Unraveling the Diagnostic Odyssey: Insights from Our Recent Survey, part 1.
Those with DYNC1H1 Associated Neurological Disorders (DAND) understand the challenges of living with unexplained symptoms, bouncing from doctor to doctor, undergoing numerous tests, and still not having a diagnosis. This experience, often referred to as a "diagnostic odyssey," is growing shorter for those with DAND as genetic testing that includes DYNC1H1 becomes more commonplace.
While the journey is a challenge, the DYNC1H1 Association (DA) is working to understand how we can use the vast wealth of information gathered during a diagnostic odyssey to accelerate research towards a cure. We conducted a survey targeting individuals who have navigated this challenging journey and registered in our Patient Contact Registry. The results shed light on the emotional, financial, and physical toll of both the diagnostic odyssey and day-to-day struggles experienced by DAND patients and their families. This information drives our decision-making, and motivates us to work harder for DAND families.
In this series of blog posts, we will be detailing the results of the survey and its impact on the research community.
Want to be a part of these results? Make sure you are enrolled in our Patient Contact Registry by clicking here.
Survey Demographics
Our survey included 50 participants from various backgrounds, ages, and locations. Birth years ranged from 1968 to 2023, with half of participants born before 2018, and half born in 2019 or later. This is expected, as many patients born prior to 2018 may not have received genetic testing or may not be followed by a geneticist. The survey should have been able to be translated within an internet browser, but may have been translated with variable quality depending on the language of the respondent. There were ten questions, mostly multiple choice with the option to write in a custom response.
Symptoms in the DAND community
The scientific literature surrounding DAND has painted a picture of an incredibly diverse disorder, where each patient has their own set of symptoms. While there are noted patterns, the lifespan impacts of DAND have been mostly unpublished. The most recent publication in Brain by Mӧller et al. (2024) follows 47 patients, roughly one third of which have variants matching those in the DA’s Patient Contact Registry and may have been recruited through the DA’s outreach efforts. A more detailed description of the Brain publication will be provided in a later blog post, so stay tuned for details. In general, however, both the Diagnostic Odyssey survey and the publication in Brain by Mӧller et al (2024) describe a highly heterogeneous disorder. No two DAND patients look identical. Instead, each individual has their own set of symptoms as unique as the genetic variant causing disease. Even in families where the gene variant has been passed from parent to child, there can be variability in symptoms and severity. This may be due to the unique gene combination in each person and/or environmental factors. In addition, three respondents indicated that the patient in their care has a genetic variant in a gene other than DYNC1H1.
Summary of the symptoms of DAND patients as reported in the DA’s Diagnostic Odyssey Survey from March to June 2024.
90% of Patients indicated either mobility challenges or muscle weakness, making this the most common symptom of DAND. Further study is required to separate out this group into subgroups focused on the cause of weakness. Lack of muscle mass, low muscle tone, and neuropathy-driven muscle atrophy are all possible causes. In addition, several patients added apraxia, a disorder that makes it difficult or impossible to make certain movements because the brain cannot communicate properly with their perfectly capable muscles. Apraxia most commonly affects speech, but it can affect movement as well. If muscle weakness is the primary symptom, often patients will either receive a diagnosis or self-label themselves with Spinal Muscular Atrophy with Lower Extremities Dominant. This is caused by the DYNC1H1 gene variant and is a part of the patient’s DAND.
60% of patients were reported to have Intellectual Disability. An IQ score of 70 or below, along with other adaptive challenges, results in a diagnosis of Intellectual Disability. Given that nearly a third of the surveyed population is aged 3 or younger, this could be an underestimation. While early signs and initial testing can occur from birth, formal testing for intellectual disability begins around age 3 when children are better able to participate in structured assessments. Psychologists and other professionals may use standardized developmental tests such as the Bayley Scales of Infant and Toddler Development or the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) to evaluate cognitive and adaptive functioning for preschool aged children. If your child has had testing through a public school or a psychological evaluation, ask for the results of intellectual functioning tests and for a formal IQ score. Many governments provide services to help support intellectually disabled individuals.
45% of patients report Orthopedic issues. Orthopedic concerns include any bone or joint issues, and patients reported a large variety of each. Hip dysplasia, scoliosis, kyphosis, congenital foot deformities like clubfoot, knee and ankle contractures, and femurs broken during or shortly after birth have all been reported by patients with DAND. Orthotics, like AFOs, SMOs, or TLSOs as well as prescribed exercises and surgeries to reduce these challenges are all commonly prescribed by orthopedic surgeons and physical therapists.
40% of patients report epilepsy. Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures resulting from abnormal electrical activity in the brain, manifesting in various forms across different age groups. DYNC1H1 is now present on many epilepsy genetic screening panels. In infancy, severe forms like infantile spasms (West Syndrome) involve sudden muscle contractions and require urgent treatment due to their association with developmental regression. In childhood, these seizures can resolve or progress into severe types like Lennox-Gastaut Syndrome that persist with multiple seizure types and cognitive impairments. Older childhood and adolescent-onset epilepsies typically require lifelong treatment. Lifelong management includes EEG and brain imaging, treatment with antiepileptic drugs, ketogenic diet, or surgery, lifestyle adjustments for safety, and psychosocial support to address mental health and quality of life impacts. Nearly 100% of patients with DAND reported having had an EEG, either within the past 5 years or in their lifetime.
ADHD (32%) and Autism Spectrum Disorder (25%). ADHD, attention deficit hyperactivity disorder, is a neurological disorder characterized by difficulty sustaining attention, high energy behavior compared to peers (hyperactivity), and impulsive behavior. Children with DAND have been reported to show symptoms on the more severe side of the ADHD spectrum, and as a result receive diagnoses fairly young regardless of gender.
