A new study published in the May issue of the peer-reviewed journal Brain has identified a rare neurologic disorder affecting infants and teenagers. Tyler Mark Pierson, MD, PhD, assistant professor in the departments of Neurology and Pediatrics at Cedars-Sinai, was one of the study’s senior authors.

Pierson and collaborators from nearly 50 institutions in the U.S. and abroad reported on the cases of 31 children with the new disorder, which they called "HPDL deficiency."

HPDL deficiency occurs in two forms. One form presents as a more severe infantile-onset epileptic encephalopathy, which consists of lower extremity spasticity associated with severe cognitive delays as a result of frequent and difficult-to-control seizures. The other, milder form presents as an adolescent-onset hereditary spastic paraplegia in otherwise normal teenagers with weakness and spasticity of the legs. Both inherited conditions are the result of abnormal activity of parts of the cerebral cortex, which is responsible for muscular tone, voluntary physical action, thought and other functions.

Pierson and his collaborators determined that all the study subjects had mutations in both copies of their human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene, inheriting one mutation from each of their unaffected parents. The HPDL gene mutations caused decreased levels and activity of HPDL proteins, which appear to be important to the functioning of mitochondria, the structures that allow cells to burn food and oxygen to generate energy.  

"This is an extremely rare disorder that has now been identified in fewer than 50 patients," said Pierson, a member of the Cedars-Sinai Board of Governors Regenerative Medicine Institute. "Our group was able to test the activity of some of the variants through a proxy protein, as no one has fully identified the function of this particular protein. Determining a method to assay protein activity was a challenge because the only other published research on HPDL was reported more than 20 years ago."

While the findings published in Brain served to identify this new genetic disorder, further study is needed to confirm the disorder’s mechanisms. "We believe the difference between the infantile and adolescent presentations of the disorder is in the amount of residual activity present in the mutant HPDL proteins as compared with the normal proteins," Pierson said. "The less activity we see in the different mutant proteins, the earlier the age of onset and the more severe the disorder."

Previous work by Jeffrey Golden, MD, vice dean of Research and Graduate Education, and director of the Burns and Allen Research Institute at Cedars-Sinai, has shown that mitochondrial activity can play a role in development of the cerebral cortex and, when reduced, lead to neurodevelopmental and epilepsy disorders. "Whether this principle is a factor in HPDL deficiency is the focus of future work in our lab, where we are hoping to build on Dr. Golden’s previous results," Pierson said.

Though questions remain, the identification of a genetic cause for HPDL deficiency may prove helpful to patients and their families, he added.

"Even without interventions that can assist the patient, families are extremely relieved to have a diagnosis," explained Pierson, one of the leaders in the Cedars-Sinai Center for the Undiagnosed Patient. "They can then join supportive communities for the particular disorder or similar disorders. This knowledge also provides peace of mind, as many families of children with undiagnosed disorders may feel confused or even guilty with regard to their child’s condition."

The study's other senior authors, besides Pierson, were from LMU Munich in Germany, Karolinska Institutet in Sweden, National Defense Medical Center in Taiwan and University College London in England. Other authors from Cedars-Sinai included Richard Lewis, MD, Katie Grand, GC, Maria Gabriela Otero, PhD, and John Graham, MD.

Conflict of interest and funding disclosure statements can be found in the published study.