IS HUTCHISON-GILFORD PROGERIA SYNDROME, A FARNESYLATION DEFECT, A TREATABLE METABOLIC DEFECT? Ferreira AC 1 , Sequeira S 1 1 Metab Unit, Dona Estefânia Hosp, CHLC, Lisboa, Portugal Introduction: Hutchison-Gilford progeria syndrome (HGPS), an extremely rare disorder, is a premature ageing syndrome caused by a de novo mutation in the LMNA gene. The most frequent mutation is p.G608G, causing an aberrant splicing of exon 11. More recently it is known that in this disorder results in intracellular accumulation of an abnormal farnesylated form of lamin A (progerin) producing premature cellular senescence. Intelligence is normal. Treatment until recently was largely supportive and death usually occurred at an average age of 13 years. As the metabolic pathway of the formation of lamin A became known the possibilities of treatment also improved. Case Report: We describe an eight year old child with failure to thrive and short stature, the characteristic facies of HGPS, alopecia, joint deformities and severe osteoporosis. Our patient is medicated with calcium, vitamin D, low dose of aspirin and is also currently integrated in an international clinical trial with a combination of pravastatin, zoledronic acid and lonafarnib (a farnesyltransferase inhibitor) drugs that act at different points of the pathway. Comments: Although the efficacy of this treatment is still currently being assessed an evaluation after one year shows some improvement of weight and hair growth. We measured the concentrations of 26 [C12-C24] long-chain fatty acids [PUFAs] in the red cells of 10 male patients with autism and 48 normal controls using the same methods of separation of their fatty acids by GC analysis of their methyl esters on a free fatty acid phase column [Dacremont and Vincent, 1995 ] . We also used innovative non-parametric statistical methods appropriate to the nature of the data. We have thus demonstrated that in 16 of these 26 fatty acids that this group of ten autistic patients had highly statistically significant reduced concentrations of their [C12-C24] Long Chain Fatty Acids in their red cells by comparison with those of a group of 48 normals Also using the known normal metabolic pathways, it was possible to locate and delineate defects in elongase and desaturase systems that normally lead to the formation of these fatty acids, ultimately leading to defects in the formation and incorporation of phospholipids sphingomyelin and sphingolipids in cellular membranes of affected patients. We speculate that this might constitute a diagnostic test. Cutis laxa is a disorder in which patients have wrinkled, abundant skin with abnormal elasticity. Skin symptoms may be associated with systemic involvement. Several new genetic defects have been discovered to cause cutis laxa. Surprisingly, a number of these syndromes are inborn errors of metabolism. These include disorders of glycosylation: COG7-CDG, ATP6V0A2-CDG as well as deficiencies in mitochondrial enzymes (P5CS and PYCR1). Despite these different etiologies, discriminating between ATP6V0A2-CDG and PYCR1-deficiency remains challenging due to overlapping features: cutis laxa, dysmorphisms, joint hyperlaxity, cognitive deficits, growth delay and late closing of the fontanel. We report on the metabolic and clinical features of eight patients with cutis laxa, diagnosed with a novel genetic defect. The four PYCR1 patients had a progeroid appearance and arthrogryposis. Two patients showed athetoid movements. MRI detected hypoplastic corpus callosum in one patient. Serum lactate and alanine were increased in two patients. The four patients with ATP6V0A2-CDG had glycosylation abnormalities and typical facial features. MRI revealed neuronal migration defects in three patients. Awareness of differences between these patient groups should lead to a timely diagnosis. We therefore suggest to measure lactate and alanine and perform cerebral MRI additional to screening for glycosylation in patients with cutis laxa.