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5-year-old son Zavier Cheng grins on a recent family trip to Taiwan. He has Angelman syndrome, a rare disease commonly characterized by a happy and affectionate demeanor. (Courtesy of Michael Cheng)

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A Moonshot to Cure Angelman Syndrome is Reachable. Where are the People Counting on It?

With the potential cure for a rare genetic disorder on the horizon, the race to speed up drug development calls for better sharing of regional data in Hong Kong.

Sitting in a bookstore café in Hong Kong’s Yau Ma Tei district on a cozy Sunday afternoon, Vivian Tam, a mother of two, flipped through a binder of laminated cards and photos taken with family and friends.

Attached at the corner of every page was a light blue sticker roughly the size of a dime, each containing a cartoon of an elephant wearing a red top hat. Above the hat is a unique five-digit ID. 

Her five-year-old son, Zavier, occasionally fidgeted and chirped “Mama”. His giddy demeanor is a common symptom of Angelman syndrome, a rare genetic disorder.   

Tam's binder of laminated cards and photos affixed with programmable stickers and an accompanying recording pen. They help Zavier, who is non-verbal, communicate and express his needs or feelings. (Crystal Chow for The Xylom)

The stickers are programmed to an accompanying voice labeling system, a pen-shaped device attached to a dark blue lanyard lined with colorful dinosaur figures. A recorded phrase plays each time Zavier places the pen over the corresponding sticker. The time they went on an amusement ride was assigned the number 15135. Judging by the beaming smiles on their faces, it was a good memory, or 11811. 

The device is meant to help non-verbal children communicate and express their needs or feelings. Currently, many of the recorded phrases stored in the pen’s memory are in Mandarin, as the device was gifted by another family dealing with Angelman’s they recently arranged to meet on a holiday in Taiwan.

“It’s not a very new technology,” said Tam. But she recognizes its “very good application” and intends to expand its use within the household by affixing those programmable stickers to Zavier’s toys, or even placing them at the bathroom door to teach him about daily routines. 

Tam uses an iPad app with a customizable, visually intuitive interface to teach Zavier how to communicate non-verbally. She hopes the software can be better utilized in classrooms designed for children with special needs. (Crystal Chow for The Xylom)

The Angelman Syndrome Foundation estimates that around half a million people worldwide have the disease; between 1995 and 2015, there were 55 molecularly confirmed cases in Hong Kong, less than three cases per year. Just the malfunctioning of a single UBE3A gene on chromosome 15 inherited from the mother sets into motion a chain reaction of events: developmental delays, speech impairment, movement and balance issues, and difficulties with sleeping and feeding. 

If Angelman’s patients are unicorns in the wild, then Zavier is a unicorn among unicorns: only around 10,000 to 15,000 other people like him have Angelman’s caused by paternal uniparental disomy, a rare but less severe variety where he inherited two functional but dormant chromosome 15 genes from his father, instead of one each from his parents. 

Tam believes it may be the reason he has yet to develop the early-childhood-onset seizures typical to Angelman syndrome patients caused by maternal deletion, the most common form of the disease where the gene is entirely missing from the 15th chromosome inherited from the mother.



Globally, research into the cure for Angelman Syndrome – predominantly funded and advanced by the Foundation for Angelman Syndrome Therapeutics (FAST), one of the world’s most prominent patient advocacy groups – has shown early potential. 

The condition’s monogenic nature, coupled with the prevalence of cases featuring a single healthy but “silent” copy of the UBE3A gene from the father, opens up two potential therapeutic approaches: either by replacing the impaired maternal copy with a functional one or activating the healthy but dormant paternal copy. These advances have also revealed insights applicable to drug development for other monogenetic neurodevelopmental conditions, including autism spectrum disorders, explained Allyson Berent, the Chief Science Officer at FAST. 

Although Berent has a veterinary medicine background, when her daughter was diagnosed with Angelman Syndrome, she channeled her time and biotechnology expertise into searching for a cure. Under her watch, FAST even founded a small biotherapeutics company and raised millions of philanthropic dollars dedicated to putting antisense oligonucleotide treatments that target mRNAs into human clinical trials. 

