Glutaric aciduria type 1: clinical guidelines

List of Abbreviations

3-OH-glutaric acid — 3-hydroxyglutaric acid

AEDs – antiepileptic drugs

GA1 — glutaric aciduria type 1

GABA — gamma-aminobutyric acid

CT — computed tomography

MRI — magnetic resonance imaging

Tandem MS — tandem mass spectrometry

CSF — cerebrospinal fluid

C5DC (glutarylcarnitine) — glutarylcarnitine

GA (glutaric acid) — glutaric acid

GCDH (enzyme glutaryl-CoA dehydrogenase) — enzyme glutaryl-CoA dehydrogenase

OMIM (Online Mendelian Inheritance in Man) — Online Mendelian Inheritance in Man database

CoA – coenzyme A

FAD – flavin adenine dinucleotide

FADH₂ – reduced form of FAD

ARVI – acute respiratory viral infection

aPTT – activated partial thromboplastin time

INR – international normalized ratio

PT – physical therapy

Terms and Definitions

“Encephalitis-like crisis” or “metabolic crisis” – a critical, life-threatening condition triggered by adverse factors that cause an increase in cellular catabolism processes and manifest as depression of consciousness ranging from sopor to coma as a result of developing cerebral edema.

“Shaken baby syndrome” – a complex of preventable serious brain injuries resulting from forceful shaking of a newborn or infant. It is one of the organic disorders known as shaken baby syndrome and most commonly occurs in children under five years of age, with infants under one year being at the highest risk.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Glutaric aciduria type 1 (glutaryl-CoA dehydrogenase deficiency, glutaric acidemia type 1, GA1) is an autosomal recessive disorder (OMIM #231670) caused by pathogenic variants in the GCDH gene, which encodes the enzyme glutaryl-CoA dehydrogenase (GCDH). Deficiency of this enzyme leads to the accumulation of glutaric and 3-OH-glutaric (3-hydroxyglutaric) acids in biological fluids and tissues, exerting a neurotoxic effect primarily on the subcortical structures of the brain. The diagnosis of GA1 is not exclusively clinical; it is established based on specific biochemical and/or molecular genetic changes detected in patients with certain clinical symptoms or at the preclinical stage during universal newborn screening [1, 2, 5].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The GCDH gene is mapped to the short arm of chromosome 19 at locus 19p13.2. To date, more than 260 different mutations have been described in the GCDH gene, with one of the most common being c.1204C>T (p.Arg402Trp), which occurs with a frequency of 12–40% in Western European countries. Certain mutations are characteristic of specific ethnic groups and isolates: mutations c.743C>T (p.Pro248Leu) and c.1093G>A (p.Glu365Lys) occur with high frequency in Turkey, while mutations c.91+5G>T and c.1262C>T (p.Ala421Val) are found in Amish communities [2, 5, 15]. Two most frequent variants (c.1204C>T (p.Arg402Trp) and c.1262C>T (p.Ala421Val)), described in most populations, have been identified in Russian patients and account for 56.38% and 11.7% of mutant alleles, respectively [31].

The enzyme glutaryl-CoA dehydrogenase (GCDH) is involved in the metabolism of the amino acids lysine, hydroxylysine, and tryptophan. The GCDH enzyme is localized in the mitochondrial matrix and is a homotetramer. Each subunit of this protein consists of 438 amino acids, and the N-terminal residue (44 amino acids) is cleaved after the enzyme is transported into the mitochondria. GCDH catalyzes two sequential reactions converting glutaryl-CoA to crotonyl-CoA (dehydrogenation and decarboxylation reactions). As a result of the blockage of this enzymatic reaction, glutaric and 3-OH-glutaric acids accumulate in biological fluids and tissues (Fig. 1) [1, 2].

FAD – flavin adenine dinucleotide, FADH₂ – reduced form of FAD, CoA – coenzyme A, CO₂ – carbon dioxide.

Fig. 1 – Diagram of metabolic processes leading to the development of glutaric aciduria type 1: metabolic blocks are highlighted in blue, pathological metabolites are enclosed in a double border.

The enzyme belongs to the group of mitochondrial matrix flavoprotein dehydrogenases involved in electron transfer to ubiquinone via an electron-transferring flavoprotein in the mitochondrial respiratory chain.

The mechanisms of GA1 development are not fully understood. The predominant involvement of the striatal system of the brain is attributed to the selective toxicity of glutaric acid and/or its derivatives. Additionally, glutaric acid and its metabolites inhibit glutamate decarboxylase (an enzyme involved in GABA metabolism), resulting in a decreased concentration of this inhibitory neurotransmitter. Patients with GA1 show a significant decrease in glutamate decarboxylase activity in the frontal cortex, caudate nuclei, and putamen, as well as a reduced GABA concentration in the cerebrospinal fluid (CSF). However, these biochemical abnormalities may be secondary and result from damage to GABAergic brain neurons.

The pathogenesis mechanisms of acute encephalitis-like crises are not yet fully clear. It is believed that glutaric and 3-OH-glutaric acids, which share structural similarities with glutamate, interact with N-methyl-D-aspartate receptors (for which glutamate is a natural activator), causing excessive intracellular accumulation of Ca²⁺ ions in postsynaptic neurons and leading to cell death. Another potential neurotoxic factor is the accumulation of quinolinic acid, an intermediate metabolite of tryptophan and lysine metabolism. Currently, the exact cause of frontotemporal atrophy and/or hypoplasia and subdural hemorrhages in GA1 is not fully understood. It is believed that during embryogenesis, 3-OH-glutaric acid may impair the formation of vascular walls, primarily cerebral vessels, leading to increased permeability and hemorrhages [2, 14].

Autopsy findings in all patients with GA1 reveal pronounced subcortical and cortical brain atrophy, and atrophic ventriculomegaly. In most cases, necrotic changes are visualized in the putamen and head of the caudate nucleus. The optic tracts, corpus callosum, internal capsule, deep white matter of the cerebellum, and brainstem are less frequently affected. A number of patients show "spongiform" degeneration of the white matter, predominantly in periventricular areas, and less frequently in the thalamus, globus pallidus, and brainstem [2, 14].

Autopsy in the majority of patients reveals fatty infiltration of hepatocytes, renal proximal tubular cells, and cardiomyocytes, which may be associated with nonspecific mitochondrial dysfunction [2, 14].

1.3 Epidemiology of the Disease or Condition

Glutaric aciduria type 1 (GA1) is among rare inherited metabolic disorders. The disease incidence in Western European countries averages from 1:30,000 to 1:100,000 live births [21, 24, 25]. A high prevalence of GA1 has been noted among Amish communities in America, Canada, and Pennsylvania at 1:300 [32, 33]. To date, more than 600 cases of this disease have been described in the literature [1, 2, 5, 26].

1.4 Features of Coding the Disease or Condition

E72.3 - Disorders of lysine and hydroxylysine metabolism.

1.5 Classification of the disease or condition

Based on the clinical course, two main subtypes of GA1 are classified: with an acute encephalitis-like course and a subacute course [2].

