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Autor: Svetlana Hadjiu Cornelia Călcîi N. Revenco I Iliciuc
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This paper reflects diagnostic criteria of mitochondrial diseases in children. It was noted that in children with multiple stroke – like episodes and neuroimaging changes, seizures, motor deficit, short stature, gastrointestinal, cardiac and ophthalmic disorders, laboratory testing should be initiated to recognize mitochondrial deficiency syndromes, particularly MELAS syndrome. The presence of red fibers in skeletal muscles and characteristic biochemical changes of mitochondrial defects support the diagnosis. Molecular genetic tests on mitochondrial DNA modifications will confirm the diagnosis. Genetic counseling should be given when there are mutations in mitochondrial DNA.


MD is part of the IEM that are rare separately, but together they performed a vast and varied group of diseases. Currently, there are over 6,000 recognized rare inherited metabolic disorders. [12]. Although rare in children, the IEM are the most complex problems that must confront pediatrics and other specialized fields. The complexity derives from the clinical syndromes that are repeated in different metabolic errors. Specific defects can lead to a wide spectrum of clinical manifestations with onset at different ages. [13] In different group of ages there are different diagnostic methods. Basic examinations that define metabolic assessment include: analysis of glucose, lactate, ammonia, amino acids in plasma and cerebrospinal fluid, assessment of uric acid level, IRM (may suggest the presence of mitochondrial disorders). In many cases, biochemical and molecular tests are needed to establish an accurate diagnosis, but their availability is sometimes impossible beaucause of the cost of investigations. This is a problem in our country to put a correct diagnosis and to make this investiagation. However, early diagnosis of IEM is indispensable and can prevent the disastrous consequences of ireversbile CNS involvement and of other organs.
In developed countries it is possible a prenatal diagnosis of many inborn metabolic diseases by finding of primary enzyme defect in fetal tissue, and emphasizing the accumulation of metabolites or macromolecular storage products in amniotic fluid or fetal cells. Recent research has revealed that the IEM diagnosis is important for the following reasons: some (phenylketonuria) benefit from specific treatment, and children with these disorders have increased chances to survival; late diagnosis involves irreversible neurological changes; for parents and relatives diagnosis is required a genetic counseling; birth of a sick child can be prevented by contraception. Obviously, are required new scientific ways of access, applying modern testing methods. A lot of studies showed that advanced technologies in fetal DNA (10th week) tend to replace prenatal diagnosis by amniocentesis. A proper diagnosis will allow the selection of the correct treatment when the IEM had irreversible impacts. [14]. Early diagnosis of IEM can prevent progression to severe consequences. Early diagnosis also enlarges the therapeutic window for prenatal diagnosis for future pregnancies. For this reasons, the clinician should know about a possible presence of metabolic diseases as the main cause of a wide spectrum of clinical symptoms. Early postnatal detection of neuro-metabolic diseases, especially MD is important for CNS prophylaxis of serious complications and improve the child’s disability. Today the meaning of enzyme replacement therapy is a new direction in medicine and, finally, there is hope in gene therapy. Anyway, some IEM can not be treated at this stage, but may become treatable in the future. [15, 16, 17]


The purpose of this paper is to underline the importance of early diagnosis and early treatment of EM. To achiev the goal we made a retrospective of previous studies, including our group of patients, witch was evaluated clinicaly and paraclinicaly and follow their dynamics on the specific treatments.

Materials and methods

The study included six children aged between 1 and 10 years, suspected for various forms of MD, hospitalized in Neurology Clinic of Hospital of Mother and Child Health Care. The children were investigated according to a standardized scheme including age of onset of MD, genetic heredity, the common neurological disturbances, the most common forms of epilepsy, neuro-imaging abnormalities , evolution under treatment, the degree of disabilities . In the study group it was observed a prevalence of EM associated with various disorders of the CNS in males, the ratio of 3: 1 (4 boys – 66.6% and 2 girls – 33.4%). Laboratory tests were performed, including: serum creatinine, creatine kinase, lactate levels, EMG, brain CT, MRI. Brain imaging was performed to confirm the presence of a demyelination process, being presented by a high-intensity signal in both: white matter and subcortical area of the brain. The study was mainly based on distinctive clinical signs, MRI and muscle biopsy.


Acute onset of MD in the study group was observed: in the newborn period – 3 children (50%), infancy – 2 children (33.4%), after 3 years – one children. The inherit predisposition was positive in 66.7% (4 children), in rest of children – 33.3% (2 children) it was not found the predisposition was uncertain. According to literature data EM is characterized by following clinical signs (Table 1).

Tabel 1. Basic syndromes in ME (S. Ilarischin)

Patients in the study group were classified according to their clinical phenotype as follows: MELAS syndrome – 2 children, NARP syndrome – 1 child, MERRF syndrome – 1 child, Leigh syndrome – 1 child, Kearns-Sayre syndrome – 1 child.
Others neurological manifestations in the study group were : mentally retardation, seizures, other paroxysmal events, headache, vomiting, abnormal muscle tone, auditory and visual disturbances, weakness, gait disorders and behavioral disorders. From extra-neurological abnormalities we can notice: low stature, hypertrophic cardiomyopathy, physical retardation, endocrine disorders, anemia, lactic acidosis. Main manifestations of neurological and extraneurological signs are summarized in Table 2.

Table 2: Neurological and extraneurological fetures in the study group

In children with epileptic seizures were observed following types of seizures: myoclonic – 1 child, tonic-clonic – 1 child, atonic – 1 child. The other clinical manifestations were hepatosplenomegaly in 2 children, facial dysmorphism- 2 children, digestive symptoms – 2 children, cardiomyopathy in 2 children, cardiac arrhythmia in one child.
The results show that the most common neurological manifestations in children’s study group were: mental retardation, pseudoseizures, ataxia, sensory hearing loss, retinitis pigmentosa, dementia, and among the most common extraneurological were: hypertrophic cardiomyopathy, low stature, lactic acidosis, physical retardation.
In all children were made following investigations: blood count, complete biochemical exam, summary of urine, ECG. All children were check by neurologist and geneticist. Ophthalmological examination was performed in all children, auditory exam – in 3 children, in 2 children was made cardiological consultation, hematological examination was done in 1 child and consulting of gastroentherologist – in 2 children. Further examinations were performed : abdominal ultrasound, brain MRI, brain CT, skeletal radiography. Three children benefit from EEG sleep induction. In tab. 3 are presented neurological examinations data.

Tabel 3: Paraclinical investigations in study group

The data presented in Table 3 reports the diagnostic methods that have been used for children in the group of study. In four cases, muscle biopsy revealed the presence of red muscle fibers. On EMG, in two cases, were observed myopathic potential, in one case – signs of peripheral neuropathy. The MRI exam detect in two cases hypodense foci, in two cases – cortical atrophy, in one case were found hyperintense areas in the basal ganglia and brainstem, in one case – calcifications in the basal ganglia and in one case – symmetrical cystic lesions and gliosis in cortex, basal ganglia and cerebellum with delayed myelination. Laboratory analysis has confirmed lactic acidosis in five cases and elevated pyruvate in blood in two cases. Examination of lactate / pyruvate ratio in CSF ​​ is essential in case of suspected MD, as biopsy tissue sampling – to assess tissue-specific changes.
Treatment of children in the group of study was symptomatic – 100%. Only one child showed satisfactory therapeutic response to conventional antiepileptic drugs and in 2 children the reducing of seizures was <50%. All children were supplemented with thiamine cofactor, carnitine and lipoic acid. Brain lesions were common in all MD which limits recovery of normal brain function. Correction of acidosis is indicated, but not all symptoms remitted. Two children showed satisfactory therapeutic response after administration of pyridoxine cofactor and one child – after administration of folic acid, other children did not show a therapeutic response to any of the therapeutic measures taken.
In all cases outcome was poor in association with mental retardation and regress in psychomotor development.


MD are part of the IEM, associated with multisystem disorder characterized by defective biochemical and genetic changes in mitochondria, with disorder of oxidation/reduction unit from the internal mitochondrial membrane in respiratory chain [1, 3, 9, 10]. EM are rare in medical practice and a symptomatic diagnostic is a major problem.
IEM concept is originally introduced by Archibald Garrod (1902-1908). He defining them as a group of various diseases with consecutive deviations from the normal course of various metabolic: amino acids, hydrocarbon , lipids, pigments, mineral salts, vitamins, mitochondria, etc. [14, 18, 19]
Normal mitochondria involves the integrity of all its structures component and functional balance, with admition with slight variations, without involvement of organellum normality.
Mitochondria are the cell’s energy engine, whitch generates ATP. The number of mitochondria in cell depends on its energy requirements, in muscle cells, for example, the number is very high. These cell’s organelles are essential for both :energy intake and for programmed cell death. [20, 21]
Each mitochondria of each cell contains many copies of the circular DNA molecules, double-stranded (mt -DNA) containing genes coding for ribosomal RNA and synthesis of various ARN-mt necessary for the biosynthesis of mitochondrial protein, as well as some of the proteins involved in the transport of electrons mitochondria (Fig. 1). The mitochondrial genome consists of 16,569 pairs of bases, containing 5.523 codons that encode for the 37 gene products. The vast majority of mitochondrial proteins, including the multi-subunit protein, involved in the transport of electrons, are encoded by nuclear genes. Mutations in these genes causes autosomal recessive disease, in which, the phenotype of the disease in different individuals from the same family tend to be very similar.
Each cells mitochondria is derived from cytoplasm of ovule; mitochondria and mt -DNA from the sperm are lost during fertilization . Mutations of mt-DNA are also inherited only from the mother. When several members of a family are affected by a particular disease, in relation to the heritage of mt- DNA mutations, inheritance model has the following character:

Tabel 1. Basic syndromes in ME (S. Ilarischin)

Figure 1. The human mitochondrial genome. The identity and relative locations of the various mitochondrial genes.

  • All female can be considered mt-DNA mutation carriers, whether or not clinical signs are present.
  • Phenotypic expression of the disease in different individuals with inherited mt-DNA mutation usually is varied, including severity of illness and diferent organ systems.
  • Hereditary metabolic diseases with mitochondrial inheritance from the male parent is excluded.

Each cell contains at least hundreds of mitochondria, mitochondria and mt-DNA can affect all or only a fraction of mitochondria. The effect of each mutation in the particular phenotype depending on the severity of mt-DNA mutations, the proportion of affected mitochondria and the susceptibility of various tissues from impairment of mitochondrial energy metabolism. Clinical phenotype varies considerably from one individual to another during the same mt-DNA mutations. A clinically healthy woman who possesses a mt-DNA mutation may produce completely healthy descendants, others descendants may die in early childhood, and some can be affected by variations clinical manifestation (with mental retardation, retinitis pigmentosum, ataxia). Thus, the absence of clinical manifestations in one of the proband relatives or insignificant presence of signs and symptoms not exclude the possibility of mutation at first. Rate of mutation in mt-DNA is much higher than that of nuclear DNA. [22, 23]

Mitochondrial damage can be caused by mutations in mitochondrial DNA or nuclear DNA, in which case all cell suffers.
The effects of mitochondrial disease may be quite different, since a poor distribution of DNA can vary from one organ to another. Mutations that in a person can cause liver disease to another person causing a brain disease. In addition, the severity of the defect can be significantly or unsignificantly. Minor defects produce only effort intolerance, without causing any serious illnesses or disabilities. Other mitochondrial defects impacting functionality of mitochondria and can have a negative effect on the whole body. As a general rule, the diseases are most serious when defective mitochondria is present in muscles and nerves, because these cells are the biggest energy consumers.
Mutations in the mitochondrial DNA often occur spontaneously. Sometimes enzymes that control the duplication of mitochondrial DNA genes, which are encoded by the nuclear DNA, are defective, resulting an increased rate of mitocondiral DNA mutations. In the mitochondrial division, DNA is randomly divided into new born mitochondria. It may happen that if only a few of the copies of mother’s DNA are mutated, many of defective copies can reach only in few molecules. Mitochondrial disease starts to become visible when the number of affected mitochondria tend a certain level, when more than half of copies of mitochondrial DNA is damaged, causing mitochondrial disease. [20, 21]
Point mutations of mt-DNA affect:

  • the genes required for synthesis of mitochondrial protein, the most common tRNA genes, the consequence being secondary damage to all respiratory chain complexes.
  • the genes encoding subunits of respiratory chain protein, with specific effect on isolated subunits.

