ESPE Abstracts

Mitochondrial diseases are multisystemic disorders which often involve endocrine system, as defective oxidative phosphorylation can lead to decreased hormones production or secretion and all steroid hormones are synthesized in the mitochondria. Endocrine dysfunctions can therefore represent the initial symptoms of these pathologies and the incidence of various endocrinopathies varies between different mitochondrial disease. Diabetes mellitus is the most frequently described endocrinopathy but hypothalamic dysfunction with multiple pituitary hormone deficiencies and end-organ dysfunctions have also been reported. In mitochondrial diseases a correlation between specific mutations and phenotype has been found. Only a few of the reported mutations in mitochondrial genes reside within MT-TG, that encodes tRNA^Gly. Here we report the second observation of a patient with a specific rare mutation in MT-TG, presenting similar endocrine features extended to a GH deficiency. The patient is an 18-year-old female. Psychomotor development was normal but mild intellectual disability was diagnosed during childhood. At 6 yo GH stimulation tests with peak respectively at 3.30 and 1.45 µg/l were performed for progressive slowing of growth rate. Recombinant human GH treatment was started. At the age of 12 for lack of spontaneous pubertal development oestrogen replacement therapy was started for diagnosis of hypogonadotropic hypogonadism. At the age of 14, L-thyroxine treatment was also started for onset of central hypothyroidism. Brain MRI showed normal midline structures. In addition to endocrinological problems, she also presented severe sensorineural hearing loss at the age of 6 for which she underwent bilateral cochlear implantation. Retinal dystrophy was diagnosed at the age of 15 and at 17 yo she underwent surgical correction of bilateral cataract. Karyotype (46,XX), array-CGH, genetic analysis with targeted resequencing using multigenic panels for hearing loss, hypogonadism and hypopituitarism were carried out without identifying pathogenic mutations. At the age of 18 she presented tonic-clonic seizures, EEG showed diffuse epileptic discharges and increased serum CPK and lactate levels were found. Brain CT scan showed diffuse basal ganglia ad cerebellar dentate nuclei calcification. The suspicion of mitochondrial pathology was raised and confirmed by muscular biopsy (diffuse ragged red fibres and COX negative fibres). Molecular analysis of mitochondrial DNA identified the m.10038G>A variant in MT-TG gene with 53% heteroplasmy level in peripheral blood and 88% in skeletal muscle. The rare variant was previously reported in an adult patient (Pool O.V. et al., Neurol Gen 2020) with several similar phenotypic features: GH deficiency, epilepsy and extensive intracranial calcification were not previously reported.