1.6 Clinical presentation of the disease or condition

GA1 typically debuts in early childhood, from 3 to 36 months of age, with a peak manifestation between 6 and 18 months. In 75% of cases, an encephalitic-like variant of the disease is observed. In 75–80% of patients, the first symptom of the disease may be macrocephaly, which is present from birth or develops in the first months of life. An encephalitic-like variant of the disease is observed in 75% of cases. Frequently, the initial manifestations of the disease in the form of an encephalitic-like crisis occur against the background of such triggering factors as traumatic brain injury, surgical interventions, or prolonged periods of fasting; in addition, an acute encephalopathic crisis may occur in children under 6 years of age during any infectious disease accompanied by elevated body temperature, as well as a febrile reaction in the post-vaccination period, which are accompanied by a high level of catabolism [28]. 24–72 hours after exposure to the "triggering" factor, symptoms develop acutely in the form of fever, episodes of regurgitation or intractable vomiting, intestinal disorders, and epileptic seizures; consciousness is frequently depressed to sopor and coma as a result of developing brain edema and swelling, which can lead to rapid fatal outcome. Several days or weeks after the crisis, various types of movement disorders (hyperkinesias: choreiform, choreoathetoid, ballistic, dystonic) may be observed, which can be generalized, focal, or distributed by a hemitype, and combined with spastic-type muscle tone alterations. The disease has a wave-like course: after experiencing encephalitic-like crises, there is a slow but incomplete recovery of neurological deficits. Subsequently, patients with severe dystonic syndrome frequently develop secondary complications, such as hypotrophy, chronic aspiration syndrome, joint subluxations, and pronounced pain syndrome [6, 12].

In 25% of cases, the disease has a subacute, benign course. In the first year of life, children are monitored with psychomotor developmental delay, and subsequently there is a gradual loss of previously acquired skills, accompanied by various types of hyperkinesias combined with spasticity. Dystonic hyperkinesias lead to impaired walking, writing, and speech functions. Many patients are monitored by neurologists for a long time with the spastic-hyperkinetic form of cerebral palsy. The subacute course of the disease can be complicated by metabolic decompensation, the appearance of new neurological symptoms, or the worsening of the existing clinical picture.

Other frequent symptoms include profuse sweating, episodes of unmotivated fever, and epileptic seizures. Some patients exhibit atactic disorders; myoclonus and tremor, ophthalmoparesis, and strabismus are very rare. In the majority of patients, intelligence is not impaired or mild cognitive impairments are observed. Among ophthalmological symptoms, retinal hemorrhages, cataracts, and retinitis pigmentosa are frequently detected. In untreated patients, death occurs within the first decade of life against the background of a severe metabolic crisis or as a result of Reye-like syndrome.

In a number of patients with GA1, subdural hemorrhages occur in 10–30% of cases during the first year of life, typically following mild traumatic brain injury. Patients with subdural hematomas and/or bitemporal arachnoid cysts combined with macrocephaly and dystonia should undergo evaluations to rule out GA1. The diagnosis of GA1 must be definitively ruled out by laboratory methods in patients with suspected shaken baby syndrome [2, 9].

Clinical and diagnostic criteria that allow for the suspicion of GA1 are presented in Appendix A4.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for establishing a diagnosis of GA1 are a tenfold or greater increase in the concentration of glutaric acid (GA), 3-hydroxyglutaric acid, and glutarylcarnitine (C5DC) in biological fluids (urine, plasma, cerebrospinal fluid) compared to the normal range, and the detection of pathogenic variants (mutations) in the GCDH gene in a homozygous/compound heterozygous state [64].

2.1 Complaints and Anamnesis

When taking the medical history and assessing complaints, it is recommended to pay attention to:

• a burdened family history (presence of a patient with a confirmed diagnosis of GA1 in the family, or a family history of sudden infant death syndrome)

• Sudden deterioration in condition (in the form of loss of previously acquired motor skills, appearance of involuntary limb movements, dystonic attacks) against the background of full health or acute respiratory viral infection, surgical interventions, or traumatic brain injury;

• consanguineous marriage;

• episodes of fever;

• poor appetite;

• feeding difficulties;

• frequent regurgitation;

• intractable vomiting;

• depressed level of consciousness;

• seizures;

• lethargy, weakness, drowsiness;

• agitation, crying;

• increased sweating;

• impaired coordination of movements;

• involuntary/involuntary movements;

• dystonic attacks;

• clinical presentation of the spastic-hyperkinetic form of cerebral palsy;

2.2 Physical Examination

During the examination, attention should be paid to the main physical manifestations of GA1:

Children in the first 3 years of life

• macrocephaly;

• prominent frontal eminences;

• hepatomegaly;

• delayed motor and psycho-speech development;

• alteration of muscle tone of the dystonic type;

• extrapyramidal disorders: alterations in muscle tone of the rigidity type and various types of hyperkinesias (choreiform, choreoathetoid, ballistic, dystonic) of varying localization (focal, generalized, hemitype);

• spastic tetraparesis (hyperactive tendon reflexes, presence of pathological plantar reflexes, spastic gait, etc.);

• periodic ataxia, tremor;

• seizures;

After 3 years

• macrocephaly;

• delayed motor and psycho-speech development;

• alteration of muscle tone of the dystonic type;

• extrapyramidal disorders: rigidity and various types of hyperkinesias: torsional, orofacial, choreiform, choreoathetoid, ballistic;

• spastic tetraparesis (hyperactive tendon reflexes, presence of pathological plantar reflexes, spastic gait, etc.);

• periodic ataxia, tremor;

• seizures;

• peripheral neuropathy;

• psychiatric disorders;

• profuse sweating;

• recurrent episodes of unexplained fever (hyperpyrexic crises);

• anorexia;

• insomnia;

• hypoglycemia following prolonged fasting;

• hepatomegaly;

• rarely, rhabdomyolysis.

Detailed physical examination findings are described in the "Clinical Presentation" section.

2.3 Laboratory Diagnostics

Please note that, in accordance with the requirements for developing clinical guidelines, each recommendation statement must be accompanied by its recommendation grade and evidence level based on the grading systems for the levels of evidence certainty (LEC) and recommendation credibility levels (RCL). For many statements, the RCL and LEC will be low due to the lack of high-design clinical studies addressing them. Despite this, they are essential elements of patient evaluation for establishing a diagnosis and selecting treatment strategies.

Comments: Tandem mass spectrometry (TMS) is used to determine the concentration of glutarylcarnitine (C5DC) in dried blood spots. The concentration of glutarylcarnitine is elevated in patients from an early age, even before the onset of clinical manifestations. This test is used during mass screening for GA1. Late-onset and mild forms of GA1 are known, in which the level of glutarylcarnitine may be within the normal range. The level of free carnitine in many patients may be decreased.

Comments: In some patients with GA1, the concentration of glutaric acid in urine and blood may be within the normal range; in such cases, a diagnostically significant marker is an elevated concentration of 3-hydroxyglutaric acid, which allows the diagnosis of GA1 to be established [2, 4, 7, 14, 19, 20].

Comments: DNA diagnostics is necessary both for verifying the diagnosis and for medical genetic counseling of families and subsequent prenatal diagnostics. In some cases, the mutant allele cannot be detected by standard DNA analysis methods; in such cases, the diagnosis must be established based on clinical and biochemical data.

Comments: During a metabolic crisis, CKP, liver enzymes, and lactic acid levels increase. Blood ammonia concentration is usually normal until late stages of metabolic decompensation.

2.4 Instrumental Diagnostics

Instrumental methods play a vital role in the diagnosis of GA1. Brain MRI findings are highly specific and detected in the vast majority of patients even at an early stage of the disease.

Comments: Anesthesia as indicated. The most frequent neuroradiological signs of GA1 include frontotemporal hypoplasia/atrophy, ventriculomegaly, subdural hematomas, delayed myelination/demyelination, and basal ganglia necrosis. These changes may occur either in isolation or in any combination. A characteristic neuroradiological feature of GA1 is symmetrical widening of the Sylvian fissures with the formation of the "apple-bite sign" or "bat wing" appearance, which occurs in 95% of cases. The majority of patients show widening of the subarachnoid spaces even at the presymptomatic stage of the disease, which does not undergo any changes on follow-up brain MRIs and is combined with normal cerebral cortex thickness and normally developed gyri.

