"Then one day we went to a barbecue at my brother John's place," Al says. "John's son Sam is exactly the same age as Isla – they were only born an hour apart. At one stage in the afternoon, Sam looked across and said, 'Come on Isla, let's go play.' I thought, 'Wow, Isla is nowhere near that.' That's when we really began to worry."

The Donnells took Isla to a paediatrician, who did some tests and told them not to stress. His main concern was autism, but Isla wasn't on the spectrum: she looked you in the eye, she got along with other children. Yet the Donnells' concerns persisted: "It wasn't just the talking," Meg says. "When it came to toilet training, Isla just didn't get it. It took her 18 months."

By this time, Al and Meg had Jude, a little brother for Isla. They were increasingly busy. Al worked in IT for a council; Meg was a management consultant. When Isla was four, Meg sent her to kindergarten, but three days later she got a call from the director. "She told me she was worried about Isla," Meg says. "She said her speech was behind and her behaviour was immature for her age." The director suggested Meg take Isla to a diagnostic centre for kids with suspected developmental delays.

At the centre, a paediatrician and psychologist tested Isla's cognitive and motor skills. They also took samples of her blood and urine. "I remember seeing the list of things they were testing for, and I felt sick," Meg says. "There were some really serious conditions there. But the doctor said, 'Don't worry, we rarely find anything.' "

A few weeks later, Meg got a call from a social worker at the centre. Could she and Al come in for a talk? "It was the 30th of May, 2013. I'll never forget it," Meg says. They were ushered into a room; there was the social worker, a psychologist, a paediatrician, and the director of clinical services. The paediatrician, a young man with dark hair and a beard, stepped forward. Isla had a genetic disorder called Sanfilippo, he said. "It's very rare. Just one in 70,000 births."

Apart from that, the doctors told them very little. And so that night, she and Al searched for Sanfilippo online. The condition, they discovered, was a death sentence, a neurodegenerative disease with no cure and no effective treatment. Children with Sanfilippo are born healthy, and progress along normal developmental paths. Within a few years, however, a defective metabolism causes waste to build up in their brain cells, leading to sleeplessness, seizures, mental retardation and dementia, together with a loss of speech and all other bodily functions including the ability to walk, talk and swallow.

Most end up on feeding tubes, in wheelchairs. Life expectancy is between 12 and 20 years. Some die before their 10th birthday. Isla was four when she was diagnosed. By then, Jude was two. Al and Meg decided to have him tested, too. Four weeks later they got the results. He also had Sanfilippo.

One of the symptoms of Sanfilippo, particularly in children, is hyperarousal, a deliriously intense 24/7 restlessness that makes most kids their age look like Zen monks. Isla and Jude, who are now seven and five, don't so much live in their home, a modern four-bedder on Sydney's northern beaches, as ricochet through it, pinballing from surface to surface. "I've thought of putting a Fitbit on them, just to see how many steps they take in a day," Meg tells me. They are also unnervingly disinhibited: the first time I visit the Donnells, Isla greets me at the door with a hearty "Hello, boy!", before grabbing my hand and pulling me into the house.

Isla is strong and wiry, with strawberry blonde hair and skin so pale it's almost translucent. Jude has thick brown hair and big brown eyes, and a mouth full of broken teeth, thanks to a fall. (Fortunately, Sanfilippo kids have a higher than normal pain threshold.) It's late afternoon: it's been a long hot day, with Isla at the local primary school, and Jude at preschool. Most kids would be flagging at this point. Not Isla and Jude. They talk almost constantly; within the first 10 minutes, Isla has asked my name at least 20 times. This is not a memory problem, Meg explains; Isla can remember the colour of the T-shirt her cousin wore during a visit a year ago. It's just that she wants to have a conversation with me but lacks the social skills to properly engage.

