Gene linked to movement disorder with Parkinson’s-like symptoms
Symptoms emerge early in life in people with mutations in the ACBD6 gene
Researchers have discovered a new early-onset movement disorder associated with mutations in the ACBD6 gene, and several symptoms are similar to those observed in Parkinson’s disease.
Genetic sequencing across more than two dozen unrelated families uncovered disease-causing mutations in the gene that were linked to a distinct neurodevelopmental disease that has progressive cognitive symptoms and motor manifestations not unlike those seen in Parkinson’s.
However, while Parkinson’s typically emerges later in life, the new disease was evident in childhood, with significant motor and cognitive deterioration by adulthood.
Given the overlap between Parkinson’s and the newly identified disease, the researchers believe that better understanding the function of ACBD6 could advance the understanding of genetic causes and cellular pathways underlying Parkinson’s.
The study, published recently in Brain, was conducted by a global team of researchers in collaboration with Centogene, a company specializing in genetic diagnostics for rare diseases. It is titled “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders.”
“Up until now, the genetic causes of neurological disorders have remained greatly unknown,” Peter Bauer, MD, chief genomic officer at Centogene and study author, said in a press release.
“This groundbreaking study has now not only helped us to understand a driving factor for 45 patients but has shed light on the way to a potential cure for a larger group of neurological disorders, and that is game changing. That is what we are striving for every day,” Bauer said.
Acyl-CoA-binding domain-containing proteins, or ACBDs, are a large family of proteins that have been suggested as important for brain development. The precise relationship between ACBD6, encoded by the ACBD6 gene, and neurological disease is not known.
Researchers used the GeneMatcher database
In the study, the researchers used a tool called GeneMatcher to connect with others worldwide who also were interested in the ACBD6 gene. Through this and other databases, the global network of clinicians and scientists ultimately were able to identify 20 distinct ACBD6 mutations across 28 unrelated families worldwide.
These families were from diverse ethnic and geographic backgrounds, including South and Central Asia, the Middle East, Europe, North and South America.
A total of 45 people — 23 males and 22 females — with the mutations were affected by a similar neurological disease. The identified disease-causing mutations mostly were predicted to lead to a loss of function of the ACBD6 gene. They were also bi-allelic, meaning they were found in both copies of the ACBD6 gene — both the one inherited from their biological mother and their father.
Patients with the disease ranged in age from 1 to 50 years at the time of the data review, with nearly half (21 people) being younger than 10.
Dominant features common to most patients as of the latest clinical follow-up included moderate-to-severe global developmental delays (100%), language impairments (98%), movement disorders (97%), altered facial features (95%), gait abnormalities (94%), mild difficulties coordinating muscle movements (cerebellar ataxia, 85%), and muscle spasticity (76%).
Dystonia was the most common movement disorder
Dystonia was the most common movement disorder, occurring in 94% of patients. Dystonia, which also is common in Parkinson’s disease, is characterized by involuntary muscle contractions and abnormal muscle tone. Patients also commonly experienced tremors, which is another hallmark feature of Parkinson’s.
As they aged, about a third of patients developed general parkinsonism, characterized by muscle rigidity, tremors, and slowed movements (bradykinesia) reminiscent of Parkinson’s disease.
Other symptoms observed in the patients included seizures, autistic features, behavioral changes, sleep disturbances, and bladder issues.
All patients with available data showed a deterioration in motor and cognitive abilities over time, “suggesting a progressive disease course and underlying neurodegeneration,” the researchers wrote.
To learn more about this new disease and its underlying mechanisms — and thus identify possible treatment targets — the scientists developed models using zebrafish and frogs that were engineered genetically to lack ACBD6.
The models exhibited many of the same features reported in the patients, including movement disorders, progressive motor impairments, seizures, smaller-than-normal head, and developmental delays.
In preliminary experiments, the researchers began to uncover a possible mechanism by which a loss of ACBD6 function may cause neurological disease, which involves a type of protein modification called N-myristoylation. This biological process helps anchor proteins to cell membranes, and plays a crucial role in various cellular functions.
Call for more studies, collaborations
The researchers said that additional studies are warranted to continue working out the clinical presentation and underlying mechanisms of the disease.
Overall, the study provides “a next step towards advancing treatments and life-changing answers for these patients, their families, and the greater neurological disease community,” said Aida Bertoli-Avella, PhD, head of research data analysis at Centogene and a study author.
The researchers credit the collaborative nature of the study with the ability to make the landmark discovery.
“This study reinforces the value of close collaboration between research labs and accredited diagnostic laboratories, like Centogene, in finding precise molecular diagnosis for families affected by undiagnosed ultra-rare disorders,” noted Reza Maroofian, PhD, of the University College London and the study’s senior author.
“These collaborations are fundamental in advancing our understanding of genetic disorders and their underlying mechanisms,” Maroofian said.
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