Fever died after 1 day, the sharp progression of the disease is behind this disease ...

*For medical professionals only

Psychomotor development in infants or children is lagging behind, and the disease progresses sharply after infectious stress, and it is necessary to be vigilant against the possibility of Leigh syndrome!

 

If infants with psychomotor development are treated at high-risk follow-up with a history of hypoxic ischemic encephalopathy, is cerebral palsy considered alone? What is the cause of the sharp deterioration of the child's condition after fever? And how to make a diagnosis and treatment plan?

Case introduction

Complaint: Male, older in April, admitted to hospital
for "fever for 1 day, poor response with pale face for 1 hour".

Current medical history: the child developed fever after 1 day of contact with the mother with respiratory infection, the heat peak was 39 ° C, and oral drug treatment in the local hospital (specifics are unknown).

1 hour ago, the child suddenly had a poor response, pale, no vomiting, no convulsions, and was rushed to our hospital for treatment
.

Past history:
"neonatal asphyxia", "neonatal hypoxic-ischemic encephalopathy", "fetal amniotic cavity infection", "neonatal pneumonia", "neonatal umbilical cord around the neck", "maternal B streptococcal (GBS) infection of newborns", "scalp hematoma with tumor production", "cardiac enzyme spectrum abnormality", "neonatal jaundice" hospitalized for 15 days
.

After discharge, there were 3 courses of rehabilitation treatment in the hospital, during which the head MR was perfected: mild cerebral edema, no abnormalities were found in hematuria tandem mass spectrometry, poor rehabilitation effect, and regression of motor development
.

At the age of 4 months, in the high-risk children in our hospital, the follow-up clinic, neurology outpatient clinic, physical examination: head up to 45 °, sitting upright and unstable, will not turn over, hands do not see the grasp, chase things slowly, less laughter, improve the skull MR: extracerebral space widening, bilateral ventricle and third ventricle widening, a small amount of bleeding in the right top subdural space, diagnosis of "high-risk children", "delayed developmental indicators", "congenital genetic metabolic diseases to be discharged", it is recommended to improve genetic testing, family members refuse
.

Personal history: the child is the first birth of the first fetus, gestational age of 40 weeks + 1 due to "intrauterine distress" in the outer hospital forcep birth, birth weight 3280g, 1 minute -5 minutes -10 minutes A score of 4-8-9 points, mixed feeding after birth, no feeding difficulties
.

Family history: Parents are physically fit, denying that close relatives are married
.
Two of the children's uncles had intellectual problems (specific etiology unknown
).

Physical examination at the time of admission: confusion, poor response, pale complexion and lips, full anterior fontanelle, equal circle of both pupils, diameter 1.
5mm, sluggish reflex to light, shallow and irregular breathing, sobbing-like breathing, breathing 18 times / min, weak breathing sounds in both lungs, unheard dry and wet rales, heart rate 180 times / min, rhythm, unheard pathological murmurs in each valve area
.
The abdomen is flat and soft, the liver and spleen are not palpated under the ribs, the bowel sounds are normal, the muscles of the extremities are low, the bilateral Pap sign is negative, and the meningeal irritation sign is negative
.
No rash
was seen on the hands and feet.
Capillary refill time (CRT): 3 seconds
.

Auxiliary examination: cranial CT:
1.
Bilateral basal ganglia, thalamus, and dorsal midbrain low-density foci; 2.
Consider chronic subdural hematoma on the right side of the top and institutionalize; 3.
The extracerebral space is slightly widened
.

Figure 1: CT of the patient's skull

Blood ketone body / lactate pyruvate ratio determination: lactic acid 7.
010 mmol / L, pyruvate 0.
280 mmol / L, 3-hydroxybutyric acid / acetoacetic acid 3.
300, lactic acid / pyruvate 25.
000
.

Blood acyl carnitine analysis: C3 4.
84 μmol/L, C4-OH 4.
21 μmol/L, C5 0.
45 μmol/L, C5-OH 0.
45 μmol/L
.

Plasma amino acid analysis: alanine 1087.
1 μmol/L
.

Urine GCMS analysis: a large amount of lactic acid and a moderate amount of pyruvate may be seen in the urine
.

Blood cultures and CSF cultures were not abnormal
.