Distribution of mutations: homoplasmic (similar in all tissues) and heteroplasmic (variable presence in mutant DNA and normal DNA from the same tissue).
The frequency of mutations: 6 – 17/100 000
Clinical syndromes – general features

  • only maternal transmission (because the mitochondria come only from the ovule, not from the sperm) in all descendants;
  • presence of limit effect : the percentage of mutant mitochondrial DNA exceed a certain limit in order to produce the clinical syndrome;
  • the presence of mitotic segregation: the percentage of mutant mtDNA in cells may change during division, which may change rapidly genotype;
  • lactic acidosis is constant;
  • the proliferation of mitochondrial mass in the skeletal muscle is responsible for the appearance of red muscle fibers which are typically negative for cytochrome c oxidase activity. [2, 3, 4, 5]

According to the investigation, some of the peculiarities of MD are:

  • are rare;
  • the affected person has neurological disorders in early ages of life;
  • acute onset of MD with neurological signs mainly occurs in infancy;
  • MD diagnosis is established, usually at age of infancy;

The reasons for delay diagnosis are:

  1. delay of early recognition of common phenotypes;
  2. false opinion that MB has particular clinical picture;
  3. the similarity of clinical manifestations to those found in other illnesses with which it is necessary to make a differential diagnosis: sepsis, intrauterine growth retardation, respiratory distress, recurrent vomiting, etc
  4. the accumulation of small molecules exert a toxic effect on the nervous system, with specific symptoms and clinical signs.
  • in study group it was a prevalence of males with MD associated with neurological symptoms;
  • in more than one third of studied patients the family anamnesis turned out to be worse, demonstrating its importance in the diagnosis of MD;
  • epilepsies have a frequent occurrence in the MD, is the most common of associated neurological manifestations followed by psychomotor retardation, tone and motility disturbances, sensory organs impairement, personality and behavior disorders;
  • in most cases administration of antiepileptic drug (DAE) is ineffective in some MD (hereditary mitocondriopatia );
  • delay of appropriate antiepileptic treatment lead to irreversible consequences until death, as a result of organic decompensation and / or adopting wrong therapeutic tactics;

Clinical symptoms appear with growing of child.

  • when the child is younger, the symptoms are less varied (acompaning systemic clinical signs);
  • during the newborn period, the most common clinical manifestations of MB are: seizures, apnea, recurrent vomiting etc .;
  • in infancy are associated: the delay in the developmental process, spasticity or hypotonia, autistic manifestations, abnormal eye movements, and choreoathetosis;
  • during the school period is specific: deterioration of school performance, loss of vision, behavioral disturbances;
  • MD have a chronic course and many of them – progressive;
  • often the problem remains hidden (“sleep”), another disease or stress can disturb the balance, facilitating the onset of clinical symptoms;
  • unfavorable prognosis in chronic forms of MD, but anyway better than in early forms;
  • death is a frequent phenomenon among MB with CNS impairment, due to disease severity and delay diagnosis and / or administration of a correct treatment.

To put a correct clinical diagnosis are nessesary following steps:

  • a detailed medical history – the most important step in suspecting MD. A positive family history is extremely informative;
  • the presence of unexplained neurological disorders: mental retardation, cerebral palsy, seizures, psychomotor retardation, abnormal motility;
  • loss of previously acquired purchases is suggestive of a progressive degeneration of the CNS;
  • if we suspect an IEM is required additional investigation.

Mitochondrial diseases may occur at any age. They have a serious natural course, fatal in early years of life, during childhood or sometimes benign. The clinical phenotype may present important elements to guide the diagnosis [6, 7, 9, 11].
Clinical symptoms are common in MD: brain, muscle, heart and sensory system. These clinical manifestations can be separated into individualized syndromes, as myopathies with external ophthalmoplegia, Kearns-Sayre syndrome, Leigh syndrome, MELAS syndrome and MERRF. Sometimes clinical symptoms does not enclose in any of the syndromes described. The symptomatology can express predominantly in CNS and muscle, but may be present signs of impairment of other organs and systems: osteoarticular system, liver, hematopoietic system, digestive and skin tissue. A mitochondrial origine must be expected in the association inexplicable signs that involves several organs that have no embryological origin [7, 8, 9, 11].
MD may occur in other disorders, and after a short time are added inevitable signs of neuromuscular impairment.
Often primary clinical manifestation in mitochondrial cytopathic desease is suffering of a single organ. None of the clinical manifestations is not sufficient to focus on the involvement of a mitochondrial defect. Later, the association signs of other organs and systems damage required laboratory tests whose results can document possible mitochondrial dysfunction. However the decisive diagnostic test is molecular analysis of mt-DNA [4, 7, 11].

