Neurodegeneration with Brain Iron Accumulation 2 (NBIA2B) is one of the PLA2G6-associated neurodegeneration (PLAN), which refers to the overlapping phenotypes that result from PLA2G6 mutations. NBIA2B is characterized by cerebellar and cerebral atrophy, increased iron deposition in the basal ganglia and an 'Eye of the tiger' sign on MRI scans. Histological investigations reveal axonal swellings or spheroids, Lewy bodies in the substantia nigra and throughout the brain as well as neurofibrillary tangles. Patients exhibit symptoms such as ataxia, dysmetria, chorea of limbs, dystonia, dysarthria, bradykinesia, hypertonia, dysphagia, spasticity, seizures, speech delay and cognitive decline. The condition also causes optic atrophy and nystagmus. Affected individuals may suffer from behavioral issues such as hyperactivity, emotional lability, impulsivity, poor attention span, and diminished social interaction. Atypical neuroaxonal dystrophy has a later onset compared to Infantile neuroaxonal dystrophy (INAD), usually affecting children between the ages of 4 to 6. However, in some cases, the condition only manifests in the teenage years. The disorder is also more slowly progressive than INAD and has a variable phenotype. It does not appear to have a racial or gender bias.
Diagnosis is made based on clinical features and brain imaging studies as well as by genetic analysis. Treatment is symptomatic and supportive. Patients benefit from pharmacological therapy such as anti-seizure medication and baclofen for dystonia, ambulatory aids, physical therapy and speech therapy.
Al-Shamsi et al. (2016) conducted a Whole Exome Sequencing (WES) study on 85 patients recruited from a metabolic center in Abu Dhabi. The patients had failed to be diagnosed using conventional methods, but WES was able to definitively diagnose 50% of the cases. One patient belonging to a consanguineous family suffered from developmental regression, hypertonia, failure to thrive, scoliosis and skin anomalies. Family history included a cousin with spina bifida and hydrocephalus. WES uncovered a homozygous variant (c.154G > A, p.V52M) in the patient’s PLA2G6 gene, associated with NBIA2B. The authors noted that the patient’s MRI findings were consistent with NBIA2B. Hence the mutation was confirmed to be pathogenic due to a consistent phenotype, biochemical findings and reported pathogenicity. Further, WES identified a homozygous variant in the ACOX1 gene (c.1165A>G) and compound heterozygous variants in the SACS gene (c.2143C>A and c.5732C>A) in the patient.