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Our multidisciplinary team of paediatric metabolic specialists at Evelina London Children’s Hospital has dramatically improved the health and prospects of two brothers from Kuwait diagnosed with Fanconi-Bickel syndrome. They successfully trialled the use of an adult diabetes medication, demonstrating for the first time that it could work in children with the syndrome.
What is Fanconi-Bickel syndrome?
Fanconi-Bickel syndrome, or GSD type XI, is a rare, metabolic genetic condition without a cure. It affects fewer than 200 people worldwide, with higher incidences in the Middle East and among blood relatives.
The syndrome is caused by a faulty gene called SLC2A2 that affects the body’s blood sugar (glucose) levels, causing them to rise after eating and fall to low-to-hypoglycaemic levels when fasting.
Fanconi-Bickel leads to leaky kidneys due to the abnormal accumulation of glycogen from glucose. The kidneys leak phosphate, sugar, protein, salts and vitamins into the urine. Insufficient calcium, vitamin D and phosphate weaken bones and muscles, leading to shorter height and severe osteoporosis.
Typical treatments for Fanconi-Bickel syndrome
The conventional treatment for Fanconi-Bickel involves regulating blood sugar and prescribing supplements to replace the lost phosphate. Unfortunately, these supplements often have adverse reactions.
Oral phosphate has a sour, metallic taste and can cause a heartburn-type burning sensation in the tummy and stomach pain. Doctors in the US prescribed effervescent phosphate tablets to Abdullah when they diagnosed Fanconi-Bickel syndrome when he was 8. He continued taking them on his return to Kuwait.
However, as is often the case, the treatment was unsuccessful. The blood levels would momentarily improve after Abdullah took the tablets, but the phosphate would immediately leak through his kidneys.
Abdullah’s mum said: “Abdullah’s blood tests became more frequent, and, after each one, doctors would increase the number of tablets until he reached 20 large effervescent phosphate tablets a day. It was difficult for him to take them as they made him feel nauseous.”
Abdullah’s younger brother, Fahad, who is 5, has the same condition. Despite being prescribed 3 tablets daily, Fahad struggled to take them due to his young age.
When Abdullah reached 16, he had severe osteoporosis and relied on a wheelchair for mobility. He couldn’t visit the bathroom unassisted. The disease also meant Abdullah was much smaller than his peers at school, affecting his mental health.
“Being gifted academically, Abdullah was disheartened even further. He’d lost all hope and would never talk about education or what he wanted to be or study in the future.”
The family begin a worldwide hunt for an answer
Abdullah transferred to an adult doctor in Kuwait when he turned 16. By now, the family were desperate to give him relief from the pain that disrupted his sleep.
However, doctors wouldn’t give Abdullah a bisphosphonate injection for his osteoporosis (to gradually increase bone density) until they’d controlled the phosphate. So, his new doctor urged the family to search abroad for alternative treatments and medical advances to improve Abdullah’s health and prevent Fahad from having the same symptoms and experiences.
After considering several options in Germany and the UK, the family chose Evelina London. The US magazine Newsweek recognises the hospital as one of the top children’s centres worldwide. It is also 1 of only 6 paediatric metabolic medicine centres in the UK, and its inherited metabolic diseases service deals with many similar metabolic disorders involving the kidneys.
Inherited metabolic service at Evelina London
The inherited metabolic service at Evelina London is one of the largest in the UK. It treats many metabolic diseases but is recognised internationally for expertise in glycogen storage, liver metabolic and neurometabolic diseases. In addition, it is uniquely placed to provide services from childhood diagnosis through adult life with a seamless transition to our adult inherited metabolic service.
Our joint work with King’s College Hospital to support metabolic patients who may benefit from liver transplantation also sets us apart.
Scientific and medical expertise suggest a solution
At this point, the family was hoping that experts at Evelina London would have a different, easier-to-take form of phosphate, as they were concerned that his younger brother Fahad would also develop the same complications that Abdullah had experienced, including bone problems.
Although no other phosphate alternative exists, Dr Helen Mundy, the clinical lead and paediatric inherited metabolic diseases consultant at Evelina London, suggested that the family try an experimental treatment.
Before Abdullah’s admission to Evelina London, a group of metabolic consultants had worked on a genetically modified mouse with a problematic gene. They found that an accumulation of glycogen in the mouse’s kidney cells caused leaky kidneys. They suggested using a medicine called Empaglifozin, which doctors use for various adult conditions, including diabetes and renal failure. The science group thought it might help to prevent glycogen accumulation and gave it to an adult over a 10-week trial.
