Major Publication: Moller et al, 2024
“The expanding clinical and genetic spectrum of DYNC1H1-related disorders” published in the journal Brain in May 2024.
Preface:
In 2022, I searched clinicaltrials.gov to find possible clinical trials and research studies to help my daughter. This had been a routine of mine, to check for possible studies every six months or so in order to give her the best possible chance of an easier adulthood. Through that search, I found “DYNC1H1-related disorder Natural History Study'' being led by Dr. Hormos Salimi Dafsari & graduate student Birk Möller of the University of Cologne in Germany. After corresponding with them, it became clear that these two individuals not only shared my interest in the topic of DYNC1H1 disorders, but have the skill, passion, and wherewithal to accelerate research. We shared the research study in the DYNC1H1 Family Facebook group, which assisted in recruiting many families to the study. After 18 months of study, interviews with 47 families, and a thorough review of the current literature, Möller, Dafsari, and their team’s manuscript was accepted for publication by the journal Brain in May 2024. Mr. Möller and Dr. Dafsari are now key members of the DA’s Scientific Advisory Board. This article is a summary of their findings. For the full text, please visit the Brain website.
Stay up to date with our upcoming events! The DYNC1H1 Association will be hosting Mr. Möller and Dr. Dafsari for a community talk about their study and to answer questions in the Fall of 2024!
Glossary:
DAND: DYNC1H1 Associated Neurological Disorder, may also be called a dyneinopathy.
Gene variant: a mutation in a part of DNA that codes for a specific protein.
Dynein: the protein coded for by the DYNC1H1 gene, responsible for moving materials around the cell, especially in neurons.
Phenotype: the set of observable characteristics of an individual resulting from the interaction of its genotype with the environment.
Genotype: The genetic code of an organism.
Autosomal dominant: A gene whose phenotype is expressed even when only one of a person’s two copies code for that phenotype.
Mutant form: a protein that has resulted from a gene variant.
Nucleotide base: one of the “rungs” of the DNA ladder, comes in either A, T, C, or G versions.
Scope of the project:
47 patients from 43 families were recruited, their genetic variants confirmed, clinical data and medical histories were collected, followed by online interviews with the patients or their families. The goal was to determine the prevalence of specific DYNC1H1-related symptoms in this 47 patient cohort, then compare them to the previously reported symptoms in the scientific literature. In addition, six patients’ dynein proteins were 3-D modeled to determine the effect of the gene variant on the structure of the dynein protein. The goals of the study were to provide further insight into this ultra-rare disease, help improve early diagnosis, and improve counseling and health surveillance of affected patients.
Who were the participants?
47 total patients
43 families
27 male patients
20 female patients
13 different countries of origin. 20 from the United states
Age range of 2 years to 59 years, with the median age of 12 years old.
The majority of patients were Caucasian, with the US and Europe comprising the vast majority of study participants. More patients were male than female, with about 17% of patients being male between 10-14 years old and 13% being female between 6-9 years old.
All patients are heterozygous, meaning they have a single copy of the mutated gene. Forty-one of these gene variants are unique from one another, and 14 had never before been documented in the literature. The gene variants were distributed throughout the entire DYNC1H1 gene, one of the largest in the human genome, comprising 4646 amino acids and 19940 nucleotide bases. Forty-one variants were missense mutations, where there was a “typo” in one of DNA’s nucleotide bases, resulting in a change in the amino acid when the gene is translated into the dynein protein. The remaining 6 patients have truncating (ending the protein early), in-frame deletion (missing 3 nucleotide bases, resulting in the reduction in size of the dynein by one amino acid), and splice site (can alter the entire amino acid sequence) variants. The patients with truncating variants, a type of mutation that results in a shortened protein, were not found to have more severe symptoms than the rest of the patient cohort.
Key Findings in DYNC1H1 Associated Neurological Disorders (DAND)
DAND is more diverse than was previously thought, including in how the disease changes over the lifespan.
This study significantly expanded the current understanding of DYNC1H1-Associated Disorders. Most significantly, a two-phase course of the disorder was revealed. This course of disease progression can be age-dependent and/or dependent on the patient’s existing neurodevelopmental disorders. Infections, initiation or recurrence of seizure activity, and pregnancy are described as possible causative factors in sudden leaps in degeneration. The authors speculate and ask for further research into the idea that viruses may trigger this exacerbation of symptoms. Certain viruses hijack dynein in order to move within human cells. Therefore, they hypothesize that if a patient has faulty dynein a damaging collection of viral particles or other toxic materials may collect because the malfunctioning dynein cannot move them properly. In other cases, no specific cause was documented. Regressions in speech, behavioral, and physical abilities are each documented. For patients with fewer background neurological symptoms, physical progression is most common, with the changes beginning anywhere from the preteen years to early adulthood. Reported symptoms aligned with both motor and sensory neuropathy. Numbness, tingling, chronic nerve pain, muscle weakness, and reduced control over movements start in the hands and feet, then move towards the trunk. In some cases, individuals require the support of a wheelchair or other assistive device to have sustained mobility. Urinary and fecal incontinence are also reported.
Mr. Möller provided further details to the DYNC1H1 Association, stating that “A non-static [progressive] disease course was discovered in 30.4% of patients, with 17.4% having
developmental regression during infancy and early childhood and 15.2% having age-dependent progression of neurodegeneration” and encourages patients to sign up with the DA’s contact registry so that the follow-up studies include a larger population. This is lower than has been self-reported by patients in the DA’s Diagnostic Odyssey Survey, the results of which are detailed here.
Figure 5 from Möller et all, 2024. Common symptoms and symptom progression from infancy/young childhood, adolescence, and adulthood.
General Statistics:
Developmental delay was detected in 61.3% of patients as a core clinical symptom.
75% of patients reported motor delays, 75% have intellectual disability, 74% have behavioral disorders, and 72% have speech delays. Motor delays were predominantly in the gross motor category, looking at larger muscle movements like sitting, standing, and walking. Only 30% of patients had fine motor difficulties in comparison. Noteworthy are that four of the patients never achieved independent walking. Seven patients experienced regression in motor skills.
Given the median age of patients being twelve, and that regressions and development of motor tend to occur after age nine, it is of the utmost importance that we continue to follow these patients and more. The DYNC1H1 Association is assisting in organizing this effort through our Patient Contact Registry. If you have not yet done so, register here.
Musculoskeletal Impacts:
Physically, 64% of patients present with lower-limb predominant muscle weakness and/or muscle atrophy. Nearly all patients with the ability to walk or under the age of three had difficulty using a typical walking gait. 9% of cases have solely motor development delays.
Almost half of patients had abnormal reflexes. Furthermore, 18% of patients report symptoms consistent with sensory neuropathy with numbness, tingling, and pain in the hands and feet as the most common complaint. Patients shared the results of EMG and Nerve Conduction Studies, which are commonly done to look for abnormality in the nerves and determine the level of neuropathy. These provided evidence of neuropathy, both in the motor neurons in charge of muscle contraction and sensory neurons in charge of touch. Only two patients shared the results of a muscle biopsy, one indicating a higher than typical amount of Type 1 “Slow Twitch” muscle fibers, and the other showing fairly typical results.
Patients were frequently born with foot deformities, other contractures, or similar orthopedic congenital anomalies.
Images of the left and right feet of a DAND affected newborn. The right foot is twisted out, and the left is pulled to the shin and puffy.
Brain Malformations:
Roughly 62% of patients reported some sort of brain malformation. Half of those malformations involved abnormal cortical gyration, caused by problems with how the neurons move and organize during brain development in the first few months as a fetus. This means patients have too many folds (polymicrogyria), too few folds (pachygyria), or no folds (lissencephaly) present on parts of most of the brain. DYNC1H1-associated disorders are one of the few that can cause all three of these brain malformations, though further study is needed to determine the presence of any genotype-phenotype correlations. Additionally, 1 in 5 patients have an abnormal corpus callosum, the “bridge” that connects the two sides of the brain, enlarged ventricles, and/or brain lesions next to the ventricles. Each of these can cause symptoms such as intellectual disability, epilepsy, and other challenges commonly seen in DAND patients. Eleven patients had microcephaly, and some of those saw head size falling off the growth curve with age.
Behavioral Health Impacts:
The most common behavioral disorders were attention deficit hyperactivity disorder (known as ADD or ADHD, 45.2%) and autism spectrum disorder (ASD, 30.9%). These varied in severity. One patient reported some relief from ADHD symptoms with medication, and outside of this study the use of medication in the management of ADHD symptoms has been reported by many families. Anxiety and/or aggressive behavior were reported in 8 of the 47 patients. Depression, tic disorders, obsessive compulsive disorder, pica, and other mental or behavioral health disorders were reported in individual patients.
