OVERVIEW: What every practitioner needs to know

Are you sure your patient has glutaric aciduria type I? What are the typical findings for this disease?

Glutaric aciduria type I (GA-I) should be considered in any patient who has a history of dystonia/dyskinesia with macrocephaly. Prior to these overt chronic neurologic symptoms, there is usually a history at 6-18 months of age (range 1 month to 6 years age) of an acute encephalopathic episode associated with an otherwise common early childhood illness, either gastrointestinal or respiratory. Subsequently, the patient develops dystonia superimposed on axial hypotonia.

The acute episodes often manifest sudden onset hypotonia, loss of head control, eventual development of seizure-like positioning, dystonias, and unusual movements. Some patients may show milder symptoms/signs prior to such an acute episode, such as hypotonia, irritability, and feeding problems. In a minority of patients, there may be a gradual progressive development of motor delays, hypotonia, dystonia, and dyskinesia.

The eventual outcome resembles several extrapyramidal movement disorders. Of note, however, is the relative preservation of intellect despite apparent severe motor dysfunctions. It is occasionally diagnosed as an adult leukoencephalopathy. Of importance is the fact that this neurologic progression accompanied by brain striatal injury may be preventable with both ongoing and emergency treatments. This has allowed active newborn screening protocols to be developed, now available throughout the United States, but these screening programs have missed some individuals later diagnosed with GA-I. Knowledge of its variable clinical presentations and laboratory findings therefore remains an important tool in the prevention of the above mentioned sequelae.

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What other disease/condition shares some of these symptoms?

Conditions whose symptoms and signs may overlap with those of glutaric aciduria type 1 include the following:

  • Any type of extrapyramidal cerebral palsy

  • Nonaccidental head trauma (child abuse)

  • Multiple inborn errors of metabolism – organic acidemias (e.g., multiple acylCoA dehydrogenase deficiency (MADD)/glutaric acidemia type II (GA-2); propionic, methylmalonic, and isovaleric acidemias; maple syrup urine disease; and many others), mitochondrial disorders, and others.

  • Acute disseminated encephalomyelitis (ADEM)

  • Viral encephalitis

  • Several stroke and stroke-like conditions

What caused this disease to develop at this time?

Glutaric aciduria type I is a potentially treatable severe condition caused by the autosomal recessively inherited deficiency of the enzyme glutaryl-CoA dehydrogenase. This enzyme is intrinsic to the metabolism of the amino acids lysine, hydroxylysine and tryptophan. Its deficiency results in the accumulation of glutaric acid and 3-hydroxyglutaric acid, which ultimately cause neuronal destruction in the striatal and basal ganglia portions of the brain, especially the caudate and putamen.

There are clearly prenatal effects since many of these children exhibit macrocephaly at birth or shortly thereafter with evident brain pathology on imaging, notably frontoparietal (or frontotemporal) atrophy (or hypoplasia) with enlarged Sylvian fissures. Enlarged collections of CSF may be noted and the stretched bridging veins may rupture, producing acute subdural hemorrhages following minor head trauma, mimicking nonaccidental trauma, i.e. child abuse.

Most children are relatively normal until an acute neurologic deterioration occurs, usually associated with an otherwise routine illness of infancy/childhood, dehydration following surgery, or even immunizations. Typically, mild fever and vomiting are followed by acute hypotonia, loss of head control, and abnormal movements (EEGs are often normal).

Although hypotonia may at times initially appear to improve, an apparent movement disorder develops with dystonias, dyskinesias, swallowing dyscoordination, tongue thrusting, and ambulatory impairments, ultimately with spasticities and poor muscle coordination. These may cause difficulty communicating verbally or with directed tasks, masking the relative preservation of intellectual functioning. Approximately 80-90% of patients develop this type of pattern, usually between 3-36 months of life but it may occur up to about 6 years of life.

In 10%-20% of patients, no such encephalopathic crisis is documented associated with subsequent neurologic impairment, and two alternate patterns of this type of presentation have been termed insidious-onset and late-onset.

