Glutaric aciduria is an autosomal recessive disease that occurs when the metabolism of amino acids and fatty acids is disrupted and is caused by mutations of several genes. Pathology is manifested by muscular dystonia, hyperkinesis and other neurological disorders in combination with severe metabolic status disorders, damage to internal organs. Diagnosis requires biochemical, molecular genetic studies, as well as computed tomography of the brain. Treatment includes lifelong diet therapy, the use of levocarnitine and riboflavin, infusion therapy to relieve crises.
ICD 10
E72.3 Disorders of lysine and hydroxylysine metabolism
General information
Glutaric aciduria (GA) is a rare disease that occurs on average 1 time per 200,000 newborns, and in Western European countries the incidence of pathology is much higher — about 1 case per 50,000 infants. There are 400 confirmed cases of the disease described in the medical literature. The disease has no pathognomonic clinical manifestations, often occurs under the guise of other neurological or metabolic disorders, which causes difficulties in timely diagnosis and treatment.
Causes
The disease refers to genetic pathologies. Depending on the localization of the gene mutation, 2 variants of glutaric aciduria are distinguished. In type 1, there is a defect in the GCDH gene, which encodes the enzyme glutaryl-KoA dehydrogenase (locus 19p13.2). Of the more than 200 variants of the mutation, R402W is the most common, detected in 12-40% of patients living in Europe. There are also mutations typical of individual entic groups and isolates.
In patients with type 2 pathology, damage to the ETFA, ETFB, ETFDH genes located respectively at loci 15q23-q25, 19q13.3-q13.4, 4q32- q35 are detected. Each of these genes is responsible for encoding individual subunits of electron transport flavoprotein, when damaged, multiple fatty acid acyl-CoA dehydrogenase (MADD) deficiency occurs. The risk of developing pathologies in a child, if both parents are carriers of mutant genes, is 25% regardless of gender.
Pathogenesis
Pathological changes are caused by metabolic disorders of lysine, hydrolysin and tryptophan, due to the insufficiency of certain enzymes of the metabolic cycle. As a result of blocking biochemical reactions, toxic metabolites — glutaric and 3-OH-glutaric acid – accumulate in the body. With type 2 HA, the metabolism of fatty acids is additionally disrupted.
The disease mainly affects the nervous system, which is associated with the selective neurotoxicity of glutaric acid, its derivatives. Glutarate also inhibits the activity of glutamic acid decarboxylase, reduces the level of GABA in the cerebral cortex and in the cerebrospinal fluid. Patients often have liver, heart muscle, and kidneys affected.
Symptoms
Type I glutaric aciduria
Clinical ghosts appear in early childhood (up to 3 years), the peak of manifestation falls on the period of 6-18 months. Usually, a detailed picture occurs under the influence of triggers: respiratory infections, injuries, operations. Along the course, the disease is divided into two variants: acute (“encephalitis-like”), which accounts for up to 75% of cases, and subacute (benign), which accounts for the remaining 25%.
The acute variant of GA debuts with macrocephaly, manifested in the first months of life. Then, under the influence of provoking factors, the condition suddenly worsens: indomitable vomiting, diarrhea opens, convulsive seizures begin. Muscle tone decreases sharply, diffuse rigidity of the musculature is noted. As a rule, there is a depression of consciousness up to sopor and coma.
A benign variant of glutaric aciduria manifests itself by a delay in the psychomotor development of children of the first year of life. In the future, the child loses previously acquired skills, he has severe disorders of walking, writing, oral speech, which is due to dystonic hyperkinesis. Also, the patient may have episodes of profuse sweating, prolonged fever of unclear genesis.
Type II glutaric aciduria
It is represented by 3 clinical forms. In the neonatal form with congenital anomalies, signs appear already from birth. Infants have multiple facial dysmorphia (hypertelorism, midline hypoplasia, low—set ears), defects in the anterior abdominal wall, and boys have hypospadias. In a matter of days, metabolic acidosis increases, accompanied by muscle hypotension, hepatomegaly, nephromegaly.
