Neurodegeneration With Brain Iron Accumulation 2a
A number sign (#) is used with this entry because this form of neurodegeneration with brain iron accumulation (NBIA), referred to here as 'NBIA2A,' is caused by homozygous or compound heterozygous mutation in the PLA2G6 gene (603604) on chromosome 22q13. See NOMENCLATURE section.
See also NBIA2B (610217), an overlapping disorder with later onset.
For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).
DescriptionNeurodegeneration with brain iron accumulation-2A is an autosomal recessive neurodegenerative disease characterized by onset in the first 2 years of life; it is also referred to as infantile neuroaxonal dystrophy (INAD). Pathologic findings include axonal swelling and spheroid bodies in the central nervous system (review by Gregory et al., 2009).
Clinical FeaturesSeitelberger (1954) first described this infantile form of degenerative encephalopathy characterized pathologically by lipid storage in the brain. Visceral changes were described by Cowen and Olmstead (1963) and by Sandbank (1965). The changes in the brain are widespread focal swelling and degeneration of axons with scattered 'spheroids' (Cowen and Olmstead, 1963). Crome and Weller (1965) described a brother and sister, who died at 12 and 18 months, respectively, with mental retardation, paralysis, and epilepsy.
Scheithauer et al. (1978) described 2 affected brothers with severe progressive myoclonic epilepsy. One brother had onset at age 10 years and death at age 23 years. Postmortem examination showed widespread and marked neuroaxonal dystrophy, severe cerebellar atrophy, and degeneration of the lateral corticospinal tracts. There was no increased pigmentation in the globus pallidus or substantia nigra, which distinguished the disorder from PKAN (NBIA1; 234200). The authors suggested that the case was a 'juvenile form' of neuroaxonal dystrophy. The same cases were reported by Dorfman et al. (1978), who noted intellectual deterioration and cerebellar ataxia.
Malmstrom-Groth and Kristensson (1982) described the first case to be reported in Scandinavia.
Nagashima et al. (1985) reported a rare neonatal form which probably had its beginnings in utero. Poor sucking, hypotonia, pendulous nystagmus, keratitis sicca with little tearing, and feeble tendon reflexes were noted soon after birth. By age 7 months he had constipation and urinary retention. By 8 months hypothalamic hypothyroidism and diabetes insipidus were demonstrated. Fever suggested a disorder of temperature regulation. At autopsy, spheroid bodies were widely distributed, particularly in the hypothalamus, infundibulum, and neurohypophysis, but also in the myenteric plexus of the colon. Hunter et al. (1987) described 2 brothers who had a remarkably similar history of prenatal onset of neurologic deterioration, gangrene of the distal limbs leading to autoamputation of digits, pathologic changes of axonal dystrophy, and minor anomalies. They died at 9 months and 14.5 months of age. Hunter et al. (1987) concluded that this should be called prenatal or connatal neuroaxonal dystrophy. Four previous cases with clinical signs at birth had all been sporadic.
Nardocci et al. (1999) reported 13 patients with INAD. Onset was between 6 months and 2 years of age. Nine patients had rapid motor and mental deterioration, although 4 patients had a slower progression. EMG showed chronic denervation, EEG showed fast rhythms, and all patients had abnormal visual evoked potentials (VEP). T2-weighted MRI showed cerebellar atrophy with signal hyperintensity in the cerebellar cortex. Two patients had hypointensity in the pallida and substantia nigra, as is usually characteristic of NBIA1. Farina et al. (1999) reported a thin optic chiasm in 4 patients with INAD.
Although brain magnetic resonance imaging (MRI) changes indicating high levels of iron had been reported only rarely in INAD, Morgan et al. (2006) found that 8 of 20 INAD kindreds (40%) with mutations in the PLA2G6 gene (603604) showed high iron in the globus pallidus. The authors concluded that INAD should clearly be included in the differential diagnosis of neurodegeneration with high brain iron.