“I was under the impression it would be a few hours a week of tough times. And that’s not what happened: It's an unpaid full-time job,” Berent said. She added that another therapy in the works involves CRISPR, a gene-editing technology that has been used in everything from creating COVID-19 vaccines to treating sickle-cell disease.

While these mostly Western-led breakthroughs offer a glimmer of hope, what barriers must be overcome to ensure their eventual accessibility to families in need in Hong Kong?


 


Vivian Tam with Zavier on the family’s recent holiday in Taiwan, where they met the family of another “Angel”—a term commonly used by advocates and families of individuals with Angelman Syndrome to emphasize their happy and affectionate demeanor. (Courtesy of Michael Cheng)

Zavier was diagnosed at the age of two, considerably earlier than most Hong Kong patients: 95% of patients get diagnosed between the ages of five and seven and a half, noted two governmental researchers in a 2016 cohort study, though this delay has been considerably reduced in recent years. Despite her formal training in biomedical sciences — Tam is currently a Senior Research Assistant at the University of Hong Kong after completing a postdoctoral fellowship — it was her husband, Michael Cheng, a licensed family therapist, who first noticed their son’s developmental delays when he was just around six months old. “It was just instincts,” recalled Cheng. “My experience told me his responses were different from other children of the same age.”

“It still took us a year and a half to find out what’s wrong. Now imagine other ordinary families if they simply follow the government’s standard procedure.” 

But even so, their diagnostic journey had not been straightforward. They spent the following year navigating through various public and private medical professionals in their quest for answers. Zavier’s initial brain scan and blood tests had turned up nothing; they were once told by their pediatrician there wasn’t a problem. It wasn’t until they paid for a private parental genetic testing service in 2019 which cost around 27,000 HKD (3,450 USD) that they finally identified his condition and became eligible for subsidized services. “It still took us a year and a half to find out what’s wrong,” said Cheng. “Now imagine other ordinary families if they simply follow the government’s standard procedure.” 

The couple’s experience with prolonged diagnostic processes mirrors the broader challenges confronting families with children affected by rare diseases in Hong Kong, some of which can be attributed to the city’s shortage of clinical genetic specialists and the limited affordability of medications.

It’s not that progress hasn’t been made. Since 2021, for instance, Hong Kong has scaled up funding to support the Hong Kong Children's Hospital (HKCH) in providing more comprehensive services to rare disease patients, including genetic and genomic testing services. The Hong Kong Genome Project, which concluded its pilot phase in late 2022, has been slated to sequence 45,000-50,000 genomes in partnerships with the HKCH and the two local medical schools over the next three years, from 2023 to 2025. By doing so, the project aims to provide early, more accurate diagnoses and personalized treatments for rare disease patients, and inform research efforts and drug development.

A recurring point of contention among rare disease advocates has been the Hong Kong government’s refusal to formulate a local official definition of rare diseases. Using the fact that there is no common definition of rare diseases worldwide, government officials reiterated a case-by-case approach to rare diseases, asserting that one such definition would make it harder to “determine the patients' appropriate treatment and support solely based on the prevalence rate” at the risk of neglecting “other more important considerations”, such as the severity of the diseases.

“The point of having a definition is to establish the eligibility for patients to access subsidized medication. But there is no medication available for like 90% of these diseases anyway.”

Local experts aren’t entirely convinced that a definition is necessary either. “I think you can continue to push for it primarily as an advocacy strategy,” said Dong Dong, an Assistant Professor from the Chinese University of Hong Kong (CUHK), adding that the key issue that needs to be addressed is the availability of medication. 

“The point of having a definition is to establish the eligibility for patients to access subsidized medication,” she explained. “But there is no medication available for like 90% of these diseases anyway.” For diseases for which medication is actually available, the question then concerns affordability — which she believes can be addressed by increasing the coverage of subsidized drugs or relaxing their clinical criteria.

