OMIM ID:
Pantothenate Kinase-Associated Neurodegeneration
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Clinically evident retinal degeneration is present in a significant number (25-50%) of individuals. However, when combined with ERG evidence the proportion rises to 68%. When present it occurs early and one series reported that it is unlikely to appear later if it was not present early in the course of the neurodegeneration. Some patients have a fleck-like retinopathy. Optic atrophy may be present in advanced cases.
Systemic Features
This is a disorder primarily of the basal ganglia resulting from progressive damage secondary to iron accumulation. There is an early onset classic form with symptoms of extrapyramidal disease beginning in the first decade of life and rapid progression to loss of ambulation in about 15 years. Others with atypical disease may not have symptoms until the second or third decades. Clumsiness, gait disturbance, and difficulty with tasks requiring fine motor coordination are common presenting symptoms. Motor tics are often seen. Dysarthria, dystonia, rigidity and corticospinal signs are often present early as well. Swallowing difficulties may be severe sometimes leading to malnutrition. Cognitive decline and psychiatric disturbances such as obsessive-compulsive behavior and depression may follow. Independent ambulation is lost in the majority of patients within one to two decades. Brain MRIs show an ‘eye of the tiger’ sign with a specific T2- weighted pattern of hyperintensity within the medial globus pallidus and the substantia nigra pars reticulata.
Genetics
Inheritance
Iron accumulation in the basal ganglia resulting from homozygous mutations in the PANK2 gene (20p13-12.3) encoding a pantothenate kinase leads to the classic form of this autosomal recessive disorder.
This is the most common of several diseases of neurodegeneration with iron accumulation in the brain known collectively as NBIAs. The group is genetically heterogeneous with many overlapping features. Mutations in PLA2G6 cause NBIA2A (256600) and NBIA2B (610217) while mutations in a FLT gene cause NBIA3 (606159). The latter does not have apparent eye signs.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.