Inborn Errors of Neurometabolism:
Not So Rare and Not So Untreatable

Inborn errors of cellular metabolism occur much more frequently than has been thought previously. To date, more than 1,000 inborn errors of metabolism (IEMs) have been identified, affecting approximately 1 in 1,000 Americans. IEMs may be rare individually, but taken collectively, they are common. They affect not just children but also adults. Many of the milder forms have been under recognized.

"All IEMs are treatable," says Marc C. Patterson, M.D., chair of the Division of Child and Adolescent Neurology and an IEM specialist at Mayo Clinic in Minnesota. Deborah L. Renaud, M.D., child neurologist and metabolic specialist who began Mayo's Neurometabolic Program, agrees. They both stress that treatment is available in all cases, whether novel, disease-modifying therapies that can affect the course of the disease or symptomatic treatments that can greatly improve quality of life for the patient and the family.

Only a handful of physicians specialize in inborn errors of neurometabolism. Two of them, Drs. Patterson and Renaud, are on the staff at Mayo Clinic in Minnesota.

The Nature of the Disorders

Today, hundreds of IEMs have had their genes sequenced and mapped and their gene mutations isolated. Together, IEMs represent deficiencies in the proteins that make a substance, break one down, store it, or move it around within a cell.

The diseases are classified into two general categories — large-molecule diseases, which affect the storage of large molecules such as lipids or glycogen, and small-molecule diseases, which affect energy metabolism, protein synthesis, the production of organic acids, and/or the urea cycle.

Neurologic Symptoms

Errors exist on a continuum of severity from benign to life-threatening. The neurologic effects of IEMs can include seizures, ataxia, muscle disease, sensory impairments, dysarthria, cataplexy, global cognitive impairment, and dementia. Patients may develop normally, but then development plateaus and rapidly deteriorates. They lose developmental milestones. This progression can occur from early childhood into adulthood.

Some patients never attain developmental milestones and succumb to illness in the first year of life. The key is variability, and diagnosis may be difficult unless the child is evaluated over a period of time.

One way to recognize a metabolic syndrome is the complexity of the neurologic symptoms such as developmental delay, with seizures, psychiatric symptoms, movement disorders, and other symptoms. Another way is to recognize the involvement of multiple organs such as the brain, heart, liver, and muscles.

Equally important, metabolic errors may not become symptomatic until mid to late adulthood. Symptoms may be subtle and slowly progressive. For example, one of Dr. Patterson's patients noted subtle problems with balance following pregnancy and a slow deterioration in neurologic function leading to diagnosis at the age of 65 years. As Dr. Patterson states, "There are quite a number of adults with undiagnosed metabolic disorders. It is not often recognized that certain IEMs can present with dementia mimicking more common disorders such as Alzheimer's disease."

Early Detection: Mayo's Biochemical Genetics Laboratory

Newborn screenings for IEMs began in 1964 with screening for phenylketonuria, a condition with neurologic consequences that is treatable through diet. Since then, approximately 50 other diseases have been added to the newborn screening panel. Dr. Renaud points out that early diagnosis can help prevent permanent neurologic damage. To do so, she adds, samples must be analyzed by a reliable, world-class laboratory.

Mayo Clinic's Biochemical Genetics Laboratory, under the codirection of Piero Rinaldo, M.D., Ph.D., does all the newborn screens for Minnesota and is a reference laboratory for biochemical genetics, analyzing fluid and tissue samples from major medical centers worldwide. Results typically provide more extensive interpretation for the clinician than do those from a clinical chemistry laboratory. Working closely with clinicians, Mayo's Clinical Biochemical Genetics team is involved in every step of evaluation, education, and treatment monitoring.

Redefining Treatment: Curative, Disease-Modifying and Symptomatic Management

Dr. Patterson emphasizes a new mindset regarding treatment of IEMs. For too long, he says, they have been approached with a degree of therapeutic nihilism. "It is a big burden of disease, but all patients are treatable. There are specific and nonspecific treatment options for every affected child and adult, making their lives better and in some cases curing the disease."

Specific Treatment
Dr. Renaud cites the example of a condition called X-linked adrenoleukodystrophy. The condition can generate adrenal insufficiency at any age, with neurologic symptoms occurring in approximately 80% of affected males and up to 50% of female carriers. There is an adult-onset form called adrenomyeloneuropathy, but for many between the ages of 3 and 10 years, the natural course of the disease is the onset of blindness, loss of all developmental skills, severe disability, and death. "We now know that bone marrow transplantation at the onset of neurologic symptoms can arrest the early-onset form of the disease. So treatment can be curative if the condition is caught early enough," states Dr. Renaud.

Bone marrow transplantation carries risks at any age, but is particularly risky in young children. To better determine if and when to intervene, Dr Renaud and colleagues have created two initiatives. The first is a disease registry to follow families in which the late-onset form has been diagnosed in one member. The second, a multi-institutional program, is developing a newborn screening test so that boys with the diagnosis at birth can be followed prospectively. Monitoring changes in neuropsychological, ophthalmologic, and MRI test results affords the greatest chance of detecting neurologic symptoms early enough to arrest the disease.

New treatment for Niemann-Pick C disease
Dr Patterson and colleagues recently evaluated a novel therapy for Niemann-Pick C disease, an inherited neurodegenerative disease caused by an intracellular lipid-trafficking defect. The disease can present at any age — from before birth to late middle age. The treatment improved or stabilized swallowing capacity, auditory acuity, and ambulation in a significant number of patients aged 12 years or older (see Lancet Neurology 2007;6:765-72). Studies of long-term outcomes are under way.

Symptomatic treatment
Dr. Renaud notes that often in small-molecule diseases, something as simple as adding a specific vitamin or changing the diet can alter disease trajectory. Dr. Patterson adds that treating seemingly unrelated physical symptoms can often improve neurologic function. For example, patients with something as correctable as constipation may experience a decrease in seizure activity and spasticity when they participate in a bowel management program.

Education is another key factor. Families may have the correct diagnosis, but not the explanation of "what having a missing piece of the chromosome means relative to symptoms like seizures," says Dr. Patterson.

Mayo's program is focused on providing all that patients and families need, including a multidisciplinary team of specialists who provide coordinated care and are involved in every step of evaluation and management.