Tonelli et al. (2010) reported a patient with infantile neuroaxonal dystrophy confirmed by genetic analysis (603604.0014 and 603604.0015). The child had a severe and rapidly progressive disease course, with onset before age 12 months, hypotonia, severe developmental delay with mental retardation, motor regression, and no eye contact. Tetraparesis developed by age 18 months. Skin biopsy showed axonal spheroids. Although brain iron accumulation was not present, MRI at age 20 months showed hyperintensities on T2-weighted imaging in the caudate and putamen, suggesting an early degeneration process, and cerebellar cortical atrophy. The mutations were predicted to result in an almost complete lack of enzyme activity, although a gain of function could not be excluded. A second unrelated patient with 2 splice site mutations in the PLA2G6 gene showed a similarly rapid disease course; brain MRI showed only cerebellar atrophy at age 19 months.
Distinction from Neurodegeneration with Brain Iron Accumulation 2B (Pantothenate Kinase-Associated Neurodegeneration)
Williamson et al. (1982) described 2 unrelated sporadic cases of neuroaxonal dystrophy in young adults and suggested that the disorder represented a transitional form between Seitelberger disease and Hallervorden-Spatz disease. Initial clinical manifestations in both patients were psychiatric, followed by extrapyramidal symptoms, dementia, cerebellar ataxia, and corticospinal dysfunction. Myoclonic seizures were not present. Pathologic examination of both patients showed generalized distribution of spheroids within the central nervous system and, in 1 patient, in peripheral nerves as well. Both patients had Lewy bodies in the pigmented brainstem nuclei, and 1 patient had Lewy bodies in the cerebral cortex. Williamson et al. (1982) noted that the 2 cases could be examples of 'juvenile' neuroaxonal dystrophy, but also noted the similarities to Hallervorden-Spatz disease and suggested that the 2 disorders could be fundamentally the same entity, possibly due to homozygosity for different alleles at the same locus.
Hortnagel et al. (2004) delineated some of the phenotypic differences between INAD (NBIA2A) and PKAN (NBIA1). INAD usually begins within the first 2 years of life and leads to death before age 10 years, whereas PKAN has a late-infantile or juvenile onset, and patients may survive into their third decade. However, there are reports of early-infantile PKAN and late-onset INAD. INAD is characterized mainly by a pyramidal syndrome with spastic tetraplegia, hyperreflexia, and visual impairment, whereas PKAN is more of an extrapyramidal syndrome with dystonia, parkinsonism, and choreoathetosis. Both disorders have axonal swellings and spheroids throughout the central nervous system, but patients with INAD may also have spheroids in peripheral tissues. PKAD is associated with iron accumulation in the basal ganglia, leading to the characteristic 'eye of the tiger' sign on brain MRI. INAD shows cerebellar atrophy with hyperintensity in the cerebellar cortex. However, both imaging and pathologic features can show overlap in both diseases.
Hortnagel et al. (2004) used linkage analysis and molecular analysis to exclude the PANK2 gene as causative in 8 INAD patients from 7 families previously reported by Nardocci et al. (1999) and Farina et al. (1999). The findings indicated that infantile neuroaxonal dystrophy and PKAN are genetically distinct disorders.
Kurian et al. (2008) reported 14 children from 9 families with neurodegeneration associated with mutations in the PLA2G6 gene. Eleven patients from 6 families were of Pakistani origin. The mean age at symptom onset was 14 months (range, 12 to 22 months), and onset was characterized by regression of psychomotor development and onset of global developmental delay. There was rapid disease progression with 5 children dying at a mean age of 9 years. The main features included bulbar dysfunction, axial hypotonia, spasticity, contractures, spinal deformities, dystonia, cerebellar features. and optic atrophy. Dysmorphic features were not readily apparent. Brain imaging of 13 patients showed cerebellar atrophy, cerebellar gliosis, white matter abnormalities, and atrophy of the corpus callosum. Ten children had evidence of increased iron deposition in the globus pallidus. Seven children had axonal sensorimotor neuropathy with spheroid body formation. Kurian et al. (2008) noted that the phenotype was very homogeneous.