Importantly, dietary therapy including restriction of offending amino acids, L-carnitine and other supplements, and especially directed emergency treatments during episodes of intercurrent illnesses have appeared to reduce the frequency of development of the severe dyskinetic/dystonic sequelae. In general there are no pathognomic signs or symptoms prior to the acute encephalopathic crises. Prospective therapy is therefore key and for that reason, identification of affected patients by expanded newborn screening protocols or directed screening of family members at risk offers the best prognosis.

Prior to the acute encephalopathic episode, the child by history may be described as irritable, jittery, or a problem feeder. Most patients are initially considered within normal limits, although some may have some mild hypotonia. There is evidence that in some children, the striatal damage may occur insidiously or progressively without overt symptoms. However, for the majority, the striatal damage appears to occur acutely in the setting of some otherwise typical childhood illness resulting in catabolism (fever, vomiting, diarrhea, trauma, post immunizations). During or just after such routine type illness, neurologic dysfunction is evident (acute hypotonia, loss of head control seizures or seizure like movements, followed by grimacing, fisting, opisthotonic posturing, rigidity and other signs of dystonia).

At the time of this acute encephalopathic crisis, nonspecific laboratory findings may include ketoacidosis, hypoglycemia, mild transaminase elevations, and mild hyperammonemia. This may be variable. Notably, urine organic acids will demonstrate in most, but not all, cases the characteristic glutaric and 3-hydroxyglutaric acid peaks, and plasma free carnitine levels are usually low with elevated acylcarnitine fraction. The ongoing progression of neurologic dysfunction may be variable, occurring over a few weeks, months or years, with or without intermittent episodes similar to the first.

Notably some individuals with the enzymatic deficiency (even with the same causal mutation) do not develop the above neurologic manifestations. There is not a straightforward genotype-phenotype correlation. Similarly, not every patient demonstrates the characteristic abnormal elevations of glutaric acid in urine and blood, even during acute episodes.

The variability in presentation clinically and by laboratory evaluation often makes it challenging to arrive at a diagnosis. Once the first neurologic decompensation has resulted in striatal and basal ganglia damage, it is not likely reversed with treatment, although subsequent treatments may prevent further damage and lessen the overall future severity of the dyskinetic/dystonic condition.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Urine organic acids suggests the diagnosis in most cases with elevated glutaric and 3-hydroxyglutaric acids.

Glutaconic acid may also be elevated, especially if there is associated ketosis. Glutaric acid elevations may be seen in a number of other conditions but 3-hydroxyglutaric acid is relatively specific. Elevated glutaric acid may be seen in urine organic acid analysis of patients with glutaric acidemia type 2, glutaric acidemia type 3, alpha-aminoadipic acidemia, short-gut syndrome, and some intestinal infections. Glutarylcarnitine (C5DC) should be evident on plasma acylcarnitine profile.

Some patients may not excrete easily identified amounts of glutaric acid into the urine and/or blood. Repeated urine organic analyses may be required. Specific determination of 3-hydroxyglutaric acid by stable isotope-dilution technique may be required. Plasma carnitine levels usually exhibit low total and free carnitine with increased ratio of acylcarnitine to free carnitine. Diagnosis by reduced levels of glutaryl-CoA dehydrogenase (GCDH) activities in skin fibroblasts and/or leukocytes assures the diagnosis. Direct sequencing of the gene (GCDH) for mutations is available. Direct gene sequencing is being utilized with increased frequency for the followup of strongly positive newborn screening results in which subsequent supporting organic acid and acylcarnitine examinations are either equivocal or absent.

Would imaging studies be helpful? If so, which ones?

Both computed tomography (CT) and magnetic resonance imaging (MRI) scans demonstrate collections of fluid over the frontal lobes and bases of brain, with atrophy (or hypoplasia) of the frontal and temporal lobes, the latter hypoplasia especially of the insular region (“widened Sylvian fissures”, “batwing appearance”). Arachnoid or subdural cysts of fluid are sometimes observed in the Sylvian fissure regions. Some of these changes may be noted on neonatal head ultrasound but are better appreciated by CT and/or MRI studies. These changes have been described as frontotemporal (occasionally frontoparietal) atrophy in the literature but may represent instead hypoplasia as they are usually present before clear evidence of clinical neurologic decompensation.

