ESPE Abstracts

Background: MADaM syndrome associated with MTX2 gene, is a very rare premature-aging syndrome, caused by a homozygous mutation in the MTX2 gene, which encodes for metaxin-2, a mitochondrial outer membrane protein involved in protein translocation into mitochondria and in TNF-a- induced apoptosis.

Case report: Term male newborn, due to a physiological pregnancy [birth weight 4230 g (1.61 SD), length 56 cm (3.24 SD), head circumference 37 cm (1.68 SD)]. Family history: consanguineous parents, one sister died at the age of 7 months with macrophage cell activation syndrome after recurrent infections. At 6 months of age, our patient had peculiar features: bulging eyes, pointed nose, full cheeks, mandibular hypoplasia, hypotonia and hepatomegaly. After several infectious episodes, he had a first hospitalization for febrile adenovirus infection at 11 months showing hypertransaminasaemia (GPT 576 U/L, GOT 415 U/L, gammaGT 573 U/L), elevated levels of ferritin (1275 ng/ml), LDH (1290 U/L), triglycerides (181 mg/dl), cholesterol (total 211 mg/dl), and marked proteinuria with macrohematuria. Imaging investigations revealed a hepatic inhomogeneous echotexture with hypoechogenic nodules within, nephropathy, cerebral and cranial anomalies, mitral valve prolapse and ASD. Subsequent respiratory infections and various pneumonias led to 24h oxygen dependency. The WGS trio showed a probable pathogenic deletion in homozygosity chr2(GRCh38):g.176315914_176356174del of the MTX2 gene with independent recessive transmission; the same variant was found in heterozygosity in both parents. In the DNA sample obtained from the deceased sister, a targeted search for the same deletion revealed the same homozygosity. At the age of 1.36 years, after dramatic clinical deterioration with severe generalized lipodystrophy [weight 8.16 kg (-2.36 DS), length 72.7 cm (-3.03 SD), HC 46.5 cm (0.41 SD)], we started compassionate treatment with Myalepta® (metreleptin) at a dose of 0.06 mg/kg/day s.c. Moreover, a percutaneous gastrostomy was performed. The treatment caused a dramatic improvement in cholesterol levels (total 137 mg/dl, LDL 87 mg/dl, HDL 39 mg/dl) and triglycerides 104 mg/dl, an improvement in liver (GPT 257 U/I, GOT 231 mg/dl) and kidney function, a marked reduction in hepatomegaly and a slight increase in body weight. The metabolic improvement persisted at 4 months of follow up.

Conclusion: This is the 9th patient diagnosed with MADaM with lipodystrophy, due to MTX2 mutation and the first to be early treated with metreleptin showing an excellent metabolic improvement, opening new hope for this rare condition.