Introduction
Methods
Guideline development
Systematic literature review
Prospective follow-up study evaluating the guideline
Diagnostic procedure
Differential diagnoses
Statement #1. The accurate diagnosis of GA-I has important practical implications when devising treatment plans and giving appropriate information to children and their families. The diagnostic work-up should be done by metabolic specialists (GCP).
Newborn and high-risk screening
Statement #2. For mass newborn screening for glutaric aciduria type I determination of C5DC in DBS by MS/MS should be used (grade B, see Suppl. Table 2).
Statement #3. In a cohort with a high disease incidence due to a single common GCDH mutation and a low excretor phenotype, DNA based methods should be considered for newborn screening. The use of MS/MS-based screening in such populations will likely lead to false negative results (grade D).
Confirmation of a positive screening result
Statement #4. For the confirmation of a positive newborn screening result, a specific diagnostic work-up is required, including a quantitative analysis of GA and 3-OH-GA in urine or blood, mutation analysis, and, if feasible, enzyme analysis (grade D).
Selective screening
Statement #5. In patients with signs and symptoms of glutaric aciduria type I, a specific diagnostic work-up should include quantitative analysis of GA and 3-OH-GA in urine or blood, GCDH gene mutation analysis, and/or enzyme analysis (grade D).
Cascade screening
Metabolic maintenance treatment
Treatment | Age | |||||
---|---|---|---|---|---|---|
0–6 months | 7–12 months | 1–3 years | 4–6 years | > 6 years | ||
1. Low lysine diet | ||||||
Lysine (from natural protein)a
| mg/kg per day | 100 | 90 | 80-60 | 60-50 | Avoid excessive intake of natural protein; use natural protein with a low lysine content; according to ‘safe levels’ (Suppl. Table 6) |
Amino acid mixtures (protein)b
| g/kg per day | 1.3-0.8 | 1.0-0.8 | 0.8 | 0.8 | |
Energy | kcal/kg per day | 115-80 | 95-80 | 95-80 | 90-80 | |
2. Micronutrientsc
| % | ≥ 100 | ≥ 100 | ≥ 100 | ≥ 100 | ≥ 100 |
3. Carnitine | mg/kg per day | 100 | 100 | 100 | 100-50 | 30-50 |
Statement #6. Metabolic treatment should be implemented by an interdisciplinary team that includes metabolic pediatricians, dietitians, and nurses. Parents and patients should have regular training and written treatment protocols (grade C).
Treatment and outcome
Dietary treatment
Statement #7. A low lysine diet (i.e., reducing lysine intake to a safe requirement) with or without additional administration of lysine-free, tryptophan-reduced amino acids supplements should be used for dietary treatment, in particular in asymptomatic patients up to age 6 years (grade C).
Pharmacotherapy
Statement #8. L-Carnitine should be supplemented in patients with glutaric aciduria type I and should be continued lifelong (grade C).
Emergency treatment
Basic principles of emergency treatment
Management of emergency treatment
Topic | Proposed strategies to avoid delay |
---|---|
Education and training of parents | Parents should be informed in detail about the natural history and the particular risks of glutaric aciduria type I, in particular the manifestation and neurological sequels of an acute encephalopathic crisis. They should be instructed precisely about the management of maintenance and emergency treatment and this knowledge should be reinforced during regular visits at a metabolic center. |
Treatment protocols | Written protocols for maintenance and emergency treatment should be given to all who may be involved (parents, metabolic centers, local hospitals) and kept updated. Parents should also receive an emergency card (preferably laminated) summarizing the key information on glutaric aciduria type I and basic principles of treatment. The telephone number of the responsible metabolic center/physician should be written on the protocol and the emergency card. Parents should take their emergency instructions and supplies of maltodextran and AA supplements when going to hospital. |
Supplies | Parents should be advised always to maintain adequate supplies of specialized dietetic products (maltodextran, lysine-free, tryptophan-reduced amino acid mixtures) and drugs required for maintenance treatment and emergency treatment at home. |
Local hospital or pediatrician | The closest hospital/pediatrician should be clearly instructed if glutaric aciduria type I has been newly diagnosed in a child. Key information (including written treatment protocols) should be provided to the local hospital/pediatrician without delay and before inpatient emergency treatment might be necessary. Inpatient emergency treatment should be started immediately in the closest hospital if necessary and follows the supervision of the responsible metabolic center which should be contacted without delay. |
