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Marriage within the family is fairly commonplace in many southern states, even though doctors always advise against such practice. Consanguineous marriage is discouraged due to risks of having a child with a rare and deadly genetic disorder, for which there is no cure. Batten Disease is one such ailment.
Named after a British paediatrician who first described it in 1903, Batten Disease is the most common form of a group of disorders called Neuronal Ceroid Lipofuscinoses (NCL), found regularly (1 in 12,500 births) in kids with neurodegenerative disorders. The two most lethal NCLs are congenital NCL and infantile NCL, both of which have no cure.
INCL or a severe form of Batten Disease is rare (worldwide prevalence is one in more than 1,00,000 births) and fatal. Children affected with this disease are normal at birth, but by 11-18 months, they manifest psycho-motor deterioration. By two they are completely blind and when they turn four, they manifest no brain activity. These children remain in a vegetative state for several more years before eventual death.
Affected children suffer mental impairment, worsening seizures and progressive loss of sight and motor skills. Eventually, children with Batten disease become blind, bedridden, unable to communicate and ultimately die. The forms of NCL are classified by age of onset and have the same basic cause, progression and outcome but are all genetically different, meaning each form is the result of a different gene.
“We provide symptomatic treatments to control jerks and seizures and counsel the parents,” says neurologist Uday Muthane, medical director of Parkinson’s Ageing Research Foundation in Bangalore. Even though there is no epidemiological data on its prevalence, considering India’s vast population base, there would be thousands of such patients in India, who have little option than to suffer silently.
“These grim facts underscore the urgent need for developing a therapy, which is currently lacking,” says Anil Mukherjee, a scientist at the National Institutes of Health, Bethesda, Maryland who conducts researches on the disease.
Chemical cure
Mukherjee and his colleagues from NIH have found an existing chemical known as NtBuHA – a hydroxylamine derivative called N-(tert-Butyl) hydroxylamine – that can tackle Batten Disease in animal studies. It opens up a new window to find out a treatment for a disease, for which there is no cure. INCL is caused by mutations in a gene called PPT1 that releases an enzyme of the same name. Children with infantile Batten disease have a genetic deficiency of an enzyme, PPT1 (palmitoyl-protein thioesterase-1). Ordinarily PPT1 breaks down ceroid, a waxy substance. Without PPT1, ceroid builds up in brain cells, and results in infantile Batten disease.
The researchers knew hydroxylamine mimics the function of the PPT1 enzyme. The compound, however, is a toxic one. After testing a panel of chemically modified hydroxylamines, they found that NtBuHA could mimic PPT1 in cultured cells from infantile Batten patients, preventing the waxy buildup, but without hyroxylamine’s toxic effects.
Next, the researchers tested NtBuHA on a strain of mice genetically modified to lack the PPT1 enzyme. They added NtBuHA to the animals’ drinking water so that it reached the animals’ brains, where it broke down and depleted the waxy deposits.
Although NtBuHA did not prevent the damage that typically occurs in the mouse form of the disease, the waxy buildup was greatly reduced in the treated mice as compared to the untreated mice. The researchers found that NtBuHA protected the neurons in the animals’ brains, slowed the deterioration in motor coordination and extended the animals’ life span.
“As there is no effective treatment for INCL, we are trying to develop an effective treatment strategy. We are currently working to collect more data to gain the approval of NtBuHA as an investigational new drug, which is required for testing this potentially new drug in a clinical trial,” Mukherjee tells Deccan Herald.
INCL is an autosomal recessive disease, which means both the mother and the father have to have a mutation in the PPT1 gene. Because it needs a defective gene from both the mother and the father who are normal for the disease to manifest in the child. It cannot be predicted that they will have an INCL child till the first affected child is born.
Promising future
The antioxidant drug is non-toxic and alleviated abnormal accumulation of proteins and consequent death found in cultured cells taken from patients with INCL. In mice carrying a PPT1 mutation, NtBuHA prevented neuronal cell loss, mitigated behavioural deterioration and increased survival rates. Critically, NtBuHA also crossed the blood-brain-barrier, making it a promising therapeutic tool for central nervous system aspects of INCL.
“For the three months of treatment period, we have not observed any adverse effects. Having said that, we may uncover that like most drugs NtBuHA also has some side effects,” he said. The findings have been reported in a recent issue of Nature Neurosciences.
“It’s a path breaking work in lysosomal disorders....in the near future, scientists might prevent accumulation of the toxic chemical and reduce severity of illness or even cure,” notes Muthane, who was formerly associated with National Institute of Mental Health and Neurosciences, Bangalore. Even though there are genetic tests, they are not available at most of the Indian cities. “After clinical symptoms, the doctors rely on skin biopsy and pathological tests for diagnosis,” says Muthane, who is not associated with the study.
The NIH team recently completed a bench-to-bedside clinical trial using two drugs. “We are currently analysing the results collected during more than 10 years,” says Mukherjee.