In most patients, subdural hygromas/hematomas are often located bilaterally, and less frequently unilaterally. The formation of bitemporal arachnoid or subependymal cysts is described, while their unilateral location is rare. Brain white matter changes occur in many patients with GA1 and are frequently combined with basal ganglia necrosis. White matter involvement is typically symmetrical, predominantly in the periventricular zones around the anterior and posterior horns of the lateral ventricles and in the centrum semiovale; in some cases, demyelination of subcortical U-fibers is detected. It remains unclear whether these areas represent foci of demyelination or hypomyelination. Involvement of the corpus callosum has been described in some patients [13, 16]. Characteristic neuroradiological changes in GA1 are presented in Appendix A5.

Comments: including video-EEG monitoring.

Comments: Frequency as indicated. For patients older than 5 years.

2.5 Other Procedures

Specialist consultations may be provided to patients at various stages of medical care, including during the disease diagnosis period.

Comments: initial and follow-up consultations are indicated with a medical geneticist, ophthalmologist, neurologist, dietitian, cardiologist, pediatric cardiologist, speech therapist-defectologist, nephrologist, medical psychologist, orthopedic trauma surgeon, pediatrician, general practitioner, neurosurgeon, surgeon, pediatric surgeon, as well as other specialists for patients with GA1 who have impaired functions of the respective organs and systems [1, 2, 7].

2.5.1 Differential Diagnosis

Differential diagnosis should be carried out with the following conditions: sequelae of perinatal nervous system injury, spastic-hyperkinetic form of cerebral palsy, congenital brain malformation, sequelae of intrauterine infection, suspected shaken baby syndrome, Canavan disease, Leigh syndrome, methylmalonic acidemia, propionic acidemia. Elevated urinary glutaric acid levels may also be observed in type 2 and type 3 glutaric aciduria and riboflavin transporter defects [20, 23, 27].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The treatment strategy aims to correct metabolic disorders through a set of measures: conservative methods (pathogenetic dietary therapy, levocarnitine), surgical methods (treatment of intracranial hemorrhages and bone deformities), and rehabilitation methods. Treatment should be initiated in all patients with a confirmed significant increase in urinary glutaric acid levels pending the results of DNA diagnostics for GA1. Intensive care methods are included in international standards for the treatment of encephalopathic crisis. Symptomatic therapy is also administered with careful selection of medications aimed at correcting neurological disorders.

3.1 Conservative Treatment

Comments: A low-lysine and low-tryptophan diet must be strictly adhered to for life. Dietary therapy in this disease aims to reduce the intake of lysine and tryptophan, which are the main precursors of neurotoxic metabolites—glutaric and 3-OH-glutaric acids. These amino acids are found in high amounts in animal proteins (fish, meat, dairy products, etc.). On average, their lysine content is 6–9% and tryptophan content is 0.6–2%. In plant-based foods (vegetables, fruits, certain grains), the content of these amino acids is minimal.

Two types of medical nutrition are used in GA1: the first is a low-lysine and low-tryptophan diet using a specialized product; this type of diet is primarily indicated for children (from birth to 18 years), although adult patients can also use this option, or they can apply the second option—a medical diet with a low total protein content.

Infants in their first year of life may be breastfed. In this case, breast milk will serve as the main source of natural protein combined with a specialized amino acid formula appropriate for the child's age. The amount of lysine in breast milk is known and is approximately 86 mg per 100 ml.

The use of the second dietary option increases the risk of nutritional deficiency of essential amino acids and other key nutrients, which can lead to various disorders: hyperexcitability, sleep disturbances, unexplained temperature fluctuations, pellagra (as a result of reduced nicotinic acid formation); for this very reason, this option can only be used in older patients. Specialized medical nutrition products based on amino acids free of lysine and tryptophan**** are presented in Appendix A6.

The minimum permissible requirements for pathogenetically significant amino acids in the diet of children of various ages are presented in Appendix A7 [1, 2, 18].

Infant patients may be breastfed. In this case, breast milk will serve as the primary source of natural protein combined with an age-appropriate specialized amino acid formula. The lysine content in breast milk is known to be 86 mg per 100 ml.

When calculating a low-protein diet with reduced lysine and tryptophan content, it must be borne in mind that lysine and tryptophan are present in almost all foods, and this should be taken into account when formulating the therapeutic diet.

A specialized diet requires monitoring of amino acid levels and their metabolites in blood plasma and urine, biochemical markers of nutritional status (total protein, protein fractions, etc.), dynamic observation of the patient's physical development and nutritional status, as well as periodic adjustment of the therapeutic diet with the calculation of its chemical composition.

Appendix A8 presents tables containing international and Russian guidelines on the daily intake standards for protein, lysine, and tryptophan, along with data on the average lysine content in certain natural foods.

3.2 Pharmacotherapy

Comments: in GA1, secondary carnitine deficiency is observed in the tissues. Its pool is rapidly depleted as it binds to glutaric acid, which is present in large quantities in patients. Products containing Levocarnitine replenish this secondary deficit, bind glutaric acid, and ensure its excretion from the body in the form of glutarylcarnitine. In the majority of untreated patients with GA 1, the concentration of total and free carnitine in blood plasma and serum is low. The starting dose of #Levocarnitine is 100 mg/kg/day for all ages; it can be reduced to 30 mg/kg/day in patients older than 6 years with a normal blood free carnitine level [20, 65].

Appendix A9 summarizes the main measures that must be performed after confirming the diagnosis of GA1.

3.3 Surgical Treatment

Comments: The decision on the advisability of neurosurgical intervention (ventriculoperitoneal shunting and evacuation of subdural fluid collections in the brain in progressive macrocephaly) is made on a case-by-case basis by a medical board of specialist physicians. Neurosurgical treatment of arachnoid cysts and subdural hematomas in patients with GA1 should be performed with extreme caution under the supervision of a pediatric neurosurgeon.

Comments: The decision on the advisability of neuro-orthopedic intervention is made on a case-by-case basis by a medical board of specialist physicians with appropriate correction of metabolic disorders to prevent the development of a crisis.

Comments: The decision on the advisability of neuro-orthopedic intervention is made on a case-by-case basis by a medical board of specialist physicians. The prescription of a double dose of levocarnitine in accordance with the instructions is due to secondary carnitine deficiency or its increased loss.

3.4 Other treatment

Treatment of neurological conditions is carried out in accordance with the relevant clinical guidelines (neurological conditions).

Comments: other NSAIDs may cause Reye's syndrome.

Comments: there are no contraindications to the prescription of any groups of antibacterial drugs.

Comments: The first-line drugs for the correction of spasticity and muscle dystonia are baclofen^** and drugs from the benzodiazepine derivative group (diazepam^**, clonazepam^**), aimed at correcting generalized and focal dystonias. The drug doses are selected individually in accordance with generally accepted standards of therapy for neurological disorders. Intrathecal administration of baclofen** can be used for pronounced dystonias and spasticity.

The second-line drugs for severe dystonic syndrome are levodopa preparations (#Levodopa+[Carbidopa]**, #Levodopa+[Benserazide]**) and #trihexyphenidyl^**, which is prescribed to children over 5 years of age [55, 67, 68].