Dr Mundy said:
“We agreed with the science of the paper and thought it was correct. Although doctors rarely give Empaglifozin to children, in 2019, we repurposed it for another rare disorder, glycogen storage disease type 1b. We also had experience in using that medicine in small children with metabolic problems with brilliant results. So, we were less nervous using it in children, even though no reports existed of using it for Fanconi-Bickel syndrome and no published results for children or adults.”
Some doctors may have hesitated to use the drug due to its side effect of lowering blood sugar, which seemed counterintuitive for patients who already had blood sugar issues. However, Dr Mundy had used it safely in children with unstable blood sugars and knew how to alter their diet to stabilise them.
To be sure, Dr Mundy asked a European consortium of metabolic consultants for their views. The Drugs and Therapeutics Committee at Evelina London reviewed the scientific evidence and agreed to the team administering Empalifozin for a different indication.
Treatment trial ends in ‘dramatic’ results
When Dr Mundy presented the family with the experimental treatment, she explained that it was being tried on Fanconi-Bickel syndrome for the first time, and she did not know how it might affect the brothers.
The boys’ mum said: “Dr Mundy asked whether we would allow this trial, and we agreed, as we were desperate and ready to try anything. She explained that the trial would occur under supervision and close monitoring.”
After admitting both boys for tests and monitoring for 5 days, the team collaborated with other specialists, including paediatric endocrinology and diabetes consultant Dr Christina Wei, consultant paediatric nephrologist Dr Nicholas Ware, and metabolic dieticians. They provided a strict meal plan to control their diet and blood sugar levels. They also gave the family a monitoring device and sent them home.
“I felt very looked after, as the doctors listened and understood me, took the time to explain things clearly and educated me on how to help my children. We started to see significant improvements.”
After stabilising their blood sugar levels, the team introduced the medicine. It was easy for the children to swallow. It came in the form of a tiny, tasteless tablet that they took twice daily (a vast improvement over the previous phosphate medication).
The team saw “quite dramatic results”, said Dr Mundy. “We stopped the phosphate medicine because it didn’t work but still managed to get the levels up to the normal range.”
The markers for bone inflammation in the blood reduced as the bone received and retained the necessary vitamins and minerals. At 16, Abdullah had already gone through puberty, so the effect on his height would be minimal, but Fahad started to grow taller.
Meanwhile, Abdullah had less pain as his bones and muscles grew stronger. He did not have to use a wheelchair continuously and began to move and walk greater distances over the 5 months of treatment. He can now go to the toilet unaided and is eating and drinking.
His mum said:
“The happiest thing for me is that Abdullah has started to dream again and think positively about the future. He dreams of playing football and driving when he’s in secondary school. He thinks about what he wants to be when he’s older. He never did before.”
Other positive side-effects
The children had always had a much-increased rate of urination and were always thirsty. When they started the medicine, urination improved as the kidney leaks improved. So, while the team monitored them for dehydration, the reverse happened – it improved.
Abdullah said: “Everything is better. I feel better. All the pain has gone. My bones are better – I can walk! Sleep used to be difficult because of the pain, but I sleep comfortably now. We advise people to come to Evelina for treatment.”
And Fahad, who was once wary of doctors, loves coming to Ocean, the space on Evelina’s ground floor where he can talk to other children and play with toys while waiting. He said: “The hospital is so nice, there’s entertainment and toys everywhere.”
Metabolic specialists working together
The siblings’ experience shows the benefits of a large multidisciplinary team of metabolic specialists who communicate with experts in different specialities and have access to excellent diagnostics.
Each part of the multidisciplinary team worked closely together, from the metabolic specialists who followed each brother throughout their journey of care to the nurses who ensured the family could deliver the team’s medical plan. Another benefit of a joined-up approach is that Abdullah could transition seamlessly at 16 from children’s to adult metabolic services at St Thomas’ Hospital.
Abdullah’s mum added: “Dr Mundy and Dr Ware are some of the most wonderful doctors. You feel you have a personal relationship with them. They take interest in the child as a whole and the amalgamation of the specialities differs from anything we’ve ever experienced back home.”
She also thanked the international team, who were more than interpreters – “they are the link between us, the doctor and the Health Office. We have experienced other hospitals in the UK, and the experience was different. The atmosphere is like a family; you don’t feel like a stranger. Thank you!”
In the future, the boys’ condition will need careful management to ensure a normal life. Although the family has not seen a metabolic doctor in Kuwait, Evelina London’s consultants want to adjust the treatment as the children grow.
