Histidinemia is a violation of amino acid metabolism (primary aminoacidopathy), in which an excessive amount of histidine accumulates in the blood. The disease is caused by a defect in the enzyme histidase, has an autosomal recessive type of inheritance. The disease manifests itself as a convulsive syndrome, impaired speech and intellectual development. Patients have a characteristic phenotype. The diagnosis is based on the determination of the level of histidine and its metabolites in blood and urine, the study of histidase activity in liver and skin biopsies. The main principle of treatment is diet therapy to limit the amount of histidine in the diet.
ICD 10
E70.8 Other metabolic disorders of aromatic amino acids
General information
Clinical manifestations of histidinemia were first described by the American pediatrician H. Gadimi in 1961, the disease received its modern name a year later thanks to his colleague V. Auerbach and co-authors. According to various data, the incidence of the disease ranges from 1:10,000 to 1:100,000 newborns, in Japan its prevalence is 1:9600, in Quebec, Canada – 1:8600. No significant sex differences were found among the sick children. Diagnosis of histidinemia is difficult, due to nonspecific symptoms and the difficulty of detecting biochemical abnormalities by routine laboratory methods.
Causes
The disease occurs in the absence, critical decrease or insufficient activity of the enzyme histidase in the blood. The cause of histidinemia is a mutation of the HAL gene on the long arm of the 12th chromosome. The pathology is hereditary, it is transmitted autosomally recessive: signs appear in children after a generation, there are no sexual differences among the sick. New data show the possibility of X-linked inheritance of histidinemia.
Pathogenesis
Histidine belongs to the essential amino acids for infants of the first year of life, since the child’s body is not able to synthesize it in sufficient quantities. In older patients and adults, it is considered a conditionally replaceable substance. Normally, the amino acid undergoes transformation to urocaninic acid and imidazole propionate, the end products of metabolism are glutamine, ammonia and methyl THC (coenzyme form of vitamin B9).
With histidinemia, a metabolic block occurs at the beginning of the chain of biochemical reactions, therefore, the exchange of histidine proceeds along a different pathway with the participation of histidine decarboxylase. However, most of the amino acid accumulates in free form in the blood and urine. Also, the level of imidazolacetic and imidazolpyruvic acids, which have neurotoxicity, increases in the body.
Classification
In clinical pediatrics, doctors mostly face a typical form of the disease when there is a deficiency of an enzyme in the liver and skin at the same time. In rare cases, the disease proceeds atypically in the following variants:
- Deficiency of histidase in the liver. At the same time, normal enzyme activity is observed in the skin, which partially compensates for its lack in the liver. The disease occurs in a milder form.
- Intermediate form. There is an incomplete block of the biochemical pathway of histidine conversion, which is caused by a moderate decrease in histidase activity. Symptoms occur later, they are less specific, severe complications do not develop.
- Combination with hyperalaninemia. It is formed with a double defect of enzymes that are responsible for the conversion of histidine and alanine. Pathology is inherited by autosomal dominant type, characterized by critical disorders in infancy.
Symptoms
The disease is characterized by polymorphic clinical signs: in some children it is asymptomatic, in others it causes severe organ and neuropsychiatric disorders. The timing of the appearance of the first symptoms varies from the newborn period to the age of 16. In the complete absence of the enzyme, pathological manifestations are observed already in the first 3-4 months of a child’s life.
Early signs of histidinemia include impaired motor and mental development, loss of previously acquired skills. Children lose interest in the world around them, show aggression. The defeat of the central nervous system manifests with generalized convulsions, and parents may also notice pathological hyper- or hypotension of the muscles of the extremities. More than 50% of patients with histidinemia have speech and intellectual development disorders up to severe mental retardation.
Patients with aminoacidopathies have typical changes in appearance caused by pathologies of pigment metabolism. Due to the reduced production of melanin, such children from birth have very light skin (corresponds to the first Fitzpatrick phototype), light brown or almost white hair on the head, eyelashes, eyebrows and other parts of the body. Also, patients with histidinemia have light gray or blue eyes.