Figure 2: After the patient's biochemical test results
were admitted to the hospital, the patient was given symptomatic treatment such as invasive ventilator to assist respiration, anti-infection, improve metabolic crisis, correct internal environmental disorders, etc.
, and repeated metabolic crisis, metabolic acidosis, and hyperlactemia during hospitalization, combined with cranial CT and hematuria tandem mass spectrometry, clinically considered Leigh syndrome
。 Vitamin B2, three-dimensional B tablets, folic acid tablets, coenzyme Q10 and levocaniptine were given to improve abnormal energy metabolism, blood purification and removal of metabolites, but due to internal environmental disorders that are difficult to correct, multiple organ failure, family members give up treatment and die
.
Gene test returns: MT-ATP6 gene mutation, 8993T>G, 98.
65% from the mother, maternal mutation rate of 51.
3%, known pathogenic mutation, nuclear gene detection is normal
.

Knowledge points

Leigh syndrome (LS), also known as subacute necrotizing encephalospinal myelopathy, is a degenerative disease of the nervous system with diverse clinical symptoms caused by mitochondrial genes or nuclear genes, and is the most common mitochondrial encephalomyopathy
in infancy and childhood.
The incidence of Leigh syndrome abroad is about 1/77,000 to 1/34,000 cases, and there is no multi-center study
of the epidemiology of Leigh syndrome in China.

Leigh syndrome has a complex etiology, and since it was first reported in 1951, more than 85 mitochondrial and nuclear gene mutations have been found to cause defects in the mitochondrial respiratory chain 5 enzyme complexes (I.
~V.
), pyruvate carboxylase or pyruvate dehydrogenase complexes, cofactor (lipoic acid, coenzyme Q10) synthesis disorders and cause disease, of which mitochondrial gene mutations cause Leigh syndrome in about 20% (maternal inheritance), Nuclear gene mutations cause approximately 80% of Leigh syndrome (autosomal recessive, autosomal dominant, X-linked), and a few are caused by
loss of copies of mitochondrial genes.

Be alert to these abnormalities

Leigh syndrome is highly phenotypic and genotypical, with a wide variety of clinical symptoms, ranging from no symptoms to severe neurologic abnormalities, and common clinical symptoms can be divided into neurologic manifestations and non-neurologic manifestations
.

1 Nervous system manifestations of central nervous system abnormalities: psychomotor development delay or regression, ataxia, dystonia, seizures, brainstem dysfunction (feeding difficulties due to dysphagia, persistent vomiting, breathing abnormalities, thermoregulation abnormalities), cranial nerve palsy (abnormal eye movements, optic nerve atrophy, pigmented retinitis), sensorineural hearing loss
.

Abnormalities of the peripheral nervous system: polyneuropathy or myopathy
.

2 Non-neurologic manifestations of cardiac abnormalities: hypertrophic cardiomyopathy, extended cardiomyopathy, arrhythmias; Renal abnormalities: tubular dysfunction, diffuse glomerular cystic injury; Abnormalities of the digestive tract: liver damage, dysphagia, vomiting, megacolon, bowel paralysis; Endocrine abnormalities: diabetes, short stature, hirsutism; Disorders of the blood system: anemia
.

Leigh syndrome can be divided into neonatal, classic, juvenile, and adult types according to the age of onset, and the clinical manifestations of different types are different, and the earlier the onset of the disease, the more severe
the symptoms.

1.
Newborn type: the initial manifestation of the disease is mostly sucking, swallowing disorders and dyspnea, followed by gradual brainstem dysfunction and serious motor development lag, often early death
.

2.
Classic infant type: this type is the most common, mostly before the age of 2 years of age, often progresses rapidly after onset, and the clinical manifestations are progressive exacerbations of psychomotor development backwardness or regression, swallowing and feeding difficulties, growth retardation, myoclonus or convulsive attacks, ataxia, ophthalmic abnormalities, respiratory rhythm changes or abnormal thermoregulation and other brainstem symptoms
.

3.
Juvenile type: often insidious onset in childhood, growth and development in the early stages of life can be normal, due to infection, fatigue, hunger, surgery and other stress-induced diseases, gradually appear spastic paraplegia, ataxia, exercise intolerance, nystagmus, strabismus, visual impairment and Parkinson-like manifestations, height and body weight are often lower than the same sex and age and race normal
.

4.
Adult type: the adult type is rare and mainly consists of atypical symptoms, such as intellectual regression, vertical gaze paralysis, headache, amnesia and visual hallucinations
.

Diagnostic methods

The diagnosis of Leigh syndrome is based on a combination of clinical manifestations, cranial imaging, biochemical testing, muscle biopsy, and genetic testing
.

Routine biochemical examination: increased blood and cerebrospinal fluid lactate levels and blood lactate/pyruvate ratio, high anion gap metabolic acidosis is the main biochemical change of Leigh syndrome, and lactate levels may be normal
in some cases.

Neuroimaging examination: cranial imaging can show bilateral symmetrical lesions such as basal ganglia, thalamus, and brainstem, and in some cases, white matter lesions, cerebral infarction, and cerebral atrophy may occur
.

Mass spectrometry: urinary lactate and pyruvate were significantly elevated in most cases, and in some cases, blood acyl carnitine was abnormally high for C3 and C5-OH, and plasma amino acid analysis was elevated
by alanine.

Tissue biopsy and enzymatic analysis: tissue biopsy shows changes in mitochondrial histology and ultrastructural examination, mitochondrial respiratory chainase activity is abnormal, but lacks specificity, and tissue biopsy and enzymatic analysis can be completely normal
in some cases.

Molecular genetic diagnosis: Mitochondrial gene and nuclear genetic testing are the gold standard
for diagnosing Leigh syndrome.

At present, the 2014 European diagnostic standards are mainly used:
1.
Various symptoms caused by neurodegenerative diseases accompanied by mitochondrial dysfunction;
2.
Mitochondrial dysfunction caused by genetic defects in the mitochondrial or nuclear genome;
3.
Imaging examination shows symmetrical lesions
of the basal ganglion, brainstem or other central nervous system.

differential diagnosis

1 Cerebral palsy refers to non-progressive central nervous system damage caused by multiple factors in the fetal or infant stage, bilateral basal ganglia and thalamus damage can be seen on cranial imaging, and early recovery can improve clinical symptoms
.

Although there is a history of perinatal asphyxia resuscitation in this case, after early evaluation and intervention, there is still a regression in motor development, metabolic acidosis and hyperlactemia in the course of the disease, and the pathogenic mutation found by mitochondrial genetic testing, so the diagnosis
of cerebral palsy can be ruled out.

2 Kernic jaundice refers to neonatal hyperbilirubinemia that is not treated in time, causing bilirubin to accumulate in the basal ganglia, thalamus and other areas, resulting in irreversible non-progressive brain damage
.

In this case, there is no history of hyperbilirubinemia in the neonatal stage, and there is a history of motor development regression, which can be excluded
by laboratory and genetic testing.

3Wernicke encephalopathy is caused by thiamine deficiency caused by malnutrition, gastrointestinal surgery, etc.
, and the clinical symptoms are mental disorders, ataxia, ophthalmolysis, etc.
, and the head imaging performance can be similar to that of the disease, and the neurological symptoms can be significantly improved
after immediate thiamine treatment.

In this case, there was no improvement
in the condition after treatment with three-dimensional B tablets.

4Wilson's degeneration is a copper metabolism disorder caused by mutations in the ATP7B gene, which can manifest as persistent liver damage, dyskinesia, dystonia, corneal K-F ring, psychiatric abnormalities, and a significant decrease
in ceruloplasmin.
Imaging of the skull shows bilateral lesions
of the legumar, thalamus, and midbrain.
Typical extrapyramidal symptoms
.

In this case, no clinical symptoms such as persistent liver damage and corneal K-F ring were observed, and no ATP7B gene mutation
was found in genetic testing.

Combined with the case analysis of children in this article:
1.
Onset of illness in infancy, backwardness and regression of psychomotor development, and rapid progression of the disease after infection stress;
2.
Cranial CT can show bilateral basal ganglia, thalamus, and dorsal midbrain low-density foci;
3.
Biochemical detection can see metabolic acidosis and hyperlactemia;
4.
Mass spectrometry detection: blood acyl carnitine analysis C3, C5-OH abnormally high, plasma amino acid analysis alanine elevation, urine GCMS analysis: a large amount of lactic acid can be seen in the urine, a medium amount of pyruvate acid;
5.
Family history of positive genetic diseases;
6.
Genetic testing: MT-ATP6 gene mutation
.

Therefore, the diagnosis of the child is: Leigh syndrome (MT-ATP6 gene mutation, classic infant type)
currently has no specific treatment plan, clinical treatment is mainly symptomatic, supplementation of mitochondrial oxidative respiratory chain in the related coenzymes, some patients can slowly develop after avoiding stress factors such as infection, and even maintain long-term stability
.

Summarize the clinical manifestations of Leigh syndrome are complex and diverse, with insidious onset and difficult to identify
at an early stage.
Children with poor psychomotor development during the follow-up of high-risk children should have a comprehensive analysis of the cause, avoid missing family genetic history, strengthen multidisciplinary collaboration, early diagnosis and early treatment, and reduce the pain of the child and the burden on
the family.





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