The generally accepted principle for prescribing #trihexyphenidyl** in children with dystonia is to start with a low dose with a gradual increase every week to a level of approximately 1-2 mg/kg, divided into 3 doses. Some patients may require higher doses. The duration of treatment is determined individually – from several weeks to several months [59]. The starting dose of #trihexyphenidyl** should not exceed 0.5–1 mg/day.

Dosages of #trihexyphenidyl** in children with dystonia according to studies:

1st week: 0.05 mg/kg x 2 times/day

2nd week: 0.05 mg/kg x 3 times/day

3rd week: 0.1 mg/kg x 3 times/day

4th week: 0.15 mg/kg x 3 times/day

5th week: 0.20 mg/kg x 3 times/day

Weeks 6, 7, 8, 9 – 0.25 mg/kg x 3 times/day [60].

or

1st week – 0.2 mg/kg/day – divided into 3 doses

2nd week – 0.5 mg/kg/day – divided into 3 doses

3rd week – 1.0 mg/kg/day – divided into 3 doses

4th week – 1.5 mg/kg/day – divided into 3 doses

5th week – 2.0 mg/kg/day – divided into 3 doses

6th week – 2.5 mg/kg/day – divided into 3 doses

Weeks 7-12 – 2.5 mg/kg/day – divided into 3 doses [61].

In adults with dystonia, #trihexyphenidyl** is usually started at a dose of 2 mg x 2-3 times/day with a gradual increase of 2 mg every 1-2 weeks (more often every 2 weeks), usually until reaching 21.5 mg [62].

The use of anticholinergic agents should be limited due to the risk of the onset or aggravation of cognitive and mental disorders [40, 63].

It should be borne in mind that severe spasticity, hyperkinesia, and dystonic attacks can lead to severe pain syndrome and protein-energy malnutrition, which in turn provoke an increase in motor disorders. Thus, the comprehensive treatment of spasticity and dystonia must necessarily include measures to prevent and relieve pain syndrome and protein-energy deficiency, taking into account dietary restrictions [41].

Comments: An alternative method of treating severe focal dystonias and spasticity is Botulinum toxin type A-hemagglutinin complex**, Botulinum toxin type A**.

Therapy is carried out similarly to that for cerebral palsy

Comments: Epileptic seizures occur in a small number of patients during or after encephalitic-like crises; they can be single and not recur in the future. In some cases, doctors mistakenly take severe hyperkinesia and dystonic attacks for epileptic seizures.

Monotherapy with phenobarbital** and oxcarbazepine** is reported to be able to stop epileptic seizures in this category of patients [27, 28]. However, in most cases, polytherapy with anticonvulsants such as levetiracetam**, lamotrigine, topiramate**, phenytoin**, carbamazepine**, and clonazepam** is used [42-47].

Comments: valproates are excreted from the body as valproylcarnitine, which depletes free carnitine reserves and inhibits the mitochondrial respiratory chain. The prescription of valproic acid preparations** is therefore undesirable [21].

3.4.1 Treatment during a metabolic crisis

It must be remembered that an acute encephalopathy-like crisis can develop in any infectious disease, vaccination, or surgical intervention, predominantly under the age of six years. Warning symptoms indicating the development of decompensation of the underlying disease include: repeated vomiting, diarrhea, neurological disorders (muscle hypotonia/rigidity, increased irritability, muscle dystonia, altered mental status). In children over 6 years of age, the risk of acute neurological disorders during crises decreases, which is associated with increased brain tolerance to acid-base balance fluctuations and the effects of toxic metabolites.

The main triggers of decompensation (factors causing protein breakdown) are

• Fasting

• Infectious processes, especially those accompanied by vomiting and diarrhea

• Fever (of any etiology)

• Intensive physical exercise

• Dietary non-compliance (excessive protein intake)

A thorough clinical evaluation of the patient's condition is necessary, including blood pressure measurement and Glasgow Coma Scale assessment if a metabolic crisis is suspected.

The main principles of treatment during encephalopathy-like crises are:

• restoring catabolic status by prescribing high-energy infusion therapy (dextrose** in combination with insulins and their analogues);

• limiting the formation of organic acids by reducing or completely eliminating the intake of natural protein (if possible, using specialized amino acid mixture-based products exclusively for 24 hours) [28];

• administration of high-dose levocarnitine;

• restoration of the blood acid-base balance.

Detailed clinical and laboratory parameters are given in Appendix A10.

Comments: Emergency therapy should be started immediately and continued throughout the period of febrile fever, after vaccination, and before and after surgery, especially in patients under 6 years of age.

High-dose #levocarnitine is prescribed at 150-200 mg/kg/day (Appendix A10) [65].

#Levocarnitine is administered intravenously at 150-200 mg/kg/24 h in 2-4 divided doses or as a bolus of 100 mg/kg over 30 minutes, followed by a slow continuous intravenous infusion of 4 mg/kg/h (maximum dose 6 g/day) [66].

If intravenous administration is not feasible, oral administration of 200 mg/kg/day in divided doses is possible.

Comments: If the patient develops vomiting, fever above 38.5⁰C, or neurological disorders, urgent hospitalization is indicated. The main principles of intensive care in an inpatient setting are presented in Appendix A10 [54]. Early initiation of intensive treatment helps prevent the development of severe neurological disorders in the majority of patients with GA1. Intravenous infusion therapy includes a dextrose** solution at 8-15 g/kg/day, insulin therapy for hyperglycemia (above 10 mmol/L) and/or glucosuria. Fluid losses should not be replenished via enteral nutrition (see Appendix A10) [28].

Infusion therapy includes:

- Intravenous administration of dextrose** at 8-15 g/kg/day (Appendix A10). In case of hypoglycemia, immediate administration of dextrose** 200 mg/kg (2 mL/kg of 10% dextrose** or 1 mL/kg of 20% dextrose**) over several minutes.

- Intravenous administration of #Levocarnitine 150-200 mg/kg/day. It is preferable to dilute Levocarnitine in dextrose** solution or add it to the daily dextrose** infusion.

During a metabolic crisis, monitoring of clinical and laboratory parameters (blood acid-base balance, glucose, electrolytes [potassium, sodium, ionized calcium, chloride]) is required every 4-6 hours, or sooner if the patient's condition worsens or improves, in patients with GA1 during a metabolic crisis to assess their condition and timely adjust therapy.

Comments: If oral intake of the mixture is not possible, feeding via a nasogastric tube is recommended. The use of a specialized formula as the sole protein source is possible for no more than 48 hours; thereafter, sources of natural protein (breast milk, infant formula, etc.) must be introduced into the diet. Calculation according to Appendix A9.

Comments: Appendix A10. Other drugs with antiemetic effects may be used in age-appropriate dosages.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Rehabilitation measures for patients with GA1 are carried out similarly to those for patients with cerebral palsy. The choice of rehabilitation method is made after establishing a rehabilitation diagnosis, taking into account the rehabilitation potential based on the International Classification of Functioning (ICF). The goal of rehabilitation measures is to improve the child's functional capabilities, reduce the activity of pathological tonic and labyrinthine reflexes, eliminate pathological synergies and spasticity, and prevent orthopedic complications.

A large number of physical rehabilitation techniques stimulate motor activity and enhance sensory input, correct postotonic postures, motor motivational, and cognitive impairments.

