{"paper_id":"b00cfb8f-5241-48ca-9294-9d2090545756","body_text":"Mitochondrial DNA depletion syndrome (MDS) is usually a severe disorder of infancy or childhood\ndue to a reduced copy number of mtDNA molecules within a mitochondrion. 1 , 2  Depletion of mtDNA results from\na replication defect, which may be caused by mutations in at least nine different\nnDNA-located genes. 3  MDS with only mild\nclinical manifestations and onset in adulthood has not been reported.\n\nThe patient is a 47-year-old Caucasian female, height 158 cm, weight 60 kg, who\ndeveloped day-time sleepiness, exercise intolerance, and myalgias in the lower-limb\nmuscles since age 46y. She slept 9-10 hours during the night and 2 hours after lunch daily.\nHer individual history was noteworthy for a number of previous disorders. In 3/96 an ovarian\nendometriotic cyst, a follicular ovarian cyst, and a hydatoid cyst of the left Fallopian tube were\nresectioned and an adhesiolysis carried out. In 10/96 she experienced a gastro-intestinal\nhaemorrhage time-linked to menstruation. Endometriosis was suspected. Since 1997 she was\ndiagnosed with migraine with up to 3-4 non-triggered attacks per month. In 2/99 she\nexperienced a second gastro-intestinal haemorrhage, this time requiring 6 blood transfusions.\nColonoscopy did not detect any source of bleeding. In 5/02 a periproctitic abscess developed and was\nadequately treated. In 3/03 erythema nodosa of the lower legs occurred, preceded by diarrhoea. Upon\nhistological examination of the colonic mucosa, Crohn’s disease was diagnosed and a therapy\nwith steroids (initially aprednisolone, since 10/03 budesonide) and mesalazine initiated, resulting\nin remission of the enteritis. In 10/06 a chronic anal fistula was diagnosed requiring surgical\nintervention. In 12/08 budenoside was discontinued. Since 08 she was taking the pill for\nendometriosis. Cerebral MRI in 5/09, carried out for work-up of headache, was normal. MRI of\nthe cervical and lumbar spine, carried out for dorsal pain, revealed only slight degenerative\nabnormalities.\nThe family history was noteworthy for thyroid cancer (grandmother from the mother’s side,\nsister), gastric cancer (second sister), clinically multisystem mitochondrial disorder [2 sisters,\nniece, aunt (sister of mother, mother (dilative cardiomyopathy, myopathy, Hashimoto thyroiditis,\nrecurrent synkopes, restless-leg syndrome, tinnitus, endometriosis, easy fatigability)], and\nsudden cardiac death (mother). Upon a family screening in 4/10 for thyroid carcinoma she, her\nsister, and her niece were found positive for the rearranged during transfection\n(RET)-oncogen mutation, which is associated with an increased risk to develop thyroid\ncancer. 4  Following these results the niece\nunderwent prophylactic thyroidectomy. In 7/10 gastrointestinal bleeding relapsed and budesonide was\nrestarted. In 8/10 budesonide was replaced by infliximab (400 mg every 8 weeks) and mesalazine was\ndiscontinued. In 10/10 recurrence of the anal fistula required surgical intervention again. In 3/11\na non-specific impaired aggregation of thrombocytes was diagnosed. Clinical exam in 4/11\nrevealed short stature, sore neck muscles, exaggerated masseter reflex, and reduced Achilles tendon\nreflexes exclusively. Hyperlipidemia was noted but serum lactate, myoglobin, and thyroid function\ntests were normal. Nerve conduction studies and needle electromyography were noninformative.\nEchocardiography and cardiac MRI revealed a bicuspid aortic valve exclusively. In 7/11 a medullary\nthyroid carcinoma was diagnosed and treated exclusively by resection. For post-operative\nhypothyroidism she took Lthyroxine. In 3/12 she reported an increase in intensity of migraine\nattacks, increasing fatigability, and myalgias. She was on a therapy with infliximab (every 8\nweeks), L-thyroxin, and the pill for endometriosis.\nDuring thyroid resection in 3/11, a muscle biopsy from the sternocleidomastoid muscle was\nadditionally taken revealing mild to moderate variation in fiber size ( Figure 1A ), predominance of type 2 fibers, single fibers with eosinophilic\ncytoplasmic bodies ( Figure 1B ), and single lobulated fibers\nexhibiting moderate subsarcolemmal accentuation of SDH ( Figure\n1C ), and NADH ( Figure 1D ) activity. Biochemical\ninvestigations of the muscle homogenate revealed reduced activity of all respiratory chain complexes\nin relation to non-collagen protein [NADH-CoQ-oxidoreductase: 6.1 U/g NCP (n,\n15.8-42.81 U/g NCP), succinate/cytochrome C-oxidoreductase: 5.41 U/g NCP (n,\n6.0-25.0 U/g NCP), cytochrome-c-oxidase: 45U/g NCP (n, 112-351 U/g\nNCP)]. Southern blot and long-range PCR were negative but real-time PCR was indicative\nof a MDS. Other clinically affected family members did not consent with a genetic investigation so\nfar. The amount of residual mtDNA was reduced to 9% of normal. For funding reasons, neither\nsequencing of any of the nine candidate genes, nor exomesequencing could be offered.