PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease

Abstract

Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy' is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.

Keywords: INAD; NBIA; Neurodegeneration with brain iron accumulation; PLA2G6; PLAN.

Fig. 1

a. Midline sagittal T1 brain MRI of Case 1 at 27 months. b. Axial T2 weighted brain MRI of Case 1 aged 39 months, demonstrating iron deposition in the globus pallidus, which is absent on earlier imaging (a). c. Midline sagittal T1 brain MRI of Case 2 aged 33 months, demonstrating classical features of typical PLAN (symbol key and Table 3) and apparent claval hypertrophy. d. Axial T2* brain MRI of Case 2 aged 33 months, at the level of the globus pallidus; note the absence of iron deposition. e. Midline sagittal T1 brain MRI of Case 3 aged 4 years and 6 months, demonstrating classical features of typical PLAN and apparent claval hypertrophy. f. Axial FLAIR brain MRI of Case 3 aged 4 years and 6 months at level of cerebellum, showing high signal of the cerebellar cortex, indicative of gliosis. There is no iron deposition. g. Midline sagittal T1 brain MRI of Case 4 aged 22 months, demonstrating cerebellar atrophy, apparent claval hypertrophy and thin smooth splenium of the corpus callosum. h. Axial T2 weighted brain MRI of Case 4 aged 22 months, at the level of the globus pallidus. There is no iron deposition. i. Midline sagittal T1 brain MRI of Case 5 aged 11 years, demonstrating cerebellar atrophy and apparent claval hypertrophy. j. Axial T2 brain MRI of Case 5 aged 16 years demonstrating iron deposition in the globus pallidus. k. Axial T2 brain MRI of Case 5 aged 16 years demonstrating iron deposition in the substantia nigra. l. Midline sagittal T1 brain MRI of a 10 year old female with hemiplegic migraine and pathogenic CACNA1A mutation, demonstrating cerebellar atrophy and apparent claval hypertrophy.

Fig. 2

Electroencephalogram, Case 2 EEG of Case 2, aged 29 months in wakefulness, demonstrating fast beta2 activity (indicated by the red oval shape).