“Sameer’s tummy was growing unusually large, and despite eating normally, he was weak and unwell,” says Ajit Yadav, father of five-year-old Sameer Kumar.
Sameer, who lives in Pasra Bazaar, Bihar, was diagnosed with a rare condition called Gaucher disease two years ago.
The rare genetic disorder is caused by an excessive accumulation of fat molecules called glucocerebroside. It is one of the leading lysosomal storage disorders observed in people and affects one in 40,000 to 60,000 individuals globally.
Although Phillipe Gaucher first identified Gaucher disease in 1882, it was not until after 1960 that American biochemist Dr Roscoe Brady and his team dug deep into the causes and came up with treatment options for the condition.
Brady’s team found that people with Gaucher lacked an enzyme in one of the cell components called lysosomes, responsible for breaking down fat molecules. As a result, the cells begin storing fat molecules.
Making it and breaking it
Regular garbage disposal is mandatory for a healthy living environment and a fracture in the system can set off a rise in diseases. Cell components called lysosomes, considered the garbage disposal units of our cells, digest cellular waste using specific enzymes.
One of the enzymes helps break down the specific fat molecule, glucocerebroside, in the lysosome. However, a mutation in the GBA gene causes a structural change in the enzyme, preventing it from reaching the lysosome. Without the enzyme, the lysosome cannot break down the fat molecule, leading to fat bulking up the lysosome and in turn, the cell.
Organs swell when their cells swell. It is usually the spleen and liver that bloat first.
“One of the first things the doctor checked was Sameer’s bloated abdomen,” says Yadav.
Studies show that over 500 different mutations can lead to Gaucher disease. However, according to the Indian Paediatrics journal, one specific mutation known as the L444P is more prevalent in the Indian population.
The genetic underpinnings
Gaucher is an autosomal recessive disorder, implying that a mutated gene is inherited from both parents. Each gene carries the code for making proteins that are the building blocks of our body; for example, enzymes are a type of protein. When the gene code is skewed, it disrupts the normal functioning of the protein, leading to a disorder.
However, if the offspring receives only a single mutated copy from either parent, the person is considered a carrier. Carriers do not have the condition but can pass it down to their future offspring.
Types and symptoms
Studies have found that there are several mutations common to different types of Gaucher and some unique to each type. As a result, the severity of Gaucher symptoms can vary and surface at different ages.
For example, type 3 Gaucher is the most common globally, seen between the age of two and early adulthood. Dr Ashwin Dalal from the Centre for DNA Fingerprinting and Diagnostics, and a member of the Gaucher Disease Task Force India, says, “Often people approach the doctor for respiratory issues like a severe cold, speech delay, bone damage and nosebleeds.”
Whereas Gaucher type 2 occurs in infants between three and six months. Seizures, poor development, and difficulty in sucking and swallowing are common symptoms. However, significant damage is seen in their central nervous system.
Gaucher type 1 is often diagnosed in adulthood with symptoms like bone damage, fatigue, abnormal bleeding and cognitive disorders.
Tackling the enzyme
When a clinician suspects the individual has Gaucher, they ask for a blood enzyme test as a first step, followed by a genetic test to confirm the condition and identify the type and mutation in the GBA gene.
Dr Dalal says genetic pre-screening is particularly useful for couples planning their family. “Consulting a clinical geneticist early on can help, especially in the case of Gaucher type 3. In addition, testing for mutations in the GBA gene can alert the family.
Enzyme replacement therapy (ERT) is the main treatment option available for Gaucher, thanks to Brady and team, who introduced it in 1990 – after thirty years of relentless efforts. Synthetic enzymes are given twice a month to supplement their lack in the body.
“We have several people with Gaucher who have been treated from childhood. One of them is an engineer now, and another has even given birth to a healthy child,” says Dr Dalal.
Despite its efficacy, ERT remains an expensive option for many.
People with Gaucher type 1 disease who are reluctant or unable to get ERT, have an alternative oral therapy known as substrate reduction therapy (SRT). It is relatively more affordable than ERT and easily administered. Dr Dalal says, “SRT works by partially blocking the production of the fat – glucocerebroside. Some Indian pharma companies are currently working to develop it for the market.”