Pantothenate kinase-associated neurodegeneration (ORPHA:157850)
Pantothenate kinase-associated neurodegeneration (PKAN) is the most common type of neurodegeneration with brain iron accumulation (NBIA; see this term), a rare neurodegenerative disorder characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation on the brain and axonal spheroids in the central nervous system.
Epidemiology
Prevalence is estimated at 1-2/1,000,000.
Clinical description
Classic PKAN (75% of cases) is characterized by early onset, usually before six years of age, and rapid progression. Atypical PKAN (25% of cases) has later onset, between 13 and 14 years of age, and slower progression. Patients present with symptoms anywhere along a continuum between the two. In classic PKAN, patients present with impaired gait and falling, often related to dystonia, rigidity, impaired balance, or spasticity, and usually lose the ability to ambulate by 10-15 years after onset. Episodes of rapid decline, which may include status dystonicus, occur interspersed with longer periods of relative stability. Developmental delay (primarily motor, sometimes global) may occur. Patients frequently develop pigmentary retinal degeneration and dysarthria. Later in disease course common complications include dysphagia, gastro-oesophageal reflux, chronic constipation, aspiration pneumonia and malnutrition. In atypical PKAN, patients present with speech difficulty, mild gait abnormalities, prominent psychiatric symptoms that may include depression, emotional lability, impulsivity, or violent outbursts, pigmentary retinal degeneration (less frequently than in classic PKAN) and both verbal and motor tourettism. Motor involvement is generally less severe and loss of ambulation occurs within 15-40 years of onset. The association of hyperprebetalipoproteinemia, acanthocytes and retinitis pigmentosa (HARP syndrome) is within the PKAN spectrum.
Etiology
PKAN is caused by mutations in the PANK2 gene (20p13-p12.3).
Diagnostic methods
PKAN is usually suspected following MRI evidence of the classic `eye-of-the-tiger' sign, a central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. Genetic analysis is required to confirm diagnosis.
Differential diagnosis
Differential diagnoses include Wilson disease (see this term), which is excluded by normal plasma ceruloplasmin concentration or copper metabolism, and other types of NBIA, which can be differentiated using MRI findings and genetic testing.
Antenatal diagnosis
Prenatal testing is available if both disease-causing mutations have been identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment aims to alleviate symptoms, including baclofen (oral or intrathecal pump) and trihexyphenidyl for dystonia and spaciticy, and botulinum toxin for patients whose quality of life is improved by treating a limited body region. Patients with PKAN do not typically benefit from L-dopa. Deep brain stimulation (DBS) may relieve some symptoms. Frequent contact with patients and treatment adjustments are required to maintain as high a quality of life as possible. Dietary assessment, gastrostomy tube feeding and dental extraction (in cases with severe orobuccolingual dystonia) may be required.
Prognosis
PKAN is a progressive disorder and lost skills are usually not regained. Rate of progression correlates with age at onset; those with early symptoms decline more rapidly. Life span is variable but premature death does occur.

                            Last update: 
                            March 2010


                            - Expert reviewer(s): 
                            Dr Allison GREGORY  - Pr Susan HAYFLICK