Trapianto di fegato in malattie mitocondriali con accumulo di tossici: il caso della MNGIE
Rita Rinaldi, MDUO di NEUROLOGIA, Azienda Ospedaliero-Universitaria di Bologna,
Policlinico S. Orsola-Malpighi, Bologna, Italy
6° Convegno Nazionale sulle Malattie MitocondrialiROMA, 27 – 28 - 29 maggio 2016
Mitochondrial Neuro-Gastro-Intestinal EncephaloMyopathy (MNGIE)
28 years of age 38 years of age
prevalence ~0.15/1,000,000Neurological Sciences, March 2016
(CNS – GUT Neuromuscular system)
TP activity <10%
TP deficiency leads to instability of mitochondrial DNA:
mtDNA multiple deletions (skeletal muscle)
mtDNA depletion (gastrointestinal smooth muscle, skeletal muscle and liver)
mtDNA point mutations (skeletal muscle, lymphocytes, fibroblasts)
mtDNA depletion in liver and COX deficiency
COX/SDH staining
COX+
COX-
1°MNGIE patient in Bologna
We also detected a partial reduction ofmtDNA copy number in our index patient
MNGIE livers (n=3)“NASH like” steatosis
V.M.A F.A. P.N.
TP in healthy liver
healthy liver MNGIE liver
IHC
TP nuclei = blue triangle
TP sinusoidal lining cell = blue arrow
TP cytoplasm = blue circle
VMA, , 25 yrs♂
Consanguineous parents (cousins)
No major remarks in the clinical history
Up to 19 yrs – doing well; however, at the age of 2 yrs, he had an episode of ‘intestinal sub-obstruction’ (apparently treated only with " laxatives ")
From 19 yrs:
•Recurrent arthritis / myalgia•Chronic diarrhea leading to a "diagnosis of IBD" •Partial response to steroid therapy + sulfasalazine
Since May 2014 deterioration of digestive symptoms with episodes of intestinal sub-obstruction; weight loss ( BMI → 13.4 ) → PN
Neurological evaluation• Mild hyporeflexia and imbalance, without ptosis,
ophthalmoparesis or segmental hyposthenia.
• Electromyography showed demyelinating sensory-motor polyneuropathy.
• Brain MRI with spectroscopy revealed moderate-to-severe hyperintensity in the cerebral and cerebellar white matter, along with brain white matter lactate increase.
leukoencephalopathy
Muscle biopsy • COX negative along with rare “ragged-red” fibers
• Ultrastructural mitochondrial abnormalities
• Muscle mtDNA analysis showed slight accumulation of multiple deletions and partial reduction of mtDNA copy number
COX-
Biochemical profiling • Markedly reduced plasma TP activity (4 nmol/h*mg; n.v. >253)
• Increased dThd and dUrd levels (4 μg/mL and 3.7 μg/mL, respectively)
• The TYMP gene sequence revealed a homozygous c.1160-1G>A mutation
1st March 2015 Orthotopic Liver
Transplantation (OLT)
Liver function and blood tests
LOD = Limit of detection (0.12ug/ml)LOQ = Limit of quantification (0.5ug/ml)(Mohamed S et al., 2014)
Plasma dThymidine and dUridine rapidly drop in post-OLT, except for a transient liver function impairment between days 60 and 135
Under the line (0-46 nmol/h*mg) the activity is considered pathologic
As expected, the TP activity in lymphocytes remained extremely impaired, except for an early post-OLT transient and limited increase, possibly due to platelet transfusions
PRE-OLT 90 days post-OLT
180 days post-OLT
300 days post-OLT
Karnofsky (performance status scale)
400 days post-OLT
30 – severely disabled40 – disabled, requires assistance50 – requires assistance and medical care60 – requires occasional assistance
PRE-OLT 90 days post-OLT
180 days post-OLT
300 days post-OLT
SF-36 (quality of life)
400 days post-OLT
PCS=Physical component summaryMCS=Mental component summary
PRE-OLT POST-OLT
EMG
RMN
D
A B
C
COX/SDH COX/SDH
pre-OLT post-OLT
PRE-OLT
POST-OLT
GastroIntestinal tractMasson’s trichrome Orcein
At over 12 months of follow-up:
• Rapid and persistent clearance of plasma nucleosides
• OLT is well tolerated, with no major complications
• No side effects to immunosuppressive therapy
• Persistence of GI disfunction
• No changes of EMG and MRI abnormalities,
•No changes in muscle and gut biopsies
Conclusions
Other two patients are now under
clinical scrutiny as candidate for OLT(both with predominant neurological
phenotype and very mild GI symptoms)
Roberto D’AlessandroDipartimento Scienze Biomediche e Neuromotorie-DIBINEM, IRCCS Istituto di Scienze NeurologicheValerio Carelli, Leonardo Caporali, Manuela Contin, Mariantonietta Capristo, Susan MohamedDipartimento Scienze Biomediche e Neuromotorie-DIBINEM, IRCCS Istituto di Scienze Neurologiche
RF‐2009‐ 1492481 Ita‐MNGIE: An Italian network for MNGIE epidemiology, molecular mechanisms
and enzyme replacement therapy by stem cell transplant
Roberto De Giorgio, Elisa Boschetti, Francesca BiancoDipartimento Scienze Mediche e Chirurgiche-DIMECLoris PironiCenter for Chronic Intestinal Failure, Digestive System DeptRita Rinaldi, Roberto D’AngeloUO NeurologiaAntonia D’ErricoPathology UnitGiovanna Cenacchi, Valentina Papa, Roberta CostaDipartimento Scienze Biomediche e Neuromotorie-DIBINEMRaffaele Lodi, Caterina Tonon, L. L GramegnaUnità di RM Funzionale, DIBINEM
Antonio Daniele Pinna, Maria Cristina MorelliTransplantation and Organ Insufficency Dept, DIMEC