The hyperactivity manifests in other ways, too, most notably at bedtime. As I soon discover, putting the kids down can take hours, and usually involves superhuman patience and some judiciously administered supplements. After dinner, Al gives each child a mouth spray of vitamin D (thought to be a soporific) and a melatonin pill. If that doesn't work, they'll try Vallergan, a sleep-inducing antihistamine. Even then, the kids might wake at three or four in the morning and come into Al and Meg's room.

"I'll take one of them back to their room and sleep there," Al says, "and Meg will stay in our bed with the other one." If they still won't stay in bed, Meg or Al has to get up and watch them, to make sure they don't do anything dangerous. Not long ago, Al discovered Isla and Jude downstairs, in the kitchen, at 4am; all the lights were on and the carving knives were out. Isla was on the counter, eating ice-cream from the tub. Jude, meanwhile, had plugged up both sinks and turned on the taps, flooding the room; water had flowed down and into the dishwasher, ruining the pump.

Sometimes, when the kids haven't slept properly for two or three weeks, they will have what Meg calls "meltdowns" – extended periods of inconsolable crying, keening or strange laughing fits. "The only thing you can do is hold them really tight, because the pressure calms them down."

Parents with Sanfilippo kids sometimes build a "safe room", where they can put their children while they do the washing or cooking, or sleep. "Al also wants to put a gate on the kitchen," Meg says. "But I'm in denial. I feel like that would be giving in. You need to pretend every now and then that you have a normal family, and you can't do that if you need to step over a gate to get into your kitchen."

After the diagnosis, doctors told the Donnells not to bother chasing cures, because there weren't any. The Sanfilippo patient population is so small – somewhere between 70 and 100 kids in Australia – that there is little incentive for drug companies to fund research. There were a few programs taking place overseas, they said, but by the time they got to market it would be too late for Isla and Jude. "I just thought, 'Fuck that,' " Meg says. Within weeks, she had quit her job and started the Sanfilippo Children's Foundation (SCF). "The idea was that if drug companies weren't going to fund research, we would."

The word "foundation" suggests a certain sophistication. In fact, Meg runs the SCF out of a small room in the old nurses' quarters of Royal Far West Hospital, in Manly. Office infrastructure is minimal: a printer, a whiteboard, and what Meg calls her "boardroom", a pine table in the corner. The real resource is people: bookkeepers, business specialists and scientific advisers, plus a tight-knit, committed cadre of family and friends.

The morning I visit the office, Meg is on the phone to one of the foundation's volunteer board members strategising about how best to approach Macquarie Bank, which has been a generous donor. Talk then turns to future fund-raisers. There is the suggestion of a golf day, but Meg is sceptical. "Golf days don't work anymore. All the men who used to play golf ride bikes now. They've all become MAMILs."

Since 2013, the foundation has raised almost $2 million, most of which has funded research in Australia, the UK, Canada and the US. But its biggest win has been in convincing the US-based biotech company Abeona Therapeutics to conduct what will hopefully be the first Sanfilippo gene therapy trial in Australia. The trial, which is still subject to regulatory approval, represents "the first real prospect of an effective treatment for Sanfilippo, together with a range of other neurodegenerative disorders," says Nicholas Smith, head of the Paediatric Neurodegenerative Diseases Research Group at the University of Adelaide, who also serves on the SCF's Scientific Advisory Board.

Gene therapy aims to replace a patient's defective gene with a healthy copy, thereby allowing the cells to function as they should. It is highly experimental: the first procedure to be fully approved was in the EU in 2013, for a condition called familial lipoprotein lipase deficiency. Researchers have been developing Abeona's Sanfilippo gene therapy technology for almost a decade; the SCF came on board three years ago. Since then, five Sanfilippo kids have died in Australia, with several more moving "beyond the cure", as some parents put it. "The process is very slow," Meg says. "It's life or death for us, but for [the researchers] it's just another trial."

