This is the second of multiple blog posts by Nancy LeGendre, PhD, former biochemical researcher and mother of two with Pitt Hopkins Syndrome. 

I want to tell a story of two families driven by a need for answers. It’s a story about strong roots and unexpected connections.  

Imagine two strong, parallel trunks that gradually separate, grow apart and rejoin later in life. One trunk holds the other up; both require soil, sun, water and serendipity to endure and thrive.

Unusual “bonding tree” found on Eastern Point in Gloucester, MA. Photo courtesy of Nancy LeGendre.

We are two mothers each with two daughters described as having global delays and/or features of autism. Our parallel journey towards diagnosis began when our girls were babies and toddlers. My daughters received their true, medical “etiological” diagnosis at ages 21 and 23. With that diagnosis we joined the ranks of an estimated 350 families affected worldwide by our unique “rare” disease. My friend’s children remain undiagnosed at almost 18 and 21 years. On May 3, 2014, my dear friend will participate in the Million Dollar Bike Ride at the University of Pennsylvania to raise money for research into rare diseases in honor of all our girls, but especially in honor of my daughters, Julia and Lilly, and their very special rare disease, Pitt Hopkins Syndrome (PTHS).

I have known Mary Jo Silva for nearly as long as developmental delay and autism have been part of our mutual daily lexicon. Jo and I met through online discussions of neurologically disordered children and autistic regression in the early ’90s. Jo’s daughter Carmen is two years younger than my Lilly and four years younger than my Julia. Carmen is strongly impacted by her disorder. Younger sister Anna has Nonverbal Learning Disability (NVLD) and hopes to attend college next fall.  

My friendship with Jo began when autism was a relatively unknown diagnosis; the prevalence of autism in 1993 was estimated at 5/10,000.  Girls with autism were uncommon. The number of affected children has multiplied by two orders of magnitude. Boys with autism continue to outnumber girls with autism, four or five to one. In 2014 we’ve begun to appreciate the vast heterogeneity of what is referred to as autism spectrum disorder (ASD).

My path and Jo’s have converged and diverged over these nearly two decades. Like Julia, Carmen lost early developmental milestones. Like Lilly, Carmen has behavioral instability and unusual health issues not generally considered part of an autism phenotype. Their regression, seizure, immune, and endocrinological irregularities are suggestive of a syndromic disorder. In the past 18 months, we’ve determined that Julia and Lilly share a mutation in the gene, Tcf4. This led to the unanticipated diagnosis of Pitt Hopkins Syndrome (PTHS).

Sisters Julia and Lilly at Good Harbor Beach in Gloucester, MA. Photo courtesy of Nancy LeGendre.

Carmen remains undiagnosed as she stands poised on adulthood with her upcoming birthday.

She struggles with significant aggression and self-abuse; Carmen has repeatedly broken her own nose. These debilitating behaviors are driven by distress which she is unable to articulate, yet her self-inflicted pain speaks volumes. Carmen has variously taken medications for anxiety, depression, seizure activity and psychosis. Medications have brought relief, but they also bring undesirable side effects and, in one instance, life-threatening complications. Unfortunately, paradoxical reactions to medications are too often considered “just part of autism.”

Carmen’s story is a call to action for diagnosis of etiology in autism and developmental delay. In order to properly treat a patient, doctors must first understand what is amiss. Anyone with severe, debilitating disease will benefit from an etiologically-relevant diagnosis. This is especially true in autism where a one-diagnosis, one-treatment-fits-all mentality is a detriment to best care.  Instead of dismissing paradoxical reactions to drugs as “due to autism,” clinicians are obligated to look harder for the etiology that drives their patient’s pain. Etiological diagnosis directs symptomatic care, and raises the hope for disease-driven therapies. Identifying the malfunctioning gene is a necessary first step towards knowledge-based medical care.

Scientists have moved away from the misguided hypothesis that defects in a handful of genes lead to the wide range of developmental disorders that fall under the umbrella term, autism. This spectrum of disorders is caused by yet uncharacterized interactions between the environment and genes involved in building and maintaining neurons. As with cancer, autism is not one disease. Defects in hundreds of genes contribute to the full autism spectrum. Each gene contributes to one rare disease; collectively these diseases have an enormous impact in lives and dollars. We’re still deciphering the alphabet of these many single-gene, rare diseases.

