The July 1998 issue of Annals of Neurology, Joel Trugman et al described the use of a drug, commonly used in Parkinsonism, called Levo Dopa, in a 3 year old girl with symptoms similar to that of CP.

This girl could neither speak nor sit up or roll over on her own. The authors were able to treat the girl with an existing medicine, Levodopa (or L-dopa), that gave her the use of her muscles.

The mother had a clinical picture that was consistent with a disease called dopa-responsive dystonia. The mother's symptoms included dystonia (slow muscle spasms that can involuntarily contort the body) and muscle cramps. It was discovered that the girl's grandmother and great-grandmother also had similar symptoms. It was suspected that the child's relatives suffered from an inherited form of dystonia that responds to L-dopa therapy: hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD).

However, that girl had been given one dose of L-dopa at the age of 18 months and had suffered a strong adverse reaction to the drug, and she flopped like a fish for four days. However, the authors decided that that was a sign that she was perhaps responding to the medicine.

Despite misgivings, the mother allowed Trugman to give her daughter tiny doses of L-dopa in the hospital.

The girl tolerated the medication and the doses were gradually increased. During the following months, she began to develop simple speech and the ability to sit up and reach for things with her arms.

One of Trugman's collaborators brought a similar patient to his attention: a 17-year-old boy who had walked a bit as a small child and learned to talk almost normally, but lost these abilities by the age of six. He also had reacted adversely to L-dopa. In his family tree there were no clinical signs of dystonia, though a great-grandfather had been diagnosed with Parkinson's disease. Like the three-year-old girl, the boy improved dramatically -- regaining speech and the use of his arms and hands -- with low doses of L-dopa. Still, Trugman was unwilling to assign a diagnosis of HPD/DRD to these cases. Though they were responding to the L-dopa, both patients' symptoms had been much more severe than those usually seen in HPD/DRD. They had also included unusual symptoms like eye-rolling and they had begun at a much earlier age.

Later the same year, 1994, other researchers provided another clue, finding that mutations in the gene that produces an enzyme called GTP-cyclohydrolase I (GCH) causes HPD/DRD. Significantly, mutations in the GCH gene are also the culprit in a hereditary form of a disorder called hyperphenylalaninemia. In hyperphenylalaninemia, excessive amounts of the chemical phenylalanine in fetuses and newborns are tied to neurological problems such as severe mental retardation and movement disorders, with symptoms that include eye-rolling.

Trugman and his colleagues noted that the young girl had mild symptoms of hyperphenylalaninemia, but didn't have elevated levels of phenylalanine. Using more sophisticated biochemical tests, however, they found subtle problems with phenylalanine. When the girl later developed overt hyperphenylalaninemia, they were able to treat the condition and even accelerate her progress, with an experimental drug called tetrahydrobiopterin.

Trugman's collaborators at the Clarke Institute of Psychiatry in Toronto, Yoshiaki Furukawa, M.D., and Stephen Kish, Ph.D., then examined the DNA from these two families in search of mutations in the GCH gene. In the case of the girl, they found that the relatives with the mild form of HPD/DRD all had the same mutation in the GCH gene.

The key to the girl's disease came from the father's DNA. The researchers found that he also had a mutation of the GCH gene, though a different change to the gene and not one that had caused him any obvious neurological damage.

The girl then possessed two different defective GCH genes, one from each parent. The combined effect of the two mutant genes was to produce a disease that neither mutation could produce on its own. The boy's genetic profile was similar; he also had received two different mutant GCH genes from his parents.

Thus, a new hereditary disease had been identified, with biochemical and clinical signs intermediate between the more severe hyperphenylalaninemia and the milder HPD/DRD, but related to the same gene as these diseases. And it can be treated with existing drugs.

The more personal ending to this medical detective story is that the girl, now seven years old, is walking and talking. She wears leg braces but has normal mental function and is doing better than ever expected in school. The boy walks with braces and functions well in a regular school classroom.

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