 

Meanwhile, some see the prospective advantages of collaboration in biomedical services as Hong Kong continues to be integrated into the Greater Bay Area. Last October, Chief Executive John Lee proposed in his Policy Address the setting up of its own drug regulatory system, resembling the U.S. Food and Drug Administration, with the aim of attracting more pharmaceutical firms to conduct research in the city. It is also said to boost the entry of Hong Kong's innovations into the region. 

“It might offer rare disease patients faster and more affordable access to drugs prescribed in mainland China,” remarked Dong, noting that Hong Kong on its own is too small and too costly to provide sufficient incentives for pharmaceuticals to carry out R&D. Roger Chung, an Associate Professor collaborating with Dong at the same school, contends that the probable outcome leans towards a patient-care model instead of importing less expensive drugs into the Hong Kong market.

Dong Dong (left) at Professor Roger Chung's (right) office at the Chinese University of Hong Kong’s School of Public Health and Primary Care. They serve advisory roles with Rare Disease Hong Kong, the city’s first patient group dedicated to advocating for and supporting individuals with rare diseases and their families. (Crystal Chow for The Xylom)

In the case of Angelman Syndrome, this could mean advocating for regulatory support to establish a rare disease patient registry. Such a registry could streamline therapy development and connect patients to clinical trials.

“...find every patient, understand where they are, so that we can identify them not by name and number, but by just region and area, age, genotype, location, and doctor - like what hospitals they go to - so that we can give that information to pharma, de-identified.”

“We align with groups in different regions that want to understand how to bring clinical trials and drug approvals to that region,” said Berent. FAST runs a “Search and Rescue initiative” in partnership with the Queensland University of Technology-hosted Global Angelman Syndrome Registry, whose mission, as Berent explained, is to “find every patient, understand where they are, so that we can identify them not by name and number, but by just region and area, age, genotype, location, and doctor - like what hospitals they go to - so that we can give that information to pharma, de-identified.”

But it is not without its challenges. “The biggest hurdle has been translation into different languages, and some countries having major concerns about patient information, particularly China,” added Berent, stressing that China or any other country that has data privacy concerns could import modules of the initiative, host the registry themselves, and then “decide how they are comfortable sharing that information with pharma”.

To convince the pharmaceuticals to progress from drug discovery to clinical trials, Berent believes that finding the patients is as crucial as getting the science right and securing the funding. And that involves understanding the regulatory environments and accounting for different cultural contexts. “What's meaningful and what's measurable in clinical trials could be different, right? What's important to a Chinese family, or somebody from Hong Kong, may be very different than what's important to me,” she explained. “If I lived in the suburbs, it might be important that my child drives, but if I live in New York City, it's just important my kid can get on the bus.”

 

For parents tending to children with Angelman Syndrome in Hong Kong, however, an arduous and prolonged journey awaits before these advances ultimately result in the approval of drugs or treatments.

Like the Chengs, Ester Fung recognizes the privilege of being able to employ a live-in foreign domestic helper — migrant workers predominantly from the Philippines and Indonesia who are recognized as “an integral part” of Hong Kong society for relieving caregiving duties for children and the elderly at a minimum wage of 4,870 HKD (623 USD). This enables both parents to sustain full-time jobs as architects while ensuring care for their child with special needs.

“The earliest I could get off work is 7 pm or 8 pm. And that doesn’t take into account the peak season,” explained Fung. “We try not to work overtime on the same day, but sometimes things get beyond your control.”

The couple’s combined income also affords them the ability to arrange weekly private physical therapy sessions for their 5-year-old daughter, who was diagnosed with the more prevalent form of Angelman Syndrome when she was one and a half years old. Their daughter exhibits symptoms more severe than Zavier’s, including sleep disruptions and feeding problems. As Fung recounted, her daughter also started experiencing seizures starting from last October.

Fung characterizes the day-to-day difficulties of caring for her daughter as an ongoing “battle” – encompassing tasks from bathing and ensuring sleep to participating in family outings. The support she receives from their helper as well as her mother-in-law does little to relieve her from the enduring stress associated with her daughter’s long-term care. 

