Pantothenate kinase-associated neurodegeneration

Pigmentary degeneration of the pallidum

Neurodegeneration with brain iron accumulation ( obsolete: Hallervorden - Spatz syndrome s, u ) is a rare neuro- degenerative disease in which, in particular, in the basal ganglia ( globus pallidus and substantia nigra) increased amounts of iron can be detected. This autosomal recessive hereditary disease from the group of Neuroaxonalen dystrophies was first described in 1922 by Julius Hallervorden and Hugo Spatz. The prevalence is estimated to be 1-3 per 1 million people affected. In Germany at least 45 people ( without unreported ) with NBIA (as of 2008).

Pathogenesis

In the majority of affected patients, especially in early onset, Mutations of a pantothenate kinase ( PANK2 ) encoding gene on chromosome 20p13 can be detected. This enzyme plays a central role in coenzyme A biosynthesis. An enzyme deficiency leads to the accumulation of cysteine, which results in an increase of free radicals in the presence of iron (thus especially in the substantia nigra and basal ganglia ), and so causes oxidative damage to the brain. It comes to an excessive deposition of iron and neuromelanin.

Course of the disease

The disease usually begins in childhood one, sometimes with pronounced symptoms as early as the first decade of life, but also occur during adult forms. First are extrapyramidal movement disorders, in particular a gait disorder with a tendency to frequent falls or leg dystonia ( 90%) in the foreground, rare psychological abnormalities (10 %). In the course of movement disorders ( dystonia, choreoathetosis, tremor) with rigid muscle tone, hyperreflexia and a retardation or dementia development occur added. Dysarthria and dysphagia are also regularly added in the course of the disease. Retinitis pigmentosa or optic atrophy may occur next. In the adult, is dominated by a Parkinson's plus syndrome with dementia, hyperreflexia and prominent dystonia, the clinical picture. The disease is progressive, that is, the neurological condition of the patient deteriorates with time more and more.

Additional diagnostics

In addition to the chemical laboratory exclusion of Wilson's disease, optionally also a Neuroacanthocytosis, in particular introduces a magnetic resonance imaging scan of the brain to substantiate the diagnosis. This shows in T2 - weighted images in the globus pallidus characteristically an iron-induced deposits hypointensity with a central, presumably caused by a gliosis hyperintensity. This characteristic finding is a " tiger's eye sign " (English eye of the tiger ) and are found in all patients with PANK2 mutations. In a genetic study can be possibly mutations in the gene PANK2 prove. A definitive diagnosis can only be made at autopsy.

Therapy

A causal therapy is not yet known; there are first attempts to treat the enzyme defect. Iron chelators such as deferoxamine have no effect, but there is with the iron chelator Ferriprox since 2007, first attempts at therapy ( deferiprone ). The deep brain stimulation for dystonia and hyperkinesis comes as the predominant symptoms possibly in question. Hypokinesen can be treated with L-DOPA, hyperkinesia with anticholinergic agents such as trihexyphenidyl hydrochloride. However, the effectiveness of L- dopa in patients with mutations in the gene PANK2 is very questionable. For muscle relaxation and, with them, pain relief often baclofen and / or benzodiazepines are used.

Designation of the disease

Because of the involvement primarily of Julius Hallervorden in the euthanasia program of the Third Reich, it has been suggested that disease (based on the genetic defect ) and pantothenate kinase -associated degeneration (or in general maintained ) as neurodegeneration with brain iron accumulation (English NBIA syndrome - to describe neurodegeneration with Brain Iron Accumulation ). The term NBIA campaigns worldwide through more and more.