MELAS syndrome (Mitochondrial Encephalopathy, lactate acidosis, stroke-like episodes) occupies a important places among causes of acute stroke in children and young people including. It is shown that 17% cases of infantile infarcts are those which appear as manifestations of MELAS syndrome. It is reported a frequency of 99% of stroke like episodes as cardinal symptom of disease, associated with myophatic phenomenon, ,, red fibers” and lactic acidosis. [3] This syndrom is described as mitochondrial myopathy, maternally inherited. [2, 3]
Acute deficiency of energetic substrates, associated with increased concentration of pathological components of respiratory chain metabolism underlying stroke episodes in such patients. Neuroimagistic fenomena are detected in the hemispheres (up to 80%), less the cerebellum and basal ganglia.
In case of suspected MELAS syndrome is important to remove their muscle biopsy, evaluat acidosis and lactate levels in the blood and CSF (cerebrospinal fluid), to improve a molecular-genetic examination for distinguish the most frequent point mutations of the gene A3243G mt-ADN, mitocondrial t-ARN [tRNA (Leu) ((UUR), found in 80% cases.

Clinical aspects:

  • onset around 15 years of age, with encephalopathy (migraine headaches, vomiting, stroke-like episodes, syncope, hemiplegia, loss of hearing);
  • myopathy in the 5th decade of life, fatigue and effort intolerance ;
  • distal sensory polyneuropathy with paresthesia and hyporeflexia;
  • cardiomyopathy in 15% of cases.

Laboratory diagnosis: lactic acidosis, increased serum CK, multifocal cortical lesions on MRI, normal EMG or presence of myopathy.
Evolution and prognosis: clinical course of the disease is variable, ranging from asymptomatic with normal development to progressive muscle weakness, lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, encephalopathy and premature death.
Treatment: The current therapeutic options for this syndrome is based on the use of antioxidants and cofactors of respiratory chain substrates like vitamins, but no significant benefit was seen with these methods.
Peculiarities of stroke in children shows that it is necessary to focus the efforts of many specialists – neurologists, neurosurgeons, geneticists, hematologists, rheumatologists etc. It is necessary to follow risk groups (stroke like episods in children). Detection of biochemical and genetic markers of metabolic disease and related conditions increasing the possibility of pathogenetic treatment, appropriate primary and secondary prophylaxis of acute cerebral stroke. [24]
Other clinical manifestations, such as seizures, diabetes, hair loss, short stature, motor deficit are part of the clinical picture. The syndrome is associated with a number of point mutations in the mitochondrial DNA, more than 80% of the mutations occurring in the loop of dihydrouridine mitochondrial tRNA, gene [tRNA (Leu) (UUR), A → G]. In young patients with multiple episodes of stroke in different vascular territories and neuroimagistic abnormalities, seizures, motor deficit, short stature, gastrointestinal, cardiac, ophthalmic disorders, should be initiated laboratory tests to evaluate MELAS syndrome. [2, 3, 7, 9]
The presence of red fibers in skeletal muscle and characteristic biochemical determinations supporting the diagnosis. Molecular genetic tests on mitochondrial DNA modifications will confirm the diagnosis. Genetic counseling should be given when there is a mutations in mitochondrial DNA. [1, 3, 7, 9]

Leigh syndrome
Genetic features: syndrome caused by a point mutation mt-DNA, associated with multiple deficiencies (of CI, CII, CIII) and the decrease in mitochondrial production of ATP
Clinical features:

  • Onset is most common in the first year of life with episodes of ataxia, vomiting and hyperventilation syndrome;
  • Manifestations of encephalopathy with verbal and motor deficits (spasticity, respiratory disorders), dystonia, vision and hearing loss;
  • Peripheral neuropathy with reduced nerve conduction, secondary axonal demyelination.

