Clinical manifestation
Except for our patient, we included 61 patients from 43 case reports written in English [5-47] and 6 written in Chinese (as reported in Additional file 1). Altogether 62 patients were included in this study, with 22 (35.5%) female and 38 (61.3%) male. The age at diagnosis was reported in 61 patients, with a median age of 25 (19.5, 30.5) years. The most commonly affected systems were the digestive and nervous systems. Twenty-one (33.9%) articles reported that patients were born to consanguineous parents (Table 1). Digestive symptoms in patients were observed for 8.5 (3, 12) years until diagnosis. The most common GI symptoms were weight loss/cachexia (47, 75.8%), diarrhea (42, 67.7%), abdominal pain (40, 64.5%), vomiting (32, 51.6%), and constipation (8, 12.9%) (Fig. 2). Less common symptoms were diverticular disease and intestinal perforation. Patients were most frequently misdiagnosed with Crohn’s disease (7, 11.3%) and celiac disease (6, 9.7%) because of the non-specificity of the symptoms. The other diseases that were misdiagnosed were anorexia nervosa and superior mesenteric artery syndrome.
Table 1. Demographic and clinical features of patients with mitochondrial neurogastrointestinal encephalomyopathy
Demographics
|
Numbers
|
Percentage or value
|
Total sample size
|
62
|
|
Age (years)
|
|
25 (19.5, 30.5)a
|
Gender
|
|
|
Female
|
22
|
35.5%
|
Male
|
38
|
61.3%
|
Consanguineous parents
|
21
|
33.9%
|
Course of GI symptoms (years)
|
|
8.5 (3, 12)a
|
Course of CNS symptoms (years)
|
|
3 (1,11)a
|
Symptoms
|
|
|
Leucoencephalopathy
|
51
|
82.3%
|
Weight loss / Cachexia
|
47
|
75.8%
|
Ptosis / Ophthalmoparesis
|
44
|
71%
|
Polyneuropathy
|
43
|
69.4%
|
Diarrhea
|
42
|
67.7%
|
Abdominal pain
|
40
|
64.5%
|
Vomiting
|
32
|
51.6%
|
Constipation
|
8
|
12.9%
|
Endoscopy
|
|
|
Normal
|
13
|
21.0%
|
Inflammation or ulceration
|
3
|
4.8%
|
Genetic Mutation
|
|
|
TYMP
|
42
|
67.7%
|
Homozygous
|
31
|
50%
|
Compound heterozygous
|
11
|
17.7%
|
POLG
|
5
|
8.1%
|
aNot normally distributed data were reported as the median and interquartile ranges (median [25%, 75%])
GI=gastrointestinal, CNS=central nervous system
Out of 16 (25.8%) patients that underwent endoscopic screening, most gastroscopy and colonoscopy examinations showed normal macroscopic findings; however, terminal ileum inflammation and ulceration in the terminal ileum or descending colon were found in three patients. In patient from our hospital, since computed tomography (CT) enterography showed thickened intestinal walls (Fig. 2), transanal enteroscopy was performed with ileal biopsies. Multiple small superficial ulcers were found in the terminal ileum (Fig. 3), one of which was linear, and the surrounding mucosa was mildly hyperemic and edema. That's why she was easily misdiagnosed as Crohn's disease before making a definite diagnosis. Neurological symptoms in patients were observed for 3 (1, 11) years before diagnosis. The most common neurological symptoms were leukoencephalopathy (51, 82.3%), ocular signs such as ptosis or ophthalmoparesis (44, 71%), and polyneuropathy (43, 69.4%) (Fig. 4). The severity of these symptoms varies considerably among patients, where some patients may suffer from cognitive impairments while others may be asymptomatic. Metabolic disorders such as liver cirrhosis, diabetes mellitus, hypertriglyceridemia, and elevated plasma lactate were observed in some patients. We performed lactate exercise test in patient from our hospital. Blood lactate levels rised from 2.5mmol/L to 6.2mmol/L and 6.3mmol/L immediately after exercise and 10 minutes after exercise respectively, suggesting the diagnosis of mitochondrial myopathy. The course of the disease and symptoms were similar between the male and female patients; however, the percentage of leukoencephalopathy was higher in the female patients than that in the male patients (90.9% vs. 81.6%, P = 0.005). In 42 (67.7%) patients, the GI symptoms appeared before the neurological symptoms. Based on the course of the symptoms, the patients were divided into the GI symptom onset and neurological symptom onset groups. The percentages of abdominal pain and diarrhea were higher in the GI symptom onset group (100% vs. 25%, P < 0.001) than that in the neurological symptom onset group (100% vs. 50%, P = 0.001). The percentages of vomiting, weight loss/cachexia, leukoencephalopathy, ptosis/ophthalmoparesis, and polyneuropathy were similar between the two groups (Table 2). Most patients were <40 years old at diagnosis (younger group), whereas seven patients were >40 years old at diagnosis (elder group). The percentage of GI symptoms, including abdominal pain, vomiting, and diarrhea, was significantly higher in the younger group than that in the elder group (Table 3).