The main areas of rehabilitation are: physical rehabilitation (procedures aimed at reducing spasticity, medical rehabilitation services for patients with central nervous system disorders, kinesiotherapy including therapeutic gymnastics, adaptive exercise (therapeutic exercises for central nervous system and brain disorders; therapeutic exercises for central nervous system and brain disorders in a swimming pool; therapeutic exercises aimed at reducing spasticity; therapeutic exercises for aphasia and dysarthria; medical rehabilitation services for children with neurological diseases using applied kinesiotherapy methods), massage (massage for central nervous system diseases), hardware-based physical rehabilitation using physical factors (electrical, magnetic, and ultrasound therapy, pulsed electromagnetic field (PEMF) therapy, mechanotherapy for central nervous system and brain disorders, robotic mechanotherapy for central nervous system and brain disorders, therapeutic exercises using apparatus and exercise machines for central nervous system and brain disorders, hydrokinesitherapy for central nervous system and brain disorders, correction of motor function disorders using biofeedback, correction of motor function disorders using computer technologies), conservative orthopedic treatment using postural management and orthoses (postural-static function recovery aids, dynamic proprioceptive correction, medical rehabilitation services for children with neuro-orthopedic pathology using medical taping methods, orthopedic device maintenance services, adjustment of removable orthopedic appliances), dysphagia correction (therapeutic exercises for dysphagia, individual therapeutic exercise sessions for dysphagia, electromyographic biofeedback training for dysphagia), medical-psychological-pedagogical developmental support technologies, and environmental adaptation (neuropsychological rehabilitation) [49].

Comment: the following may be used: medical speech-language pathology assessment for dysphagia, medical speech-language pathology assessment for aphasia, medical speech-language pathology assessment for dysarthria, medical speech-language pathology procedure for dysphagia, medical speech-language pathology procedure for aphasia, medical speech-language pathology procedure for dysarthria, medical speech-language pathology tonal-rhythmic procedure, and medical speech-language pathology procedure using interactive information technologies.

5. Prevention and Dispensary Observation

Since January 1, 2023, expanded neonatal screening has been carried out in the Russian Federation for the early diagnosis of a number of hereditary diseases, including glutaric aciduria type 1.

5.1 Prevention

Comments: Preventive measures include genetic counseling and prenatal diagnosis, which is performed using molecular genetic analysis of a chorionic villus biopsy [2, 15].

Comments: vaccination should preferably be performed by or under the supervision of specialists experienced in working with patients with metabolic disorders.

During the post-vaccination period, vaccinated individuals should be closely monitored with repeated body temperature measurements, which are necessary for the immediate administration of antipyretic therapy if a fever >38.5°C is diagnosed (paracetamol** or ibuprofen**). The patient's level of consciousness, body temperature, and feeding tolerance must be re-assessed every 2 hours. If parents have received appropriate training, maltodextrin solutions or comparable carbohydrate supplements can be administered orally or via a nasogastric tube, gastrostomy, or jejunostomy to ensure an adequate energy supply [28].

5.2 Dispensary monitoring

Comments: Plasma amino acid levels in patients with GA1 are typically determined with the following frequency: every 1–2 months for patients under one year of age, every 3–6 months for children under 6 years of age, and every 6–12 months for patients over 6 years of age. Tryptophan and lysine level testing is prescribed for all patients who develop feeding issues (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1).

Comments: Blood levels of free carnitine and acylcarnitines in patients with GA1 are typically measured with the following frequency: every 2 months for patients under one year of age, every 3 months for patients aged 1 year to 6 years, and every 6–12 months for patients over 6 years of age (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1). It should be noted that acylcarnitine levels may increase upon the administration of levocarnitine.

Comments: A complete blood count (CBC) in patients with GA1 is typically performed with the following frequency: every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1).

Comments: Blood albumin testing is typically prescribed to patients when feeding problems arise. Blood calcium, phosphorus, and hepatic transaminase levels are tested with the following frequency: every 3 months for patients under one year of age, every 6 months for patients aged 1 year to 6 years, and every 12 months for patients over 6 years of age (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1).

Comments: Urinalysis in patients with GA1 is typically performed with the following frequency: every 6 months for patients under 6 years of age, and every 6–12 months for patients over 6 years of age (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1).

Comments: Brain neuroimaging is typically performed when establishing the diagnosis, as well as following an encephalitic crisis or the onset of progressive neurological symptoms in the absence of contraindications (see Appendix A11. Biochemical and Instrumental Monitoring of Patients with GA1). Anesthesia is used according to clinical indications.

Comments: Performed in patients over 5 years of age according to clinical indications.

Comments: including EEG with video monitoring. In the absence of seizures — at least once a year; in the presence of epileptic seizures — according to clinical indications.

Comments: Frequency in the absence of abnormalities is at least once a year; in the presence of liver pathology, as clinically indicated.

Comments: Frequency in the absence of abnormalities is at least once a year; in the presence of pathology, as clinically indicated.

Comments: Dietary therapy is adjusted by medical geneticists or dietitians with a frequency of 1 time per month during the 1st year of life, then every 3 months and as clinically indicated up to 3 years of age; every 6 months after 3 years of age [50, 51].

Comments: initial and follow-up consultations are indicated with a medical geneticist, ophthalmologist, neurologist, dietitian, cardiologist, pediatric cardiologist, speech and language therapist (defectologist), nephrologist, medical psychologist, orthopedic surgeon, pediatrician, general practitioner, neurosurgeon, surgeon, pediatric surgeon, ophthalmologist, physical therapy (exercise therapy) physician, as well as physicians of other specialties for patients with GA1 presenting with functional disorders of the respective organs and systems [1, 2, 7].

Comments: Frequent neurological complications of GA1 include:

• extrapyramidal disorders (in more than 95% of cases, developing after a prior acute toxic-metabolic crisis);

• epileptic seizures (4-40%);

• subdural hemorrhage (10-30%);

• bilateral arachnoid cysts

Comments: The child's parents must always have an information leaflet detailing emergency measures during the onset of a metabolic crisis. Appendix A12 outlines measures aimed at preventing the development of recurrent encephalopathic-like crises [7, 20].

6. Organization of Medical Care

Indications for planned hospitalization in a medical organization:

1. provision of diagnosis and treatment requiring prolonged (day or round-the-clock) medical observation and monitoring of clinical and laboratory parameters;

2. the need for various types of expert evaluations or examinations in a medical organization when they cannot be performed on an outpatient basis (including issuing a conclusion of a federal concilium / medical commission).

Indications for emergency hospitalization to a medical organization:

1. acute life-threatening conditions and complications threatening development, including a metabolic crisis requiring emergency treatment, including intensive care, as well as round-the-clock medical monitoring and special diagnostic and therapeutic procedures.

Indications for patient discharge from a medical organization:

1. absence of a threat to the patient's life and risk of complications requiring emergency treatment upon completion of diagnostic procedures.

2. stabilization of the patient's condition and main clinical and laboratory parameters of the pathological process, no need for prolonged medical supervision (day or inpatient care);

3. the need to transfer the patient to another medical facility or social care institution.

Specifics of organizing medical care for patients with GA1

• Patients with GA1 are frequently hospitalized in the early childhood pathology, neurological, infectious disease, or intensive care units during an encephalopathic-like crisis (initial or recurrent). The duration of hospitalization depends on the speed of diagnosis verification, correction of metabolic disorders through intensive care and initiation of pathogenetic dietary therapy, as well as the timing of positive central nervous system and other organ dynamics, and the rate of biochemical recovery, averaging 21 days.

• Upon discharge from the hospital, the child must undergo outpatient follow-up care by a pediatrician, neurologist, and medical geneticist; patients with symptomatic epilepsy require follow-up by an epileptologist. Consultations with other specialists (ophthalmologist, orthopedist, physical therapy physician, etc.) are scheduled according to clinical indications.

• Patients must undergo comprehensive annual health assessments in a day hospital setting (hospitalization duration of at least 10 days), where necessary rehabilitation measures are also carried out.

