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

From Undiagnosed to Diagnosed:  The Journey

My husband and I are proud, loving, and often exhausted parents to two adult daughters, Julia, age 24, and Lilly, age 22, with Pitt Hopkins Syndrome (PTHS)

Lilly and Julia. Photo courtesy of the LeGendre family.

I consider myself fortunate to recall Julia’s first year of life in blissful ignorance of any serious problems or dream-defying “detours” that might lie ahead.  I recall that year as a new Mom primarily as one of delight and joyful cluelessness.  Our pediatrician dismissed my initial concerns, such as delayed babbling and mildly late motor milestones at nine months as the worries of a nervous, first-time Mom. 

Not long after her first birthday, Julia had a new pediatrician who was to remain as our daughters’ primary doctor for the next twenty years.  By the time I was pregnant with my second child, developmental differences for Julia were apparent to all.  We were encouraged by our doctors to perform high resolution karyotyping on Lilly in utero.  Neither that testing nor a subsequent work up for Fragile X for Julia was revealing.  

Our lives became a whir of medical specialist appointments, therapies, insurance and service battles familiar to all families of a child with special needs.  In spite of speech (ST), physical (PT) and occupational therapies (OT), the gap between their chronological and developmental age widened.  We were fortunate to see autism expert, Margaret Bauman of Ladders and Massachusetts General Hospital (MGH).  Dr. Bauman used the term “atypical autism” to describe our particular version of autism spectrum disorder (ASD).  She referred us to neurogeneticist, Marvin Natowicz, then at MGH.  Our search for an etiological reason for our daughters’ delays began in earnest with Dr. Natowicz.

By the time they were six and four years, our urgency for an answer had increased.  Julia had experienced a significant developmental regression, while Lilly’s development had stalled.  Julia’s previously robust dramatic play skills slowly disappeared, along with most of her nascent language ability.  She no longer insisted on my attention to her joy in discovery of the world.  My child increasingly withdrew into a world that, for her, was chaotic and frightening.  

Sensory integration (SI) therapy was added to the growing list of interventions for both Julia and Lilly.  Neurological regression is a hallmark for certain diseases, and Dr. Natowicz began his investigation by looking for biochemical evidence of a lysosomal storage disorder (LSD).  Malfunctioning storage enzymes cause biomolecules to build up inappropriately until this excess is toxic to cells and neurons.  The weeks we spent waiting for the results of that testing on both of our young children were long, completely terrifying weeks. 

Relieved, at least for a while, we would add a number of new acronyms to our lexicon over the next nineteen years.  “Within normal limits” (WNL) does not mean that your child is well; it is a technological way of saying, “It’s probably not this disorder, but we don’t know what it is.”  Much later, we would learn that a “variant of unknown significance” (VUS) in a gene of interest for a known disorder is another way to say “your child has a base change at this position, but we don’t really know what it means.  It might be significant for disease, but we can’t tell you that with confidence.”  Interpretation of genetic results is both an art and a science in the early decades of the 21st century.

We began working with Dr. Natowicz in 1994, and we continued with him until he left Boston for the Cleveland Clinic in 2000.  In our case, Dr. Natowicz endorsed yearly visits for work up for inborn error of metabolism or other genetic error.  In addition to storage disorders, testing by Dr. Natowicz included screening plasma and urine for purine disorders, disorders of creatine metabolism, microarray testing for chromosomal error, and investigation of amino acid pathologies.  

We saw three additional geneticists at MGH over the next ten years.  In that timeframe, Julia and Lilly were investigated for biochemical indicators of mitochondrial disease, as well as for Angelman Syndrome, Smith Lemli Opitz, Rett Syndrome, and Congenital Disorders of Glycosylation.  The last of these geneticists was convinced that one of my daughters had the appearance of an individual with Sanfilippo Syndrome, a form of storage disorder.  She ordered gene sequencing for Sanfilippo’s and for Niemann Pick C, another aggressively progressive storage disease.  In so doing she reopened the Pandora’s box of our earliest investigations.  The lesson for us from these studies on our children in 2010 was that “no” means “no, based on available technology.”  

Heading into the next decade, David Sweetser, became our daughters’ fifth and final geneticist at MGH.  By 2012, state of the art technologies for investigation of complex disease with CNS involvement were oligo-based microarray for chromosomal error, and whole exome sequencing (WES), a base-by-base reading of all “coding areas” of the genome.  Microarrays can discern partial, whole and multi-gene rearrangement, while WES screens for single-to-few base mutations within genes.  Earlier microarrays for our daughters were non-informative.  However, “oligo” arrays are able to find smaller changes within chromosomes, and this testing revealed minor errors for both Julia and Lilly. Ultimately, each had a different finding, so these were not considered relevant to their common neurological disease.  

Research based WES was initiated for our family of four in the spring of 2012. By January 2013 we had received confirmation of those findings; after 19 years of investigation via biochemical and genetic analysis, a single base change in the gene, transcription factor 4 (TCF4), was found for both Julia and Lilly.  As this change does not occur for either parent, it is relevant to their shared disorder.  

After 19 years of searching, we learned that our daughters have an extremely rare, genetic cause of synaptic dysfunction called Pitt Hopkins Syndrome.  

Estimates are that fewer than 250 people have been molecularly identified with this disorder worldwide.

By the time of our daughters’ diagnosis, we no longer had an expectation of cure or even for recovery.  The question we most desperately needed an answer to was whether our children have a “one hit, it-is-what-it-is disorder,” or if their particular condition was progressive.  Storage diseases are progressive, often resulting with death in young adulthood.  

What is their prognosis?  Julia has mainly been stable since her long year of regression from five to six years of age.   Still, doubt lingers.  She had achieved urinary continence at six and a half years and then lost those critical toileting skills at age 12.  Lilly’s course has included seizures, disrupted sleep, urinary retention and behavioral instability.  Both are treated for significant constipation.  In 2010 when our geneticist reopened investigation for a storage disorder, Lilly was also having more difficulty with gait, especially on stairs.  

Our children’s diagnosis of Pitt Hopkins at the age of 21 and 23, respectively, was cause for great celebration because clinical data suggest that PTHS is not a progressive disorder.  Although the disorder results in cognitive disability, limited language, GI distress, seizures and breathing anomalies, children with PTHS are relatively stable.  Their happy disposition is noteworthy by all who meet them.

A great part of our new “good” fortune comes by virtue of knowing exactly which gene is affected.   There’s significantly more optimism in driving gene-based research.  Our hope is that in knowing which gene to target, we’ll know “what line to be in” when treatment modalities for synaptic disorders may become available.

In hindsight, I am happy that we didn’t have this answer in Julia’s first blissful year of life.  The outlook for PTHS includes lifelong cognitive disability.  From the perspective of having our now adult children, we’re pleased with this diagnosis.

Thus we began 2013 with a newly extended Pitt Hopkins family, giving us 200-plus reasons for shared hope, joy, optimism and expectation.  The latter is fueled both by a nexus of younger families with the necessary energy to push for funding and research, as well as by enthusiastic and dedicated scientists newly funded by the Pitt Hopkins Research Foundation (PHRF).  

Lilly on left, and Julia “on her phone!”. Photo courtesy of the LeGendre family.

Please visit the Pitt Hopkins Research Foundation website at to learn more about these ongoing efforts.