Last updated:
8/13/2024
Years published: 2024
NORD gratefully acknowledges Ben Esmaili, BS, Kayla Ruiz, BS and Sean Dailey, BS, Stanford University MS Program in Human Genetics and Genetic Counseling, Hetanshi Naik, PhD, MS, CGC, Associate Professor, Department of Genetics, Stanford University School of Medicine, and Juan P. Ramos, DO, MS, Pediatric-Medical Genetics Resident, Department of Pediatrics, Division of Medical Genetics, Stanford University, for the preparation of this report.
Summary
GM3 synthase deficiency is a rare genetic condition that can affect several different body systems. Many individuals with this condition have symptoms of severe infantile irritability with feeding difficulties, vomiting, seizures, low muscle tone, poor vision, hearing impairment, a small head, growth failure and frequent infections. Some people with this condition may have additional symptoms, such as uncontrolled and abnormal movements, abnormal lateral curvature of the spine (scoliosis) and gastrointestinal issues. Many individuals have severe-to-profound developmental delays and intellectual disability, with few individuals meeting early developmental milestones.
The condition is rare, with more than 100 patients reported in medical literature. Many of these individuals come from Old Order Amish or La Réunion Island ancestry, but the condition has been reported in other populations as well.
GM3 synthase deficiency is an autosomal recessive condition caused by changes (variants) in both copies of the ST3GAL5 gene.
There is currently no effective treatment for GM3 synthase deficiency. Affected people should be cared for by a multidisciplinary team of specialists.
Introduction
GM3 synthase deficiency was first described as an autosomal recessive infantile-onset epilepsy syndrome associated with developmental delays and blindness in the Old Order Amish population. Since then, the condition has been reported in other populations. It has also been called “salt and pepper developmental regression syndrome” due to the skin color changes and developmental delay in individuals with the condition.
GM3 synthase deficiency is a rare genetic neurological disorder that impairs proper brain development. Individuals with this condition may experience a diverse range of physical, developmental and behavioral symptoms that affect various body systems. The symptoms can differ significantly from person to person.
Symptoms usually start within the first few weeks or months of life. These symptoms include:
As the affected babies get older the following symptoms may present:
GM3 synthase deficiency is caused by changes (variants) in both copies of the ST3GAL5 gene. The ST3GAL5 gene makes a protein called GM3 that is responsible for producing a type of protein called gangliosides, which are compounds found in the brain in high concentrations and are responsible for a variety of bodily processes, including brain development and function. Disease-causing variants in ST3GAL5 prevent the proper formation of proteins that help with ganglioside formation, which leads to abnormal brain development and causes the symptoms seen in GM3 synthase deficiency.
Inheritance of GM3 synthase deficiency inheritance is autosomal recessive. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
GM3 deficiency is very rare and, as of 2023, only about 100 patients have been reported in the medical literature in different populations. Individuals with this condition generally have normal prenatal imaging and appear normal at birth but usually develop symptoms between 2 weeks and 3 months of life. GM3 synthase deficiency is most prevalent in the Old Order Amish population of North America with an estimated carrier frequency of 1.7%. This means that 1.7% of the individuals in this population have a variant in one copy of the ST3GAL5 gene and are not affected with GM3 synthase deficiency but can pass this variant to their children. The carrier frequency for individuals in the La Réunion Island population as well as other populations is currently unknown.
Diagnosis may be suspected based on the signs and symptoms that the affected person has. The signs and symptoms vary according to the age of the person:
Laboratory tests may detect differences in the sugar compounds (i.e., O-glycans, N-glycans) that are necessary for biological function. Additionally, a fat compound (GM3 ganglioside) may be absent or present in low amounts in the blood (this blood test is only available at specialized centers).
Genetic testing that identifies disease-causing variants in both copies of the ST3GAL5 gene confirms a diagnosis of GM3 synthase deficiency.
Clinical Testing and Work-Up
Individuals diagnosed with GM3 synthase deficiency can benefit from a comprehensive evaluation, focusing on assessing their growth, behavior, development and other characteristic symptoms associated with the condition.
There are currently no treatments approved for GM3 synthase deficiency by the U.S. Food and Drug Administration (FDA). Treatment involves managing symptoms through a multidisciplinary approach. A thorough evaluation by various healthcare specialists is necessary to develop a personalized treatment plan, with the aim of enhancing function, reducing complications and improving overall quality of life. Several different specialists may be involved in a patient’s care to address specific symptoms.
A neurologist can assess concerns related to hypotonia, movement disorders and seizures.
Orthopedics, often in collaboration with physical and occupational therapy, aims to enhance gross and fine motor skills, mobility, activities of daily living, while also addressing the need for adaptive devices.
A pediatric psychiatrist and developmental pediatrician can conduct evaluations for motor, adaptive, cognitive and speech-language. They can also play a crucial role in facilitating early behavioral interventions and creating tailored education plans.
Gastrointestinal and feeding assessments involve consulting a gastroenterologist and nutritionist to evaluate and address common complications like gastroesophageal reflux disease (GERD), constipation, frequent vomiting and difficulty swallowing. Audiologic and ophthalmologic evaluations can identify hearing and vision impairments and provide any suggested treatments or adaptive devices.
Genetic counseling is recommended for individuals affected by GM3 synthase deficiency and their families. The genetic counselor can provide information about how this condition can be passed down in families, coordinate genetic testing and offer additional resources and support.
Given the rarity of GM3 synthase deficiency, participation in clinical trials is crucial in advancing our understanding of the condition and exploring the effectiveness of potential treatment options. In one such study, completed in 2018, researchers investigated the advantages of a specific diet, with the hopes that it may help alleviate symptoms. Although initial observations hinted at some short-term improvements, the long-term outcomes of the study did not appear to result in significant changes in the progression of the disease. Still, these findings provide valuable insights into GM3 synthase deficiency and continue to guide future research directions and potential treatment strategies.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/
All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Kulcsarova K, Baloghova J, Necpal J, Skorvanek M. Skin conditions and movement disorders: hiding in plain sight. Mov Disord Clin Pract. 2022;9(5):566-583. doi:10.1002/mdc3.13436
Heide S, Jacquemont ML, Cheillan D, et al. GM3 synthase deficiency in non-Amish patients. Genet Med. 2022;24(2):492-498. doi:10.1016/j.gim.2021.10.007
Wang H, Sency V, McJarrow P, et al. Oral ganglioside supplement improves growth and development in patients with ganglioside GM3 synthase deficiency. JIMD Rep. 2019;45:9-20. doi:10.1007/8904_2018_134
INTERNET
Cruz V, Xin B, Wang H. GM3 Synthase Deficiency. 2023 Jul 20. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK593237/ Accessed August 13, 2024.
Wallace SE, Gillentine MA. Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the La Réunion Island Population. 2022 Dec 8 [Updated 2023 Oct 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK587320/ Accessed August 13, 2024.
GM3 synthase deficiency. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/12059/gm3-synthase-deficiency Accessed August 13, 2024.
GM3 synthase deficiency: MedlinePlus Genetics. Last updated July 1, 2014. https://medlineplus.gov/genetics/condition/gm3-synthase-deficiency/ Accessed August 13, 2024.
GM3 synthase deficiency. Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=370933 Accessed August 13, 2024.
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