The second variant of type II GA is the neonatal form without congenital malformations. It manifests in the neonatal period, is characterized by severe acidosis, non-ketotic hypoglycemia, and resembles the previous form of the disease in symptoms. A distinctive feature is the involvement of the myocardium in the process, which is manifested by severe cardiomyopathy, arrhythmia, heart failure.
Also, with glutaric aciduria II, a form with a late onset is possible, which is called ethylmalonic / adipine acidemia. Clinical symptoms occur in preschool or school age, extremely rarely in adults. It is characterized by vomiting, hypoglycemia, and metabolic acidosis. Patients suffer from severe muscle pain, muscle weakness, myopathic syndrome.
Complications
Encephalitis-like crises lead to damage to the cerebral basal nuclei, therefore, after their relief, patients are concerned about various hyperkinesis, muscular dystonia. The more seizures the patient suffers, the more severe the neurological deficit. On the first day of the crisis, brain edema and death are possible. The long-term consequences of glutaric aciduria include chronic aspiration syndrome, hypotrophy, joint subluxation.
In 10-30% of cases, subdural hemorrhages are observed in the first year of life, which resemble the “baby shaking” syndrome, which requires differential diagnosis. Often there are ophthalmological complications: ophthalmoparesis, retinal hemorrhages, strabismus. In the absence of treatment, patients die in the first decade of life on the background of a metabolic crisis or a Reye-like syndrome.
Diagnostics
A patient with suspected development of glutaric aciduria is examined by a pediatrician, neurologist, geneticist. The examination takes into account the typical clinical signs of the disease, the time and order of their appearance, family history. To confirm GA, advanced diagnostics is required using various laboratory and instrumental methods, the main of which are:
- Biochemical analysis. In the blood and urine, there is an increased level of organic acids, acylcarnitine, while the indicator of glutaric acid exceeds the norm by 10 or more times. To clarify the diagnosis, the activity of glutaryl-CoA dehydrogenase in leukocytes, fibroblasts of the skin is determined.
- DNA diagnostics. Molecular genetic research to establish the mutation variant by exon sequencing, fluorescent hybridization is carried out in specialized centers. According to the indications, such an analysis is performed prenatally using chorion biopsies.
- CT scan of the brain. Characteristic signs are frontal-parietal hypoplasia, ventriculomegaly, subdural hematomas. There are also multiple foci of demyelination, necrosis of the basal ganglia. With type 1 GA, the expansion of Sylvian slits in the form of “bat wings” is revealed.
Treatment
Conservative therapy
Treatment should be started as early as possible, immediately after receiving positive results of biochemical tests, without waiting for DNA diagnostics. Those suffering from glutaric aciduria are prescribed a special diet with a restriction of tryptophan and lysine (meat, fish, dairy products). Correction of protein metabolism is carried out by therapeutic protein mixtures. Drug therapy of genetic pathology includes:
- Levocarnitine. The drug binds glutaric acid, promotes its excretion from the body in the form of a non-toxic metabolite. It is taken for life to control the symptoms of the disease.
- Riboflavin. It is recommended in rare cases of riboflavin-sensitive form of type 1 GA to reduce neurological complications of the disease. Improves the metabolic status of the patient.
- Infusion therapy. In encephalitic crisis, the administration of glucose solutions with insulin is indicated to maintain energy metabolism, restore acid-base balance, and remove excess toxic metabolites.
- Symptomatic remedies. With exacerbations of glutaric aciduria, it is possible to use antipyretics, antiemetics, antibiotics. Benzodiazepine tranquilizers are used to stop seizures.
Surgical treatment
With subdural hematomas, arachnoid cysts, the help of pediatric neurosurgeons is required. The issue of removal of volumetric cerebral formations is solved individually, taking into account their size, localization, degree of neurological function impairment. With type 2 GA with congenital malformations in the first or second years of life, their surgical correction is performed, plastic surgery is performed on the face.
Prognosis and prevention
The life expectancy of patients depends on the timeliness of diagnosis, compliance with medical prescriptions. Despite complex therapy, the prognosis of glutaric aciduria remains unfavorable, a high mortality rate in childhood remains. Prevention of the disease involves genetic counseling of families with burdened heredity, prenatal diagnosis of suspicious cases.
