Understanding genetics of common, rare disorders advance treatment in pediatric neurology

 Almost 3 million children in the United States have epilepsy, making it the most common childhood brain disorder in the country, according to estimates from the American Academy of Pediatrics.

Other neurological conditions frequently seen in children include headaches and migraines, which — according to the National Headache Foundation — affect 20% of school-aged children in the United States, and developmental disabilities, with approximately one in six children, or 17%, receiving a diagnosis of a developmental disability between 2009 and 2017, according to data from the CDC.

However, rare disorders are “frequently a consideration” for patients with developmental disabilities or epilepsy, according to Sumit Parikh, MD, director of neurogenetics at Cleveland Clinic. In addition, it appears that some of the more common conditions treated by pediatric neurologists, such as developmental delays and epilepsy, are the result of genetic disorders when they occur in the absence of a clear underlying cause, such as brain injury or infection. 

Parikh spoke with Healio about the management of these conditions, both common and rare, and the advances in genetics that have improved the care that these patients receive.

Question: What are the most common conditions treated by pediatric neurologists — and how often do they see rare diseases?

Answer: Developmental delays, headaches/migraines, seizures and epilepsy are some of our most common diagnoses. Rare disorders are frequently a consideration for our patients with unexplained developmental disability or epilepsy.

We are learning that most individuals with developmental disability or epilepsy, in the absence of a clear underlying cause such as brain injury or infection, have these symptoms because of genetic disorders. As our knowledge and testing has gotten better, we are able to look for thousands of conditions, many that are individually quite rare. We are now able to easily find a genetic cause for these symptoms in almost half of cases.

Developmental disabilities due to genetic causes can lead to isolated severe expressive language delay, autism and a more global problem involving delays in communication, learning and motor abilities. As recently as 10 years ago, our testing was limited to looking for chromosomal level abnormalities and Fragile X Syndrome. We are now able to quickly assess hundreds of thousands of genes for many different conditions. Whole exome sequencing, which looks at the exonic regions of all 20,000 genes, is routinely performed. Whole genome sequencing, which attempts to look for mutations, copy number variants and trinucleotide repeat disorders across the genome, has just entered the clinical arena. As a result, the list of disorders that can be diagnosed has grown exponentially.

Almost all causes of seizure disorders that do not respond to treatment and are not due to a prior injury or to focal lesions in the brain are being found to have a genetic cause. This is especially true for seizure disorders that start in infancy or childhood. Identifying the underlying condition can now sometimes change clinical management. There are now known conditions that we may need to treat with a non-seizure medication, such as quinidine for migrating partial seizures of infancy, or MPSI, that are caused by mutations in the KCNT1 gene, or carbamazepine in an infant, which is not typically done, for KCNQ2-related epilepsy. We know of a condition that can be transmitted from a healthy father to his daughter and lead to refractory seizures in infancy called PCDH19-related epilepsy. There are disorders, such as Glucose Transporter Type 1 Deficiency Syndrome, or GLUT1 Deficiency Syndrome, where the ketogenic diet is used as treatment.

Question: What are the major challenges in treating these patients?

Answer: Many of these disorders are rare or have only recently been discovered, so treatment options are often limited. We can offer active surveillance for ongoing problems that may develop in the context of the condition and provide preventative and supportive care in these cases.

The challenges for treating these disorders varies depending on the type of disorder, but our care is primarily supportive. In general, as each disorder is rare and has often only discovered in the past 10 years, our knowledge about each one is still limited, but expanding. Families can sometimes find additional information through other families in support groups, but there are many conditions for which such a support group does not exist.

In some cases, we are able to connect families with researchers who specialize in the child’s specific condition. For instance, a rare disorder known as CDKL5 Disorder that is now often recognized by the early onset of infantile spasms, low muscle tone and developmental delays along with certain facial characteristics, has a very active family support organization that is also performing research. Centers of Excellence for this disorder have formed across the country.

For these disorders, the sooner the diagnosis is made, the sooner we can connect the family with specialists.

Question: What are some of the biggest breakthroughs in the specialty in recent years?

Answer: Advances in genetic therapies has enabled us, for a select few disorders such as spinal muscular atrophy and Duchenne muscular dystrophy (DMD), to provide individualized treatment that can help halt or slow the progression of the disease. For example, the FDA approved Zolgensma (onasemnogene abeparvovec-xioi, AveXis Inc.) in 2019, an adeno-associated virus vector-based gene therapy that targets the cause of spinal muscular atrophy. In addition, the FDA approved Viltepso (viltolarsen, NS Pharma) this month; the drug, which is given as an injection, is indicated for patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. It is the second FDA-approved targeted treatment for patients with this type of mutation, which affects approximately 8% of patients with DMD.

Select other disorders have new medications available that may help with slowing disease progression. Hematopoietic stem cell transplant (HSCT) can be useful in slowing down progression for certain metabolic lysosomal and peroxisomal disorders, such as Krabbe disease and X-linked adrenoleukodystrophy (XALD). HSCT-based gene therapy has advanced for XALD.

It is an exciting time, as there is much more interest in developing treatments and therapies for rare diseases.

There have been advances in the more common disorders, too. Patients with refractory headaches or seizures can now benefit from advances in treatment options and a host of new medications. Erenumab (Aimovig; Novartis, Amgen) is a newer treatment for refractory headaches and migraines that has been very beneficial for some patients. Our list of antiseizure medications has grown to over 20 agents.

For some chronic disorders, such as cerebral palsy or brain injury-related spasticity, the use of botulinum and baclofen pumps has allowed for more personalized management of symptoms with fewer side effects. In brain injury-related spasticity, for example, botulinum toxin can reduce spasticity and, therefore, improve rehabilitation outcomes.

Question: What are the greatest unmet needs in pediatric neurology?

Answer: There is still a national shortage of pediatric neurologists, especially in more remote parts of the country. The wait lists to be seen, even in cities with many pediatric neurologists, often stretch out for weeks, if not months. These patients are generally complex and require a coordinated and multidisciplinary approach to care. Patient visits often require more time than that provided by hospital systems. Ongoing chronic symptoms lead to these patients needing to be followed for many years. Due to the complexity of care required, transitioning these patients to adult neurology colleagues has sometimes been challenging and some pediatric neurologists follow the patients through adulthood.

References:

• American Academy of Pediatrics. Epilepsy in children: Diagnosis & treatment. https://www.healthychildren.org/English/health-issues/conditions/seizures/Pages/Epilepsy-in-Children-Diagnosis-and-Treatment.aspx. Accessed August 13, 2020.
• CDC. Increase in developmental disabilities among children in the United States. https://www.cdc.gov/ncbddd/developmentaldisabilities/features/increase-in-developmental-disabilities.html. Accessed August 13, 2020.
• Enslin JMN, et al. Front Neurol. 2020;doi: 10.3389/fneur.2020.00126.
• FDA. FDA approves targeted treatment for rare Duchenne muscular dystrophy mutation. https://www.fda.gov/news-events/press-announcements/fda-approves-targeted-treatment-rare-duchenne-muscular-dystrophy-mutation. Accessed August 13, 2020.
• National Headache Foundation. Children’s headache disorders. https://headaches.org/resources/childrens-headache-disorders/. Accessed August 13, 2020.