Basal ganglia lesions (caudate and putamen), ventriculomegaly, and variable white matter changes (bilateral striatal degeneration) appear subsequent to the encephalopathic crises. Increased MRI T2 and FLAIR weighted image signal intensities are observed in subcortical periventricular white matter and extend to subcortical U fibers. Prefrontal subdural hygromas and even subdural hemorrhages may be evident and be confused with nonaccidental trauma, i.e., child abuse.

Confirming the diagnosis

Separate algorithms exist for patients being screened as newborns compared to patients presenting with an acute neurologic crisis versus ongoing encephalopathic type workup. In all cases, however, the diagnosis in some small but distinct percentage of patients will be missed unless GCDH enzymatic activity analysis is ultimately performed.

Population wide newborn screening is performed by tandem mass spectroscopy analysis (MS/MS) generating acylcarnitine profiles from newborn blood spots. Individuals at increased risk for GA-1 are identified by presence of the metabolite C5DC. Screening cutoff values for followup are determined by the individual laboratory sites, often varying by state, province or country. Any positive result mandates a workup for confirmation, including a quantitative analysis of glutaric acid and 3-OH glutaric acid in urine or blood, such as by GC/MS, mutation analysis of the GCDH gene, and, if feasible, GCDH enzyme analysis.

The observation of elevated levels of 3-OH glutaric acid (3-OH GA) should be followed by mutation analysis and start of treatment, while awaiting mutation analysis results and/or arrangements for enzymatic analysis since the latter is the best confirmation of the condition. Note that some percentage of patients with glutaric aciduria type 1 may be of the low excreting phenotype and followup MS/MS may be equivocal or even normal.

There have been false negatives on primary newborn screens in patients subsequently diagnosed with glutaric aciduria type I. For this reason, all initial positives need to have follow up investigations, usually analysis of urinary glutaric acid and 3-OH glutaric acid, initially by sending urine for organic acid analysis via GC/MS. Similarly, plasma acylcarnitine profile should be sent to a laboratory for quantitative analysis rather than newborn screening analysis.

Urine organic acid analysis will identify the presence of other metabolites if inborn errors of metabolism other than GA-1, such as GA-2 (multiple acyl-CoA dehydrogenase deficiency) or other conditions causing abnormally elevated acylcarnitine peaks (i.e., occasional renal disease conditions).

Note that elevated C5DC in an infant may also reflect a maternal GA-1 condition. Finding two known disease causing mutations from GCDH gene sequencing will also establish the diagnosis and may then be used to screen other family members. In local populations with a known high incidence of the disorder and known mutations, DNA screening may also be performed.

Selective screening of patients presenting clinically with signs/symptoms suggestive of possible GA-1 (neurologic type and/or ketoacidotic presentation with or without macrocephaly) should always include urine quantitative organic acid analysis (looking for GA but especially 3-OH GA). Some centers may use blood screening methodologies for these metabolites.

Acylcarnitine profiles on these patients may be helpful but are not alone sufficient to rule out the diagnosis. If high suspicion exists despite negative laboratory studies, either DNA sequence analysis (sensitivity may be as high as 98-99%) and/or enzymatic analysis should be pursued. A more complete discussion of the strength of evidence may be found in the reference by Kolker S, et al, JIMD, given below.

If you are able to confirm that the patient has glutaric aciduria type I, what treatment should be initiated?

As soon as there is suspicion for the presence of glutaric aciduria type I (GA-1), treatment should begin, since there is no alternative method that ensures at least the possibility of prevention of the striatal degeneration. Outcomes of patients with GA-1 have clearly been shown to improve if they are started on treatment during the asymptomatic period. The best outcomes are observed by starting treatment within the first months of life.

Once neurologic signs/symptoms are apparent, there are no reversals of pathology with treatments although further brain damage may be prevented.

The treatments involve ongoing dietary restrictions of lysine intake along with supplementation with carnitine, and immediate institution of emergency protocols (explained below) to reverse catabolism as well as ensure carnitine intake and restriction of lysine.

For known GA-I children presenting in acute febrile or similarly catabolic states, intravenous fluids containing 10% glucose (D10) with 37.5-75 mEq/L NaCl (0.25 or 0.5 NS (normal saline)) should be started to run at one and one half to twice maintenance rate calculated for weight for 24 hours. Low amounts of insulin may be used if persistent hyperglycemia occurs but this is usually not a problem. Concurrently, carnitine 50 mg/kg intravenous dosing every 6 hours is given. Supplementation of calories using intravenous lipids (20% intralipids infused at 1/10 rate of IV fluids or equivalent per preference of local critical care staff) is also recommended by some.

Antipyretic therapy (i.e., ibuprofen) for abrogation of febrile state is important. Directed therapies towards the source of the acute illness, such as specific antibiotics, are indicated. When tolerated, change to enteral feeds is begun by gradual increase to replace intravenous fluids.

All previously diagnosed patients should carry with them an emergency protocol letter directing this type of treatment for presentation at local emergency centers when sick. The letters should explain the diagnosis and contact information for the metabolic specialist following the patient and instructions for both the emergency intravenous protocols and the followup enteral lysine restricted diet and carnitine supplementation (usually 100 mg/kg/day but may be individually adjusted for known monitored plasma carnitine levels).

Most centers do not use routine anticonvulsants unless a specific diagnosis of epilepsy is made. Valproic acid therapy should likely be avoided since it may compete with glutaryl-CoA for esterification with carnitine.

The above intravenous emergency protocol (or similar type advocated by local metabolic specialist) could be used in any child presenting in a changing state of mental status with neurologic findings with or without ketoacidosis in which GA-1 is among the differential diagnoses. Obtaining urine and blood for the above mentioned laboratory studies (urine for organic acids, plasma for acylcarnitine analysis) as close as possible to the initial time of presentation is extremely important to ensure best possibility for diagnosis by presence of the GA and 3-OH GA peaks, prior to their potential loss with ongoing intravenous fluids and resolution of catabolism.

Following identification by newborn or other screening in presymptomatic patients, most centers institute a diet restricted in lysine by the use of synthetic amino acid formulas lacking lysine to supplement a directed low protein diet to which specific amount of lysine supplement may be added as needed. Tryptophan intake also needs to be carefully considered. The patients are followed closely by quantitative plasma amino acids and their dietary intakes of lysine, tryptophan and/or protein adjusted accordingly in close discussion with metabolic nutritionists. Protocols allowing some amount of breast feeding are available and encouraged by many centers.

Supplementation with L-carnitine (50-100 mg/kg/day) is prescribed to support mitochondrial functions associated with acyl-CoA compounds and to prevent carnitine deficiency which otherwise occurs in most patients with untreated GA-1. Riboflavin supplementation (100 mg/day) is advocated by some since its derivative is a known cofactor of the enzyme, but ongoing studies have not clearly demonstrated its efficacy in preventing the long term complications of GA-1.

As described below, the best outcomes are those associated with therapy instituted during the presymptomatic period of time (age 0-6 years) prior to the classically described acute episode associated with the then overt neurological signs/symptoms. This means that any intercurrent illness, especially if associated with fever, irritability, vomiting and/or diarrhea, needs to be immediately evaluated with the help of a metabolic specialist so that the emergency protocol can be instituted urgently. Similarly, any plans for surgery in which the patient will not be receiving their prescribed caloric dietary intake should be discussed with the metabolic specialist to determine if the emergency protocol should be instituted during and immediately after surgery.

Many metabolic centers have protocols for initiating home emergency treatment if parents are adequately trained. Advice on routine childhood immunizations may be variable between metabolic centers but the majority appear to feel that they may be given with appropriate close followup for any clinical indication for precautionary initiation of emergency protocol, ie., fever or mental status change. Antipyretics given during the times surrounding immunizations are recommended.

After 6 years of age, encephalopathic crises appear to be rare but nonetheless associated illnesses need to be closely evaluated by communication with the metabolic specialist. Based on the individual circumstances of the illness, it may be suggested to use the emergency protocol depending on the severity of the febrile or gastroenteritis associated illness. Any worrisome signs or symptoms of neurologic involvement similarly mandate prompt medical response and emergency protocol.

Longer term therapies include ongoing dietary supervision of prescribed lysine restricted diets under the supervision of metabolic nutritionists and the continuation of L-carnitine, adjusted to usually 50-100 mg/kg/day. If the patient suffers from the described associated movement disorder, multidisciplinary care is generally required from a combination of neurologist, physical and occupational therapists including speech and communication, orthopedist, dietician/nutritionist, and metabolic physician familiar with the disorder. Use of baclofen and benzodiazepines are often first line therapies for the movement disorder associated dystonia and spasticity.

