Disordered Metal-Metabolism: A Primary Cause of Autism?

AP 19dec00

NAPERVILLE, IL -- Researchers in Naperville, Ill., have revealed findings that may explain the cause of autism. Biochemist, William J. Walsh, Ph.D. and Physician, Anjum Usman, M.D. presented their findings this fall concerning autistic patients' abilities to metabolize metals at the 10th Annual HRI-Pfeiffer Symposium. The Health Research Institute (HRI) has examined blood, urine, and hair chemistries for 503 patients in the autism spectrum. The study population was composed of patients diagnosed with (a) classical autism, (b) Asperger's Syndrome, or (c) pervasive developmental disorder with autistic tendencies. Metal-metabolism disorders of unusually high incidence and severity were found in all three groups.

A total of 85 percent (N equals 428) exhibited severely elevated Cu/Zn ratios (see footnote at end of release) in blood, suggesting a disorder of metallothionein (MT), a short linear protein responsible for homeostasis of Cu and Zn. The severity of the Cu/Zn imbalance was far greater than that of any other population we have studied over the past 25 years. The average Cu/Zn ratio was 1.78 (N equals 428) compared to 1.15 in a normal population (N equals 87) tested over the same time frame.

An additional 6 percent of the population (N equals 30) exhibited a pyrrole disorder associated with severe zinc deficiency. These autistic pyrolurics exhibited an average urine kryptopyrrole level of 79 mcg/dl, the highest ever observed in a defined population. Severe zinc depletion can result in improper induction and functioning of MT.

The remaining study subjects (N equals 45) included patients who were taking aggressive zinc and B-6 therapy at the time of blood sampling, which could mask the presence of a Cu/Zn or pyrrole disorder. Careful analysis of the medical histories and chemistry data indicated that 499 of the 503 autistics exhibited evidence of a metal-metabolism disorder. We believe that the remaining 4 subjects may have been misdiagnosed.

Overall, more than 99 percent of the 503 autistic subjects exhibited clear evidence of a metal-metabolism disorder. This suggests that an inborn error of metal-metabolism may be a fundamental cause of autism. To examine this possibility, the expected consequences of a MT defect on child development was investigated.

In humans, the MT family is a group of four cysteine-rich metal binding proteins that are induced and regulated in response to metal toxicity, cellular stress, neuronal development, and inflammation. Examination of the primary functions of MT and recent studies of MT-knockout mice indicate that the primary consequences of MT disorders in a newborn include:

1. Abnormal Cu and Zn levels in blood and hippocampus,
2. Impaired neuronal development, especially in the first 30 months of life, which could result in incomplete maturation of the G.I. tract and brain,
3. Absence of MT's protective detoxification of Cd, Pb, Hg, and other heavy metals, resulting in greatly-increased vulnerability to these toxics, and
4. Impaired immune function.

The consequences of a MT dysfunction in a newborn are very similar to classic symptoms of autism, Aspergers syndrome, and PDD. For example, incomplete maturation of the G.I. tract could be responsible for the severe malabsorption and other digestive problems exhibited by most autistics. In another example, about 50 percent of the 503 autistic families in this study reported ``regressive autism'' in which autism symptoms appeared in a normally developing child, soon after exposure to a toxic metal. We believe that regressive autism is caused by a genetic error of metal metabolism followed by victimization by a toxic metal in the first 30 months of life. After the age of 30 months, the brain and G.I. tract may be sufficiently mature to prevent the onset of autism.

In summary, these biochemical findings suggest that an inborn error of metal metabolism (perhaps a MT disorder) may be the primary cause of autism. We are presently engaged in an experimental investigation of metal-metabolism genetics in an attempt to identify the autism gene(s).

Footnote: Serum Cu (mcg/dL) and plasma Zn (mcg/dL) levels analyzed by LabCorp and Smith-Kline-Beecham