New Zealand Organisation for Rare Disorders
PO Box 38-538,
Wellington Mail Centre
Phone: +64 4 471 2226
Charities Commission Registration CC22512
One Family's Journey with Mucolipidosis type 3
In 1987, doctors gave Nelson couple Jenny and Paul Noble a diagnosis of a rare disease, Mucolipidosis type 3, in two of their three children. They had a choice of accepting the advice to just get on with their lives as best they could, or searching for information and treatments for their children. Jenny spoke to NZORD Executive Director, John Forman, about their story. She outlined their quest for information, how this helped them get better management of the complications of ML3, and detailed dramatic recent improvements following the trial of a drug called Pamidronate.
Jenny recounts: "Hayden was born in November 1981, David in October 1983 and the youngest, Sarah in January 1986. Life was great. We had three normal, healthy children - or so we thought.
"At five years of age Hayden's growth and learning ability seemed to be behind his peers. Physiological assessments showed Hayden was functioning at a level two years behind a normal five-year-old.
"After six months in a special education kindergarten, Hayden went back to school with one-on-one help. Several months later, Hayden was again slipping behind in the classroom and playground.
"We were getting desperate to put a name to our son's problems. After describing all Hayden's difficulties to our family doctor, we found ourselves sitting in a paediatric clinic waiting to see a specialist."
"On 6 November 1987, we were given a diagnosis of Mucolipidosis Type 3 (ML3), a rare genetic disorder. Finally we had a name, but what did this mean for Hayden, and what about David and Sarah?
"Blood and urine samples were sent away for analysis. David's results came back negative, and Sarah's inconclusive. A skin biopsy confirmed that Sarah also had ML3. We were in total shock. How could this have happened to two of our children, and why us?
"We were given a two-line explanation of ML3 and told to get on with our lives. We were told as parents we would suffer more than our children, because they would never know what a normal life is like."
This was the critical decision time for the Nobles, and typical of the issues faced by so many people affected by rare diseases. Do we just accept it all and cope as best we can, or do we put energy into seeking answers and treatment?
Jenny continues their story: "We were desperate to know what life had in store for us, but there were no other families in New Zealand who had children with ML3. We contacted the MPS Society in Australia (a support group for Mucopolysaccharidosis and related diseases) and information poured in. We could start making decisions on the care that Hayden and Sarah would need.
"This was the start of much treatment and travel in the early years. Hayden and Sarah had many surgical procedures to lessen the degree of their deformity and disability.
"When Hayden was young he had his tonsils and adenoids out and two sets of grommets inserted in his ears to prevent recurring glue ear. We were told many young children have these problems, but in fact it was a warning sign of ML3. Sarah also had her adenoids removed and grommets inserted in her ears. We were learning that we needed to actively manage the children's treatment regime, to ensure it was appropriate for ML3.
"By eight years old Hayden was facing major spinal surgery to stabilise Kyphosis/Scoliosis. Before we made any decisions we travelled to America to meet with Doctor Steven Kopits an expert in the care of Little People. We were given advice on the kind of spinal surgery that Hayden should have and Doctor Kopits discovered Carpal Tunnel Syndrome in both children.
"With hope of understanding more about ML3 we travelled on to England to attend our first international conference. It was wonderful to meet other families with ML3 children and speak to Doctors about the health issues we were facing."
Dealing with problems of Carpal Tunnel Syndrome was one area where the knowledge gained by the Nobles in their search and their travels, was actually ahead of the experience of New Zealand doctors. That was not always an easy situation to manage, notes Jenny. Without realizing it at the time, they were at the forefront of similar situations where inquisitive families were becoming very well informed about the rarest and most obscure diseases, and able to give important information to local specialists.
As Jenny explains: "Arriving back in New Zealand both children were tested for Carpal Tunnel Syndrome. The results and the severity of the condition astounded doctors and operations were immediately organised. After two operations the condition improved. International experts then suggested that the children could have compression above or below the Carpal Tunnel. An investigative operation was required. After a lot of persuading on our part, the operations took place. Compression was found in the palms of both children. The operations were very successful and neither Hayden nor Sarah has needed further surgery for Carpal Tunnel Syndrome."
Jenny then outlines the many skeletal problems that both Hayden and Sarah had, and the significant deterioration in mobility that emerged for both of them. She describes Hayden's journey before Pamidronate:
"At nine years old Hayden had major surgery to stabilise the curvature of his spine, as per the advice of Doctor Kopits. Today the rods are still in his back and the whole area has remained stable, although there is continued deterioration in a limited area (L2).
"In 1996 Hayden began suffering from unexplained neck pain, which was causing headaches and chronic tiredness. An MRI scan showed an area of the spinal cord was swollen and there was no spinal fluid protecting the cord. International experts again advised us an operation was necessary, but there were delays before it took place.
"A post-operative MRI looked as though the surgery had been successful, but 15 weeks afterwards Hayden started to experience problems with his balance. Twice we were sent home after emergency trips to the hospital because they didn't understand Hayden's illness. Finally Hayden was re-admitted to hospital for extensive testing and we were told that ML3 had infiltrated the spinal cord and he was experiencing cell death of the nervous system.
"Hayden's spinal cord had swollen again and the spinal fluid was no longer around the top of the cord. After a two-week course of steroids, Hayden was able to walk with a walking frame and seemed to be making good progress. But two weeks after stopping treatment he began to fall again and was now having problems with his bowel and bladder.
"The steroids were re-started and Hayden became mobile again. This treatment continued for a year, but Hayden became more and more reliant on his wheelchair. It was decided the drugs were doing more harm than good and they were stopped. Hayden was now a paraplegic and any further surgery came with a high risk."