Holidays | Metabolic specialists/centers in the vicinity of the holiday resort should be informed in writing about the disease and the recent treatment before the start of the holidays. The emergency card and treatment protocols should be translated before the start of the holidarys if necessary. |
Infectious diseases | During infectious disease the responsible metabolic center/metabolic specialists should be informed (by parents or local hospitals/pediatricians) without delay to allow supervision of the emergency management. Parents should be instructed to call their doctor and/or metabolic consultant as soon as a temperature of 38.5°C is noted and an intercurrent illness is suspected either, an upper respiratory infection, gastrointestinal infection or if increased irritability develops. |
Vomiting/diarrhoea | Vomiting and diarrhoea is particularly dangerous – even in the absence of fever. Please follow the recommendations for “infectious diseases” (see above). |
Surgery | If a surgical intervention is planned, the responsible metabolic center/specialist should be informed before such interventions to discuss the specific risks of affected patients with surgeons and anaesthesiologists, to recommend a protocol for the postsurgical metabolic management and to allow supervision of this period. If possible, the postsurgical metabolic management should be performed in a metabolic center. In general, fasting should be avoided, glucose infusions applied, and carnitine dosage doubled. |
Statement #9. Emergency treatment should start without delay and should be performed aggressively during febrile illness, surgery and immunization within the vulnerable period for acute encephalopathic crises (up to age 6 years) (grade B).
A. Oral carbohydratesa
| Maltodextran | |||
---|---|---|---|---|
Age (years) | % | kcal/100 mL | KJ/100 mL | Volume (mL) per day orally |
Up to 0.5 | 10 | 40 | 167 | min. 150/kg |
0.5-1 | 12 | 48 | 202 | 120/kg |
1-2 | 15 | 60 | 250 | 100/kg |
2-6 | 20 | 80 | 334 | 1200-1500 |
6-10 | 20 | 80 | 334 | 1500-2000 |
>10 | 25 | 100 | 418 | 2000-2500 |
B. Protein intake | ||||
Natural protein | Stop for 24 to a maximum of 48 hours, then reintroduce and increase stepwise until the amount of maintenance treatment is reached within 48 (-72) hours. Prolongation of inadequately low protein intake increases the risk of protein catabolism. | |||
AA mixturesb
| If tolerated, AA mixtures should be administered according to maintenance therapy (see also Table 1) | |||
C. Pharmacotherapy | ||||
L-Carnitine | Double carnitine intake: eg 200 mg/kg per day p.o. in infants | |||
Antipyretics | If body temperature raises above 38.5°C (101 F), antipyretics, such as ibuprofen or paracetamol (each 10-15 mg/kg per single dose, 3-4 doses daily, maximum daily dose 60 mg/kg body weight) should be administered. |
A. Intravenous infusions | ||
---|---|---|
Glucose | Age (years) | Glucose (g/kg per day IV) |
0-1 | (12-) 15 | |
1-3 | (10-) 12 | |
3-6 | (8-) 10 | |
6-10 | (6-) 8 | |
>10 | 3-6 | |
Insulin | If persistent hyperglycemia > 150 mg/dL (> 8 mmol/L) and/or glucosuria occurs, start with 0.05 IE insulin/kg per h IV and adjust the infusion rate according to serum glucose | |
B. Protein intake | ||
Natural protein | Stop for 24 to a maximum of 48 hours, then reintroduce and increase stepwise until the amount of maintenance treatment is reached within 48 (-72) hours. Prolongation of inadequately low protein intake increases the risk of protein catabolism. | |
AA mixturesa
| If tolerated, lysine-free and tryptophan-reduced AA mixtures should be administered orally or by nasogastric tube according to maintenance therapy (see also Table 1). | |
C. Pharmacotherapy | ||
L-Carnitine | (50-) 100 (-200) mg/kg per day i.v. – adjusted to oral dosage (see Table 1) | |
Antipyretics | If body temperature rises above 38.5°C (101 F), antipyretics, such as ibuprofen or paracetamol (each 10-15 mg/kg per single dose, 3-4 doses daily, maximum daily dose 60 mg/kg body weight) should be administered. | |
Sodium bicarbonate | If acidosis; alkalination of urine also facilitates urinary excretion of organic acids | |
D. Monitoring | ||
Blood | Glucose, blood gases, electrolytes, calcium, phosphate, complete blood cell count, creatinine, urea nitrogen, C-reactive protein, amino acidsb, carnitine, blood culture (if applicable), amylase/lipasec, creatine kinasec. | |
Urine | Ketone bodies, pH | |
Vital signs | Heart rate, blood pressure, temperature, diuresis; Glasgow Coma Scale if reduced consciousness; assessment for neurological signs (hypotonia, irritability, rigor, dystonia) |
Statement #10. Emergency treatment in children after age 6 years should be considered at least during severe illness. It should be performed similarly to that in the age group 0-6 years with adaptation to the individual (GCP).
