- Case report
- Open Access
Childhood mitochondrial encephalomyopathies: clinical course, diagnosis, neuroimaging findings, mtDNA mutations and outcome in six children
© Lu and Huang; licensee BioMed Central Ltd. 2013
Received: 15 July 2013
Accepted: 21 September 2013
Published: 26 September 2013
Mitochondrial dysfunction manifests in many forms during childhood. There is no effective therapy for the condition; hence symptomatic therapy is the only option. The effect of symptomatic therapy are not well known. We present clinical course, diagnosis and effect of current treatments for six children suffering from mitochondrial encephalomyopathy identified by clinical demonstrations, brain MRI findings and DNA mutations. Two were male and four were female. Their age ranged between 2 and 17 years. Skeletal muscle biopsies were obtained in three and one showed misshaped and enlarged mitochondria under electron microscope. mtDNA mutation frequency was >30%. Five children were diagnosed with MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) and one with Leigh’s syndrome (LS). All were given cocktail and symptomatic treatments. One of the five MELAS children died from severe complications. The other four MELAS children remain alive; four showed improvement, and one remained unresponsive. Of the four who showed improvement, two do not have any abnormal signs and the other two have some degree of motor developmental delay and myotrophy. The LS child is doing well except for ataxia. Until better therapy such as mitochondrial gene therapy is available, cocktail and symptomatic treatments could at least stabilize these children.
Mitochondrial disorders are a group of metabolic diseases, which may cause any symptom, may present at any age, have harmful effects on any tissue and occur by any inheritance pattern . Mitochondrial dysfunction causes a huge burden of disability. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a more frequently identified mitochondrial disorder.
Currently, there is no effective remedy for mitochondrial disorders. Potential therapies such as stem cell transplantation and gene therapy are only in preliminary stages, making cocktail (i.e. supplementation with carnitine, coenzyme Q10, thiamine, L-arginine, folate, etc.) and symptomatic treatments the only options for clinical treatment. A combination of nutraceutical compounds often referred to as “mitochondrial cocktail” is based upon a rational attempt to target the final common pathways of mitochondrial dysfunction and provision of alternative energy sources . In this context, we present clinical diagnostic aspects, cocktail and symptomatic treatments, efficacy of such treatment and course of mitochondrial encephalomyomathy (ME) in six children.
Clinical characteristics and laboratory findings on admission
At the time of disease onset
Laboratory finding (serum)
Lactic acid (mmol/L) (<2.0 normal)
Creatine kinase (IU/L) (22 ~ 270 normal)
Brain MRI findings
Twitching,stroke like episode
Deafness, twitching, glossolalia, mobility limitation
Patchy T1 and T2 abnormal signals in right temporal, occipital and parietal lobes and left parietal lobes.
Mobility and speaking limitation, amyotrophy, monophasia
Spotted T1 and T2 abnormal signals in left corona radiata.
Vomiting, lethargy, hypophrenia, speaking and mobility limitation
Multiple patchy T1 and T2 abnormal signals in bilateral cerebellar hemisphere, both occipital lobes and right parietal lobe.
Vomiting, headache, lethargy
Vomiting, headache, lethargy, positive reflex
Large patchy T1 and T2 abnormal signals in left temporo-occipito-parietal lobes.
Pitting edema, tachycardia, blurred vision, seizures
Pitting edema, tachycardia, blurred vision, seizures
Large patchy T1 and T2 abnormal signals in bilateral temporo-occipito-parietal lobes.
Progressive motor retardation, tremor, ptosis
Progressive motor retardation, tremor, ptosis
Abnormal signals in bilateral cerebral peduncle and brainstem tegmental area.
Mitochondrial DNA mutations from blood samples
Patient’s mother’s mutation frequency
Special features of two siblings (patient 1 and patient 2):
Figure 1 shows clinical courses of mitochondrial diseases in six patients. Three patients were admitted to hospital at the onset of the disease, while the other three admitted with some time delay (about one to two years after disease onset). Until the latest follow up in October 2012, five patients were stabilized with cocktail and symptomatic treatments and, one was free from all symptoms. One patient died at home due to recurrence of a stroke-like episode with severe complications.