Complications
In the absence of timely and correct treatment, histidinemia progresses. The toxic effect on the central nervous system provokes a gradual increase in the clinic of brain edema. At the same time, the child has a risk of compression of the brain stem with a violation of vital functions, disconnection of the cortex and subcortical structures of the central nervous system. In rare cases, histidinemia is accompanied by congenital anomalies of kidney and bone development, iron deficiency anemia, which aggravates the patient’s condition.
Diagnostics
The primary examination of the child is carried out by a neonatologist or pediatrician. To get a complete picture of the disease, it is necessary to clarify with parents the timing and features of the appearance of symptoms, find out the family history, cases of genetic diseases in the closest relatives. During physical examination, attention is paid to the anthropometric data, the neurological status of the patient. To confirm histidinemia, the following studies are prescribed:
- Blood test. The main sign of the disease is an increase in the level of histidine in the blood of more than 120 mmol / l, with a complete metabolic block, the indicators reach 290-1420 mmol / l. The highest level of amino acid is determined on an empty stomach and after exercise. At the same time, the amount of urocaninic acid in the blood decreases.
- Urine analysis. Histidinemia is characterized by an increased content of free histidine and imidazolpyruvate. The second substance is determined by a color reaction with ferric chloride and gives the same color as phenylpyruvate, which requires special care from the doctor when interpreting the results.
- Pharmacological tests. To clarify the diagnostic information, an oral stress test with a solution of L-histidine chloride is performed. The child is given a drink of the mixture and histidine level tests are performed after 1, 2, 4, 6 and 24 hours. With histidinemia, there is a long-term accumulation of free amino acids in the body.
- Examination of biopsies. For the most accurate confirmation of the diagnosis, an analysis of skin and liver samples is recommended. In the laboratory, the inhibition of enzyme activity in both biopsies is determined with a typical form of histidinemia, or the normal level of the enzyme in the skin and reduced in the liver (with an atypical form).
The disease can be diagnosed prenatally in pregnant women, in whose family there were cases of histidinemia. For this purpose, an amniocentesis is prescribed to study the activity of histidase in the amniotic fluid. With genetic aminoacidopathy, the enzyme level will be reduced. Early diagnosis makes it possible to develop delivery tactics and the nature of feeding the newborn in order to prevent the development of clinical symptoms.
Differential diagnosis
A practicing pediatrician needs to distinguish histidinemia from other types of hereditary aminoacidopathies. The clinical picture of the disease is similar to phenylketonuria, a more common pathology that requires specific biochemical studies to exclude. It is also necessary to exclude citrullinemia, ornithinemia, maple syrup disease. In difficult cases, the consultation of a geneticist is indicated.
Treatment
Conservative therapy
The only way to correct the pathological manifestations of the disease is to limit the intake of histidine with food. Diet therapy should ensure the minimum requirement of the child’s body for amino acid (about 16-34 mg / kg of body weight per day). Complete exclusion of histidine is impossible, given its importance for the processes of growth and development. The nature of feeding depends on the age of the child:
In the first half of life, the optimal nutrition is mother’s milk, if breastfeeding is impossible, adapted infant formula is prescribed.
In the second half of life, complementary foods are introduced at the same time as for healthy children. At the same time, the first course should be vegetable purees, and animal products are given in limited quantities under the control of biochemical parameters of blood and urine.
In the second year of a child’s life and later, it is necessary to adhere to food restrictions: reduce the amount of meat (beef, chicken), eggs and dairy products in the diet.
Diet therapy shows high efficiency in the elimination of convulsive syndrome in histidinemia. However, it does not help to eliminate intellectual and speech disorders that occur due to late diagnosis or rapidly progressing brain damage. In this case, a neurologist, a psychologist, a speech therapist and a correctional teacher are involved in the treatment of children. According to the indications, symptomatic medications are prescribed.
Prognosis and prevention
The probability of regression of symptoms depends on the form of the disease and the timeliness of the start of diet therapy. The best prognosis is for patients with an intermediate variant of histidinemia, who rarely have neuropsychiatric complications. With a typical severe form of the disease, there is a possibility of intellectual decline up to disability. Given the hereditary nature of the pathology, effective preventive measures have not yet been developed.