• Rehabilitation measures, including therapeutic exercise (physical therapy) and physiotherapeutic procedures, must be performed every 3 months.

7. Additional Information

If dietary therapy and levocarnitine administration are initiated in the neonatal period prior to the development of clinical symptoms, the majority of patients experience an almost asymptomatic disease course. Failure to follow recommendations for the emergency management of metabolic crises results in a poor prognosis, characterized by structural brain damage and progressive neurological symptoms.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care

Criteria for evaluating the quality of specialized medical care

References

Appendix A1. Working Group Composition

Anisimova Inga Vadimovna — Candidate of Medical Sciences, Head of the Medical Care Organization Department, Medical Geneticist at the Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

Akhadova Leila Yadullaevna — Candidate of Medical Sciences, Leading Neurologist, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department

Baydakova Galina Viktorovna — Candidate of Biological Sciences, Head of the "Metabolom" Shared Research Facility, Leading Research Fellow, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists

Batysheva Tatyana Timofeevna — Professor, Doctor of Medical Sciences, Chief freelance pediatric specialist in medical rehabilitation of the Russian Ministry of Health, Chief freelance pediatric specialist in neurology of the Moscow Healthcare Department, Director of the Scientific and Practical Center for Pediatric Psychoneurology, Honored Doctor of the Russian Federation, Head of the Department of Pediatric Neurology, Physical and Rehabilitative Medicine, Peoples' Friendship University of Russia (RUDN University)

Borovik Tatyana Eduardovna — Professor, Doctor of Medical Sciences, Head of the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Bushueva Tatyana Vladimirovna — Doctor of Medical Sciences, Leading Research Fellow at the Laboratory of Nutrition for Healthy and Sick Children, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Bykova Olga Vladimirovna — Doctor of Medical Sciences, Head of the Research Department, Scientific and Practical Center for Pediatric Psychoneurology of the Moscow Healthcare Department, Professor at the Department of Pediatric Neurology, Physical and Rehabilitative Medicine, RUDN University

Vashakmadze Nato Dzhumberovna — Doctor of Medical Sciences, Head of the Department of Orphan Diseases and Prevention of Disabling Conditions, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery, Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University (RNRMU) of the Russian Ministry of Health

Vishnyova Elena Alexandrovna — Doctor of Medical Sciences, Deputy Director for Research at the Research Institute of Pediatrics and Child Health, Central Clinical Hospital of the Russian Academy of Sciences (Ministry of Science and Higher Education), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov RNRMU of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Globa Oksana Valerievna — Candidate of Medical Sciences, Neurologist-Epileptologist, Pediatrician, Leading Research Fellow at the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Zhurova Nataliya Vyacheslavovna — PhD in Medical Sciences, Leading Researcher, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery, Member of the Union of Pediatricians of Russia, Member of the Association of Medical Geneticists

Zakharova Ekaterina Yuryevna — Doctor of Medical Sciences, Head of the Laboratory of Hereditary Metabolic Diseases, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Society for the Study of Inborn Errors of Metabolism (SSIEM).

Kuzenkova Lyudmila Mikhailovna — Professor, Doctor of Medical Sciences, Head of the Center for Pediatric Psychoneurology, Head of the Department of Psychoneurology and Psychosomatic Pathology, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Kurkina Marina Vladimirovna — Research Fellow, Academician N.P. Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists

Kutsev Sergey Ivanovich — Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Director of the Academician N.P. Bochkov Research Centre for Medical Genetics, President of the Association of Medical Geneticists

Mikhailova Svetlana Vitalievna — Doctor of Medical Sciences, Head of the Department of Medical Genetics, Russian Children's Clinical Hospital of the Russian Ministry of Health

Nazarenko Lyudmila Pavlovna — Professor, Doctor of Medical Sciences, Deputy Director for Research and Clinical Work, Head of the Laboratory of Hereditary Pathology, Research Institute of Medical Genetics, Tomsk National Research Medical Center, Member of the Association of Medical Geneticists

Nikolaeva Ekaterina Aleksandrovna — D.Sc. in Medicine, Chief Researcher, Department of Clinical Genetics, Veltischev Research and Clinical Institute of Pediatrics, Pirogov Russian National Research Medical University of the Russian Ministry of Health; Professor, Department of Innovative Pediatrics and Pediatric Surgery, Institute of Continuing Education and Professional Development; Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists

Pechatnikova Natalia Leonidovna — Head of the City Center for Orphan and Other Rare Diseases in Children and Adolescents, Morozov Children's City Clinical Hospital of the Moscow Healthcare Department

Pushkov Aleksandr Alekseevich — Ph.D. in Biology, Leading Researcher, Laboratory of Molecular Genetics and Cell Biology, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists

Pushkov Aleksandr Alekseevich — Ph.D. in Biology, Leading Researcher, Laboratory of Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health, Member of the Association of Medical Geneticists (AMG).

Repina Svetlana Afanasevna — Ph.D. in Medicine, Medical Geneticist, Bochkov Research Centre for Medical Genetics, Member of the Russian Society of Medical Geneticists, Member of the Association of Medical Geneticists (AMG).

Savostyanov Kirill Viktorovich — D.Sc. in Biology, Head of the Medical Genetic Center, Head of the Laboratory of Medical Genomics, National Medical Research Center for Children's Health of the Russian Ministry of Health; Professor, Department of Pediatrics and Public Health, National Medical Research Center for Children's Health of the Russian Ministry of Health; Member of the Association of Medical Geneticists (AMG)

Sviridova Valeriya Valeryevna — Medical Geneticist, Department of Medical Care Organization, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Junior Researcher, Laboratory of Mutagenesis, Research Centre for Medical Genetics named after Academician N.P. Bochkov

Selimzyanova Liliya Robertovna — PhD in Medical Sciences, Head of Department, Research Institute of Pediatrics and Child Health, Academician B.V. Petrovsky National Research Centre of Surgery, Associate Professor at the Department of Pediatrics and Pediatric Rheumatology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Associate Professor at the Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Smirnova Olga Yakovlevna — Medical Geneticist, Senior Researcher, Department of Standardization and Study of Evidence-Based Medicine Fundamentals, Research Center No. 2, Petrovsky National Research Centre of Surgery

Sparber Petr Andreevich — Ph.D. in Medicine, Junior Researcher, Laboratory of Functional Genomics, Research Centre for Medical Genetics; Medical Geneticist, Research Centre for Medical Genetics; Member of the Russian Society of Medical Geneticists

Strokova Tatyana Viktorovna — D.Sc. in Medicine, Professor of the RAS, Head of the Department of Pediatric Gastroenterology, Hepatology and Dietetics, Clinic of the Federal Research Centre of Nutrition and Biotechnology

Subbotin Dmitry Mikhailovich — Medical Geneticist, Research Centre for Medical Genetics named after Academician N.P. Bochkov, Member of the Association of Medical Geneticists

Fedoseenko Marina Vladislavovna — Ph.D. in Medicine, Head of the Department for the Development of Scientific Approaches to Immunization of Patients with Health Deviations and Chronic Diseases, Leading Researcher, Pediatrician, Research Institute of Pediatrics and Child Health of the Central Clinical Hospital of the Russian Academy of Sciences of the Ministry of Science and Higher Education of the Russian Federation; Associate Professor, Department of Faculty Pediatrics, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the Union of Pediatricians of Russia

Fisenko Andrey Petrovich — Professor, D.Sc. in Medicine, Director of the National Medical Research Center for Children's Health of the Russian Ministry of Health, President of the Professional Public Organization (Association) of Pediatric Doctors «Initiative of Pediatric and Neonatological Specialists in the Development of Clinical Practices» on pediatric issues.

