Adrenoleukodystrophy: Mayo's multidisciplinary approach
X-linked adrenoleukodystrophy (ALD) is the most common peroxisomal disorder, affecting about 1 in 20,000 males. In ALD, the body's inability to break down very long-chain fatty acids results in the accumulation of these substances in the myelin sheath. Almost half of males with X-linked ALD develop the cerebral form of the disease, generally during childhood. Progressive white matter destruction occurs with progressive loss of developmental skills as well as spasticity and blindness.
Bone marrow transplantation can arrest progression of the cerebral form of ALD. But the procedure has significant risk and must be performed early in the disease course. New protocols for diagnosis and treatment of children with ALD, aimed at reducing side effects and improving outcomes, are available at Mayo Clinic in Rochester, Minn.
"We hope to halt the condition before the child develops significant neurological problems," says Deborah L. Renaud, M.D., co-director of the Mayo Clinic Peroxisomal Disorders Program. "We've learned that if the bone marrow transplant is done after it is apparent the child has the cerebral form of ALD but before neurological symptoms develop, we can arrest those symptoms. Within three to six months, we usually see a stabilization of the white matter on MRI."
Unfortunately, many of the children seen at Mayo have progressed too far for transplant eligibility. "These little boys present because of findings detected on an MRI or a CT scan that was done for another reason, or because the boys are experiencing symptoms," Dr. Renaud says. "These children may present in elementary school with learning difficulties and symptoms similar to attention deficit disorder. But they've never had symptoms of ADD before; they were not hyperactive toddlers."
Early diagnosis and treatment
The Mayo Clinic Peroxisomal Disorders Program offers multidisciplinary care and disease-specific stem cell transplantation for people with X-linked ALD. Patients include presymptomatic boys, boys and men with the cerebral form of ALD (leukodystrophy), and men and women with the adult-onset form of ALD (adrenomyeloneuropathy, or AMN) as well as patients with only adrenal insufficiency.
Although ALD is linked to mutations on the ABCD1 gene, the disease can present differently within the same family. "The most severe form tends to affect males between 3 and 10 years of age," Dr. Renaud notes.
At Mayo, children of family members with ALD are followed prospectively for signs of neurological symptoms. Presymptomatic boys are evaluated every six months with high-resolution 3 tesla MRI and spectroscopy.
"We believe the MRI may change at least six months before the child has symptoms," Dr. Renaud says. "With this protocol, we may be able to catch any changes in the MRI sooner, and have a better chance of getting the stem cell transplant done in a timely fashion."
Detailed neuropsychological testing to detect early changes in attention and learning also is done, along with screening for adrenal insufficiency. Symptoms related to adrenal insufficiency occur separately from neurological symptoms and may appear as early as age 3 months. "Adrenal insufficiency can be life-threatening, especially in children who can't tell you how badly they feel," Dr. Renaud says.
Aida N. Lteif, M.D., chair of Pediatric Endocrinology and Metabolism, is an expert in adrenal insufficiency and a critical part of Mayo's multidisciplinary treatment team. Other clinicians include neurologists, neuroradiologists, ophthalmologists, neuropsychologists, endocrinologists and bone marrow transplant specialists. Patients generally can see all of these specialists as needed in a single visit over several days.
Stem cell transplantation
Children who qualify for stem cell transplantation are treated according to a protocol developed by Dr. Renaud and Shakila P. Khan, M.D., co-director of the Peroxisomal Disorders Program and Mayo's principal investigator for the multi-institutional Pediatric Blood and Marrow Transplant Consortium. Dr. Renaud and Dr. Khan did an extensive literature review of bone marrow transplant protocols, many of which were designed to treat leukemia. "But in treating ALD, we're not killing a cancer. We're just trying to inject cells that produce the ALD protein," Dr. Renaud says.
The new Mayo protocol is reduced intensity, eliminating components that aren't necessary for treating ALD and that pose risks to children. Although bone marrow transplant carries risk at any age, it is particularly risky in young children. Morbidities include infection, bleeding, anemia and graft-versus-host disease. "We've worked on all the components of the protocol to make it as safe as possible," Dr. Renaud says.
Mayo's Biochemical Genetics Laboratory has developed a high-throughput version of a newborn screening test for ALD. Dr. Renaud expects the test — which could greatly facilitate early diagnosis and testing — to be validated sometime this year.
Boys with X-linked ALD can be monitored for signs of neurological disease and adrenal insufficiency, and given lifestyle guidelines. Because head injury can accelerate development of cerebral ALD, boys with ALD are advised not to play contact sports. Monitoring should be lifelong. People with Addison's disease also should be tested for ALD, and their family members screened. Notes Dr. Renaud: "You could save a life by proving that a family has ALD."
Feb. 28, 2014