Signs and Symptoms
In 2021, GEMIN5 gene was first linked to a wide variety of signs and symptoms with varying severity:
Cerebellar volume loss
Cerebellar atrophy is caused by degeneration of the cerebellum, the part of the brain that coordinates muscle activity. Conversely, cerebellar hypoplasia is a developmental condition in which the cerebellum of the brain fails to develop properly. Both Cerebellar atrophy and cerebellar hypoplasia can result in impaired muscle coordination, a loss of balance, unsteady gait, slurred speech, difficulty swallowing or chewing. More research is needed to understand this key question: whether GEMIN5 gene mutations cause cerebellar atrophy or hypoplasia. Find out how you can join us in advancing this research (link to Join Us).
Ataxia
Ataxia comes from the Greek word for “disorder” and describes a lack of coordination while performing voluntary movements. In this case it is the result of cerebellar volume loss and is characterized by a lack of muscle coordination and balance, resulting in one or more of the following: slurred speech, trouble eating and swallowing, challenges with fine motor skills, difficulty walking (unsteady gait), eye movement abnormalities, and tremors.
Seizures or Epilepsy
Characterized by unpredictable seizures, this symptom can vary widely in the type and frequency of seizures. Seizures often go unnoticed and can be confused with unsteady gait in young children.
Cognitive Impairment/developmental delay
Recent studies of the cerebellum have revealed that in addition to playing a major role in the coordination of motor skills, the cerebellum is also critical for cognition. These symptoms most often result in developmental, speech and language delays in children. You may notice issues with verbal expression, difficulty expressing or receiving information, slower processing time, problems developing motor skills.
Hypotonia
Hypotonia is defined as decreased muscle tone. Infants and young children experiencing this symptom are often described as “floppy” and may have poor head control. Signs of hypotonia at any age include decrease in strength, poor reflexes, hyperflexibility, speech difficulties, decrease in activity endurance and impaired posture.
Testing
GEMIN5 gene mutations can be discovered through genetic testing. While GEMIN5 can be tested individually, it is included on some multi-gene ataxia panels. Additionally, GEMIN5 mutations can be found through Whole Exome Sequencing (WES)—a comprehensive genetic test that sequences the protein-coding regions of the approximately 25,000 genes in an individual. Recently WES has become more readily available, affordable, and common for the diagnosis of conditions believed to have a genetic basis.
Testing by WES must be requested by a doctor and the results sent to a medical facility. Families interested in genetic testing should discuss that option with their doctor, who may recommend genetic counseling and a genetics evaluation to determine the appropriate diagnostic test.
Research
In 2016 Dr. Deepa S. Rajan and Dr. Udai Pandey at Children’s Hospital of Pittsburgh (CHP) began investigating possible disease linked to GEMIN5 after a young patient visited Dr. Rajan’s clinic with many of the symptoms listed above, and subsequently received a GEMIN5 variant of unknown significance result on WES testing.
Since then, the CHP team has worked diligently to build a strong case, both in the clinic and in the lab, to prove the link between GEMIN5 mutations and disease. Their extensive research was published in Nature, an important scientific journal, on 07 May 2021. You can read the full article here. (Kour, S., Rajan, D.S., Fortuna, T.R. et al. Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder. Nat Commun 12, 2558 (2021). https://doi.org/10.1038/s41467-021-22627-w)
In the meantime, various research groups around the world have been studying the basic science of GEMIN5 for over 20 years.
Here is a very brief summary of what is currently understood about the basic science of the GEMIN5 gene:
GEMIN5 is a large gene made up of 1508 amino acids. It is responsible for making a protein called Gemin5, which has many important jobs and is involved in regulating multiple aspects of cell function.
GEMIN5 is a critical gene that is expressed in every cell of the body.
GEMIN5 makes up one of nine genes in what is known as the SMN Complex. Deficits in another gene in the complex, SMN1, cause Spinal Muscular Atrophy (SMA). Within the last few years the FDA has approved two life changing treatments for SMA, including a gene therapy which given to children under the age of 2 has been successful in slowing and sometimes stopping the progression of the disease in its tracks. This new therapy has offered so much hope for SMA families and is an incredible demonstration of what a strong research network and patient-led organization can accomplish!
Reference: The SMN Complex: An Assembly Machine for RNPs D.J. BATTLE, M. KASIM, J. YONG, F. LOTTI, C.-K. LAU, J. MOUAIKEL, Z. ZHANG, K. HAN, L. WAN, AND G. DREYFUSS
While the research team at Children’s Hospital of Pittsburgh works to understand how and why certain mutations (or “pathogenic variants”) in the GEMIN5 gene cause the symptoms discussed above, Gemin5.org exists to support this research. As science and medicine continue to advance, our goal is the development of life-improving treatment options, and with hope, a cure, for our loved ones.
If you have a Gemin5 diagnosis, you can join the collaboration by reading more here and by contacting Children’s Hospital of Pittsburgh’s Center for Rare Disease Therapy at www.chp.edu/rarecare, 412-692-RARE, or rarecare@chp.edu. Additionally, Gemin5.org is working on a patient-led registry which will be a crucial tool for our community. More info on that soon. Please contact us with any questions.