AADC Deficiency Panel Discussion

AADC Deficiency: Screening and Diagnosis

As part of the roundtable moderated by Philip Pearl, MD, of Boston Children’s Hospital and Harvard Medical School, the attendees of this virtual discussion focused on key diagnostic aspects of aromatic L-amino acid decarboxylase (AADC) deficiency.

Dr. Hwu emphasized that clinical recognition of some of the specific physical manifestations is the first step to diagnose this very rare condition. In the past few years, a testing panel has been developed for AADC deficiency. “Once you make one diagnosis, it’s not too difficult to identify the second patient,” said Dr. Hwu.

Dr. Pearl pointed out that the movement disorders are the most prominent sign in AADC deficiency, especially the oculogyric crises. Dr. O’Malley added that this movement disorder is so rare, you don’t want to miss it. Yet, the presentation of AADC deficiency in these infants is not necessarily all that specific. “There are so many diagnoses that we consider—the celebral palsy mimickers—that fall into that category,” said Dr. O’Malley. However, she will consider AADC deficiency in any infant with hypotonia of undetermined etiology, or in a full-term baby with a normal birth history (and without clear evidence of injury) who is profoundly hypotonic and not reaching developmental milestones.

Dr. O’Malley cautioned that when children with spasticity or other movement disorders are referred to her, she carefully reevaluates the listed diagnosis. Is it really cerebral palsy? Oculogyric crises can start to give you a clue, but it is not specific for AADC deficiency. She tests for AADC deficiency frequently, but reported a low diagnosis rate. The ability to test for this genetic disorder provides the ability to identify more patients and then learn more about it.

Dr. Marks also has a low threshold for genetic testing, especially for children presenting with a movement disorder. “Even in preemies with a typical history for cerebral palsy,” stated Dr. Marks, “if the picture is not quite typical, we have found kids with a number of disorders that mimic cerebral palsy.” This is especially true in the presence of more dystonia than expected from the typical preterm infant.

Often, oculogyric crises are mistaken for seizures, said Dr. Marks. That means that epilepsy specialists may see these infants before the movement disorder physicians. Once the EEG rules out seizures, the infant will be referred to a movement disorder specialist. “Anytime you see the oculogyric crisis, you have to consider the neurotransmitter pathway,” he advised.

This convenient genetic testing panel (or “cerebral palsy-mimic panel”) has identified several children with other very rare genetic disorders, including Angelman’s syndrome, Rett syndrome, and even AADC deficiency. The roundtable participants included:

Philip L. Pearl, MD
Director, Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital
William G. Lennox Chair and Professor of Neurology, Harvard Medical School
Boston, MA

Warren A. Marks, MD
Medical Director, Movement Disorders
Cook Children’s Jane and John Justin Neurosciences Center
Fort Worth, TX

Paul Wuh-Liang Hwu, MD, PhD
Professor, Department of Pediatrics and Medical Genetics
National Taiwan University Hospital
Tapei, Taiwan

Irina A. Anselm, MD
Director of the Mitochondrial Program and Co-Director of the Neurometabolic Program, Boston Children’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Boston, MA

Jennifer O’Malley, MD, PhD
Clinical Assistant Professor, Neurology & Neurological Sciences, Stanford Medicine
Pediatric Neurologist, Stanford Children’s Health
Stanford, CA

AADC Deficiency: Recognition and Characterization

As part of the roundtable moderated by Philip Pearl, MD, of Boston Children’s Hospital and Harvard Medical School, the attendees of this virtual discussion focused on key diagnostic aspects of aromatic L-amino acid decarboxylase (AADC) deficiency.

Dr. Pearl noted that AADC deficiency was first described in 1990 by Drs. Keith Hyland and Peter Clayton, who saw identical twins with the disorder. They were able to document AADC deficiency, and this was linked to the DDC gene dysfunction.

Dr. Anselm recalled her first case of AADC deficiency, which appeared in a 17-year-old male in 1998. This young person had not been diagnosed appropriately at any point in his life until then.

This genetic disorder is extraordinarily rare, with a prevalence of around 1,800 persons globally. The estimated incidence of AADC deficiency varies quite a bit, depending on the country. However, only 130 cases have been reported in the literature. Many cases are undiagnosed and perhaps unreported, according to these subspecialists. The roundtable participants included:

Philip L. Pearl, MD
Director, Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital
William G. Lennox Chair and Professor of Neurology, Harvard Medical School
Boston, MA

Warren A. Marks, MD
Medical Director, Movement Disorders
Cook Children’s Jane and John Justin Neurosciences Center
Fort Worth, TX

Paul Wuh-Liang Hwu, MD, PhD
Professor, Department of Pediatrics and Medical Genetics
National Taiwan University Hospital
Tapei, Taiwan

Irina A. Anselm, MD
Director of the Mitochondrial Program and Co-Director of the Neurometabolic Program, Boston Children’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Boston, MA

Jennifer O’Malley, MD, PhD
Clinical Assistant Professor, Neurology & Neurological Sciences, Stanford Medicine
Pediatric Neurologist, Stanford Children’s Health
Stanford, CA

AADC Deficiency Treatment

As part of this expert roundtable, Paul Wuh-Liang Hwu, MD, PhD of the Taipei National University Hospital, described current approaches to treatment of aromatic L-amino acid decarboxylase (AADC) deficiency.

