To the Editor We read with interest the article by Suzuki et al. about three patients
harbouring the m.3243A>G mutation manifesting as mitochondrial myopathy, encephalopathy,
lactic acidosis, and stroke-like episodes (MELAS) syndrome and intestinal pseudo-obstruction
(Table) (1). We have several comments and concerns.
Table.
A Comparison of the Three Described Patients.
P1
P2
P3
Sex
f
f
f
Height (cm)
140
np
147.5
Weight (kg)
25.1
np
47.8
Age at onset (y)
10
12
39
First manifestation
SLE
SLE
Diabetes
Presentation
vomiting, headache,
multiple strokes
staggering gait,
cerebral atrophy,
headache, vomiting
bradykinesia, rigidity,
multiple strokes
seizures,
forced crying/laughing,
blurring, seizures,
bloating
abdominal pain,
abdominal pain,
vomiting, dystonia
bloating
muscle weakness,
hypoacusis, myopathy
gait ataxia, neuropathy,
increased reflexes,
cerebral atrophy,
hot cross bun sign,
urinary retention
NOO involved
4
2
5
Creatin kinase (U/L)
105
np
16
Lactate (mg/dL)
14.7
np
19.4
Degree of progression
np
np
np
Age at death (y)
23
22
54
Cause of death
Aspiration pneumonia
Renal failure
Aspiration pneumonia
Genetic cause
m.3243A>G
m.3243A>G
m.3243A>G
Sampled tissue
blood
blood
blood
Heteroplasmy rate
np
np
np
NOO: number of organs, SLE: stroke-like episode, np: not provided
Mitochondrial disorders (MIDs) may accompany neuropathy of the peripheral nerves,
including affection of the autonomic fibers (2). As such, intestinal pseudo-obstruction
can occur due to autonomic neuropathy. Were there indications for autonomic neuropathy
in any of your cases, such as increased sensitivity to light, dry mouth, dry eyes,
orthostasis, abnormal heart rate variability, obstipation, urinary dysfunction, impotence,
or dry skin? Were instrumental investigations carried out to search for autonomic
neuropathy?
The hot cross bun sign is a non-specific morphological feature on magnetic resonance
imaging (MRI) and has not only been described in multisystem atrophy-C, spinocerebellar
ataxia-2 (SCA2) and SCA3 but also in Alzheimer’s disease, natalizumab-induced, progressive
multifocal leucencephalopathy, neurosarcoidosis, late-onset SCA11, single large-scale
mtDNA deletions, paraneoplastic syndromes, SCA34, leptomeningeal metastasis, SCA23,
HIV-related multifocal leucoencephalopathy, brainstem stroke, familial amyotrophic
lateral sclerosis, cerebrotendineous xanthomatosis, Parkinson syndrome, and Creutzfeld-Jacob
disease.
Atrophy of the cerebellum or brainstem is a frequent finding in MIDs and may even
be the dominant feature of the phenotype (3). Cerebellar atrophy has been reported
in Leigh syndrome, Kearns-Sayre syndrome, Myoclonus epilepsy associated with ragged-red
fibers (MERRF) syndrome, external ophthalmoplegia, Neuropathy, Ataxia, and Retinitis
Pigmentosa (NARP) syndrome, Leukoencephalopathy and Brainstem and Spinal cord involvement
and Lactate elevation (LBSL), ponto-cerebellar hypoplasia-6, and non-specific mitochondrial
multiorgan disorder syndrome (MIMODS). The causes of phenotypic heterogeneity within
or between families are versatile and include a variable heteroplasmy rate in different
individuals (4) as well as haplotype, mtDNA-polymorphisms, and nuclear mutations.
Work-up for phenotypic heterogeneity should also include determination of the heteroplasmy
rate in different affected and non-affected tissues, such as hair follicles, buccal
mucosa, skin fibroblasts, muscle cells, and urine bladder cells.
Gastrointestinal compromise is a frequent manifestation in MIDs and may not only include
pseudoobstruction but also poor appetite, gastroesophageal sphincter dysfunction,
constipation, dysphagia, vomiting, gastroparesis, diarrhoea, pancreatitis, and hepatopathy
(5). Rare gastrointestinal manifestations of MIDs include dry mouth, paradontosis,
tracheoesophageal fistula, stenosis of the duodeno-jejunal junction, atresia or imperforate
anus, liver cysts, pancreas lipomatosis, pancreatic cysts, congenital stenosis or
obstruction of the gastrointestinal tract, recurrent bowel perforations with intra-abdominal
abscesses, postprandial abdominal pain, diverticulosis, and pneumatosis coli (5).
Were any of these manifestations present in any of the patients?
Overall, this interesting case study would profit from the determination of the heteroplasmy
rates in different tissues, prospective investigations for MIMODS, investigations
for autonomic neuropathy, and from a more extensive family history. Gastrointestinal
abnormalities should be regarded as typical manifestations of MIMODS.
The authors state that they have no Conflict of Interest (COI).