The authors declare no financial support or conflicts of interest that need to be disclosed.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Medical geneticists;

2. General practitioners (family physicians);

3. Pediatricians;

4. General practitioners;

5. Dietitians;

6. Neurologists;

7. Ophthalmologists;

8. Trauma and orthopedic surgeons;

9. Epileptologists;

10. Psychiatrists;

11. Nephrologists;

12. Functional diagnostics physicians;

13. Laboratory geneticists;

14. Clinical laboratory diagnostics physicians;

15. Medical students;

16. Residents in training.

Table 1 Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence (LE) for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Federal Law No. 323-FZ of November 21, 2011, "On the Fundamentals of Healthcare Protection in the Russian Federation".

2. Decree of the Government of the Russian Federation No. 890 of July 30, 1994, "On State Support for the Development of the Medical Industry and Improvement of the Provision of Medications and Medical Devices to the Population and Healthcare Institutions" (with amendments and addenda)

3. Order of the Ministry of Health of the Russian Federation No. 274n dated April 21, 2022, "On Approval of the Procedure for Providing Medical Care to Patients with Congenital and (or) Hereditary Diseases"

4. Government Decree No. 403 of April 26, 2012, "On the Procedure for Maintaining the Federal Register of Persons Suffering from Life-Threatening and Chronic Progressive Rare (Orphan) Diseases Leading to Reduced Life Expectancy of Citizens or Their Disability, and Its Regional Segment"

5. Order of the Russian Ministry of Health No. 203n of May 10, 2017, «On Approval of Criteria for Assessing the Quality of Medical Care»

6. Order of the Ministry of Health of the Russian Federation No. 834n of December 15, 2014, «On Approval of Unified Forms of Medical Documentation Used in Medical Organizations Providing Outpatient Medical Care and Procedures for Filling Them Out»

7. Order of the Russian Ministry of Health No. 1051n dated November 12, 2021, "On Approval of the Procedure for Giving Informed Voluntary Consent to Medical Intervention and Refusal of Medical Intervention, the Form of Informed Voluntary Consent to Medical Intervention, and the Form of Refusal of Medical Intervention"

8. Order of the Russian Ministry of Health No. 1094n dated November 24, 2021, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Forms for Medicinal Products, the Procedure for Issuing Said Forms, Their Accounting and Storage, Prescription Form Forms Containing Prescriptions for Narcotic Drugs or Psychotropic Substances, the Procedure for Their Manufacture, Distribution, Registration, Accounting and Storage, as Well as the Rules for Issuing Prescription Forms, Including in the Form of Electronic Documents"

9. Order of the Russian Ministry of Health No. 302n of May 16, 2019, "On Approval of the Procedure for Minors Undergoing Dispensary Observation, Including During the Period of Education and Upbringing in Educational Organizations"

10. Directive of the Government of the Russian Federation No. 3053-r dated December 31, 2018 "On Approval of Lists of Medical Devices Implanted into the Human Body When Providing Medical Care within the Framework of the State Guarantee Program for Free Medical Care to Citizens and Dispensed by Prescription for Medical Devices Upon Provision of a Set of Social Services"

11. Order of the Ministry of Health of the Russian Federation No. 354n dated June 6, 2013, "On the Procedure for Conducting Pathological Autopsies" (registered by the Ministry of Justice of the Russian Federation on December 16, 2013, registration No. 30612).

Drug information: https://grls.rosminzdrav.ru/

Main regulatory legal acts governing the provision of palliative medical care

1. Federal Law No. 323-FZ of November 12, 2011, "On the Fundamentals of Protecting Citizens' Health in the Russian Federation" (Article 36. Palliative Medical Care)

2. Order of the Russian Ministry of Health No. 345n, Russian Ministry of Labor No. 372n dated May 31, 2019, "On approval of the Regulations on the organization of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations, and other non-profit organizations operating in the field of health protection."

3. Order of the Russian Ministry of Health No. 348n dated May 31, 2019, "On approval of the list of medical devices intended to maintain human organs and body systems, provided for home use."

4. Order of the Russian Ministry of Health No. 505n dated July 10, 2019, "On approval of the Procedure for the transfer by a medical organization to a patient (their legal representative) of medical devices intended to maintain the functions of human organs and body systems for home use in the provision of palliative medical care."

5. Order of the Ministry of Health of the Russian Federation No. 831 dated October 3, 2019, "On Approval of the Departmental Target Program 'Development of the Palliative Medical Care Delivery System'".

Other regulatory and legal documents used in the development of the clinical guidelines:

1. International Statistical Classification of Diseases and Related Health Problems (ICD-10);

2. Order of the Ministry of Health of the Russian Federation No. 205n of May 2, 2023, «On Approval of the Nomenclature of Positions of Medical Workers and Pharmaceutical Workers».

3. Order of the Ministry of Health and Social Development of the Russian Federation No. 541n of July 23, 2010, «On Approval of the Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section „Qualification Characteristics of Healthcare Worker Positions“».

4. Federal Law No. 489-FZ dated December 25, 2018, "On Amendments to Article 40 of the Federal Law 'On Compulsory Medical Insurance in the Russian Federation' and the Federal Law 'On the Basics of Protecting the Health of Citizens in the Russian Federation' regarding Clinical Guidelines."

5. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development and Revision of Clinical Guidelines, Their Template Form, and Requirements for Their Structure, Composition, and Scientific Validity of Information Included in Clinical Guidelines".

6. Order of the Russian Ministry of Health No. 804n dated October 13, 2017, "On approval of the nomenclature of medical services."

7. Order of the Ministry of Labor and Social Protection of the Russian Federation No. 585n of August 27, 2019, "On Classifications and Criteria Used in Carrying Out Medico-Social Examination of Citizens by Federal State Medico-Social Examination Institutions";

8. Order of the Ministry of Health and Social Development of the Russian Federation dated August 9, 2005, No. 494, "On the procedure for the use of medicinal products in patients for vital indications"

9. Information Letter of the Russian Ministry of Health on the possibility of procuring a medicinal product by trade name (https://www.rosminzdrav.ru/news/2019/12/18/13043-minzdrav-podgotovil-informatsionnoe-pismo-po-vozmozhnosti-zakupki-lekarstvennogo-preparata-po-torgovomu-naimenovaniyu);

10. Directive of the Government of the Russian Federation No. 3551-r dated December 11, 2023, "On Approval of the List of Specialized Medical Nutrition Products for Disabled Children"

Appendix A4. Clinical and diagnostic criteria allowing suspicion of glutaric aciduria type 1 [16]

Appendix A5. Neuro-radiological brain changes (MRI) in patients with glutaric aciduria type 1

Figure. «Bite apple» or «bat wing» effect, necroses in the basal ganglia area [2]

Figure. Subdural hematomas [2]

Appendix A6. Specialized amino acid-based products free of lysine and tryptophan

Appendix A7. Estimated lysine and tryptophan requirement in patients with glutaric aciduria type 1 depending on age

[21, 28]

Appendix A8. Recommended protein intake norms and average lysine content in various food products (reference information for drawing up a therapeutic diet for patients with glutaric aciduria type 1)

Table 1 - Recommended protein intake norms for healthy children of various ages [1,3,18,22]

Table 2 - Average lysine content in proteins of various foods [18,20].

Appendix A9. Complex of mandatory measures to be carried out for a patient after the establishment of the diagnosis of glutaric aciduria type 1

[21] 

* specialized amino acid-based product free of lysine and tryptophan.

