PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron; neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies.
- Defects in PLA2G6 are the cause of neurodegeneration with brain iron accumulation type 2B (NBIA2B) a neurodegenerative disorder associated with iron accumulation in the brain, primarily in the basal ganglia. It is characterized by progressive extrapyramidal dysfunction leading to rigidity, dystonia, dysarthria and sensorimotor impairment.
- Defects in PLA2G6 are the cause of neurodegeneration with brain iron accumulation type 2A (NBIA2A) also known as Seitelberger disease. NBIA2A is a neurodegenerative disease characterized by pathologic axonal swelling and spheroid bodies in the central nervous system. Onset is within the first 2 years of life with death by age 10 years.
- Defects in PLA2G6 are the cause of Parkinson disease type 14 (PARK14). An adult-onset progressive
neurodegenerative disorder characterized by parkinsonism, dystonia, severe cognitive decline, cerebral and cerebellar atrophy and absent iron in the basal ganglia on magnetic resonance imaging.
- PLA2G6 mutation underlies infantile neuroaxonal dystrophy (INAD)
- PLA2G6 mutations are related at the Karak's syndrome.
This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
PLA2G6-Associated Neurodegeneration, 2012
Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease.
INAD usually begins between ages six months and three years with developmental regression, hypotonia, progressive psychomotor delay, and progressive spastic tetraparesis. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid. Many affected children never learn to walk or lose the ability shortly after attaining it. Severe spasticity, progressive cognitive decline, and visual impairment typically result in death during the first decade.
The clinical picture is characterized by psychomotor regression and hypotonia, which progress to spastic tetraplegia, visual impairment and dementia. Disorders of the district eye (optic atrophy, nystagmus or strabismus) are often present.
Another clinical feature is cerebellar atrophy.
Infantile neuroaxonal dystrophy: What's most important for the diagnosis?, 2008
Clinical Description
Psycomotor regression is associated with increasing hypotonia with muscular weakness of such a degree as to suggest a diagnosis of myopathy. Muscular atrophy may be present. Pyramidal tracts sings with extensor plantar respinses are regulary present. Visual symptons and signs, including strabismus, pendular nystagmus , inordinate eye moviments, optic atrophy and failng vision are generally early and prominent.
Over time, affected persons develop a spastic tetraparesis, with symmetric pyramidal tract signs on clinical examination.
An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T2-weighted MRI. For this reason, conditions included in the neurodegeneration with brain iron accumulation (NBIA) category should also be considered in the differential diagnosis of INAD.
Individuals with INAD have not been found to have an eye-of-the-tiger sign wich correlates with Karak's syndrome, also caused by mutations in PLA2G6, more precisely, it is due to a missense mutation.
PLA2G6, plays an essential role in the homeostasis of the cell membrane. The mutations alter the phospholipid metabolism and cause an abnormal accumulation of iron in cells. The pathognomonic sign of the disease is the presence of axonal damage and 'spheroid bodies'' in the central and peripheral nervous system, and they are seen with biopsies of the skin, nervous system, conjunctiva and rectum.
Pathogenesis
The full-length PLA2G6 cDNA encodes an 806-aa protein with a lipase motif and seven ankyrin repeats.
Sequence analysis of PLA2G6 revealed a mutation in exon 15, which resulted in the deletion of valine at position 691 of the encoded protein, PLA2 group VI (cytosolic, calciumindependent).
The same PLA2G6 mutation was also reported in patients unrelated to each other, which corroborates its association with the disease phenotype.
V691 of PLA2 group VI (cytosolic,calcium-independent),which is deleted in our patients, is
extremely well conserved throughout evolution and resides within immediate proximity to a putative calmodulin-binding site of the phospholipase.
Molecular diagnosis of INAD can (thanks to the discovery of the mutation in PLA2G6), at least in part, replace the invasive biopsies used in the diagnosis of this disease thus far.
PLA2G6 mutations causing INAD are likely to result in loss of function.
PLA2G6 mutation underlies infantile neuroaxonal dystrophy, 2007