Some centers have experience with use of botulinum toxin as adjunct therapy in some cases and trihexyphenidyl (anticholinergic properties) may be considered for use by some centers if initial therapies are not satisfactory. In general, if the patients do not have a clear epileptic condition, there is no role for routine anticonvulsant therapies.

What are the adverse effects associated with each treatment option?

All children with GA-I and macrocephaly (75% of the patients) are at risk for subdural hemorrhage at any age but especially during peak periods of macrocephaly (late infancy), reflecting the relatively increased subdural space and stretched bridging veins. As such, their presentation at emergency departments may initiate a protocol for workup of possible child abuse. Similarly, suspected non-accidental trauma cases associated with subdural hemorrhage should have GA-I in the differential and biochemical workup should be initiated. This particular adverse effect of GA-I is not affected by treatment regimens.

The lysine restricted dietary protocols can result in nutritional and vitamin deficiencies if not appropriately monitored by knowledgeable nutritionists. Of note is that breast feeding may be encouraged but must be supplemented with the above mentioned lysine restricted formulas. The main reported adverse effects of carnitine therapy are GI upset and/or fishy odor due to trimethylamine formation by bowel bacteria from undigested carnitine, but these occur in a minority of patients when using the stated doses.

As previously noted, these routine treatments do not necessarily protect against acute encephalopathic crises, and frequent utilization of the emergency protocols necessitate frequent emergency visits with IV placements with low index of suspicion, which is frustrating to patient families.

Chronic use of baclofen and benzodiazepine may produce antibodies (baclofen) or tachyphylaxis that eliminates their effectiveness. Overdosage of benzodiazepines with potential for respiratory depression needs to be carefully monitored.

Use of the anticholinergic trihexyphenidyl has been associated with blurred vision and dry mouth, which may be temporary. Confusion, memory deficit, and abnormalities in intraocular pressure may be associated with its use and require a reduction in dosage.

What are the possible outcomes of glutaric aciduria type I?

At the onset, the family needs to understand the variability in outcomes of glutaric aciduria type I (GA-I). However, there is good evidence that adherence to the above described protocols of presymptomatic treatments has significantly reduced the morbidity and mortality associated with the condition.

The association of neurologic disease manifested by movement disorder with concomitant brain injury that can be documented by imaging studies can be seen in 90% of untreated patients. In contrast, adherence to the prescribed lysine restricted dietary protocols, carnitine supplementation, and liberal use of the emergency protocols during episodes of intercurrent illness has reduced both the development and severity of the otherwise acquired dystonic/dyskinetic movement disorder.

Optimal treatment of infants diagnosed early apparently prevents brain deterioration in 80-90% of these patients. It is therefore considered a treatable disease and thus newborn screening has been widely applied.

Approximately 10%-20% of the untreated patients never demonstrate an apparent encephalopathic crisis but nonetheless demonstrate the acquisition of the severe neurologic condition (insidious onset type GA-I).

Patients who have documented basal ganglia injury will not have reversal of symptoms but treatment protocols will prevent further deterioration of the neurologic condition.

Presence of macrocephaly (75%) does not help in the prognosis for overt neurologic disorder but does suggest increased risk for subdural hemorrhage and therefore warrants closer monitoring of the child.

Overall the family needs to understand that there will need to be close ongoing communication with the metabolic and other specialists throughout the childhood years but especially during the years of highest sensitivity for neurologic damage, i.e., ages 0-6 years.

What causes this disease and how frequent is it?

Glutaric aciduria type I (GA-I) is due to deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase, which is involved in the catabolism of the amino acids L-lysine, L- OH-lysine, and L-tryptophan. It is an autosomal recessive disorder occurring at an estimated frequency of 1 in 100,000 newborns in the general worldwide population.

However, there are communities with much higher frequencies due to genetic founder effects and historical consanguinity. These incidences can be as high as 1 in 300 in some studies, usually referring to the Saulteaux/Ojibway (Oji-Cree native) Indians of Canada and Old Order Amish of Lincoln/Lancaster Counties of Pennsylvania USA, with other relatively higher than typical incidences in certain Irish communities and the Lumbee in North Carolina, USA. Overall the incidence is thought to be 1/50,000 in the USA, with similar numbers in some areas of northern Europe (ie., 1/30,000 in Sweden, 1/80,000 in Germany) but much lower prevalence in Australia (<1/300,000).

More than 100 disease causing mutations have been so far described without a major predominance of any particular allele (the R402W mutation accounts for estimated 10-20% of Caucasian alleles) except in the above cited specific populations. Therefore, whenever the disease is suspected in a patient, sequence analysis of the GCDH gene for further directed family studies is mandated. There does not appear to be a clear cut genotype-phenotype correlation, with symptomatic outcome not clearly dependent on genotype specificity nor residual enzymatic activity.

The observed period of vulnerability for development of neurologic sequelae appears to be mainly (but not exclusively) during the ages of 0-6 years.

How do these pathogens/genes/exposures cause the disease?

As described above, neurologic deterioration appears to follow an unpredicted course associated with otherwise routine childhood illness that creates a catabolic state in the patient without sufficient glutaryl-CoA dehydrogenase activity to meet the demands of the situation. Inability to meet this ill-defined catabolic threshold for the patient’s particular deficient enzymatic state apparently leads to the striatal degeneration of the brain observed in the majority of patients.

It is unclear if the identified organic acid metabolites, glutaric and 3-OH glutaric acids, are themselves toxic to the cells in these specific neural pathways of the striatum or if they simply identify the process that produces other coexisting toxic metabolites. Therefore, prevention of reaching this catabolic threshold seems to be the best therapeutic option in most, but not all patients.

It appears that ongoing brain injury, perhaps even during the prenatal period, may occur in some initially normal-appearing patients in whom treatment protocols do not prevent the associated development of neurologic sequelae.

How can glutaric aciduria type I be prevented?

Genetic counseling for known GA-I in a family is that for any known autosomal recessive disorder. Recurrence risk is 25% of offspring of the same parents as the index case. Mutational analysis is usually used to confirm the disorder in the index case and carrier status of the parents seeking counseling.

Prenatal diagnosis is available if the mutational basis of the disease in the family is determined, using cultured cells from amniotic fluid or chorionic villous sampled cells. Determination of increased glutaric acid levels in amniotic fluid by stable-isotope-dilution techniques or enzymatic analysis of cultured prenatally obtained cells has been used in the past and is still available. However, the preferred recommendation for prenatal studies is fast becoming molecular testing for known mutations causing GA-I in the individual family under consideration.

What is the evidence?

Kolker, S, Christensen, E, Leonard, JV. “Diagnosis and management of glutaric aciduria type I – revised recommendations”. J Inherit Metab Dis. 2011. (An excellent state of the art subspecialist committee review and expression of guidelines for diagnosis and treatment.)

Hedlund, GL, Longo, N, Pasquali, M. “Glutaric Acidemia Type I”. Am J Med Genet C Semin Med Genet. vol. 142C. 2006. pp. 86-94. (An NIH Public Access Manuscript which is an excellent comprehensive summary of the condition as well as offers specific treatment protocol examples.)

Goodman, SI, Frerman, FE. “Chapter 95: Organic Acidemias Due to Defects in Lysine Oxidation: 2-Ketoadipic Acidemia and Glutaric Acidemia. in OMMBID: the Online Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill Companies, Inc. 1-21”. (An excellent comprehensive review of all aspects of biochemistry and genetics of the disease and its clinical complications.)

Hoffman, GF, Schulze, A. “Chapter 7: Organic Acidurias – subsection Glutaric Aciduria Type I pp.108 – 112 in Sarafoglou K, Hoffmann GF, Roth KS (eds). Pediatric Endocrinology and Inborn Errors of Metabolism (2009)”. McGraw Hiill Medical. (An excellent short review of all clinical and genetic aspects of GA-1 with useful tables for quick reference.)

Herringer, J, Boy, SPN, Ensenauer, R. “Use of Guidelines Improves the Neurological Outcome in Glutaric Aciduria Type I”. Ann Neurol. vol. 68. 2010. pp. 743-752. (Excellent case examples and overall analysis of 52 patients treated in Germany.)