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.

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

“…However, one common feature is that all are associated with NBIA phenotypes showing pathological features of demyelination. 8, 38, 39, 40, 41 The proteins encoded by these genes are still not well characterized but there is mounting evidence for myelin-related functions 41, 42, 43 (Supplementary Table 4). Another 16 transcripts relating to myelin also showed decreased levels in Hfe − / − × Tfr2 mut brain (all P <0.05), including transcripts for the iron transporter transferrin that is expressed in oligodendrocytes and is essential for myelination.…”

Mitochondria from a mouse model of the human infantile neuroaxonal dystrophy (INAD) with genetic defects in VIA iPLA 2 have disturbed Ca 2+ regulation with reduction in Ca 2+ capacity

“…INAD is characterized by progressive motor and sensory impairment. "Classic" INAD displays early symptoms of onset, seen between 6 months and 2 years of age, followed by a loss of ambulation within 5 years (Gregory et al, 2008;Illingworth et al, 2014). The genome screening in families with INAD identified mutations on chromosome 22q12-q13 in the PLA2G6 gene.…”

“…In certain cases, the symptoms of INAD appear for the first time late in childhood and progress slowly. This type of disease is designated as "atypical NAD" (Gregory et al, 2008;Illingworth et al, 2014). However, there is no clear mechanistic link between mutations in PLA2G6 and development of INAD pathology.…”

Bilateral symmetrical basal ganglia and thalamic lesions in children: an update (2015)

“…15). Neuroimaging of PLAN/INAD shows marked cerebellar atrophy in addition to iron accumulation of the globus pallidus and substantia nigra [104]. Finally, although most of the NBIA disorders are inherited in an autosomal recessive manner, the only X-linked NBIA disorder is the disease entity known as beta-propeller proteinassociated neurodegeneration (BPAN) [105].…”