Mitochondrion is a vital organelle and its dysfunction can cause various diseases at various levels in cells, tissues, organs and systems. The final result of mitochondrial diseases is the failure for the cell to produce energy in the form of adenosine triphosphate (ATP) leading to multisystem dysfunction . These diseases start in childhood and progress subsequently with significant suffering that result in heavy burdens on affected families. Mitochondrial encephalomyopathy is one of the most frequent clinical phenotype of childhood mitochondrial disorders . For several decades, cocktail and symptomatic treatments remain the only seemingly effective therapy , but the outcome of mitochondrial disease with these treatments is unknown.
Mitochondrial diseases occur due to mtDNA mutations or deletions. Other mitochondrial diseases due to mitochondrial structural defect, nDNA mutations, intergenomic signaling defects between nDNA and mtDNA, etc. are not easily diagnosed . For many years the most frequently reported mitochondrial disease has been MELAS .
Early diagnosis of mitochondrial diseases and effective treatment is a challenge in the medical world. A careful clinical examination and search for typical symptoms  is the key that leads to initial diagnostic work-up. Because of highly variable phenotypes of mitochondrial diseases, they are often undiagnosed or misdiagnosed as other neuromuscular diseases, developmental delay, encephalopathy, etc. Six patients we described above also had presentations easily leading to misdiagnosis such as vomiting, neuromuscular dysfunction, epilepsy, ataxia, speech delay and ocular disorders. They had a mean time delay for diagnosis of 1 (1.1 ± 0.8) year.
The neuroimaging often give early clues for diagnosis of ME. The brain MRI findings of above six patients showed characteristic abnormal signals in occipital, temporal, parietal lobes and basal ganglia. Typical “protean” manifestations with time were also characteristically observed. Skeletal muscle biopsy and mutational studies help in the diagnosis in the absence of straightforward radiological findings. Observation of mitochondrial ultrastructure in a muscle under electron microscope is useful although all patients may not show the changes . In the present case series one of the three muscle biopsied patients showed misshaped and enlarged mitochondria indicative of mitochondrial dysfunction. The clinical phenotype, MELAS in the above five cases corresponded with m.3243A > G mutation with a mutation frequency of 32.3% to 53% (mean value, 42.9% ± 9.2%). Leigh’ syndrome had m.13513G > A mutation with a mutation frequency of 75%. This aspect shows that there is no direct relationship between the clinical severity and the mutation frequency. The threshold mutation rate of MELAS usually reported in the literature is >70-80% . Quantitative analyses of the mutation among siblings (Figure 4) showed different mutation loads in blood and urine [in patient 1: 34% and 59.7% respectively and in patient 2: 53% and 75.3% respectively]. The mutation loads in blood is lower than in urine. Usually the blood specimen is used to study mutation frequency instead of urine because of the more complicated processing of the urine sample.
The serum biomarkers, such as lactic acid, ammonia, creatine, and glucose are useful to some extent though they lack specificity. The high levels of lactic acid and creatine in all six patients reflected metabolic disorder and muscle damage.
Currently, cocktail therapy enhancing respiratory chain function  and symptomatic therapy  remain the only treatment options for mitochondrial disorders. We achieved a stabilization rate of 83.3% (5/6) with these treatment options.
Symptomatic treatment focused on the following symptoms: lactic acidosis, epilepsy, respiratory failure, cardiac arrhythmia, malnutrition and abnormalities of muscle tone. We used sodium bicarbonate to treat lactic acidosis when the patient had recurrent stroke-like episodes and presented with shock. To treat epilepsy, we used carbamazepine or diazepam instead of sodium valproate, which has been associated with liver disease. Invasive or non-invasive mechanic ventilation was used for respiratory failure. Regular anti-arrhythmia regimen will delay progression of cardiomyopathy and heart failure. Because of bulbar or pseudobulbar complications of mitochondrial disease, we used nasogastric tube feeding in small children with dysphagia and increased risk of aspiration pneumonia. We cooperated with physiotherapists to treat the patients with dystonia and spasticity, which gave some improvement.
In conclusion, from our clinical study, we believe cocktail and symptomatic treatments, at present, can stabilize childhood mitochondrial diseases to some extent. The long term benefits of these treatment modalities however need to be explored further.
Written informed consent was obtained from the parents of these patients for publication of these cases and accompanying images.
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