Without the foundation, it's unlikely the trial ever would have come here. Yet not everyone has been supportive. Some Sanfilippo parents initially objected to Meg using "Sanfilippo" in the foundation's name, as she wasn't authorised to speak for all the families. She also caught flak from the broader rare genetic diseases community, elements of which regarded her focus on Sanfilippo as "too exclusive"; other groups feared Meg might poach their funding. Then there was the metabolic specialist who told Meg it was "unethical" to start a foundation, since other parents might feel pressured to donate.

From the start, media has been a large part of the foundation's strategy. The Donnells have appeared on television and in magazines and newspapers, often with Jude and Isla. This has also made Meg a target. "We've been called media whores," she says. After appearing on 60 Minutes in 2014, the Donnells were accused on social media of only being interested in saving their own kids.

"I felt bad for Meg," one Sanfilippo parent tells me. "She was treated very badly." Meg still "hates" doing media. "It never gets any easier. You feel so exposed and conflicted. You have to pull on the heartstrings, you have to make the condition real for people. But as a mother I have to be aware that there's a fine line between making people care and exploitation."

To have a kid with Sanfilippo is to test the outermost limits of hope. Hope of a cure, hope of a treatment … hope that your kid doesn't have it. When Isla first got tested, it was difficult to get a urine sample: Meg had to let her run around on the grass at home until she went, then catch the urine in a container. "When we were waiting for the second round of tests to confirm the diagnosis, I remember holding onto the thin hope that maybe something like a grasshopper had jumped into the sample and tainted it. That's how desperate I was."

Lots of kids with Sanfilippo have digestion problems. The Donnells therefore maintain the healthiest diet possible – minimal gluten, sugar and processed food (they bake their own bread) – topped up by a panoply of doctor-recommended vitamins and minerals, including zinc, magnesium, cod liver oil, vitamin D, folinic acid and the antioxidant CoQ10.

There are also the endless rounds of therapy – speech therapy, behavioural therapy, occupational therapy – the cost of which Meg estimates at about $20,000 a year. The main goal is to build skills, such as speaking clearly, and concentrating, that will help the kids cope better with school. (Isla has been at school for two years now; she has a full-time teacher's aide to assist her in class; Jude will start this year.)

School has, however, been a mixed blessing. It gives Meg and Al time to do chores, and to go to work, the benefits of which are psychological as much as financial. ("It's so crazy at home that I go to work for a break," Al says.) But it also reminds them of everything they have lost and will lose. "I used to get jealous a lot," Meg tells me. "Seeing other kids doing stuff ours can't. You'd see girls playing clapping games in the playground, and Isla can't do that. She wouldn't understand why they're doing it. Then I'd go into her classroom and see stories the other kids had written, but Isla can't even write her name."

Playdates and sleepovers are out of the question; the kids have to be watched all the time. Besides, Jude might decide to trash their kitchen, or tear a cupboard off the wall, as he recently did at his grandmother's house. Occasionally they get carers for the kids, but this, too, can be fraught. A while back they had a woman who spent one afternoon with the kids and never came back. Sometimes the carers don't show up at all. Jude bit another one: she had to get a tetanus shot.

Perhaps their most reliable companion is Remy, a black Labrador that failed his guide dog course and got passed on to the Donnells. "Remy loves Jude because he's always dropping his food," Al says. Sometimes, when Jude can't get to sleep, Al brings Remy in to sit by his bedside.

At the moment, Meg and Al have three hours of respite a week. In order to get more, they would have to sign a letter saying that the kids were at risk of abuse or neglect, something Meg is not prepared to do. "When I tell the caseworkers that, they say, 'Embellish.' "

If anything, it's Al and Meg who are at risk of neglect. You get the feeling they have been so tired for so long that they no longer feel tired. They can't remember the last time they had a proper conversation, or slept through the night, or stayed in bed and read the papers or, for that matter, had sex. Their marriage is hanging by a thread. This is what Sanfilippo does; it wrecks relationships, and scours people out, making them strangers to themselves. Meg tells me about a mother whose son required a feeding tube, and "how she held off having it put in because she was worried it would prolong his life unnecessarily".

