Advertisement

Cerebral imaging in adult mitochondrial disorders

      Highlights

      • The most common cerebral abnormalities on imaging in adult MIDs are white matter lesions, grey matter lesions, atrophy, optic atrophy, stroke-like lesions, and calcifications.
      • Cerebral imaging is of paramount importance for diagnosing and monitoring cerebral involvement in MIDs.
      • Cerebral imaging in MIDs contributes to the understanding of the pathogenesis of cerebral involvement in MIDs.

      Abstract

      Objectives

      Among the organs/tissues affected in mitochondrial disorders (MIDs), the brain is the second most frequently affected. Cerebral imaging may correlate with clinical findings but not necessarily. This review summarises and discusses current knowledge and recent advances concerning cerebral abnormalities on imaging in adult MIDs (≥18y).

      Methods

      Systematic literature review.

      Results

      The most common cerebral abnormalities in imaging in adult MIDs are, as in pediatric MIDs, white matter lesions, grey matter lesions, atrophy, optic atrophy, stroke-like lesions, calcifications, and ischemic stroke. Cerebral lesions may remain stable over years but some may undergo dynamic changes within shorter or longer period of times. Typical dynamic lesions are stroke-like lesions and grey matter lesions in the sense of progression or regression. Since cerebral lesions on imaging may or may not go along with clinical manifestations, it is crucial to screen all MID patients for cerebral involvement, which can be effectively accomplished by application of the MRI.

      Conclusions

      Cerebral imaging is of paramount importance for diagnosing and monitoring cerebral involvement in MIDs. Cerebral imaging in MIDs contributes to the understanding of the pathogenesis of cerebral involvement in MIDs.

      Keywords

      Abbreviations:

      AHD (Alpers Huttenlocher disease), CPEO (Chronic progressive external ophthalmoplegia), CCT (Cerebral compute tomography), DNA (Deoxyribonucleic acid), FLAIR (Fluid-attenuated inversion recovery), GML (Grey matter lesion), KSS (Kearns Sayre syndrome), LBSL (Leucoencephalopathy with brain stem and spinal cord involvement and lactic acidosis), LCN (Laminar cortical necrosis), LHON (Leber's hereditary optic neuropathy), LS (Leigh syndrome), MDS (Mitochondrial depletion syndrome), MELAS (Mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes), MERRF (Myoclonic epilepsy with ragged red fibers), MID (Mitochondrial disorder), MILS (Maternally inherited Leigh syndrome), MIMODS (Mitochondrial multiorgan disorder syndrome), MNGIE (Mitochondrial neuro-gastro-intestinal encephalopathy), MPAN (Mitochondrial membrane protein associated neurodegeneration), MRI (Magnetic resonance imaging), MRS (Magnetic resonance spectroscopy), NARP (Neurogenic muscle weakness, ataxia, and retinitis pigmentosa), PCH-6 (Pontocerebellar hypoplasia type-6), PDH (Pyruvat-dehydrogenase), PS (Pearson syndrome), SCA (Spinocerebellar ataxia), SL-episode (Stroke-like episode), SLL (Stroke-like-lesion), WMLs (White matter lesions)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Cerebral imaging in paediatric mitochondrial disorders.
        Neuroradiol. J. 2018 Jan 1; (1971400918786054)https://doi.org/10.1177/1971400918786054
        • Finsterer J.
        • Carvalho E.H.T.
        Cerebral manifestations of mitochondrial disorders.
        Can. J. Neurol. Sci. 2017; 44: 654-663
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Cerebral involvement in mitochondrial disorders on imaging.
        Childs Nerv. Syst. 2016; 32: 2059-2060
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Involvement of the spinal cord in mitochondrial disorders.
        J. Neurosci. Rural Pract. 2018; 9: 245-251
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        • Daruich A.
        The eye on mitochondrial disorders.
        J. Child Neurol. 2016; 31: 652-662
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Letter to the editor: endocrine compromise in mitochondrial disorders.
        J. Endocr. Soc. 2018; 2: 570-571
        • Finsterer J.
        • Kothari S.
        Cardiac manifestations of primary mitochondrial disorders.
        Int. J. Cardiol. 2014; 177: 754-763
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Phenotypic heterogeneity of MELAS.
        Mol. Genet. Metab. Rep. 2016; 10: 18-19
        • Finsterer J.
        • Frank M.
        Gastrointestinal manifestations of mitochondrial disorders: a systematic review.
        Ther. Adv. Gastroenterol. 2017; 10: 142-154
        • Finsterer J.
        • Scorza F.A.
        Renal manifestations of primary mitochondrial disorders.
        Biomed. Rep. 2017; 6: 487-494
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Mitochondrial vasculopathy.
        World J. Cardiol. 2016; 8: 333-339
        • Finsterer J.
        Hematological manifestations of primary mitochondrial disorders.
        Acta Haematol. 2007; 118: 88-98
        • Finsterer J.
        • Zarrouk-Mahjoub S.
        Affection of immune cells by a C10orf2 mutation manifesting as mitochondrial myopathy and transient sensory transverse syndrome.
        Acta Neurol. Belg. 2017; 117: 969-970
        • Finsterer J.
        • Melichart-Kotig M.
        • Wöhrer A.
        Mitochondrial disorder mimicking rheumatoid disease.
        J. Cardiol. Crit. Care. 2018; (in press)
        • Finsterer J.
        • Wakil S.
        Abnormalities of skin and cutaneous appendages in neuromuscular disorders.
        Pediatr. Neurol. 2015; 53: 301-308
        • Cheng F.B.
        • Shen P.P.
        • Zhou H.W.
        • Meng H.M.
        • Yang Y.
        • Feng J.C.
        Adult-onset leukoencephalopathy with brain stem and spinal cord involvement in Chinese Han population: a case report and literature review.
        Neurol. India. 2013; 61: 161-163
        • Martikainen M.H.
        • Ellfolk U.
        • Majamaa K.
        Impaired information-processing speed and working memory in leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL) and DARS2 mutations: a report of three adult patients.
        J. Neurol. 2013; 260: 2078-2083
        • Claeys K.G.
        • Abicht A.
        • Häusler M.
        • Kleinle S.
        • Wiesmann M.
        • Schulz J.B.
        • Horvath R.
        • Weis J.
        Novel genetic and neuropathological insights in neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP).
        Muscle Nerve. 2016; 54: 328-333
        • Rajakulendran S.
        • Pitceathly R.D.
        • Taanman J.W.
        • Costello H.
        • Sweeney M.G.
        • Woodward C.E.
        • Jaunmuktane Z.
        • Holton J.L.
        • Jacques T.S.
        • Harding B.N.
        • Fratter C.
        • Hanna M.G.
        • Rahman S.
        A clinical, neuropathological and genetic study of homozygous A467T POLG-related mitochondrial disease.
        PLoS ONE. 2016 Jan 6; 11e0145500https://doi.org/10.1371/journal.pone.0145500
        • Hikmat O.
        • Tzoulis C.
        • Knappskog P.M.
        • Johansson S.
        • Boman H.
        • Sztromwasser P.
        • Lien E.
        • Brodtkorb E.
        • Ghezzi D.
        • Bindoff L.A.
        ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?.
        Eur. J. Neurol. 2016; 23: 1188-1194
        • Waschbisch A.
        • Volbers B.
        • Struffert T.
        • Hoyer J.
        • Schwab S.
        • Bardutzky J.
        Primary diagnosis of Wolfram syndrome in an adult patient—case report and description of a novel pathogenic mutation.
        J. Neurol. Sci. 2011; 300: 191-193
        • Castiglioni C.
        • Verrigni D.
        • Okuma C.
        • Diaz A.
        • Alvarez K.
        • Rizza T.
        • Carrozzo R.
        • Bertini E.
        • Miranda M.
        Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review.
        Eur. J. Paediatr. Neurol. 2015; 19: 497-503
        • Gelfand J.M.
        • Duncan J.L.
        • Racine C.A.
        • Gillum L.A.
        • Chin C.T.
        • Zhang Y.
        • Zhang Q.
        • Wong L.J.
        • Roorda A.
        • Green A.J.
        Heterogeneous patterns of tissue injury in NARP syndrome.
        J. Neurol. 2011; 258: 440-448
        • Haast R.A.M.
        • Ivanov D.
        • IJsselstein R.J.T.
        • Sallevelt S.C.E.H.
        • Jansen J.F.A.
        • Smeets H.J.M.
        • de Coo I.F.M.
        • Formisano E.
        • Uludağ K.
        Anatomic & metabolic brain markers of the m.3243A>G mutation: a multi-parametric 7T MRI study.
        Neuroimage Clin. 2018; 18: 231-244https://doi.org/10.1016/j.nicl.2018.01.017
        • Altmann J.
        • Büchner B.
        • Nadaj-Pakleza A.
        • Schäfer J.
        • Jackson S.
        • Lehmann D.
        • Deschauer M.
        • Kopajtich R.
        • Lautenschläger R.
        • Kuhn K.A.
        • Karle K.
        • Schöls L.
        • Schulz J.B.
        • Weis J.
        • Prokisch H.
        • Kornblum C.
        • Claeys K.G.
        • Klopstock T.
        Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry.
        J. Neurol. 2016; 263: 961-972
        • Hallmann K.
        • Zsurka G.
        • Moskau-Hartmann S.
        • Kirschner J.
        • Korinthenberg R.
        • Ruppert A.K.
        • Ozdemir O.
        • Weber Y.
        • Becker F.
        • Lerche H.
        • Elger C.E.
        • Thiele H.
        • Nürnberg P.
        • Sander T.
        • Kunz W.S.
        A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
        Neurology. 2014; 83: 2183-2187
        • Gocmen R.
        • Guler E.
        Teaching NeuroImages: MRI of brain findings of Wolfram (DIDMOAD) syndrome.
        Neurology. 2014; 83: e213-e214
        • Visser N.A.
        • Braun K.P.
        • Leijten F.S.
        • van Nieuwenhuizen O.
        • Wokke J.H.
        • van den Bergh W.M.
        Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations.
        J. Neurol. 2011; 258: 218-222
        • Spiegel R.
        • Mandel H.
        • Saada A.
        • Lerer I.
        • Burger A.
        • Shaag A.
        • Shalev S.A.
        • Jabaly-Habib H.
        • Goldsher D.
        • Gomori J.M.
        • Lossos A.
        • Elpeleg O.
        • Meiner V.
        Delineation of C12orf65-related phenotypes: a genotype-phenotype relationship.
        Eur. J. Hum. Genet. 2014; 22: 1019-1025
        • Olgiati S.
        • Doğu O.
        • Tufekcioglu Z.
        • Diler Y.
        • Saka E.
        • Gultekin M.
        • Kaleagasi H.
        • Kuipers D.
        • Graafland J.
        • Breedveld G.J.
        • Quadri M.
        • Sürmeli R.
        • Sünter G.
        • Doğan T.
        • Yalçın A.D.
        • Bilgiç B.
        • Elibol B.
        • Emre M.
        • Hanagasi H.A.
        • Bonifati V.
        The p.Thr11Met mutation in c19orf12 is frequent among adult Turkish patients with MPAN.
        Parkinsonism Relat. Disord. 2017; 39: 64-70
        • Stewart J.D.
        • Tennant S.
        • Powell H.
        • Pyle A.
        • Blakely E.L.
        • He L.
        • Hudson G.
        • Roberts M.
        • du Plessis D.
        • Gow D.
        • Mewasingh L.D.
        • Hanna M.G.
        • Omer S.
        • Morris A.A.
        • Roxburgh R.
        • Livingston J.H.
        • McFarland R.
        • Turnbull D.M.
        • Chinnery P.F.
        • Taylor R.W.
        Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children.
        J. Med. Genet. 2009; 46 (d): 209-214
        • Bonfante E.
        • Koenig M.K.
        • Adejumo R.B.
        • Perinjelil V.
        • Riascos R.F.
        The neuroimaging of Leigh syndrome: case series and review of the literature.
        Pediatr. Radiol. 2016; 46: 443-451
        • Schulte E.C.
        • Claussen M.C.
        • Jochim A.
        • et al.
        Mitochondrial membrane protein associated neurodegenration: a novel variant of neurodegeneration with brain iron accumulation.
        Mov. Disord. 2013; 28: 224-227
        • Jackson C.B.
        • Bauer M.F.
        • Schaller A.
        • Kotzaeridou U.
        • Ferrarini A.
        • Hahn D.
        • Chehade H.
        • Barbey F.
        • Tran C.
        • Gallati S.
        • Haeberli A.
        • Eggimann S.
        • Bonafé L.
        • Nuoffer J.M.
        A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly.
        Eur. J. Pediatr. 2016; 175: 517-525
        • Van Goethem G.
        • Luoma P.
        • Rantamäki M.
        • Al Memar A.
        • Kaakkola S.
        • Hackman P.
        • Krahe R.
        • Löfgren A.
        • Martin J.J.
        • De Jonghe P.
        • Suomalainen A.
        • Udd B.
        • Van Broeckhoven C.
        POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement.
        Neurology. 2004; 63: 1251-1257
        • Zsurka G.
        • Becker F.
        • Heinen M.
        • Gdynia H.J.
        • Lerche H.
        • Kunz W.S.
        • Weber Y.G.
        Mutation in the mitochondrial tRNA(Ile) gene causes progressive myoclonus epilepsy.
        Seizure. 2013; 22: 483-486
        • Ardissone A.
        • Piscosquito G.
        • Legati A.
        • Langella T.
        • Lamantea E.
        • Garavaglia B.
        • Salsano E.
        • Farina L.
        • Moroni I.
        • Pareyson D.
        • Ghezzi D.
        A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders.
        Neurology. 2015; 84: 2193-2195
        • Miyawaki T.
        • Koto S.
        • Ishihara H.
        • Goto Y.
        • Nishino I.
        • Kanda F.
        • Toda T.
        A case of neurologic muscle weakness, ataxia, and retinitis pigmentosa (NARP) syndrome with a novel mitochondrial mutation m.8729 G>A.
        Rinsho Shinkeigaku. 2015; 55: 91-95
        • Alsemari A.
        • Al-Hindi H.N.
        Large-scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype.
        Clin. Case Rep. 2015; 4: 111-117
        • O’Byrne J.J.
        • Tarailo-Graovac M.
        • Ghani A.
        • Champion M.
        • Deshpande C.
        • Dursun A.
        • Ozgul R.K.
        • Freisinger P.
        • Garber I.
        • Haack T.B.
        • Horvath R.
        • Barić I.
        • Husain R.A.
        • Kluijtmans L.A.J.
        • Kotzaeridou U.
        • Morris A.A.
        • Ross C.J.
        • Santra S.
        • Smeitink J.
        • Tarnopolsky M.
        • Wortmann S.B.
        • Mayr J.A.
        • Brunner-Krainz M.
        • Prokisch H.
        • Wasserman W.W.
        • Wevers R.A.
        • Engelke U.F.
        • Rodenburg R.J.
        • Ting T.W.
        • McFarland R.
        • Taylor R.W.
        • Salvarinova R.
        • van Karnebeek C.D.M.
        The genotypic and phenotypic spectrum of MTO1 deficiency.
        Mol. Genet. Metab. 2018; 123: 28-42
        • Roubertie A.
        • Leboucq N.
        • Picot M.C.
        • Nogue E.
        • Brunel H.
        • Le Bars E.
        • Manes G.
        • Angebault Prouteau C.
        • Blanchet C.
        • Mondain M.
        • Chevassus H.
        • Amati-Bonneau P.
        • Sarzi E.
        • Pagès M.
        • Villain M.
        • Meunier I.
        • Lenaers G.
        • Hamel C.P.
        Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction.
        J. Neurol. Sci. 2015; 349: 154-160
        • Lugar H.M.
        • Koller J.M.
        • Rutlin J.
        • Marshall B.A.
        • Kanekura K.
        • Urano F.
        • Bischoff A.N.
        • Shimony J.S.
        • Hershey T.
        • Washington University Wolfram Syndrome Research Study Group
        Neuroimaging evidence of deficient axon myelination in Wolfram syndrome.
        Sci. Rep. 2016; 621167
        • Ikawa M.
        • Yoneda M.
        • Muramatsu T.
        • et al.
        Detection of preclinically latent hyperperfusion due to stroke-like episodes by arterial spin-labeling perfusion MRI in MELAS patients.
        Mitochondrion. 2013; 13: 676-680
        • Ge Y.X.
        • Shang B.
        • Chen W.Z.
        • Lu Y.
        • Wang J.
        Adult-onset of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome with hypothyroidism and psychiatric disorders.
        eNeurologicalSci. 2016; 6: 16-20
        • Whitehead M.T.
        • Wien M.
        • Lee B.
        • Bass N.
        • Gropman A.
        Black toenail sign in MELAS syndrome.
        Pediatr. Neurol. 2017; 75: 61-65
        • Mezuki S.
        • Fukuda K.
        • Matsushita T.
        • Fukushima Y.
        • Matsuo R.
        • Goto Y.I.
        • Yasukawa T.
