Parkinsonism-Dystonia, Infantile, 1

A number sign (#) is used with this entry because infantile parkinsonism-dystonia-1 (PKDYS1) is caused by homozygous or compound heterozygous mutation in the SLC6A3 gene (126455), which encodes a dopamine transporter (DAT1), on chromosome 5p15.

Description

Infantile parkinsonism-dystonia, also known as dopamine transporter deficiency syndrome (DTDS), is an autosomal recessive complex motor neurologic disorder with onset in infancy. Affected individuals show hyperkinesia with orolingual and limb dyskinesia, dystonia, and chorea, or hypokinesia with parkinsonian features, such as bradykinesia, rigidity, and tremor. Other features may include axial hypotonia, pyramidal tract signs, and eye movement abnormalities. Many patients are misdiagnosed as having cerebral palsy. Cognitive function appears to be less severely affected, but most patients die in the teenage years. There is no effective treatment. Laboratory studies show an increased ratio of homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF), which represents an increased ratio of dopamine to serotonin metabolites (review by Kurian et al., 2011).

Genetic Heterogeneity of Infantile Parkinsonism-Dystonia

See also PKDYS2 (618049), caused by mutation in the SLC18A2 gene (193001) on chromosome 10q25.

For an overlapping phenotype, see tyrosine hydroxylase deficiency (605407), also known as autosomal recessive Segawa syndrome.

Clinical Features

Kurian et al. (2009) reported 2 unrelated but consanguineous families in which 3 individuals had infantile onset of parkinsonism and dystonia. One family was of Pakistani origin and the other of European descent. Two patients were initially misdiagnosed with cerebral palsy. All had features of progressive parkinsonism, dystonia, pyramidal tract signs, and hypertonicity at examination between 6 and 12 months of age. There was evidence of global developmental delay, but later studies showed no psychiatric or behavioral abnormalities. CSF analysis showed markedly elevated concentrations of HVA, with normal 5-HIAA levels. All patients showed a poor clinical response to multiple therapeutic agents. All parents were unaffected.

Kurian et al. (2011) reported 11 children with dopamine transporter deficiency confirmed by genetic analysis, including the 3 patients reported by Kurian et al. (2009). The patients were ascertained from 7 pediatric neurology centers. All children presented with a movement disorder with onset in early infancy (range 0.5 to 7 months). Before diagnosis, 7 children had been misdiagnosed with cerebral palsy. Symptoms were somewhat variable, but included neonatal irritability and early feeding difficulties, a hyperkinetic syndrome with dystonia and chorea, a predominantly hypokinetic syndrome with parkinsonism, or a mixed hyperkinetic and hypokinetic movement disorder. Other prominent features were axial hypotonia, orolingual dyskinesia, pyramidal tract symptoms, eye movement abnormalities, choreiform movements, dystonia, including status dystonicus with oculogyric crises, and gastrointestinal complications. Parkinsonian symptoms, such as bradykinesia, rigidity, hypomimia, and tremor, tended to occur later. All patients had cognitive impairment and lack of speech, but reception and understanding were good. CSF analysis showed an increased HVA:HIAA ratio in all patients. One patient who underwent testing showed complete loss of DAT activity in the basal ganglia on DaTSCAN imaging. There was no effective and sustained treatment for the symptoms. Four patients died between 9 and 16 years of age.

Puffenberger et al. (2012) reported 2 Mennonite sisters with infantile parkinsonism-dystonia. The proband developed irritability and feeding difficulties soon after birth, followed by generalized rigidity and dystonia during early infancy. She had impaired motor development and severe rigid parkinsonism by late childhood. She could not speak or use her hands to communicate, and it was difficult to assess cognitive function or thought content. Brain structure was normal. Cerebrospinal fluid showed increased HVA. Treatment with L-DOPA was ineffective. A similarly affected sister had died.

Inheritance

The transmission pattern of PKDYS in the families reported by Kurian et al. (2009) and Puffenberger et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By linkage analysis followed by candidate gene sequencing of a consanguineous Pakistani family with infantile parkinsonism-dystonia, Kurian et al. (2009) identified a homozygous mutation (L368Q; 126455.0002) in the SLC6A3 gene. A similarly affected individual from a second family had a different homozygous mutation (P395L; 126455.0003). In vitro functional expression studies showed that both mutant proteins had no dopamine uptake activity.

In 8 unrelated patients with dopamine transporter deficiency syndrome, Kurian et al. (2011) identified homozygous or compound heterozygous mutations in the SLC6A3 gene (see, e.g., 126455.0005-126455.0007). None of the patients shared a mutation, suggesting the absence of mutational hotspots. In vitro functional expression studies in HEK293 cells showed that the mutations caused a loss of transporter function and decreased expression of the normal protein.

By homozygosity mapping followed by exome sequencing of a Mennonite family in which 2 sisters had infantile parkinsonism-dystonia, Puffenberger et al. (2012) identified a homozygous splice site mutation in the SLC6A3 gene (126455.0004). No carriers of this mutation were found among 201 Mennonite control samples.

Pathogenesis

This disorder is due to loss of function of the presynaptic dopamine transporter. Defective reuptake of dopamine is thought to lead to accumulation of dopamine in the synapse, which is catabolized and causes increased CSF levels of HVA. Poor dopamine reuptake leads to depletion of presynaptic stores of dopamine for extraneuronal release. Excess extraneuronal dopamine may also result in decreased production of dopamine and to downregulation or desensitization of dopamine receptors, thus mimicking dopamine deficiency (review by Kurian et al., 2011).