Over one hundred diseases related to inherited defects of complex
lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only a few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system. Complex
lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes,
spastic paraparesis, neurodegeneration with brain
iron accumulation and
peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from
Boucher-Neuhauser syndrome via
Gordon Holmes syndrome to
spastic ataxia and pure
hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic
ichthyosis; (4)
Retinal dystrophies with syndromic and non syndromic
retinitis pigmentosa,
Leber congenital amaurosis,
cone rod dystrophy,
Stargardt disease; (5) Congenital
bone dysplasia and segmental overgrowth disorders with congenital
lipomatosis; (6) Liver presentations characterized mainly by transient neonatal
cholestatic jaundice and non alcoholic
liver steatosis with
hypertriglyceridemia; and (7) Renal and immune presentations. Lipidomics and molecular functional studies could help to elucidate the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders.