- Email: [email protected]
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) mimicking refractory celiac disease
Accepted Manuscript Title: MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY (MNGIE) MIMICKING REFRACTORY CELIAC DISEASE Authors: Nicola Imperatore, Raffaella Tortora, Nicol`o Gerbino, Nicola Caporaso, Antonio Rispo PII: DOI: Reference:
S1590-8658(17)30849-6 http://dx.doi.org/doi:10.1016/j.dld.2017.04.017 YDLD 3440
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
20-3-2017 24-4-2017
Please cite this article as: Imperatore Nicola, Tortora Raffaella, Gerbino Nicol`o, Caporaso Nicola, Rispo Antonio.MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY (MNGIE) MIMICKING REFRACTORY CELIAC DISEASE.Digestive and Liver Disease http://dx.doi.org/10.1016/j.dld.2017.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
MITOCHONDRIAL
NEUROGASTROINTESTINAL
ENCEPHALOMYOPATHY
(MNGIE) MIMICKING REFRACTORY CELIAC DISEASE
AUTHORS: Imperatore Nicola, Tortora Raffaella, Gerbino Nicolò, Caporaso Nicola, Rispo Antonio.
AFFILIATION: Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine “Federico II” of Naples, Italy.
CORRESPONDENCE: Nicola Imperatore (MD) Gastroenterology, School of Medicine “Federico II” of Naples, Italy Via S. Pansini 5, 80131, Naples, Italy TEL +39817464270 – FAX +390817464270 Email: [email protected]
AUTHORSHIP STATEMENT ALL authors approved the final version of the article, including the authorship list. The manuscript, including related data, figures and tables has not been previously published and the manuscript is not under consideration elsewhere.
Dear Editor, Refractory celiac disease (RCD), a rare entity affecting 1–2% of patients with celiac disease (CD), is defined as persistent symptoms/signs of malabsorption with small intestinal villous atrophy despite a strict gluten-free diet (GFD) for more than 12 months [1].
1
In effect, it has been reported that a previous diagnosis of RCD is confuted in most cases in referral centres [2]. Here we report a rare case of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a subject with suspicion of RCD. In 2014, a 25-year-old, HLA-DQ2-predisposed woman, with a first-degree relative suffering from CD, received a diagnosis of CD because of symptoms (diarrhoea, abdominal pain, weight loss, asthenia and muscular pains), positive serology (anti-tissue transglutaminase and anti-endomysial antibodies), and compatible histology (Marsh 3). After a 6-months follow-up period on a strict GFD, the patient presented normal CD serology and slight improvement of bowel function; however, asthenia and muscular pains persisted and no weight increase was observed. After 2 years from CD diagnosis and despite the rigorous GFD, the patient presented a recurrence of diarrhoea (7-8 bowel movements/day), abdominal pain, significant weight loss (at least 16 Kg, BMI 13.7), asthenia, paresthesias in the fingers of hands and feet, and occasional muscle cramps. Esophagogastroduodenoscopy and histology were performed again, showing duodenal lymphocytic infiltrate and “focal” villous atrophy. Because of a suspicion of RCD, the patient underwent a course of steroids and parenteral nutrition, without benefit. As a consequence, the patient was admitted for the first time at our tertiary centre for CD and Food Intolerances. CD serology was confirmed to be normal, as well as other laboratory parameters. Connective tissue, endocrine, and metabolic diseases were excluded by blood exams; other malabsorption conditions such as Crohn’s disease or Whipple’s disease, small intestinal bacterial overgrowth, microscopic colitis, intestinal lymphoma, infectious intestinal diseases and amyloidosis were ruled out by appropriate serological, radiological and endoscopic/histological investigations. Interestingly, the evaluation of patient’s face revealed bilateral palpebral ptosis and large forehead; moreover, a neurological examination revealed a
2
slight form of ataxia, weakness of quadriceps muscles, absent ankle tendon reflexes and sensorineural deafness. A subsequent electroneurographic-electromyographic study showed a demyelinating sensory-motor polyneuropathy while brain magnetic resonance imaging (MRI) revealed a diffuse leucoencephalopathy. On the basis of the clinical, neurophysiological, and MRI findings, we hypothesized the presence of a complex neurological syndrome so that the patient underwent a left deltoid muscle biopsy that showed one ragged-red fibre and few cytochrome-c-oxidase negative fibres. PCR analysis showed multiple mtDNA deletions; direct sequencing of thymidine phosphorylase (TYMP) showed the homozygous G1443A splice acceptor site mutation; thymidine phosphorylase activity in the buffy coat was absent (1.2 nmol/h*mg; normal value > 250), while thymidine (dThd) and deoxyuridine (dUrd) levels were increased (17.2 𝜇M and 18.5 𝜇M, respectively). The diagnosis of MNGIE was then confirmed. Currently, the patient follows a strict GFD. The intestinal symptoms have been treated by rifaximine and antispasmodic drugs with partial clinical benefit. At present, our patient is in waiting list for allogenic hematopoietic stem transplantation. MNGIE is a rare multisystemic autosomic recessive disorder triggered by the TYMP gene mutations that produce severe biochemical defects of thymidine phosphorylase activity, which, in turn, cause marked increases in thymidine and deoxyuridine nucleoside levels in blood, urine and tissues [3, 4]. These genetic alterations lead to ptosis, progressive external ophthalmoplegia,
gastrointestinal
dysmotility,
cachexia,
peripheral
neuropathy
and
leucoencephalopathy. The only therapeutic options are allogenic hematopoietic stem cell transplantation and, more recently, liver transplantation [5, 6]. This is the first case in the literature reporting on CD/MNGIE overlap syndrome; because of its rarity, different diagnoses other than refractory CD should be always considered in case of apparent non-response to GFD.
3
FINANCIAL DISCLOSURE: none to declare
Specific author contributions: Nicola Imperatore: planning the study, drafting the article, collecting and/or interpreting data Raffaella Tortora: collecting and/or interpreting data Nicolò Gerbino: collecting and/or interpreting data Nicola Caporaso: critical revision of the paper Antonio Rispo: critical revision of the manuscript
Guarantor of article: Dr Nicola Imperatore
CONFLICT OF INTEREST: None declared
AUTHORS WITH NOTHING TO DECLARE SHOULD PROVIDE A STATEMENT TO THAT EFFECT. POTENTIAL COMPETING INTERESTS: none
4
REFERENCES
1. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656-76 2. van Wanrooij RL, Bouma G, Bontkes HJ, et al. Outcome of Referrals for Non-Responsive Celiac Disease in a Tertiary Center: Low Incidence of Refractory Celiac Disease in the Netherlands. Clin Transl Gastroenterol. 2017;8:e218 3. Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011;134:3326-32. 4. Giordano C, Sebastiani M, De Giorgio R, et al. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol. 2008;173:1120-8. 5. D'Angelo R, Rinaldi R, Pironi L, et al. Liver transplant reverses biochemical imbalance in mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrion. 2017. pii: S15677249(16)30250-1. 6. De Giorgio R, Pironi L, Rinaldi R, et al. Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Ann Neurol. 2016;80:448-55.
5
S1590-8658(17)30849-6 http://dx.doi.org/doi:10.1016/j.dld.2017.04.017 YDLD 3440
To appear in:
Digestive and Liver Disease
Received date: Accepted date:
20-3-2017 24-4-2017
Please cite this article as: Imperatore Nicola, Tortora Raffaella, Gerbino Nicol`o, Caporaso Nicola, Rispo Antonio.MITOCHONDRIAL NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY (MNGIE) MIMICKING REFRACTORY CELIAC DISEASE.Digestive and Liver Disease http://dx.doi.org/10.1016/j.dld.2017.04.017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
MITOCHONDRIAL
NEUROGASTROINTESTINAL
ENCEPHALOMYOPATHY
(MNGIE) MIMICKING REFRACTORY CELIAC DISEASE
AUTHORS: Imperatore Nicola, Tortora Raffaella, Gerbino Nicolò, Caporaso Nicola, Rispo Antonio.
AFFILIATION: Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine “Federico II” of Naples, Italy.
CORRESPONDENCE: Nicola Imperatore (MD) Gastroenterology, School of Medicine “Federico II” of Naples, Italy Via S. Pansini 5, 80131, Naples, Italy TEL +39817464270 – FAX +390817464270 Email: [email protected]
AUTHORSHIP STATEMENT ALL authors approved the final version of the article, including the authorship list. The manuscript, including related data, figures and tables has not been previously published and the manuscript is not under consideration elsewhere.
Dear Editor, Refractory celiac disease (RCD), a rare entity affecting 1–2% of patients with celiac disease (CD), is defined as persistent symptoms/signs of malabsorption with small intestinal villous atrophy despite a strict gluten-free diet (GFD) for more than 12 months [1].
1
In effect, it has been reported that a previous diagnosis of RCD is confuted in most cases in referral centres [2]. Here we report a rare case of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in a subject with suspicion of RCD. In 2014, a 25-year-old, HLA-DQ2-predisposed woman, with a first-degree relative suffering from CD, received a diagnosis of CD because of symptoms (diarrhoea, abdominal pain, weight loss, asthenia and muscular pains), positive serology (anti-tissue transglutaminase and anti-endomysial antibodies), and compatible histology (Marsh 3). After a 6-months follow-up period on a strict GFD, the patient presented normal CD serology and slight improvement of bowel function; however, asthenia and muscular pains persisted and no weight increase was observed. After 2 years from CD diagnosis and despite the rigorous GFD, the patient presented a recurrence of diarrhoea (7-8 bowel movements/day), abdominal pain, significant weight loss (at least 16 Kg, BMI 13.7), asthenia, paresthesias in the fingers of hands and feet, and occasional muscle cramps. Esophagogastroduodenoscopy and histology were performed again, showing duodenal lymphocytic infiltrate and “focal” villous atrophy. Because of a suspicion of RCD, the patient underwent a course of steroids and parenteral nutrition, without benefit. As a consequence, the patient was admitted for the first time at our tertiary centre for CD and Food Intolerances. CD serology was confirmed to be normal, as well as other laboratory parameters. Connective tissue, endocrine, and metabolic diseases were excluded by blood exams; other malabsorption conditions such as Crohn’s disease or Whipple’s disease, small intestinal bacterial overgrowth, microscopic colitis, intestinal lymphoma, infectious intestinal diseases and amyloidosis were ruled out by appropriate serological, radiological and endoscopic/histological investigations. Interestingly, the evaluation of patient’s face revealed bilateral palpebral ptosis and large forehead; moreover, a neurological examination revealed a
2
slight form of ataxia, weakness of quadriceps muscles, absent ankle tendon reflexes and sensorineural deafness. A subsequent electroneurographic-electromyographic study showed a demyelinating sensory-motor polyneuropathy while brain magnetic resonance imaging (MRI) revealed a diffuse leucoencephalopathy. On the basis of the clinical, neurophysiological, and MRI findings, we hypothesized the presence of a complex neurological syndrome so that the patient underwent a left deltoid muscle biopsy that showed one ragged-red fibre and few cytochrome-c-oxidase negative fibres. PCR analysis showed multiple mtDNA deletions; direct sequencing of thymidine phosphorylase (TYMP) showed the homozygous G1443A splice acceptor site mutation; thymidine phosphorylase activity in the buffy coat was absent (1.2 nmol/h*mg; normal value > 250), while thymidine (dThd) and deoxyuridine (dUrd) levels were increased (17.2 𝜇M and 18.5 𝜇M, respectively). The diagnosis of MNGIE was then confirmed. Currently, the patient follows a strict GFD. The intestinal symptoms have been treated by rifaximine and antispasmodic drugs with partial clinical benefit. At present, our patient is in waiting list for allogenic hematopoietic stem transplantation. MNGIE is a rare multisystemic autosomic recessive disorder triggered by the TYMP gene mutations that produce severe biochemical defects of thymidine phosphorylase activity, which, in turn, cause marked increases in thymidine and deoxyuridine nucleoside levels in blood, urine and tissues [3, 4]. These genetic alterations lead to ptosis, progressive external ophthalmoplegia,
gastrointestinal
dysmotility,
cachexia,
peripheral
neuropathy
and
leucoencephalopathy. The only therapeutic options are allogenic hematopoietic stem cell transplantation and, more recently, liver transplantation [5, 6]. This is the first case in the literature reporting on CD/MNGIE overlap syndrome; because of its rarity, different diagnoses other than refractory CD should be always considered in case of apparent non-response to GFD.
3
FINANCIAL DISCLOSURE: none to declare
Specific author contributions: Nicola Imperatore: planning the study, drafting the article, collecting and/or interpreting data Raffaella Tortora: collecting and/or interpreting data Nicolò Gerbino: collecting and/or interpreting data Nicola Caporaso: critical revision of the paper Antonio Rispo: critical revision of the manuscript
Guarantor of article: Dr Nicola Imperatore
CONFLICT OF INTEREST: None declared
AUTHORS WITH NOTHING TO DECLARE SHOULD PROVIDE A STATEMENT TO THAT EFFECT. POTENTIAL COMPETING INTERESTS: none
4
REFERENCES
1. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108:656-76 2. van Wanrooij RL, Bouma G, Bontkes HJ, et al. Outcome of Referrals for Non-Responsive Celiac Disease in a Tertiary Center: Low Incidence of Refractory Celiac Disease in the Netherlands. Clin Transl Gastroenterol. 2017;8:e218 3. Garone C, Tadesse S, Hirano M. Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011;134:3326-32. 4. Giordano C, Sebastiani M, De Giorgio R, et al. Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion. Am J Pathol. 2008;173:1120-8. 5. D'Angelo R, Rinaldi R, Pironi L, et al. Liver transplant reverses biochemical imbalance in mitochondrial neurogastrointestinal encephalomyopathy. Mitochondrion. 2017. pii: S15677249(16)30250-1. 6. De Giorgio R, Pironi L, Rinaldi R, et al. Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy. Ann Neurol. 2016;80:448-55.
5