helps Diagnose CLN2 Disease Inexpensively The test can be applied withminor modi cations for mass throughput. A tripeptidyl peptidase 1 assay for dried blood specimens may be used to diagnose CLN2 disease. The test has been shown to be reliable, convenient and inexpensive.

quality of samples and for CLN2 simultaneously, they measured the activities of two additional lysosomal enzymes as controls. These were palmitoyl peptidase 1 and ß-galactosidase. Of all samples, 1.7% were excluded from the study because of sub- normal activity of more than one enzyme. For all samples with subnormal tripeptidyl peptidase 1 activity and good sample quality, they reviewed clinical information. Consequently, they obtained adequate clinical and molecular genetic data for 51 patients. All had doubtless evidence of CLN2 disease, including 7 atypical patients, as shown by symptoms of progressive brain disease and the presence of known path- ogenic CLN2 variants. The test’s sensitivity could not be evaluated directly. The investi- gators’ neuronal ceroid lipofuscinose clinic is a major reference center for these disorders, however, and the team has never received feedback that a patient with normal tripeptidyl pepti- dase 1 activity who received the test of dried blood specimens was diagnosed later with CLN2 disease. Their success rate constitutes convincing circumstantial evidence of high sensitivity. Dr. Lukacs explained that CLN2 disease is a lysosomal storage disorder that belongs to the neuronal ceroid lipofuscinoses class and leads progressively to dementia, blindness and early death. It is caused by a deficiency of the lysosomal enzyme tripeptidyl peptidase 1. The disease has gained recent interest as enzyme replacement therapy has become available. Diagnosis must be timely for the therapy to be effective. Signs and symptoms of CLN2 disease typically begin between ages 2 and 4 years. Initial features usually include recurrent seizures and ataxia. Affected children also develop myoclonus and vision loss. CLN2 disease affects motor skills and speech development. This condition also causes developmental regression, intellectual disa- bility that worsens gradually, and behavioral problems. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. Some children with CLN2 disease do not develop symptoms until later in childhood, typically after age 4 years. These indi- viduals tend to suffer from milder features overall than children diagnosed earlier, but with more severe ataxia. They tend to survive into adulthood. Dr. Lukacs concluded that the tripeptidyl peptidase 1 test of dried blood specimens was shown to be reliable, convenient, and inexpensive as a first diagnostic step for suspected CLN2 disease. The test can be applied with minor modifications for mass throughput, as are newborn screening programs. He noted, “Our assay can provide a convenient tool for identify- ing CLN2 disease in the newborn. Furthermore, new substrates for mass spectrometry may also allow for multiplexed testing of CLN2 and other lysosomal diseases.”

This fnding of a controlled evaluation was reported at the WORLDSymposium 2019. Zoltan Lukacs, PhD, of the Hamburg University Medical Center in Germany, and colleagues set out to investigate the diagnostic reliability of a test for tripepti- dyl peptidase 1 deficiency in dried blood specimens. Dr. Lukacs’s team developed the assay to detect CLN2 disease.

Dr. Zoltan Lukacs

Dr. Lukacs told Elsevier’s PracticeUpdate , “CLN2 disease is important, particularly because therapy has become available recently. Therapy allows patients to develop normally rather than face dementia and death. In the longer term, we expect newborn screening to be an option for detecting this disorder.” Over a 12-year period, they have received 3882 dried blood specimens for testing tripeptidyl peptidase 1 activity. To check for

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