PLA2G6 mutation underlies infantile neuroaxonal dystrophy

Abstract

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum. Progressive white-matter disease and reduction of the N-acetyl aspartate : chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiological diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent). These findings highlight a role of phospholipase in neurodegenerative disorders.

Figure  1.

Pedigrees of the investigated families. A, Kindred 1, in which 5 affected individuals and 15 unaffected individuals were available for genetic analysis. B, Kindred 2, in which one affected individual and two parents were available for genetic analysis. A high rate of consanguinity and an autosomal recessive pattern of inheritance can be observed.

Figure  2.

MRI studies. Patient X1:2 is shown at age 3 years (A and B) and, in a follow-up study, at age 9 years (C–H). A, PD-weighted brain MRI showing early atrophy of the cerebellum, with prominent folia and fourth ventricle. B, T2-weighted brain MRI of the supratentorial region is unremarkable; there are no signs of iron deposition in the globus pallidum. C–E, PD-, T2*-, and T2-weighted brain MRI, respectively, showing the development of iron deposition in the medial and lateral parts of the globus pallidum, as well as significant brain atrophy. Note absence of the tiger eye sign. F–H, T1-, T2-, and PD-weighted brain MRI, respectively, showing abnormal signal, in the medial part of the putamen, that was not present at an earlier age. Brain MRI of patient IV:4 is shown at age 2 years (I–L). I, T2-weighted brain MRI showing severe atrophy of the cerebellum, with very prominent folia and fourth ventricle. J–L, T2-, T2*-, and PD-weighted brain MRI, respectively, at the level of the basal ganglia, showing normal signal intensity of the globus pallidum and putamen, with no evidence of brain atrophy. M, MRS (echo time [TE]=144 ms) of the white matter of patient X1:2 at age 9 years, showing conversion of the normal pattern of NAA:Cr and NAA:Cho ratio to significant reduction of NAA. N, MRS of the brain (TE = 144 ms) of patient X1:2 at age 3 years, showing normal ratio of NAA to Cho and Cr.

Figure  3.

Fine mapping of the 22q13.1 locus in kindred 1. A, Disease-associated haplotype is boxed. Minimal homozygosity locus associated with the disease is defined between the markers TR1_C and TR4_272 (region between the red lines). Sequences of TR1_C and TR4_272 are available on request. B, Schematic presentation of the defined locus. Markers TR5_1177, TR1_B, TR1_C, TR1_A, TR1_1045, TR_9, TR_7, TR_8, TR2_2045 and TR4_272 were designed using Tandem Repeats Finder. Primer sequences are available on request.

Figure  4.

Mutation analysis of the 2070_2072delTGT mutation in exon 15 of PLA2G6. Sequence analysis is shown for an unaffected individual (A), an obligatory carrier (B), and an affected individual (C). D, ClustalW sequence alignment of human PLA2 group VI (cytosolic, calcium-independent) to orthologues. The V691del (boxed) of this protein is highly conserved throughout evolution. Conserved residues are indicated with asterisks. E, Deleted valine residing within a putative calmodulin-binding site of this phospholipase. Schematic is adapted from Jenkins et al.