Autism Spectrum Disorder (ASD) affects communication, social interaction, and behavior. Patients with ASD will often have specialized interests, difficulty sustaining conversations, and suffer from sensory processing challenges. This can result in challenging behaviors, possibly due to high demands on an individual's ability for emotional regulation. Patients with DAND range from requiring high to low amounts of support to cope with their autism symptoms.
While 17 patients indicated an ADHD diagnosis and only 13 reported an Autism diagnosis, 9 of those reported both ADHD and Autism together. In the general population, individuals with autism will have an ADHD diagnosis with about half the frequency seen in the DAND population. In addition, individuals with ADHD outside of the DAND population only have an additional autism diagnosis roughly 10% of the time. Given our sample, this may mean that DAND patients with ADHD are 5 times more likely than the general population to have autism as well (Canals et al, 2024).
Visual Impairment 25%. Conditions that affect sight in any way affect one in four DAND patients. Impairments are caused by more typical eye-sightedness issues that can be corrected with glasses, to cataracts, to cortical visual impairment. Congenital cataracts have been well established as part of the spectrum of DAND disease for nearly a decade (Gelineau-Morel et al, 2016), and can be corrected with surgery. Cortical Visual Impairment (CVI) is more challenging to identify, diagnose, and treat. There are no physical issues with the eye in patients with CVI. Instead, the brain is unable to process the information from the eye properly. While physical eye issues can be diagnosed at a standard eye doctor, CVI generally requires a neurologist or neuro-ophthalmologist for diagnosis.
CVI can cause a variety of visual problems that range from mild to severe. Children with CVI may have difficulty responding to visual stimuli, seeing certain parts of their surroundings, recognizing faces and objects, identifying items in cluttered spaces, reaching for objects while looking at them, and understanding what they are looking at. Parents may notice that their child with CVI reacts slowly to visual cues, prefers looking at moving objects, and uses a specific part of their vision, such as peripheral vision. Additionally, some children with CVI may stare at light sources like lamps or the sun, while others may be sensitive to light (Chokron et al, 2021).
Neuropathy (12%). Neuropathy is a condition resulting from damage to the peripheral nerves, which can cause a range of symptoms. Common symptoms include numbness, tingling, and pain, often starting in the hands and feet. Individuals may also experience muscle weakness, loss of coordination, and sensitivity to touch. The severity of symptoms can vary, potentially affecting daily activities and overall quality of life. If this is the primary symptom experienced by a patient, the patient may either receive a diagnosis of Charcot-Marie-Tooth type 2O (the letter O, not twenty), or self-label as such.
Symptom Progression in DAND
Pie Chart showing that 54% of patients are reportedly stable in condition, while 46% report some level of progression of symptoms.
When families receive a genetic diagnosis, often they are left with more questions than answers. This is especially true for a condition as wide-ranging as DYNC1H1 Associated Neurological Disorders (DAND). The most common question is, “What does this mean for the future?”. This is especially true because DAND patients are often diagnosed with a type of spinal muscular atrophy or Charcot-Marie-Tooth type 2, both which are known neurodegenerative conditions with both short and long term progressive paths. Conversations with families and research in the literature indicates that DAND patients may be stable or experience progression. Our Diagnostic Odyssey survey asked “In the past two years, would you consider the patient’s condition to be progressive (getting worse), or stable (staying the same)?”. 50 patients responded, with over half replying that they have been stable, and 17% stating that they have been experiencing progression. The two other options were “Stable in some areas, progressive in others” and “Stable, but have experienced progressions in the past”. Of the nearly 1 in 4 responses indicating that they experienced progression, but only in certain skills areas, comments described seizure recurrence, behavioral difficulties, and reduced mobility as possible areas of progression. The remaining 8% who reported historical progressions made similar reports.
Neuropathy diseases like Charcot-Marie-Tooth disease have two established patterns of progression. The first is that a patient experiences a steady increase in neuropathy symptoms beginning in the pre-teen years or early adulthood. The second is a sudden jump in those symptoms, often linked with viral infections, hormonal changes from puberty or pregnancy, or traumatic injury. In DAND, the symptom progression can extend beyond neuropathy and loss of motor strength to include seizure recurrence, loss of speech & communication skills, or/and increase in mental health or behavioral health disorders. For more information, see our upcoming Research Update on “The expanding spectrum of DYNC1H1-related disorders”.
Summary
Those with DYNC1H1 Associated Neurological Disorders (DAND) experience a wide range of symptoms, making each individual’s combination of symptoms highly unique. A recent survey of DAND patients revealed common symptoms such as mobility challenges, muscle weakness, and intellectual disabilities. Additionally, many patients reported orthopedic issues, epilepsy, autism, ADHD, visual impairments, and neuropathy. Each patient’s symptoms are unique, varying in severity and presentation, reflecting the diverse impact of the DYNC1H1 gene variants.
People with DYNC1H1 Associated Neurological Disorders (DAND) experience a wide range of symptoms. The results of the Diagnostic Odyssey survey highlighted common issues like trouble moving, weak muscles, and learning difficulties. Many also have bone and joint problems, seizures, autism, ADHD, vision problems, and nerve pain. Each person's symptoms are unique, with different levels of severity and combinations. While this large variety of challenges from person to person may seem isolating, the DYNC1H1 Association is here to help bring the community together to support one another. Together, we can find treatments for each of these symptoms and make the Treatment Odyssey a much shorter journey.
