Two siblings diagnosed in Singapore with world's first known cases of Jamuar Syndrome

·Senior Reporter
·6-min read
From left to right: Anand Menezes, Atira, Seana and Suman Menezes. (PHOTO: courtesy of the family via KKH)
From left to right: Anand Menezes, Atira, Seana and Suman Menezes. (PHOTO: courtesy of the family via KKH)

SINGAPORE — It was in 2003 when the Menezes family welcomed their first child Atira – or “prayer” in Hebrew – into the world.

For the first three months, the baby girl’s developmental milestones were nothing out of the ordinary and she could roll over easily.

However, at about six months old, Atira was unable to sit up - the first sign that something was not quite right with her.

“That was when we realised that something was amiss,” said her mother Suman, 42, a former psychiatric counsellor turned homemaker, during a Zoom conference on Tuesday (28 July).

“We took her to her local pediatrician who advised us to wait and watch but also to start off physiotherapy, which we did.”

The discovery of Atira’s initial condition was to eventually lead to the diagnosis of a syndrome linked to a rare protein-linked genetic mutation for the first time in the world.

Two-and-a-half years later, Atira had her first seizure. She remained on anti-seizure medication till the age of five, the same year she started walking.

When Suman became pregnant with her second daughter Seana, she and her husband Anand, 47, remained positive that the child – whose name means “gift of God” in Welsh – would hit the normal developmental milestones.

In 2011, the Menezes family marked two major milestones in their lives: Suman gave birth to Seana and a few months later, they uprooted themselves from India to Singapore when Anand was offered a job here in the information technology sector.

It was a few months into their stay in Singapore that Suman observed that Seana, like her elder sister, began to exhibit similar traits – encountering the first of several prolonged seizures before turning four.

While the siblings’ condition remained a mystery, the family’s first step towards finding the truth started in 2015 when they were referred to Dr Saumya Jamuar, a senior consultant in genetics service at the KK Women’s and Children’s Hospital, and his team.

Dr Jamuar, who is also the head of SingHealth Duke-NUS Genomic Medicine Centre, had asked the family if they would like to enrol their children in the BRIDGES (Bringing Research Innovations for the Diagnosis of Genetic diseases in Singapore) programme, which uses advanced genomic technologies and computation tools to look into undiagnosed diseases of young children.

Since 2014, the programme have recruited over 470 families and made the diagnosis from about 120 families.

After some discussion, the couple decided to participate in the programme.

“It was close to three years that this whole study took place. We (and the children) were called in multiple times to provide blood (and skin tissue) samples,” Anand said.

While both siblings exhibited symptoms like an unsteady gait, speech impairment, and epilepsy, no specific abnormalities came up in their magnetic resonance imaging (MRI) scans. They also tested negative for Angelman syndrome, a genetic disorder that mainly affects the nervous system of individuals with similar symptoms.

Then in late 2018, a team of clinicians and researchers from the KKH and the Agency for Science, Technology and Research’s (A*STAR) Institute of Medical Biology (IMB) gave the family the answer they were looking for: an official diagnosis.

Both Atira and Seana were eventually the first in the world to be diagnosed with Jamuar Syndrome – named after the doctor whom they were referred to – caused by a mutation in a protein-coding gene called the UGDH (UDP-Glucose 6-Dehydrogenase).

The unique genetic variant Ala82Thr shared by the sisters, and also present in one of their parents, has never been associated with a human disease before.

“The probability of a set of parents such as in the Menezes’ case, who each have one healthy UGDH gene and one UGDH gene-with-variant, having a child with Jamuar Syndrome is 25 per cent,” said Dr Jamuar. No one in their extended families has the syndrome.

Dr Saumya Jamuar, a senior consultant in genetics service at the KK Women’s and Children’s Hospital and the head of SingHealth Duke-NUS Genomic Medicine Centre. (PHOTO: KKH)
Dr Saumya Jamuar, a senior consultant in genetics service at the KK Women’s and Children’s Hospital and the head of SingHealth Duke-NUS Genomic Medicine Centre. (PHOTO: KKH)

Working towards effective treatment

About half of over 7,000 known rare diseases, such as Jamuar Syndrome, affect children, and 30 per cent of these affected children die by the age of five.

These represent significant numbers from the healthcare perspective and is a challenge for a patient undergoing diagnosis over a period of time, said Dr Jamuar.

“These patients, because of the symptoms, are often not recognised, and on average see eight physicians, have two to three misdiagnosis and take an average of 7.6 years before they get the correct diagnosis,” he noted.

Apart from the Menezes siblings, children from 18 other families across the world, in countries like the Netherlands, the US, Italy, Ukraine, and Saudi Arabia, were found to carry mutations in the same UGDH gene. Another UGDH mutation Arg317Gln was found in 11 children with epileptic encephalopathy in Saudi Arabia.

The team’s findings, published in peer-reviewed open access scientific journal Nature Communications in January, indicate that the mutations are likely to be a frequent cause of recessive epileptic encephalopathy, which is characterised by epileptic seizures, and speech and developmental delays of varying severity.

“As there are multiple heterogeneous causes of these symptoms, some of which may be genetic, it is best for the child to be brought to a paediatrician or a physician who can assess the child first, to confirm the delay. And if delay is present, to quantify the degree of delay and take note of other symptoms. If appropriate, genetic testing for a set of overlapping genetic conditions (including Jamuar syndrome) can be performed in these children,” said Dr Jamuar.

With the discovery, doctors can now focus on finding treatments that are best suited for the Menezes siblings and manage their symptoms based on the underlying diagnosis, he added.

Both sisters continue to receive therapy and are currently on anti-epileptic treatment. They have been given a higher dose of vitamin C as the enzyme is dependent on it, but there was no effect, said Dr Jamuar.

“We now know where to look for in terms...of designing strategies for treatment,” he pointed out.

The sisters, now 16 and nine, are currently attending Divinity Kindergarten where they receive physiotherapy as well as occupational and speech therapies. Currently, Atira is nonverbal, while Seana is able to speak words and occasional sentences.

The news of an official diagnosis has brought comfort to both Suman and Anand, who are Christians, even if treatment options are limited at this early stage. They remain hopeful and do not plan to have a third child as the sisters are “a handful”, said Suman jokingly.

“As human beings, we do (question) why this has happened to us but we have come to a point where we understand that we know that God has a purpose and plan for all of us,” the Singapore resident added.

“Yet, we feel that this diagnosis – our children's diagnosis – can benefit the world in some way.”

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