GM3 Synthase Deficiency - Causes, Symptoms, and Treatment

Introduction

GM3 synthase deficiency is a rare genetic disorder of glycosylation due to abnormalities in the formation of complex ganglioside species. Gangliosides are present in glycocalyces of vertebrate nervous systems. ST3GALS gene provides instruction to an enzyme called GM3 synthase. GM3 synthase deficiency occurs with the symptoms of recurrent epilepsy and difficulties in brain development. It is caused by gene mutations in the ST3GAL5 gene. It occurs in early life within the first few weeks. Most of the time, it affects infants. The patient becomes irritable. The screening of GM3 synthase deficiency is technically challenging and not available everywhere. The treatment is available for GM3 synthetase deficiency. GM3 synthase deficiency can prevent from normal growth of the affected child. This article explains the causes, symptoms, and treatment of GM3 synthetase deficiency.

What Is GM3 Synthase Deficiency?

GM3 synthase deficiency is a rare neurological disorder in which there is an alteration in brain development. Glycocalyx is a glycosphingolipid subgroup consisting of one or more sialic acids. Glycocalyx encloses every cell in nature and functions as recognition, adhesion, and signaling. Gangliosides 9GSLs) anchor the outer membrane. They combine with sphingomyelin, cholesterol, and proteins to form functional lipids. Gangliosides comprise 1.5 % of dry brain weight and 80 % of brain matter. The healthy brain tissue manufactures the large majority of its GSLs. This process is characterized by multistep growth and modification as GSLs traffic through the tissue. Accordingly, restoring plasma gangliosides by any means will not necessarily reconstitute their proper function.

Ganglioside is responsible for nerve growth and signaling in the brain. Once the gangliosides are affected, it results in improper growth, the small size of the brain, irritability, blindness, deafness, and psychomotor arrest. The Amish population of the northeastern United States is most commonly affected by ganglioside deficiency. It is caused by the mutation (alteration in the gene structure) in the ST3GAL5 gene. The incidence of this disease is one per 1200 births. The deficiency of GM3 affects the brain and causes neurological defects.

What Causes GM3 Synthase Deficiency?

Synthetase deficiency is associated with ST3GAL5 and GM3 (glycoside) deficiency. The deficiency is associated with ST3GAL5 or B4GALMT1 gene mutations. The mutation is first identified through family-based mapping of the gene. Ganglioside extends 2 to 2.5 mm in the brain between phospholipid and protein. The function of ganglioside is to communicate with the protein layer. Ganglioside deficiency releases GRIA2-AMPA receptors that reduce their abundance, which in turn critically alters the behavior and plasticity of central excitatory synapses and could be an important mechanism of disability in the ST3GAL5 gene. However, the exact cause of the disease is not known.

What Are the Symptoms Of GM3 Synthase Deficiency?

• Developmental delay.

• Slow weight gain.

• Increased or decreased muscle tone.

• Visual detachment.

• Restless.

• Poor sleep.

• Constipation.

• Gastroesophageal reflux.

• Feeding difficulty.

• Joint dislocation.

• Some older patients were observed by characteristic patterns of skin depigmentation, referred to as salt and pepper in African American patients.

• Hearing loss.

• Poor eye movements.

• Visual impairment.

• Poor neurological development, such as short head growth and slow brain functions.

• Epileptic encephalopathy (a severe epileptic condition that developed in childhood, affecting the movement of the limbs and brain).

• Poor driving response.

• Self-injurious behavior such as banging, biting, or scratching of their limbs.

Signs:

• Chorea (a movement disorder that causes involuntary irregular and unpredictable muscle moment).

• Athetosis (a disease in which nerve impulse is uncoordinated that causes slow, involuntary, writhing movements of fingers, hands, toes, and feet.

• Hyperkinesia (excessive movement of the limbs).

• Dyskinesia (a condition in which involuntary erratic movement of different body parts such as the face, arms, legs, and neck occur), and tremor (a condition in which uncontrolled shakiness movement of hands occurs).

• Dystonia (a condition in which muscle twists and spasms occur).

• Signs of dysmyelination (defective myelin sheath which regulates signaling in the brain) and loss of body parts developed with advancing age.

• Dyssomnia (poor sleep-wake cycle).

How To Diagnose GM3 Synthase Deficiency?

Early diagnosis helps in treating the disease at an early age. If the onset of neurological deterioration is detected before, pre-symptomatic therapies can be given to treat patients symptomatically.

The following are the ways to diagnose GM3 synthetase deficiency:

• Clinical Examination - The skin patches, neurological defects, insomnia, chorea, dystonia, hearing impairments, or visual impairments confirm the GM3 synthetase deficiency.

• Electrocardiogram (ECG) - ECG monitors brain signaling and functioning. During ECG, patients with GM3 synthetase deficiency were diagnosed with epileptic seizures.

• Neuroimaging - Magnetic resonance imaging shows images of the brain. Children with GM3 deficiency have slow brain growth. Neurological changes can be depicted, and slow brain growth can be diagnosed.

• Audiological Test - The audiological test depicts the symptoms such as hearing loss or deafness.

• Ophthalmological Test- The ophthalmological test used to diagnose vision or visual impairment.

• Blood Test - The level of glycocalyx is checked in the blood plasma of the patients.

What Are the Treatment Of GM3 Synthase Deficiency?

The majority of parents found children irritable. Parents found these behaviors to be both more distressing and less treatable than seizures. The patients can be given symptomatic treatment. However, milk and diet modification can help with GM3 synthetase deficiency.

The following are the treatment options for GM3 synthetase deficiency:

• Medication- The patients with epileptic attacks were given anti-epileptic drugs such as Benzodiazepines, Phenobarbital, and Valproic acid. Less commonly used adjuncts were Lamotrigine, Topiramate, Carbamazepine, Oxcarbazepine, Levetiracetam, and Gabapentin. Benzodiazepines are given for proper sleep.

• Non-pharmacological Intervention - The children suffering from irritability and insomnia (improper sleep) should be employed with non-pharmacological intervention such as rocking, bouncing, stimulation withdrawal, bathing, and herbal remedies.

• Intake Of Buttermilk Extract - Buttermilk lipid extract is mildly enriched in gangliosides. Buttermilk is proven effective in some patients. G500 was deemed safe and easy to administer.

• Injectable GM1 - Injectable GM1 has therapeutic potential for humans with ST3GAL5 deficiency to restore gangliosides in the brain. Injectable GM1 has been developed for a few clinical applications. The injection is injected intravascularly.

• Liver Transplantation - The liver is known to synthesize and export GM3 and GD3, most of which (94 %) are associated with low-density lipoprotein (LDL); thus, liver transplantation can potentially normalize circulating gangliosides. It is successfully employed in this disease.

Conclusion

GM3 synthetase deficiency is a rare genetic disorder that affects the brain. The abundance and ubiquity of gangliosides throughout the nervous system create obstacles in treatment. Early diagnosis can be made through new advancements and technology as it facilitates the treatment of pre-symptomatic events. Other symptoms, such as irritability, can be managed through non-pharmacological intervention. The medication for insomnia and epilepsy is discussed above. The prognosis of this disease is poor, but early diagnosis and proper medical intervention can improve the quality of life.