MappingMorgan et al. (2006) performed genomewide linkage studies in 12 families with INAD. Using polymorphic microsatellite markers, they mapped an INAD locus to a 6.0-Mb region of chromosome 22q12.3-q13.2 (lod score of 4.78 at D22S692), with evidence of locus heterogeneity.
DiagnosisAicardi and Castelein (1979) reported 8 cases of late infantile neuroaxonal dystrophy and reviewed 76 previously reported cases. Most patients showed a progressive disorder starting within the first 2 years of life with motor and mental deterioration, bilateral pyramidal tract signs, marked hypotonia, and early visual disturbances. Seizures were not reported. EEG showed high voltage, fast rhythms, and EMG results were consistent with chronic denervation. Axonal endings consistently showed spheroid bodies, which could also be detected in skin and conjunctiva. Aicardi and Castelein (1979) noted that both clinical and pathologic features were necessary for diagnosis.
Ramaekers et al. (1987) outlined the diagnostic difficulties.
Ozmen et al. (1991) demonstrated in 4 patients that the diagnosis can be made by ultrastructural examination of biopsied skin.
Molecular GeneticsMorgan et al. (2006) identified mutations in the PLA2G6 gene (603604) in 31 families with INAD and in the original family with Karak syndrome. They identified a total of 44 unique mutations.
Khateeb et al. (2006) studied affected individuals from 2 unrelated Bedouin Israeli kindreds. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidus. 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 radiologic diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1, and an underlying mutation common to both affected families was identified in PLA2G6 (603604.0004).
Gregory et al. (2008) found PLA2G6 mutations in 45 (79%) of 56 patients with INAD1 and in 6 (20%) of 23 patients with idiopathic NBIA (see, e.g., 603604.0006-603604.0008). No PLA2G6 mutations were found in 11 patients with clinical evidence of INAD, including 5 in whom spheroids were reported on peripheral nerve biopsy. All 28 patients with 2 null mutations or homozygous for any mutation had early onset and rapidly progressive disease, consistent with INAD. Patients with the less severe phenotype of NBIA tended to have compound heterozygous missense mutations, consistent with residual protein function.
HeterogeneityHistorically, the diagnosis of INAD has required histopathologic evidence of dystrophic axons. However, Morgan et al. (2006) found that the presence of spheroids on biopsy did not absolutely correlate with mutations in PLA2G6. Five individuals with clinical and pathologic features of INAD were negative for PLA2G6 mutations. Linkage data supported the existence of 1 additional INAD locus.
PathogenesisDrecourt et al. (2018) found that cells derived from NBIA patients with PLA2G6 mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that NBIA results from defective endosomal recycling and should be regarded as a disorder of cellular trafficking, whatever the original genetic defect.
NomenclatureThis disorder, caused by mutation in the PLA2G6 gene, is referred to in OMIM as NBIA2A because the original phenotype was described as a form of neurodegeneration with brain iron accumulation (NBIA; Morgan et al., 2006). Some references in the literature (see, e.g., Chinnery et al., 2007) use the designation 'NBIA2' to refer to a similar disorder caused by mutation in the FTL gene (134790). OMIM refers to NBIA caused by mutation in the FTL gene as NBIA3 (606159).
Kurian et al. (2008) proposed that disorders due to PLA2G6 mutations be referred to as 'PLA2G6-associated neurodegeneration (PLAN).'
Animal ModelMalik et al. (2008) found that Pla2g6-null mice developed age-dependent neurologic impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. Neuropathologic analysis showed numerous spheroids in the brain similar to those observed in human INAD. Spheroids contained tubulovesicular membranes and stained strongly with anti-ubiquitin antibodies. Onset of motor impairment correlated with increased spheroids throughout the neuropil in nearly all brain regions.