\n\nMDSs are characterised by severe reduction of the mtDNA copy number. 1  Residual mtDNA copy levels may be as low as 1-2% of that of normal.\nIn up to 50% of the cases, mtDNA depletion may be caused by mutations in at least nine different\ngenes ( POLG1, PEO1, RRM2B, SUCLG1, SUCLA2, DGUOK, MPV17, TK2, TYMP ). 1-6  Among these, mtDNA depletion is most commonly\ncaused by mutations in the  POLG1  gene, encoding the catalytic subunit of DNA\npolymerase-gamma, the only polymerase to replicate mtDNA. 1 , 7  In the majority of the cases\nwith MDS, however, the underlying genetic defect remains undetected. The phenotypic expression of\nmutations in these 9 genes is quite variable. 2 \nUsually, infants or children are affected and the cerebrum, the liver, or the skeletal muscles are\npredominantly affected, alone or in combination (myopathic, encephalo-myopathic, or\nhepato-cerebral MDS). 2 , 8 , 9  Patients with POLG1 mutations\nmanifest as non-syndromic hepato-cerebral depletion syndrome,\nAlpers-Huttenlocher syndrome (AHS), infantile onset spinocerebellar ataxia (IOSCA),\nnon-syndromic encephalomyopathic depletion syndrome, or Leigh-syndrome. 9  Whether the MDS in the presented patient was due to\nlong-term treatment with infliximab remains speculative but previous studies have shown that\ninfliximab at least induces apoptosis of monocytes. 10  An argument against the presence of a MDS in the presented case is that the family\nhistory suggestss a maternal trait of inheritance whereas all other MDS so far reported follow an\nautosomal recessive trait.\nContrary to previous descriptions, the phenotype in the presented patient was mild. Why mtDNA\ndepletion in the presented patient resulted in only minor abnormalities, remains speculative but\ncould be explained by the low rate of depleted mtDNA in tissues other than the muscle or by a\nmutation in a gene so far not reported in association with MDS. Probably, mtDNA depletion was absent\nor only mild in tissues other than the muscle. Possibly, the mild phenotype at onset will turn into\na more severe presentation during the disease course, but given the stable presentation during the\nfirst year after onset and the benign course in other family members, such a scenario is rather\nunlikely. Assuming, that any of the nine genes so far associated with MDS was mutated in the\npresented patient, the ones most likely involved are the  TK2, SUCLA2 ,\n RRM2B, SUCLG1, POLG , or  TYMP  genes since they have been found most\nfrequently associated with myopathy. 2 , 8  Among these, mutations in TYMP were found in adult\npatients with MNGIE. 11  Also twinkle mutations\nwere associated adult-onset MDS. 5  Exercise\nintolerance has been reported as a phenotypic feature of  DGUOK  mutations and\nmigraine or migrainelike headache as a feature of  PEO1  mutations.  12 , 13  Hypersomnia\nor other sleep disorders and myalgias have not been reported in association with MDS. It must be\nadmitted, however, that the phenotype of the presented patient fitted to none of those previously\ndescribed in MDS. However, muscle biopsy was taken from the sternocleidomastoid muscle and though it\nshowed some changes, myopathological alterations may vary considerably between muscles.\nWhether the C-cell carcinoma was causally related to the MDS remains speculative, but\npreliminary observations in our cohort of patients with mitochondrial disorders suggest that the\nprevalence of malignancies is increased among these patients. It remains also unclear if\nendometriosis was causally related to the mitochondrial disorder. Arguments for a causal relation\nare that mtDNA polymorphisms were made responsible for the development of endometriosis and that\nmitochondrial biomarkers are increased in eutopic endometriosis. 14 , 15  It remains also unclear, if\nCrohn’s disease was causally related to the MDS. Since some of the mitochondrial disorders go\nalong with non-specific colitis, 16  it is\npossible that the gastrointestinal problem was actually a manifestation of the MDS, but missing\nreports about an association between MDS and enteritis and unequivocal histological abnormalities\nargue against such an assumption.\n\nIn conclusion, MDS may start in adulthood, may be associated with a mild phenotype, and may not\nsignificantly progress during the first year after onset. In an adult patient with severe tiredness,\nexercise intolerance, hypersomnia, and a family history positive for mitochondrial disorder, MDS\nshould be considered. Endometriosis, colitis, or malignancy may be a phenotypic feature of a\nmitochondrial disorder.","source_license":"CC-BY-4.0","license_restricted":false}