Management of neurologic complications
Management of movement disorders
Statement #11. In all patients with GA-I, expert neurological evaluation should be performed by a neuropediatrician and/or later on by a neurologist to identify clearly the kind and severity of movement disorder. In addition, dietitians, physicotherapists, occupational therapists, orthopedists, seating and speech specialists and providers of communication aids, should be consulted to provide multi-disciplinary support for children with movement disorders (GCP).
Dystonia rating scales
Drug therapy
Statement #12. Baclofen and benzodiazepines as monotherapy or in combination should be used as first line drug treatment for focal and generalized dystonia. Intrathecal baclofen should be considered as additional therapy for generalized dystonia and spasticity. Trihexyphenidyl should be considered as second line treatment for dystonia, particularly in adolescents and adults. Botulinum toxin A should be considered as additional therapy for severe focal dystonia (grade D).
Neurosurgery
Antiepileptic therapy
Statement #13. Diagnosis, choice of antiepileptic drug therapy and management of seizures in GA-I should follow existing guidelines – except for the use of valproate which should be avoided in this condition. The diagnosis of epilepsy and choice of antiepileptic drugs should be made by a pediatric neurologist or pediatrician with expertise in childhood epilepsy. In adulthood, patients with epilepsy should be followed and antiepileptic therapy should be monitored by an adult neurologist (GCP).
Subdural haemorrhage and arachnoid cysts
Statement #14. Children with subdural haemorrhage and/or bitemporal arachnoid cysts should be investigated for glutaric aciduria type I, in particular if occuring in combination with macrocephaly and/or a movement disorder (grade D).
Statement #15. Glutaric aciduria type I should be excluded in children with suspected shaken baby syndrome using the recommendations for selective screening (see also statement #5, Fig. 1) (grade D).
Statement #16. Neurosurgical intervention for arachnoid cysts and subdural haemorrhages in affected patients should be undertaken very cautiously in close consultation with the pediatric neurosurgeon (grade D).
Monitoring therapy
Investigative procedures
General aims
Clinical monitoring
Statement #17. Therapy should be accompanied by regular professional monitoring. Monitoring should be intensified at any age if there are new complications (disease- or therapy-related) or non-adherence to treatment (GCP).
Routine biochemical monitoring
Parameter | Rationale | Frequency at age | ||
---|---|---|---|---|
0-2 years | 2-6 years | > 6 years | ||
Amino acids (plasma) | General nutritional status | Every 1-2 months | Every 3 months | Every 6-12 months |
Tryptophan (plasma; HPLC) | Tryptophan depletion | In children with feeding problems; or if clinical presentation suggests tryptophan depletion; or if amino acid supplements do not contain tryptophan. | ||
Carnitine (plasma or serum) | Avoid depletion, check for non-adherence | Every 1-2 months | Every 3 months | Every 6-12 months |
Complete blood cell count, ferritin | Routine surveillance, avoid depletion of iron, folate, or cobalamin | Every 6 months | Every 6 months | Every 6-12 months |
Albumin | General nutritional status | If concerns exist about the nutritional status and in children with feeding problems | ||
Calcium, phosphate, alkaline phosphatase | Bone statusa, check for compliance | Every 3 months | Every 6 months | Every 12 months |
Transaminases | Routine surveillance | Every 3 months | Every 6 months | Every 12 months |
Statement #18. Urine analysis of GA and 3-OH-GA is not informative for therapy monitoring (grade D).
Statement #19. Amino acids in plasma (ideally 3-4 h postprandially) should be monitored during dietary treatment (grade D).
Statement #20. Carnitine status in plasma should be monitored in all patients to detect secondary carnitine depletion (grade D).
Biochemical monitoring during acute illness
Neuroradiological monitoring
Statement #21. Neuroradiologic investigations should be performed in case of neurologic deteroriation but are not generally recommended for regular follow-up monitoring (GCP).