“My greatest concern is what happens when we can no longer care for her,” lamented Fung, noting the notoriously long wait for subsidized care homes for mentally disabled adults. In 2023, data from local authorities revealed that the wait for the hostels for severely and moderately “mentally handicapped” individuals is 14.2 years and 12.8 years on average, respectively.

“My greatest concern is what happens when we can no longer care for her.”

Fung also expresses disappointment at the limited insights provided by medical specialists. “Sometimes, during the follow-up consultations, I asked our genetics doctor for more information, and they would say they don’t know much then simply advise me to contact the founder of [Hong Kong Angelman Syndrome] Foundation,” she said, referring to the local patient support group with which she has already been familiar. “But I consider these questions rather basic for a specialist – like whether there are drugs under study or entering clinical trials in other countries.”

Considering the lack of specialized knowledge locally, some experts believe that mutual learning among medical professionals in Hong Kong and mainland China could be beneficial. China currently has a significantly more extensive array of rare disease policies, including a national list covering a total of 207 rare diseases, most recently updated in September 2023– a stark contrast with Hong Kong’s rare disease database, which covers merely 30

“I can justify Hong Kong’s bias towards mainland China,” said Dong, noting that doctors may have liability concerns with using drugs only approved in mainland China but not Hong Kong, and patients may not feel physically comfortable crossing the border to receive care. “But we should be more open-minded when it comes to the field of rare diseases.” 


Tam regularly documents and posts snippets of Zavier’s everyday experiences—from his playtime with friends and family to his physical therapy sessions at school—on Facebook and Instagram under the handle “Zavier Smiles”. Tam attributes her acceptance of her son’s diagnosis and commitment towards raising awareness to her background in biomedical sciences. (Courtesy of Michael Cheng)

“This has nothing to do with politics, but simply because they have more experience than we do,” she suggested.  

In exchange, she believes, Hong Kong has much to contribute, particularly in providing a more comprehensive range of nursing and rehabilitative care services that are relatively lacking in China, and bringing a mindset that’s less grounded in hierarchy and more in gender equity.

“I can justify Hong Kong’s bias towards mainland China, but we should be more open-minded when it comes to the field of rare diseases. This has nothing to do with politics, but simply because they have more experience than we do.”

Globally, there is a growing call for better recognition of rare diseases as a public health priority. In December 2021, the United Nations General Assembly adopted a resolution ensuring more equitable, inclusive health and social policies are implemented and integrated into broader sustainable development goals. 

“Rare disease patients do require more resources,” said Chung, who also served as the founding Associate Director of the CUHK Institute of Health Equity. “They are more vulnerable, have shorter life expectancies, diminished quality of life, and lower social health status. Many of them even have to wait for years before receiving formal diagnoses.” 

The pandemic laid bare the challenges and disparities faced by rare disease patients and their caregivers, especially those from a socioeconomically disadvantaged background. A 2021 study, for instance, finds that rare disease patients were 3.4 times more likely to die from COVID-related complications compared to the general population in Hong Kong. But instead of focusing solely on the notion of “exacerbation”, Chung recommends reflecting on the issue through the lens of “amplification.” 

“We may one day encounter similar problems ourselves,” said Chung. “They are simply magnified within the experiences of this special group of individuals.”


 

This story was supported by The National Press Foundation’s Covering Rare Diseases Fellowship.

Correction (March 1st, 2024): An earlier version of the story misspelled Ester Fung's last name. We regret the error.

Correction (March 2nd, 2024): An earlier version of the story incorrectly described the mechanism of Angelman syndrome. We regret the error.

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Crystal Chow

Crystal Chow is an independent bilingual journalist from Hong Kong, primarily covering climate change, health equity, politics and culture in Asia. Her bylines include Undark Magazine, Initium Media, and Oxpeckers, where she won a Asian Environmental Journalism Award for a transational investigation into abalone smuggling from South Africa to China. Crystal holds an MSc in Global Energy and Climate Policy from SOAS, University of London.

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