Introduction:
The lysosome is a cell organelle responsible for breaking down carbohydrates, proteins, and lipids, with the help of enzymes. A lysosomal storage disorder is characterized by the lack of these enzymes, which leads to the inability of lysosomes to break down products. Thereby, excess toxins get accumulate in various organs of the body resulting in their damage. This article reviews the inherited lysosomal storage disorder - GM1 gangliosidosis, its causes, characteristic features, diagnosis, and management.
What Is Adult GM1 Gangliosidosis?
Adult GM1 gangliosidosis is a type of lysosomal storage disorder that causes the destruction of the nerve cells in the brain and spinal cord. It is an inherited disorder also known as Beta-galactosidase-1 (GLB1) deficiency.
What Are the Subtypes of GM1 Gangliosidosis?
According to the onset of symptoms at a different age, GM1 gangliosidosis is classified into three subtypes as follows:
1) Type 1 (Infantile) - The symptoms usually begin at six months. The infant may appear normal but gradually shows symptoms of developmental delay and weakening of muscles.
The other signs and symptoms include -
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Loss of acquired skills.
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Sudden exaggerated response to loud noise.
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Intellectual disability.
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Corneal clouding.
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Loss of vision.
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Facial abnormalities, along with a typical feature called cherry-red spot in the eye.
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Hepatosplenomegaly (enlarged liver and spleen).
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It becomes difficult for the infant to survive long.
2) Type 2 (Late Infantile or Juvenile) - The symptoms may arise at 18 months or five years. This form progresses slowly, but the affected children may not have features like cherry-red spots and facial abnormalities. However, it dramatically affects survival.
3) Type 3 (Adult form) is a chronic form, and the symptoms may appear during the teenage years. The life expectancy and characteristic features vary from one to another.
How Is Adult GM1 Gangliosidosis Caused?
The leading cause of all inherited disorders is the mutation (change) in specific genes. Likewise, a particular change in the GLB1 gene results in adult GM1 ganglioside. The GLB1 gene provides the basic instructions for producing an enzyme called beta-galactosidase (β-galactosidase). It is located in the lysosome, responsible for breaking down and recycling different molecules and compounds like GM1 ganglioside. In addition, the brain requires GM1 ganglioside to carry on normal function.
Therefore, due to the lack of beta-galactosidase activity, the compound called GM1 ganglioside is not broken down and thus accumulates in the nerve cells (neurons) of the brain and other organs. It results in the arousal of various signs and symptoms, and their severity depends on the enzyme activity. If there is reduced activity of beta-galactosidase, the symptoms are severe; when the enzyme activity is high, the symptoms may be mild.
What Are the Clinical Features of Adult GM1 Gangliosidosis?
As mentioned above, the symptoms may differ from one person to another based on the enzyme activity.
The typical features are listed down:
1) Neurological Abnormalities -
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Seizure.
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Ataxia: The cerebellum of the brain controls various muscle movements, coordination, and balance. In GM1 gangliosidosis, the excess accumulation of GM1 ganglioside in the cerebellum's nerve cells leads to its dysfunction. As a result, the affected individual may have poor muscle control and balance.
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Dementia: Loss of thinking ability and memory.
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Generalized dystonia: Repetitive twitching or contractions of almost all muscle groups in the body. Muscle contractions occur involuntarily.
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Disturbances in speech and swallowing: Due to the damage of nerve cells, speech, the ability to pronounce, and the act of swallowing are all disturbed.
2) Skeletal Abnormalities -
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Joint stiffness.
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Brachydactyly (short fingers and toes).
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Kyphoscoliosis (abnormal curvature of the spine in the side-to-side direction).
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Short stature - The structure of the long bones is significantly affected, resulting in short stature.
3) Facial Abnormalities -
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Macroglossia - The tongue appears big in width and length.
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Mandibular prognathism - The low jaw may protrude forward from its normal position.
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Frontal bossing.
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Large and low-set ears.
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Long philtrum.
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Gingival enlargement or hypertrophy.
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Broad nasal tip.
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Depressed nasal bridge.
4) Eye Abnormalities - The adult form of GM1 gangliosidosis does not possess the typical cherry-red spots in the eyes. Other features like corneal clouding and optic atrophy may be present.
5) Other Features -
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Hepatosplenomegaly.
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Inguinal hernia - Bulging of intestines into the abdomen.
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Dermal melanocytosis (flat, blue-color birthmark may be present).
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Angiokeratoma corporis diffusum is characterized by reddish skin lesions all over the body.
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Coarse skin.
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Hirsutism
How Is Adult GM1 Gangliosidosis Diagnosed?
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Physical Examination - The doctor may look for the characteristic features of GM1 gangliosidosis; they may also enquire about the age of onset of such symptoms to differentiate it from other genetic disorders.
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Magnetic Resonance Imaging (MRI) - The MRI of the brain is an essential tool in diagnosing adult GM1 gangliosidosis. The imaging may show features like cortical atrophy and loss of neuronal cells.
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Molecular Genetic Testing - The mutation in specific genes is detected using genetic testing. The defect in the GLB1 gene denotes lysosomal disorder (GM1 gangliosidosis).
What Are the Related Disorders?
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Wilson Disease - A rare genetic disorder characterized by the excess build-up of copper in the liver, brain, and other body organs. It causes muscle stiffness, brownish discoloration eyes, fatigue, abdominal pain, and disturbances in speech and swallowing. Medications and surgery may aid in managing Wilson's disease.
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Huntington's Disease - Another inherited disorder that occurs as a result of a defect in a specific gene. The brain's nerve cells are extensively damaged, leading to cognitive and psychiatric disorders. The characteristic features include repetitive jerking, muscle contractions, impaired gait, insomnia, etc.
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Leigh Disease - A rare neurological disorder that affects infants and may progress to adulthood. The infants may have poor suckling ability, increased crying, vomiting, seizures, irritability, etc. The doctor may provide supportive care to manage such symptoms.
Can Adult GM1 Gangliosidosis Be Treated?
Until now, no specific medications or procedures have been found to treat adult GM1 gangliosidosis. However, the doctor may provide speech therapy, medications to control seizures, physical therapy, and diet management that provides symptomatic relief.
The treatments under investigation include:
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Gene therapy.
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Enzyme replacement therapy.
Conclusion:
The adult form of GM1 gangliosidosis is a rare lysosomal disorder. It significantly impacts the patient’s life expectancy. In addition, the quality of life is impaired due to various skeletal abnormalities. Therefore, even though the disease is not preventable, the doctor may help provide the necessary treatment. In addition, excellent knowledge of the healthcare specialist is essential for identifying such disorders and providing the required support to the patient and the family.
