Timothy syndrome (TS) was first identified about 20 years ago as a multisystem rare
disease featuring the co-occurrence of a Long QT (LQT) interval in the heart and syndactyly
(fusion of the fingers and/or toes). However, over the years as more patients received a TS
diagnosis, the need for a greater understanding of how the disease presents became
apparent. To help address this need, we are excited to share that the first Natural History
Study of Timothy Syndrome was published last month in the Orphanet Journal of Rare Diseases. A Natural
History is an observational study that reports on the symptoms of a disease to track its
progression in patients over time. By conducting a Natural History study of TS, we sought to
compile information about the various symptoms afflicting TS patients, focusing on the most
common and life-threatening features. This work can serve as a detailed resource for
families and physicians managing a TS diagnosis. Additionally, we aimed to bring attention
to TS symptoms that have not been reported on collectively. We hope that researchers will
focus on understanding these symptoms to continue improving TS patients’ quality of life.
TS is caused by variants, or changes, in the gene CACNA1C, which codes for part of a
calcium channel (Ca V 1.2) that is present in every cell in the body. The first identified TS
patients shared the same variant, Gly406Arg, though occurring in two different ways. The
instructions for creating the calcium channel subunit are contained in parts of the CACNA1C
gene called exons. Ca V 1.2 is produced using instructions containing either Exon 8A or Exon
8 of CACNA1C, but never both. Thus, original TS patients were termed TS1 (containing a
Gly406Arg variant in Exon 8A) or TS2 (containing a Gly406Arg variant in Exon 8). Since this
time, patients have been diagnosed with TS with the same or different CACNA1C variants.
Additionally, while several original patients passed away at an early age, others have since
grown into adults, calling for a need to understand the disease’s symptoms as patients age.
Together, these cases have raised many questions about the progression of TS and how it
changes between patients with different CACNA1C variants.
We decided to conduct the first TS Natural History Study to ask patient families
comprehensively about their experiences with TS to address two broad questions: (1)
Which symptoms arise or subside as patients age? and (2) How do symptoms change
between patients with different CACNA1C variants? We believed that compiling this data
would address these questions and identify potentially new areas of TS research that need
attention to fully understand the disease’s mechanisms.
To conduct the Natural History Study, we disseminated a 150-question survey via Google
Forms to TS families. To achieve this, we benefitted invaluably from Katherine Timothy’s
admirable dedication to TS families since the disease’s origins. Through her connections,
we were able to contact and invite all known TS families (105) to participate in our survey,
yielding a response rate of 83%. Our comprehensive list of questions ranged from across
organ systems (including cardiac, neurodevelopmental, endocrine, immune,
gastrointestinal, and musculoskeletal involvement), to educational experiences, medications
and treatment regimens, and cause of death (where relevant). We also included data from
the literature where appropriate, although this data primarily focused on the cardiac
manifestations of the disease.
Our results confirmed several common features across patients that have been reported
previously, including cardiac concerns, neurodevelopmental delays, hypoglycemia (low
blood sugar), and syndactyly. However, our study also highlighted potentially life-threatening
symptoms beyond the cardiac features. Notably, several parents reported their child’s death
was related to respiratory concerns and hypoglycemia. Arguably, managing these
symptoms should now be seen as critical as managing cardiac symptoms, as any of the
three can be life-threatening. Additionally, we identified several areas of extra-cardiac
symptoms that have not been previously reported, including kidney dysfunction,
constipation, vision concerns, and dental concerns. While TS parents have previously noted
many of these symptoms anecdotally about their children, this was the first time this
information was collected systematically across TS patients to report them to the medical
and research communities. More research is needed to understand the cause of these
symptoms, and how to manage them, as TS individuals grow out of childhood.
Our study included individuals with the canonical TS mutations (these individuals are
termed TS1 Gly406Arg and TS2 Gly406Arg) and individuals with other mutations in
CACNA1C who have received a TS diagnosis. We also included individuals with a
CACNA1C variant who were diagnosed with non-syndromic LQT (rather than TS), due to
their apparent lack of extra-cardiac symptoms. Intriguingly, we found that TS1 and TS2
individuals had the most frequent occurrences of some symptoms, like severe
bone/joint/skin abnormalities and cardiac concerns. However, we found that any individual
with a CACNA1C variant seems to have the potential to develop cardiac and extra-cardiac
symptoms. For example, gastrointestinal concerns were noted at a comparable frequency
across groups. Thus, we argue that TS should be considered a spectrum of symptoms of
various severity. While Gly406Arg variants seem to confer a severe form of the disease,
there does not seem to be a clear pattern among other variants.
Overall, this Natural History study paints a broader picture of the multi-system nature of TS,
containing information on symptoms afflicting a comprehensive list of organ systems and
current treatment regimens for patients. We hope it will serve as a resource to patient
families and physicians navigating a TS diagnosis. We also intend it to be a starting point
for new areas of TS research to further our understanding of the disease and improve the
lives of TS patients.
We would like to extend our sincere gratitude to the TS families who responded to our
survey and made this study possible. Additionally, we are grateful to Katherine Timothy for
initiating this work and continuing it through her decades-long commitment to TS families
and to Andy Golden for his work in formalizing this project into a Natural History Study to
share with the research and medical communities . Andy unfortunately passed away during
the preparation of the manuscript. We are immensely thankful for all of his efforts to improve
the lives of TS patients and their families through research and advocacy.
Click here to read the full TS Natural History Study
Summary written by Kerry A. Larkin
Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institute of Health, Bethesda, MD, USA
Department of Cell Biology, Yale School of Medicine, 295 Congress Ave, New Haven, CT, USA
