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NBIA (neurodegeneration with brain iron accumulation; formerly Hallervorden-Spatz syndrome, HSS) is a rare juvenile, progressive form of neurodegeneration. A well defined subclass of NBIA is associated with mutations of the PANK2 gene (pantothenate kinase associated neurodegeneration, PKAN).
Two forms of PKAN are distinguishable based on clinical parameters:
a) classical form (approx. 75%): patients present early, mostly around the 3. or 4. year of life and always before the age 10, with symptoms like unsteady gait and posture. Dystonic motor symptoms (often beginning with head and extremities and spreading to the trunk), rigidity and choreoathetosis may follow. Some patients show spasticity, hyperreflexia and pyramidal signs. Dysarthria is also a common feature. A progressive cognitive decline is seen in many children with PKAN. Many patients have pigmentary retinopathy, some of them also optic atrophy. Red blood cell acanthocytosis has been reported in a subset of individuals with PKAN.
b) atypical form (approx. 25%): The age of onset is usually delayed (rarely until the 3. decade), the disease course often more benign than for the classical form. Initially psychiatric features like depression and psychosis may be prominent symptoms. Speech problems are a common early sign. Extrapyramidal symptoms, dystonia and rigidity are often less severe. Ambulation may be conserved for a relatively long time. Retinal abnormalities are less common that in classical PKAN. Some patients develop dementia. In some case epilepsy has been described.Both forms of PKAN are typically characterized by specific changes visible on T2 weighted MRI scans. Within the pallidum and the substantia nigra a hypointense zone with an embedded hyperintense nucleus is seen (so called ‘eye of the tiger’ sign). The hyperintense nucleus is often absent in NBIA cases other than PKAN.
PKAN s inherited in an autosomal recessive manner. Both parents of an affected child are likely to be heterozygous, i.e. non-symptomatic mutation carriers. The a priori risk for each child of such a couple is 25% to be homozygous (or compound heterozygous, respectively) mutation carrier and to develop PKAN.
The gene associated with PKAN was identified on chromosome 20p13 in 2001. Almost all patients with patient with a well defined PKAN phenotype (including the full ‘eye of the tiger’ sign) have mutations within the PANK2 gene. PANK2 encodes pantothenate kinase 2 protein, which is involved in the synthesis of coenzyme A from vitamine B5. Molecular genetic diagnostics for PKAN are performed by direct sequencing of the entire coding region of the PANK2 gene and its exon/intron boundaries. Classical PKAN is more often associated with truncating mutations, i.e. nonsense, frameshift or splice site mutations, whereas atypical PKAN is more often caused by missense mutations. Yet, a general discrimination of both subtypes only by the molecular genetic findings is usually not possible.
There are currently only symptomatic therapies available for PKAN. Trials with high doses of vitamin B5 and/or coenzyme Q10 are under clinical evaluation.
Dr. med. S. Wieczorek
Humangenetik
Gebäude MA 5
Ruhr-Universität
Universitätsstr. 150
44801 Bochum
GermanyTel.: +49 234 32 23831
Fax: +49 234 32 14196
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