With nearly a third of patients in this study too young or only recently of age to be tested for most behavioral challenges, and the majority pre-pubescent, it is of the utmost importance to continue to follow these patients in order to continue to build an accurate profile of the disease. Help us do so by getting involved: www.dync1h1.org/get-involved
Seizures & Epilepsy:
Half of the patients reported having seizures, and nearly every type of seizure was reported. In the table below, the types of seizures, number of patients reporting that type, and the percentage of patients out of the 23 seizure-experiencing patients are detailed.
Generalized motor seizures were the most commonly reported.
Some patients reported increased seizure activity during viral infections with COVID, and some reported increasing physical or visual symptoms after seizure onset. About half of patients with seizures had EEG recordings showing varying patterns indicative of seizure activity. More information will be coming soon, as the results of an epilepsy-focused study on a large group of DAND patients, also co-authored by Dr. Dafsari, were recently published in Epilepsia. The DA will be posting a summary of the results on at the end of July 2024.
Other organ systems - Gastrointestinal, Urinary, Cardiovascular, and Sleep:
Just over half of all patients experienced some combination of gastrointestinal challenges, from constipation (about 40%), and reflux (10%). The authors hypothesize that the constipation is likely caused due to the intestines not pushing food along over the course of digestion in a proper manner, likely due to dysfunction in the nervous system. Similarly, multiple patients reported fecal or urinary incontinence in the form of neurogenic bowel or bladder, where incontinence is due to a nervous system issue as opposed to any problem within the bowel or bladder itself. Similarly, several patients reported difficulties with heart palpitations, low blood pressure, and difficulty controlling body temperature due to nervous system dysregulation. Sleep disturbances were present in nearly 1 in 3 patients, with 1 in 5 reporting fatigue or excess sleepiness. Sleep disturbances are common comorbidities with ADHD and Autism spectrum disorder.
Why is this study important?
This paper documents, in detail, the symptoms and experiences of nearly five times the largest previously studied cohort, and does so with the largest age range as well. In addition, its focus on disease progression and symptom diversity breaks with the previous focus on neurological symptom snapshots in time.
There have been multiple publications on DYNC1H1-Associated Neurological Disorders, with over a dozen published case studies in the past two decades. In the vast majority of these, one family or patient is studied or the variants are studied without documenting symptoms except in the most general of terms. In May 2020, The American Journal of Medical Genetics in May 2020 published one of the first comprehensive reviews of reported DYNC1H1 variants (Amabile et al., 2020), characterizing four new patients in detail and 103 previously reported patients in summary. A few months later, in August 2020, a study that followed 10 pediatric patients was published in the Journal of Human Genetics (Becker et al,, 2020). That study, also co-authored by Dr. Dafsari, is the source of the triple venn diagram commonly utilized by patients attempting to make sense of their or their loved ones symptoms. The new paper by Möller et al. renders that venn diagram out of date, as it shows that each patient has their own profile of symptoms.
The now-outdated triple venn diagram published in 2020 that attempted to detail the overlap of symptoms in DAND patients.
Both 2020 papers also built on previous attempts at a genotype-phenotype correlation. Both papers agree that patients with primarily motor symptoms likely have variants in the range of amino acids 200 -1200, with primarily intellectual disability occurring in the 3000 - 4000 range. In contrast, this 2024 publication dives more deeply into the wide-ranging molecular mechanisms that dynein is responsible for, leading to a greater focus on the etiology of each person’s unique symptom set and how it develops with time.
We are grateful to the entire research team for their attention to DYNC1H1-related disorders and their willingness to dedicate themselves so fully to this worthwhile cause. We look forward to continuing future partnerships with them and similarly minded researchers.
Are you interested in being a part of our growing research network? We host regular scientific talks that look to bridge the gap between basic and clinical research, and have an engaged patient community that grows every week. Join us by visiting www.dync1h1.org/research-network
Topics of interest for future study:
Drug Repurposing trials in DYNC1H1 variants (iPSC models currently in development)
Natural History: Medication effects on seizure control, ADHD, and behavioral health symptoms.
Natural History: Toileting and DAND
DYNC1H1 immune system effects, specifically around hypogammaglobulinemia
Ciliopathies of the lungs in DYNC1H1 deficiency on ciliogenesis or ciliary beating
Follow-up studies either with longitudinal observational studies in a cohort of patients with DYNC1H1-related disorders before and after viral infections, or with molecular studies from patient fibroblasts that are investigated before and after viral infection in cellular assays.