Laboratory diagnosis: lactic acidosis, especialy in CSF (compared to blood), cytochrome oxidase deficiency in muscle biopsy, symmetrical focal, bilateral lesions on MRI.
Leigh disease is due to failure of mitochondria to function normally. Brain’s cells contain mutant mitochondrial DNA, leading to inefficient functioning of mitochondria. This causes a lack of energy in cells that result in inhibition of CNS and motor functions, the persons not being able to control their movements. Other symptoms include: loss of appetite, vomiting, irritability, seizures, generalized weakness, heart problems. There is still no cure for this disease, currently being administered vitamin B1.
Evolution and prognosis: the disease evolves with progressive mental and motor regression, death occurring in about 2 years of disease onset. [2, 3, 7, 9]

Syndrome LHON (Leber’s optic hereditary neuropathy)
Genetic features: syndrome is characterized by the presence of several point mutations of mt-DNA in genes of respiratory chain complex Ia, the most common being: G11778A, G3460Aşi T14484C.
Clinical aspects:

  • Onset is in men, around 30 years of age with loss of view (often the only manifestation of disease);
  • Painless vision loss is progressive, evolving variable depending on the severity of mutations or by optic nerve atrophy with blindness;
  • Associated manifestations: cardiomyopathy, dystonia and spastic paraparesis. [2, 3, 7, 9]

MERRF syndrome (progressive myoclonic epilepsy with ragged red fibers)
Genetic features: In 80-90% of cases there is a heteroplasmic mutation 8344 (transition A-> G) in the gene coding transfer RNA (tRNA-lysine). This mutation is associated with a wide variability of symptoms. The transmission isbased on maternal origin.
Clinical aspects: onset during childhood or adulthood. This syndrome associates: progressive myoclonic epilepsy, ataxia, and myopathy. Intellectual degradation is more or less severe and rapid. In a few observations are found lipomas in the cervical region. Muscle biopsy shows RRF appearance and frequently reflects a deficiency of complexes I and IV [2, 3, 7, 9].

NARP syndrome (neuropathy, ataxia, retinitis pigmentosa)
Genetic features: It is due to a heteroplasmic mutation located in position 893 in the gene of ATPases.
Clinical features: starts usually after 5 years and include: motor deficit due to a sensomotor axonal neuropathy, ataxia, retinitis pigmentosa, pyramidal and extrapyramidal syndrome, progressive dementia and seizures. Typically there is no deficiency of lactic acidosis respiratory chain complexes.
Neurological and neuromuscular disorders which are caused by disorders in the mitochondrial respiratory chain, have been recognized with increasing frequency in the past 30 years. Mutations in mitochondrial or nuclear genome producing an error in synthesis of essential energy product, leading to a variety of problems in the clinical and functional diagnosis [3, 4, 6, 9, 11 ].
The diagnosis of mitochondrial diseases is heterogeneous and complicated. Diagnosis is often a long process, with a general clinical assessment, followed by metabolic screening and neuroimagery, and finally, genetic tests and more invasive biochemical and histological analyzes. [5, 7]


  1. MD in children are rare and represent one of the most complex problems in neurology. The complexity arising from various clinical syndromes (mental retardation, ataxia, deafness, short stature, seizures, retinitis pigmentosa, cardiomyopathy), present of phenotypic manifestations and multiple biochemical defects identified. Specific defects can lead to a wide spectrum of clinical manifestations with onset at different ages. In many cases, biochemical and molecular tests are needed to establish an accurate diagnosis.
  2. History of disease, heredity history, linked to sex and family, the notion of sudden death in infancy, unexplained presence of neonatal deaths, psychomotor retardation and other neurological signs are suggestive for diagnosis.
  3. Often MD is characterized by epileptic syndrome and it should be suspected when epilepsy is resistant to antiepileptic treatment and is associated with symptoms such as: mental retardation and motor disorders.
  4. Diagnostic methods depend on the age of the child. Basic examinations include: analysis of plasma and CSF glucose, lactate levels, ammonium, amino acids in plasma and CSF assessment of serum uric acid etc.
  5. A method of choice in diagnosing EM is brain MRI. In some cases results are pathognomonic in metabolic disorders (eg MRI picture characteristic for mitochondrial cytopathy).
  6. Genetic tests are important for detection of mitochondrial disorders and should be performed in children who have suffered an ischemic stroke.
  7. The corect diagnosis helps us to appreciate the prognosis of disease and improve quality of life in children.
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