Appendix A10. Basic principles of inpatient therapy

[7,19,20, 28, 54]

¹during encephalitic-like crises, it is necessary to increase energy intake up to 120% of the normal daily energy requirement in order to prevent the development of neurological disorders; during acute conditions, the energy requirement increases by 30-40% of the physiological norm;

Appendix A11. Biochemical and instrumental monitoring of patients with glutaric aciduria type 1

 [21]

* If insufficient bone mineralization is suspected, additional tests are required (e.g., vitamin D status, parathyroid hormone, bone age and density radiological studies).

Appendix A12. Measures aimed at preventing recurrent encephalitic-like crises

[7,20, 21]

Appendix B. Physician Action Algorithms

Screening algorithm for glutaric aciduria type I

Appendix C. Patient Information

What is glutaric aciduria type 1?

Glutaric aciduria type 1 (GA1) is an inherited disorder caused by mutations in the gene responsible for the function of the glutaryl-CoA dehydrogenase (GCDH) enzyme. This enzyme is required for proper protein metabolism in the body. If the enzyme is non-functional or its activity is reduced, glutaric and 3-OH-glutaric (3-hydroxyglutaric) acids accumulate in cells, blood, and urine, exerting a damaging effect on all tissues, but primarily on the cells of the nervous system.

How does glutaric aciduria type 1 manifest?

GA1 typically manifests between 3 and 36 months of age. In most cases, the first symptoms develop acutely as a so-called encephalopathic or metabolic crisis (a life-threatening condition presenting with altered mental status, vomiting, and seizures). An encephalopathic crisis can be triggered by an infection, surgery, prolonged fasting, or excessive physical exertion. The consequences of an encephalopathic crisis may include neurological impairments (loss of previously acquired motor skills, involuntary limb movements—hyperkinesia, etc.).

There is another variant of the disease—subacute—in which metabolic crises are extremely rare, and the manifestations resemble cerebral palsy. In the first years of life, the child develops involuntary movements such as dystonia and hyperkinesia. The limbs are most commonly involved, but hyperkinesia can later spread to the neck, tongue, and trunk. Children experience difficulties with walking.

Intellect in GA1 is generally spared; however, frequent metabolic crises lead to severe brain damage and patient disability.

How is glutaric aciduria type 1 diagnosed?

Physicians may suspect the disease based on clinical symptoms. Subsequently, laboratory tests and instrumental examinations are performed. Upon the appearance of symptoms, the physician orders laboratory testing using tandem mass spectrometry on dried blood spots to determine acylcarnitine concentrations. In GA1, there is an elevated concentration of glutarylcarnitine (C5DC) and, in many patients, a decreased concentration of free carnitine (C0). Analysis of urine organic acids reveals elevated concentrations of glutaric acid and some of its derivatives.

Neonatal screening is performed in only a few regions of the Russian Federation.

Molecular genetic diagnostic methods have been developed for GA1: identification of pathogenic variants in the GCDH gene responsible for the development of this disorder. It is important to perform this testing because genetic data make prenatal and preimplantation genetic diagnosis possible for the family.

How is glutaric aciduria type 1 inherited?

GA1 is an inherited disorder transmitted in an autosomal recessive manner. This means the disease manifests only if both parents are carriers and, while unaffected themselves, pass on two mutated genes to the child. Most families with a child affected by this disorder have no prior history of the condition. The recurrence risk for parents who already have an affected child is 25% for each pregnancy.

Siblings of an affected child may have the disease even if they were asymptomatic at the time of family screening. In such cases, testing must be performed to initiate therapy as early as possible and avoid complications. They may also be carriers, just like their parents. It is important to inform other family members that they may be carriers, meaning they also carry a risk of having a child with this disorder.

All families with GA1 must undergo genetic counseling and receive complete information from a geneticist regarding the recurrence risk of the disease in the family, and discuss all aspects of disease inheritance with a specialist. In Russia, medical genetics clinics operate in every region.

How are patients with glutaric aciduria type 1 treated?

GA1 belongs to the group of inherited metabolic disorders for which metabolic correction methods have been developed; however, treatment efficacy largely depends on the timing of correct diagnosis and initiation of pathogenetic therapy. Before starting therapy, all potential risks, side effects, and, most importantly, treatment expectations should be discussed with the physician. It is important to understand that dietary therapy will not cure the disease, but will minimize the risk of developing severe complications.

Patients with GA1 are prescribed a specialized diet with restricted protein intake and the use of specialized formulas. In addition, the child will require ongoing high-dose levocarnitine supplementation, which helps excrete toxic metabolites and replenishes secondary carnitine deficiency in cells.

Main goals of dietary therapy:

• Normal physical and intellectual development.

• Weight and height gain appropriate for age.

• Prevention of catabolic states that can lead to metabolic crises

If the child shows no signs of a metabolic crisis or infectious disease, treatment is carried out in a standard maintenance regimen, in which dietary lysine intake is strictly controlled and the child receives a specialized medical formula (lysine-free, low-tryptophan) to ensure an adequate protein intake for growth and development.

How are patients with glutaric aciduria type 1 treated during a metabolic crisis?

A metabolic crisis is a critical, life-threatening condition triggered by adverse factors that cause enhanced protein breakdown and lead to the production of toxic metabolites.

What can trigger a metabolic crisis:

• prolonged fasting

• infection

• heavy physical and emotional exertion

Initial symptoms of a metabolic crisis: increased drowsiness, behavioral changes, irritability, loss of appetite. The crisis is often triggered by an infection, so early manifestations may begin with fever, nausea, diarrhea, and vomiting. Blood sugar levels may be reduced. If treatment is not initiated in a timely manner, the child may develop shortness of breath, seizures, and coma.

When should you seek medical attention immediately?

Clinical deterioration typically occurs when the body lacks energy and begins searching for it by all possible means, one of which is the breakdown of its own tissues (catabolism). This must be avoided under any circumstances. The first thing we must do is try to replenish energy using glucose. Give the child carbohydrates, such as fruit juice or sweet tea. If the temperature exceeds 38.5°C, the child refuses to eat, vomiting occurs, and/or the child's behavior differs from usual, urgent hospitalization is required.

It is necessary to hospitalize the child urgently to ensure the intake of high calories, reduction or exclusion of protein for prevention, additional carnitine administration, and infusion therapy. Metabolic crises are extremely dangerous. Irreversible brain damage can develop precisely during this period.

It is important for parents to master diet calculation skills and for all family members living with the child to be aware of the signs of a metabolic crisis.

What monitoring is required for patients with glutaric aciduria type 1?

Regular examinations are necessary for patients with GA1. The table provides an approximate list and schedule of tests, but in each case, you should coordinate your examination plan with your attending physician.

How do patients with GA1 receive treatment in the Russian Federation?

GA1 is a rare inherited metabolic disorder included in the list of rare (orphan) diseases funded by regional budgets. Following diagnosis, the patient must be enrolled in the regional segment of the registry for life-threatening rare (orphan) diseases to ensure subsequent provision of necessary medical nutrition and medications. Responsibilities for maintaining the registry vary by region, but most often this falls to medical geneticists; therefore, consulting a regional medical geneticist after diagnosis is mandatory.

How can family and loved ones help?

Do not forget — the success of treatment also depends on the family. Recommendations must be followed, dietary relapses must not be allowed under any circumstances, and attention should be paid to rehabilitation and scheduled examinations. All family members must know that the child needs a special diet, and close relatives must master the skills of diet calculation.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.