Table 2. Clinical features between GI symptom onset and neurological symptom onset group in mitochondrial neurogastrointestinal encephalomyopathy
Demographics
|
GI symptom onset group
|
neurological symptom onset group
|
p value
|
Leucoencephalopathy
|
36 (85.7%)
|
4 (66.7%)
|
0.118b
|
Weight loss / Cachexia
|
32 (100%)
|
4 (100%)
|
|
Ptosis / Ophthalmoparesis
|
30 (83.3%)
|
4 (100%)
|
0.628b
|
Polyneuropathy
|
31 (86.1%)
|
3 (75%)
|
0.714b
|
Diarrhea
|
33 (100%)
|
2 (50%)
|
0.001b
|
Abdominal pain
|
32 (100%)
|
1 (25%)
|
<0.001b
|
Vomiting
|
23 (92%)
|
3 (75%)
|
0.194b
|
Constipation
|
7 (16.7%)
|
0 (0%)
|
|
bChi-squared test, All P-values were two-sided, with P-values <0.05 considered as statistically significant
GI=gastrointestinal
Table 3. Clinical features between younger gourp (age less than 40 years old) and elder group (age over 40 years old) in mitochondrial neurogastrointestinal encephalomyopathy
Demographics
|
Younger group
|
Elder group
|
p value
|
Leucoencephalopathy
|
45 (83.3%)
|
6 (85.7%)
|
0.873b
|
Weight loss / Cachexia
|
41 (100%)
|
5 (100%)
|
|
Ptosis / Ophthalmoparesis
|
38 (86.4%)
|
5 (83.3%)
|
0.841b
|
Polyneuropathy
|
38 (86.4%)
|
4 (80%)
|
0.700b
|
Diarrhea
|
37 (97.4%)
|
4 (66.7%)
|
0.006b
|
Abdominal pain
|
36 (92.3%)
|
3 (60%)
|
0.032b
|
Vomiting
|
30 (96.8%)
|
1 (25%)
|
<0.001b
|
Constipation
|
8 (14.8%)
|
0 (0%)
|
0.275b
|
bChi-squared test, All P-values were two-sided, with P-values <0.05 considered as statistically significant
Genetics
Overall, 47 patients underwent genetic sequencing, among which 42 patients had TYMP mutations and 5 patients had POLG mutations. In total, 31 (73.8%) patients had homozygous TYMP mutations and 11 (26.2%) had compound heterozygous mutations. Most mutations were point mutations. No differences in the sex, age at diagnosis, course of symptoms, and clinical features were observed among the patients with TYMP and POLG mutations.
Treatment and Prognosis
Only a few reports on the treatment and prognosis of MNGIE were found in the literature. Because of severe malnutrition and cachexia, most patients relied on nutrition support beginning from enteral nutrition and transiting to parenteral nutrition accompanied by progressive intestinal depletion. Ten patients received or were waiting to receive allogeneic hematopoietic stem cell transplantation (HSCT), among which three patients showed clinical improvement after transplantation and restored enzyme activity to normal levels. However, four patients died due to infection after transplantation, and one patient was too weak to endure HSCT. In some reports, hemodialysis, peritoneal dialysis, repeated platelet infusion, and enzyme administration in the encapsulated red cells temporarily alleviated the symptoms. One patient underwent liver transplantation, after which the serum levels of toxic nucleosides rapidly normalized. The patient’s clinical conditions were stable at 400 days of follow-up, suggesting that liver transplantation may be a treatment choice.