        • Uchiumi T.
        • Kang D.
        • Kitazono T.
        • Ago T.
        Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report.
        BMC Neurol. 2017; 17: 217https://doi.org/10.1186/s12883-017-1001-4
        • Iizuka T.
        • Goto Y.
        • Miyakawa S.
        • Sato M.
        • Wang Z.
        • Suzuki K.
        • Hamada J.
        • Kurata A.
        • Sakai F.
        Progressive carotid artery stenosis with a novel tRNA phenylalanine mitochondrial DNA mutation.
        J. Neurol. Sci. 2009; 278: 35-40
        • Finsterer J.
        Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction.
        Pediatr. Cardiol. 2009; 30: 659-681
        • Kato H.
        • Uchigata M.
        • Iijima M.
        • Shimizu S.
        • Nonaka I.
        • Goto Y.
        Fatal cerebral hemorrhage in mitochondrial encephalomyopathy. Clinical and pathological data of a case.
        J. Neurol. 2006; 253: 529-530
        • Sakharova A.V.
        • Kalashnikova L.A.
        • Chaĭkovskaia R.P.
        • Mir-Kasimov M.F.
        • Nazarova M.A.
        • Pykhtina T.N.
        • Dobrynina L.A.
        • Patrusheva N.L.
        • Patrushev L.I.
        • Protskiĭ S.V.
        Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessel walls in a patient with cerebral artery dissection associated with MELAS syndrome.
        Arkh. Patol. 2012; 74: 51-56
        • Zhu K.
        • Li S.
        • Chen H.
        • Wang Y.
        • Yu M.
        • Wang H.
        • Zhao W.
        • Cao Y.
        Late onset MELAS with m.3243A > G mutation and its association with aneurysm formation.
        Metab. Brain Dis. 2017; 32: 1069-1072
        • Lee N.
        • Kim J.E.
        • Yoo H.J.
        • Gu J.
        • Kim H.
        • Chung J.
        • Koh Y.
        • Kim H.K.
        Acquired dysfibrinogenemia caused by autoantibody inhibiting fibrin polymerization in a patient with MELAS syndrome and bleeding tendency.
        Ann. Clin. Lab. Sci. 2016; 46: 696-700
        • Huang C.C.
        • Wai Y.Y.
        • Chu N.S.
        • Liou C.W.
        • Pang C.Y.
        • Shih K.D.
        • Wei Y.H.
        Mitochondrial encephalomyopathies: CT and MRI findings and correlations with clinical features.
        Eur. Neurol. 1995; 35: 199-205
        • Pénisson-Besnier I.
        • Reynier P.
        • Asfar P.
        • Douay O.
        • Sortais A.
        • Dubas F.
        • Emile J.
        • Malthièry Y.
        Recurrent brain hematomas in MELAS associated with an ND5 gene mitochondrial mutation.
        Neurology. 2000; 55: 317-318
        • Iizuka T.
        • Sakai F.
        • Suzuki N.
        • Hata T.
        • Tsukahara S.
        • Fukuda M.
        • Takiyama Y.
        Neuronal hyperexcitability in stroke-like episodes of MELAS syndrome.
        Neurology. 2002; 59: 816-824
        • Delgado G.
        • Gállego J.
        • Tuñón T.
        • Zarranz J.J.
        • Villanueva J.A.
        Necrotising haemorrhagic encephalomyelopathy in an adult: Leigh’s disease.
        J. Neurol. Neurosurg. Psychiatry. 1987; 50: 224-227
        • Vaphiades M.S.
        • Phillips P.H.
        • Turbin R.E.
        Optic nerve and chiasmal enhancement in leber hereditary optic neuropathy.
        J. Neuroophthalmol. 2003; 23: 104-105
        • Saracchi E.
        • Tremolizzo L.
        • DiFrancesco J.C.
        • Brighina L.
        • Costantino G.
        • Frigeni B.
        • Brioschi M.
        • Piatti M.L.
        • Fumagalli L.
        • Marzorati L.
        • Curtò N.A.
        • Ferrarese C.
        Cerebellar hematoma in a carrier of the A3243G MELAS mutation.
        Neurol. Sci. 2011; 32: 365-366
        • Park M.H.
        • Woo H.M.
        • Hong Y.B.
        • Park J.H.
        • Yoon B.R.
        • Park J.M.
        • Yoo J.H.
        • Koo H.
        • Chae J.H.
        • Chung K.W.
        • Choi B.O.
        • Koo S.K.
        Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy.
        Neurogenetics. 2014; 15: 171-182
        • Zhang J.
        • Liu M.
        • Zhou L.
        • Zhang Z.B.
        • Wang J.M.
        • Jiang Y.W.
        • Wu Y.
        DARS mutations responsible for hypomyelination with brain stem and spinal cord involvement and leg spasticity: report of two cases and review of literature.
        Zhonghua Er Ke Za Zhi. 2018; 56: 211-215
        • Hirayanagi K.
        • Okamoto Y.
        • Takai E.
        • Ishizawa K.
        • Makioka K.
        • Fujita Y.
        • Kaneko Y.
        • Tanaka M.
        • Takashima H.
        • Ikeda Y.
        Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families.
        J. Neurol. Sci. 2017; 378: 177-181
        • Colombelli C.
        • Aoun M.
        • Tiranti V.
        Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron.
        J. Inherit. Metab. Dis. 2015; 38: 123-136