As many families with more than one affected child will discover, there is great anxiety in wondering if the symptoms in the first child will also present with the same severity in the second child. Jenny describes Sarah's journey before Pamidronate, but also relates how their travels and their searching brought them into contact with Professor David Sillence of Westmead Children's Hospital in Sydney, a specialist in Skeletal Dysplasia.
"Sarah was still walking at age 12, but huge changes in her hip joints were making her very unsteady on her feet. We found with both children that once puberty started the bone destruction (a secondary symptom of ML3) sped up.
"By 13, Sarah was immobile and confined to a wheelchair. In May 2000, tests at Westmead Children's Hospital showed Sarah had stopped walking because of gross destructive bone disease in her hips, pelvis and cervical spine. We were dealing with severe osteoporosis.
"While in Sydney, we discussed with Professor Sillence at great length how we should treat this condition. Because of the level of Sarah's bone disease and pain we agreed to try a drug called Pamidronate. Hayden would also trial this drug.
"Bone deterioration and chronic pain were the only symptoms for which we had been unable to find a treatment for Hayden and Sarah. We had tried many drugs for chronic pain but nothing had ever really worked. Although Pamidronate had never been tried in ML3 children before, we felt that if it reduced the pain we had nothing to lose."
Professor Sillence had experience in trialing the use of Pamidronate in children with another severe bone disease, Osteogenisis Imperfecta, commonly known as Brittle Bone disease. He'd had some remarkable success with those trials, leading to wider application of the drug to treat that condition. Similar dramatic improvement for Hayden and Sarah has led the Nobles to use the expression "our miracle drug Pamidronate."
Jenny explains: "Pamidronate is a synthetic compound that binds to bone to prevent absorption of bone by osteoclasts. Osteoclasts are bone cells, which break down bone tissue. In normally functioning bones, these cells are followed by cells called osteoblasts that lay down new tissue.
"So in effect Hayden and Sarah were destroying more bone than they were making. Using Pamidronate slows the process down and allows them to make bone by preventing the osteoclasts from destroying bone. Hayden and Sarah began treatment with Pamidronate in August 2000.
It is with obvious delight that Jenny answers her own question, "So what has Pamidronate done for Hayden and Sarah?" She rattles off a list of milestones:
"2 weeks after the first infusion Hayden and Sarah were totally pain free.
3 months after treatment Sarah got out of her wheelchair and walked with a walking frame.
4 months after treatment Sarah was up on crutches.
5 months after treatment all other drugs for pain relief were removed.
6 months after treatment the first bone biopsy showed their first increase in bone density.
7 months after treatment their blood levels were within normal/high range.
11 months after treatment Sarah was able to kneel down on the floor and cross her legs while sitting.
12 months after treatment Hayden has had a 25% bone growth on his L2 vertebrae and both young people are still pain free.
"Before Pamidronate", says Jenny, "life was stressful for everyone. We hated putting shoes and socks on Hayden, he always cried out in pain and every movement in the shower was agony for Sarah. We never went on family holidays, travelling long distances was not an option.
"Pamidronate has given us so much relief. After 12 months of treatment pain is not an issue. Hayden and Sarah can do a lot more for themselves and we hear laughter instead of tears."
For most families this would be more than enough success, but more was to come. After 20 months of Pamidronate they had completed the trial study and presented the data at the Australian MPS conference in 2002, and the International Symposium on MPS and Related Diseases & Scientific Lysosomal Storage Disorders Congress in Paris, 2002.
At both of these conferences Jenny took the stage to give a joint presentation of the trial results with Dr Grace David, a member of the professional team - a very fitting tribute to the contribution she and Paul had made to progressing the knowledge this far. Jenny spoke with such confidence about aspects of the official name for bone disease in Mucolipidosis type 3, Secondary Metabolic Bone Disease, that many would not have known she was a parent rather than a health professional.
Jenny now completes the story so far: "Hayden and Sarah have come a very long way since I began writing their story. Sarah has regained her balance and walks around the house without support. Hayden has not had chest infections since commencing Pamidronate and his quality of life has improved dramatically.
"But our greatest surprise came two days after arriving home from the Australian Conference. Hayden stated that he could stand up. I must confess we looked at him and said it was not possible but he was adamant he could stand. We got Sarah's walking frame and much to our delight we watched him stand and take four steps.
"I can't describe our emotions that day. How could this be happening? Paraplegics just don't stand up, let alone walk?
"Pamidronate is slowing down osteoclast activity in Hayden and Sarah and the bone biopsy results show their bone density is now within a normal range. "Pamidronate has brought the internal parts of the bone back into normal bone density range. We are now taking a more aggressive approach with Pamidronate to try to stop the resorption of the outer layer of bone.
"Hayden and Sarah's journey with Pamidronate has become a major medical break-through in the management of bone disease in ML3. Both Hayden and Sarah are walking and totally pain free."
But we should not expect that to be the end of the story by any means. Jenny is a remarkable woman indeed. Starting out as a typical kiwi mum from Upper Hutt with three young children, she now talks with confidence about osteoblasts, osteoclasts and periosteal resorption. She has had her name included in the list of authors when the trial results were published late in 2002 in the Journal of Inherited Metabolic Diseases, and is helping Professor Sillence and his team put together an international clinical trial for a wider group of ML3 patients. In her spare time she is taking the lead in organizing the first New Zealand Scientific and Family Conference for Lysosomal diseases, to be held in Auckland in September 2003.
In 2002, at her initiative, a meeting of Paediatric Society and Ministry of Health officials took place with her and me also present, to work on the dilemmas of transition from paediatric to adult health services, for those with chronic and complex diseases. One result of that meeting is NZORD's position statement on transition.
I'm sure we haven't heard the last of the Noble's story. Their early decision to get to know the disease and to work towards its treatment and cure, is now paying handsome dividends for them. Let's hope it continues to do so.