Benefits of etiological, gene-based diagnosis include:

  1. Misdiagnosis and delays in diagnosis of rare disease patients result in unnecessary office visits, diagnostic tests, hospitalization and inappropriate or inadequate treatment.
  2. Knowledge of etiology helps to support medical decisions and improve clinical management.
  3. Diagnosis directs urgent care for patients in emergency situations, especially young children or adults who are unable to provide subjective feedback on how they feel, what hurts or where.  
  4. Family counseling requires accurate diagnosis of an affected child.  If the disease gene is known, parents may be advised of reproductive risks in subsequent pregnancies.  Families may be able to manage risk by diagnostic testing prior to conception, or in early pregnancy.
  5. Some diseases present with chronic health concerns, while others have degenerative trajectories.  Early detection enables urgent pre-symptomatic treatment and proactive care for best lifetime outcomes.
  6. Families of loved ones with rare diseases benefit from shared experiences and therapeutic strategies.  Disease communities are essential in supporting families and researchers alike.
  7. Molecular diagnosis facilitates research into disease mechanism, drives the development of cell line and animal models of disease, and leads to identification of therapeutic targets for drug development.  Research may lead to cure or eradication of single-gene diseases in the future.

We feel cause for celebration in receiving a diagnosis for our daughters, both now young adults. We’re further blessed to have a friend who, despite not having an answer for her own daughters’ complex etiologies, has committed to cycle 34 miles in order to raise research dollars for PTHS.

Mary Jo and Carmen Silva. Photo courtesy of Nancy LeGendre.

The Pitt Hopkins Research Foundation (PHRF) has been chosen as one of 12 rare disease organizations to participate in the first annual Million Dollar Bike Ride hosted by the Center for Orphan Disease Research and Therapy (CODRT) at the University of Pennsylvania, and organized jointly with Rare Disease Cycling. This event will raise money for rare disease research throughout the world. The cycling fundraiser, which starts and finishes on the University of Pennsylvania campus on May 3, 2014, will bring together cyclists and disease communities united in the goal of developing novel therapies for their varied disorders.

The Rare Diseases Act of 2002 defines a rare disease as “any disease or condition that affects fewer than 200,000 persons” for a prevalence of 1 in 1,500 people. Orphan disease refers to the past tendency for these diseases to be ignored by the pharmaceutical industry because the cost of drug development precluded efforts to seek treatments on a disease-by-disease basis. Collectively, rare diseases affect over 25 million people in the United States alone. The CODRT joins researchers, clinicians, patient communities, and private disease foundations with both small biotechnology and large pharmaceutical companies.

Methodologies and tools developed for one disorder often have applicability in other disorders. Research dollars can more efficiently be applied to joint therapeutic strategies by building on partnerships among investigators, academic institutions, industries, and funding agencies.

The Million Dollar Bike Ride will directly fund these efforts through the CODRT of the University of Pennsylvania. In addition, the University will match up to $50,000.00 raised by each cycling team, further supporting research efforts within that disease community.  

For more information on the Million Dollar Bike Ride, visit their website here.

To donate to the Pitt Hopkins Pedalers in honor of Julia and Lilly, please visit the Pitt Hopkins Pedalers Donation Page.

If you make a contribution, please write a note of thanks to my dear friend, and fellow parent of daughters with rare, undiagnosed disease, cyclist Mary Jo Silva. I’m proud and deeply honored to be her friend.  Thank you for your timely contribution.  

Addendum:  Carmen’s parents have asked me to tell you that she is a very lovely young woman. The family has made the heart-wrenching decision to live apart over several years in order for Carmen to receive the best medical, psychological and behavioral services.  They maintain two homes, one in the US, and one where Dad is employed, in Grand Cayman.  Anna has lived variously with Mom in the US and with Dad on Grand Cayman; all travel back and forth as possible.  Carmen loves the Caribbean Sea and snorkels at every opportunity.  Time spent in the sea has afforded her the world’s best sensory integration, as well as occupational and physical therapies.  Carmen loves to draw and is a wonderful cook.  Anna is a loving sister who wants to study French and become a teacher.