Dr. Hwu said that for typical infant cases, it is very difficult to treat their symptoms. It is possible to use dopamine-based medications to help manage some patients, “but for the more severe cases,” Dr. Hwu noted, “we saw more complications from the medication” and less benefit. More recently, he has utilized a rotigotine transdermal patch (used to treatment Parkinson’s disease), which he finds easier to use than oral dopamine agonists.

Patients don’t often show signs of AADC deficiency until they are older than 3 months. Once those signs of abnormal movement do appear, feeding can become more difficult. He generally tries the rotigotine patch, along with vitamin B6, and focuses on improving the feeding of those babies and on their weight. Once they reach about 18 months of age, they can consider the newest modality—gene therapy (Note: gene therapy is still under clinical investigation and is not yet approved by the US Food and Drug Administration for the treatment of AADC deficiency).

Dr. Hwu described gene therapy as “not really a cure, but actually a way of improving symptoms.” Once dopamine levels are restored, then patients have an extended period of rehabilitation, where they slowly recover their ability to control abnormal movement and improve their dystonia. The roundtable participants included:

Philip L. Pearl, MD
Director, Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital
William G. Lennox Chair and Professor of Neurology, Harvard Medical School
Boston, MA

Warren A. Marks, MD
Medical Director, Movement Disorders
Cook Children’s Jane and John Justin Neurosciences Center
Fort Worth, TX

Paul Wuh-Liang Hwu, MD, PhD
Professor, Department of Pediatrics and Medical Genetics
National Taiwan University Hospital
Tapei, Taiwan

Irina A. Anselm, MD
Director of the Mitochondrial Program and Co-Director of the Neurometabolic Program, Boston Children’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Boston, MA

Jennifer O’Malley, MD, PhD
Clinical Assistant Professor, Neurology & Neurological Sciences, Stanford Medicine
Pediatric Neurologist, Stanford Children’s Health
Stanford, CA

AADC Deficiency: Patients in the Real World Setting

As part of the virtual roundtable moderated by Philip Pearl, MD, of Boston Children’s Hospital and Harvard Medical School, participants in this discussion spoke to the real journey of patients with aromatic L-amino acid decarboxylase (AADC) deficiency.

Dr. Anselm described a patient who was finally diagnosed with AADC deficiency at age 17, with “horrible oculogyric crises and dystonic spasms,” and had been untreated. She pointed out that “the uncertainty of what is going on with their children is so painful for their families.” Patients with severe cases of AADC deficiency are not so amenable to treatment; the side effects of dopamine agonists, including the dyskinesias, make the therapeutic decision extremely challenging.

Serious complications in patients with AADC deficiency add further complexity to both the clinical picture and their practical care. Older patients are at risk for a range of disorders. For example, Dr. Anselm noted severe scoliosis and restrictive lung disease requiring a tracheostomy and death (likely by cardiac arrest) in two of her older patients.

Dr. O’Malley emphasized that although we tend to focus on the most severe cases, there seems to be a wide variety of severity, depending on the patient’s type of mutation. Because of that wide variability, Dr. O’Malley has a low threshold to test.

The key, Dr. O’Malley believes, is to focus on how to maximize function for these patients. In young children, AADC deficiency has profound implications for development. Even in those with less-severe symptoms, Dr. O’Malley said, “Most patients can also benefit from better control of the dysautonomia.”

At Dr. Marks’ center, their neurologists made the decision to incorporate physiatry. “We thought it made much more sense to get on the same page,” he said, “and kind of divvy up the management of these patients so that we both learn from each other.” Dr. Marks emphasized taking the holistic approach in neurologic disease, in terms of the whole child and the whole family. For example, treating only the movement disorder does not resolve the skeletal issues, the respiratory involvement, the feeding problems, the social and economic implications associated with AADC deficiency. “This is huge for families,” said Dr. Marks, “when you have to work, but you’ve got to be home taking care of a child who is dependent on you for everything.” The roundtable participants included:

Philip L. Pearl, MD
Director, Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital
William G. Lennox Chair and Professor of Neurology, Harvard Medical School
Boston, MA

Warren A. Marks, MD
Medical Director, Movement Disorders
Cook Children’s Jane and John Justin Neurosciences Center
Fort Worth, TX

Paul Wuh-Liang Hwu, MD, PhD
Professor, Department of Pediatrics and Medical Genetics
National Taiwan University Hospital
Tapei, Taiwan

Irina A. Anselm, MD
Director of the Mitochondrial Program and Co-Director of the Neurometabolic Program, Boston Children’s Hospital
Assistant Professor of Neurology, Harvard Medical School
Boston, MA

Jennifer O’Malley, MD, PhD
Clinical Assistant Professor, Neurology & Neurological Sciences, Stanford Medicine
Pediatric Neurologist, Stanford Children’s Health
Stanford, CA