GM3 Synthase Deficiency

GM3 Synthase Deficiency

Overview

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.

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.

Symptoms

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:

Irritability with inconsolable crying

Feeding difficulties and episodes of vomiting (emesis), preventing typical growth and development

Poor muscle tone (hypotonia)

Acquired microcephaly, meaning that the baby’s head was a normal size at birth but did not grow appropriately over time

Vision and hearing problems at birth, with most failing newborn hearing screening

As the affected babies get older the following symptoms may present:

Frequent seizures in infancy with many patients developing an epileptic disorder

Seizures worsen over time

Multiple types of seizures are possible, including epileptic myoclonic jerks, focal motor seizures and infantile spasms

Seizures tend to not be fully controlled by anti-seizure medication (refractory seizures)

Movement disorders that cause the muscles to contract involuntarily (dystonia) or move involuntarily (hyperkinetic movements)

Severe developmental delays and intellectual disabilities due to limited brain development, more evident as the children get older

Many cannot sit up without support, stand, or walk, and many do not develop language skills

Vision and hearing problems (when not present at birth) or worsening of these problems as the affected children get older

Hearing impairment is caused by damage to the inner ear (sensorineural hearing loss)

Changes in the coloring of the skin (pigmentation), including dark spots (hyperpigmentation) and light patches (hypopigmentation) on the arms, legs and face

Skin changes are not typically seen at birth and develop later, and they might become less apparent as an individual ages

Recurrent infections, most commonly ear infections and respiratory infections like pneumonia (however, the immune system seems normal)

Gastroesophageal reflux (GERD)

Constipation

Scoliosis later in life

Causes

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.

Affected populations

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.

Disorders with Similar Symptoms

Symptoms of GM3 synthase deficiency overlap with the following disorders. Comparisons may be useful for a differential diagnosis:

Congenital disorders of glycosylation has symptoms that include seizures, poor muscle tone (hypotonia), developmental delay, growth issues, hearing impairment and vision issues (e.g., optic nerve damage).

Infantile epileptic spasms syndrome (IESS) has symptoms that include seizures in infants (infantile spasms) and loss of developmental milestones previously acquired (developmental regression) or no progress toward the next developmental milestone (developmental stagnation).

Pitt-Hopkins-like syndrome 1 (PTHSL1) is also seen in the Old Order Amish population and has symptoms that include seizures and developmental delay.

Fragile X syndrome has symptoms that include developmental delay and intellectual disability.

Rett syndrome has symptoms that include developmental delay and seizures. 

SAMHD1-related Aicardi-Goutières syndrome (AGS) is also seen in the Old Order Amish population and has symptoms that include smaller than expected head size (microcephaly), seizures, feeding difficulties, poor muscle tone (hypotonia) during the newborn period and irritability.

Developmental and epileptic damage to the brain (encephalopathy) can result in seizures, vision difficulties, poor muscle tone (hypotonia) and involuntary muscle contractions (dystonia).

Diagnosis

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:

Early signs and symptoms: Signs and symptoms of GM3 synthase deficiency generally begin during infancy and can include severe irritability, seizures, developmental delay, vision issues, poor muscle tone (hypotonia), smaller than expected head size (microcephaly) and feeding difficulties.

Late signs and symptoms: Signs and symptoms tend to evolve from infancy and become more noticeable as the individual develops. Signs include severe developmental delay and intellectual disability, involuntary muscle contractions (dystonia) and increased muscle tone (spasticity), abnormal curvature of the spine (scoliosis), epilepsy or recurrent seizures that are poorly controlled with medications, vision loss, changes to the color of the skin (pigmentation) and difficulties growing or gaining weight (failure to thrive).

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.

Standard Therapies

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.

Type of Doctor Department : A geneticist or pediatric neurologist