June 8, 2011 (Toronto, Ontario) — More than 60% of adult patients with galactosemia, a rare autosomal recessive metabolic disorder, have motor dysfunction — with almost a third of them having symptoms — despite long-time adherence to a galactase-restricted diet, a new study has found.

It's important to detect motor complications in these patients because they can be treated, said the study's lead author, Ignacio Rubio-Agusti, MD, who is working jointly with the Sobell Department of Motor Neuroscience and Movement Disorders and the Charles Dent Adult Metabolic Unit at the National Hospital for Neurology & Neurosurgery (NHNN), London, United Kingdom, United Kingdom.

One of the most surprising findings of the study was the relatively high prevalence of dystonia among these patients, rarely reported in previous large case series, said Dr. Rubio-Agusti.

The study results were presented here at the Movement Disorder Society 15th International Congress of Parkinson's Disease and Movement Disorders.

Toxic Effect

Patients with classic galactosemia have mutations of the GALT gene, resulting in deficient function of the enzyme responsible for metabolizing the sugar galactose. This leads to an accumulation of metabolites that has a toxic biological effect, explained Dr. Rubio-Agusti.

Dr. Ignacio Rubio-Agusti

The disorder usually presents in infancy after exposure to dietary galactose and can be fatal. Infants with the disorder are put on a galactose-restricted diet, which avoids foods containing lactose, found in dairy products but also in smaller amounts in other foods. "It's virtually impossible to eliminate galactose completely from diet, but even if you could, you wouldn't prevent exposure to galactose, which is also produced in the body, from glucose," said Dr. Rubio-Agusti.

Even with dietary restrictions, affected surviving children develop long-term complications, such as premature ovarian failure and neuropsychiatric features, including cognitive problems, learning difficulties, behavioral changes, such as withdrawn personality, and speech difficulties.

Previous large case series reported motor complications in 20% to 40% of these patients, but this research included mostly children and the motor problems were relatively poorly defined.

"For example, not all the subjects included in the studies were assessed regarding motor function, and in the largest series, patients were only assessed with a questionnaire," said Dr. Rubio-Agusti. "The exact phenotype of these complications is not well defined."

In this study, Dr. Rubio-Agusti and his colleagues aimed to assess adult patients with a long disease course. "We wanted to do a detailed description of the phenomenology. Previous studies have sometimes used generic terms such as 'clumsiness.' Is that a coordination problem? Is it pyramidal weakness?"

The investigators analyzed 42 patients (27 female) attending the adult metabolic clinic at the NHNN, all but 2 of whom had their conditions diagnosed within 2 months of birth. All patients had followed a galactase-restricted diet since diagnosis. The study population was relatively young; the median age was 27 years, and most patients were between the ages of 20 and 38 years.

The study found that 26 patients (62%) had motor complications. Of these, 21 (81%) had tremor and 14 (54%) had dystonia. Tremor and dystonia were often associated, noted Dr. Rubio-Agusti. As well, 1 patient (4%) had parkinsonism, 6 (23%) had cerebellar features, and 3 (11%) had pyramidal features.

"We were surprised at the high prevalence of dystonia, which has not been often reported in previous large case series," said Dr. Rubio-Agusti.

Neurologic and Psychiatric Features

Other neurologic features, such as speech difficulties, were present in 62% of patients with motor complications but only 12% of those with no motor complications. Psychiatric features were detected in 35% of the patients with motor complications but in none of those without motor complications.

"The fact that patients with motor dysfunction have a higher rate of other neurological and psychiatric features is telling you that there is a common pathophysiology; the same problem is affecting the brain in different areas," said Dr. Rubio-Agusti.

Another interesting finding, he said, was that the rate of premature ovarian failure was also higher in patients with motor complications (93% vs 66%). "We're wondering whether there might be a common pathophysiologic mechanism there, too."

Researchers also separated the patients into those with symptoms due to motor dysfunction (31%) and those without symptoms. They found that dystonia and tremor combined was much more common in the symptomatic group (7 vs 3). The groups also differed in the types of dystonia and tremor.

"They're quite different; for instance, you only find head tremor in the symptomatic group, and kinetic tremor is much more frequent in the symptomatic group," said Dr. Rubio-Agusti. "Features like generalized dystonia, head tremor, and kinetic tremor are more likely to result in symptoms of motor dysfunction."

About a third of patients with no symptoms had clear evidence of motor dysfunction when carefully examined, although "they didn't have any complaints in this regard, such as being shaky or clumsy," he noted. "We think that these patients might have been missed in the past because they may not have been carefully examined due to the fact that they didn't report any symptoms."

It's very important to correctly identify symptomatic patients because they often respond well to treatments such as botulinum toxin injections for head tremor and trihexyphenidyl and clonazepam for arm tremor and generalized dystonia, said Dr. Rubio-Agusti.

Diet Not Enough

The study illustrates that a restrictive diet isn't enough to prevent long-term neurologic complications in many galactosemia patients, commented Jonathan Mink, MD, professor of neurology, University of Rochester, New York, in a statement from the Movement Disorders Society.

"In galactosemia, early treatment with a galactose-restricted diet reduces the toxic burden of accumulated galactose and its metabolites but does not reverse the enzyme deficiency."

Dr. Mink added that it's unknown whether other interventions may reduce the risk for the neurologic complications in these patients.

Dr. Rubio-Agusti has disclosed no relevant financial relationships.

Movement Disorder Society (MDS) 15th International Congress of Parkinson's Disease and Movement Disorders: Abstract 166. Presented June 6, 2011.

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