Al doesn't cry anymore, "or not the howling I used to do". Meg is different. Sometimes she breaks down. She'll yell at the kids, she'll yell at Al. She'll swear she can't do it anymore, go into her room, slam the door and cry under the sheets. Then, after a time, she'll come back out and carry on.

It's dinnertime in the Donnell house. Al is in the kitchen, Isla is on the couch. Meg and Jude sit side by side, flicking through a picture book. Hallelujah, by Leonard Cohen, is playing on the iPad. "It's Isla's favourite song," Meg tells me.

Love is not a victory march, Cohen sings, as if the Donnells didn't already know.

Jude soon tires of the book, and slams it shut. "DON'T WANT IT!" he yells.

A moment later, he turns to Meg. "Mumma, I love you." "I love you too, handsome." "Kiss?" he says.

He leans toward Meg. Meg leans toward him. They meet in the middle. It's just a kiss. A tiny victory, a muted Hallelujah.

Stuck to a wall in the foundation's office is what Meg calls her "research map", a diagram showing all the Sanfilippo-related research programs going on worldwide. There are only about 20 of them. "If it was cancer, there would be thousands," she says.

Among the potential treatments, which include stem cell therapy and enzyme replacement, gene therapy is thought to be the most promising. But clinical trials are rare: Abeona's is the only one currently underway, with another three expected to begin in the next two years. Every trial represents an urgent hope for Sanfilippo parents, who have been known to search the world chasing spots for their children. There is a catch, however. Once a child with Sanfilippo has participated in one trial, he or she cannot take part in another, since investigators wouldn't know what benefits, if any, are attributable to which therapy.

"You only get one shot," Meg says, "so you have to be tactical in choosing which trial you apply for. Do you go for an enzyme replacement trial now, or wait and hope you get into a gene therapy one that might happen in a year or two?"

Getting it wrong has dire consequences. In 2014, the US-based Shire Pharmaceuticals began trialling a new enzyme replacement therapy for Sanfilippo. Every fortnight for two years, 21 children between the ages of one and four had the enzyme injected directly into their spinal fluid. In August 2016, however, investigators announced that the treatment had failed to slow cognitive decline and closed it, leaving the children ineligible for other trials. "The families were devastated," Meg says.

It's not known how many children will be involved in the Abeona trial, nor whether Isla and Jude will be among them. Even if they are, the best Meg and Al can hope for is to "freeze" the disease's progression, since reversing the damage is impossible. "There's also a chance that the trial has no effect at all," she says. "Or that they cancel it, like Shire did. You just never know."

For parents already wrestling with life-anddeath decisions, the vagaries can be maddening. "If you were diagnosed 10 years ago, you just had to get on with your life," Meg says. "Now there are these trials, which is great, but it also means you have this hope hanging over your head all the time."

One day, I ask Al if he has ever seen a psychiatrist. No, he says. After the diagnosis, his boss offered him counselling sessions. "I went along, but the counsellor was dumbfounded. She said: 'Whoa! I thought you were going to tell me your marriage was breaking up, not that your kids were dying.' "

We're in the supermarket. Al has deposited Isla and Jude in the trolley, so they can't escape. Afterwards, we drive past Manly wharf, so Jude can watch the ferries. Then it's up to the old St Patrick's Seminary at North Head. The building is massive, all weathered sandstone, with turrets and spires. It was converted into a business and hospitality college long ago, but to Isla it's a castle. Out the front, near the entrance, there's a statue of a young woman, a graduate, brandishing a diploma. This is the princess who lives in the castle. Isla and Jude don't know they're dying. Meg and Al haven't told them. What would be the point?

That night, they play their favourite game. It's simple: Jude and Isla race Remy along the upstairs hallway, and into the bedroom at the end. Al holds onto the dog to give the kids a head-start. Then he lets him go, and he bounds down, herding Isla and Jude into the room.

I can't see them now, the bedroom is dark, but I can hear their laughter. They're screaming with joy now, as loud as always. It's a beautiful sound, and it fills the house.