A Hereditary, Childhood Form of Parkinsonism

Abstract and Commentary

By Sabiha Merchant, MD, and Steven Weinstein, MD. Dr. Merchant is Attending Pediatric Neurology; Director, Pediatric Epilepsy Fellowship, New York Presbyterian Hospital. Dr. Weinstein is Director of the Pediatric Comprehensive Epilepsy Program, Weill Cornell Medical College. Neither Dr. Merchant and Dr. Weinstein report any financial relationships relevant to this field of study.

Synopsis: Dopamine transporter deficiency (DAT) is a rare inherited disorder that causes a Parkinsonian syndrome in infants and young children.

Source: Kurian MA, Li Y, Zhen J, et al. Clinical and molecular characterisation of hereditary dopamine transporter deficiency syndrome: An observational cohort and experimental study. Lancet Neurol 2011;10:54-62.

Parkinsonian disorders typically present in adults but rare forms exist in early infancy. A multitude of etiologies exist and this paper describes a cohort of children with a deficiency of the dopamine transporter (DAT) due to mutations of SLC6A3. The identification of the molecular basis of this disorder has the potential to lead to specific therapeutic strategies and perhaps allelic variations to provide insight into adult onset disorders.

An international multicenter study was performed to characterize the clinical and molecular characteristics in 11 children with hereditary dopamine transporter deficiency syndrome (DAT). Patients were identified from seven pediatric neurology centers, movement disorder and neurotransmitter specialists, laboratories performing CSF neurotransmitter analysis, and a review of published cases in PubMed.

Patients presented between 0.5 and 7 months of age with Parkinsonism, hyperkinesia, or a combination. Video movies of the children created by the parents and the clinics were reviewed independently by three neurologists. The history was reviewed to identify any risk for intrauterine and perinatal injury (cerebral palsy), and, although the results were not provided, an evaluation was performed to exclude a metabolic basis for the neurological findings—assessment for a mitochondrial disorder, MRI search for iron accumulation, and measurement of CSF neurotransmitters to exclude a biosynthesis defect. An elevated ratio of homovanillic acid to 5-hydroxyindoleactic was suggestive of DAT and prompted further genetic evaluation for SLC6A3 mutations.

The clinical phenotype was an early infancy presentation with irritability, feeding difficulty, and movement disorders. All children had generalized dystonia within one year of clinical presentation. As the disease progressed, axial hypotonia and pyramidal tract features became more obvious. By age 3 years, all had pyramidal tract findings and severe gross motor delay. Basal ganglia, as visualized on MRI, had no gross structural defects or signal abnormalities. GI motor deficits, sleeping difficulties, pneumonias, and orthopedic complications developed. Features of DAT were almost indistinguishable from patients who had defects of dopamine biosynthesis, but may be suggested by the high incidence of dystonic crises in DAT. Cognitive impairment was mild and speech delays were thought to be due primarily to the motor difficulties. Death occurred in 4 of 5 children who survived to age 9 due to respiratory complications and cardiac failure.

Evaluation of CSF neurotransmitters was the most sensitive indicator of the disorder that prompted genetic analysis. An elevated homovanillic acid to 5-hydroxyindoleactic ratio distinguished DAT from synthesis defects in which both levels were low. Mutations in the autosomal recessive gene SLC6A3 were found in each case leading to defective trafficking of dopamine reuptake into the presynaptic neuron resulting in cerebral dopamine deficiency. It is postulated that dopamine accumulates extraneuronally, resulting in dopamine degradation. Serotonin biosynthetic pathways were unaffected.

Therapeutic interventions that had little of no efficacy, including muscle relaxants, dopamine agonists, anticholinergics, antiglutaminergics, GABA agents, and deep brain stimulation in one child. Partial response to carbidopa was seen in two patients with residual DAT activity.

Commentary

The paper emphasizes that many of childhood movement disorders require an extensive evaluation both to identify systemic metabolic disorders and disorders of dopamine synthesis, transport, and metabolism. Correct identification may allow for more accurate prediction of the time course of a progressive disorder. The authors did not discuss whether acquired enzymatic deficits may develop in adults in response to environmental factors. We do not know what effect the aging process has on this enzyme system.