Neuroaxonal Dystrophies (NAD) are neurodegenerative diseases characterized by axonal “spheroids” occurring in different age groups. The identification of mutations delineated new molecular entities in these disorders. We report neuropathological data of a new form of NAD, characterized by a precocious prenatal onset, different from classical and connatal Infantile Neuroaxonal Dystrophy (INAD).We studied 5 fetuses examined after pregnancy termination and 2 term neonates deceased just after birth, 4/7 from consanguineous parents. All subjects presented severe fetal akinesia sequence with microcephaly. In 4/7 cases, a molecular study was performed. In all cases, “spheroids” with typical immunohistochemical features were identified, with variable spreading in the central and peripheral nervous system. Basal ganglia, brainstem, cerebellum and spinal cord involvement was constant. Associated CNS malformations, unusual in INAD, were associated including hydrocephalus (2), callosal agenesis/hypoplasia (2), olfactory agenesis (1), cortical (3) and retinal (1) anomalies. None cases demonstrated mutations in PLA2G6, found in INAD.The clinical and neuropathological features of these fetal cases are different from those of “classical” INAD. The absence of mutations of PLA2G6, in addition, suggests that the fetal NAD is a new entity, distinct from INAD, with different molecular basis. Associated malformations suggest a wide phenotypic spectrum and probable genetic heterogeneity. Finally, fetal NAD is an additional etiology of fetal akinesia.
Typical MRI features of PLA2G6 mutation-related phospholipase-associated neurodegeneration (PLAN)/infantile neuroaxonal dystrophy (INAD)
