Glutaric aciduria type 1

Glutaric acidemia type 1 (or "Glutaric Aciduria", "GA1", or "GAT1") is an inherited disorder in which the body is unable to breakdown completely the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (glutaric acid, glutaryl-CoA, 3-hydroxyglutaric acid, glutaconic acid) can accumulate and cause damage to the brain (and also other organs^[1]), but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may also occur.

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Signs and symptoms

The severity of glutaric acidemia type 1 varies widely; some individuals are only mildly affected, while others have severe problems. GA1 can be defined as two clinical entities: GA1 before the encephalopathic crisis and GA1 after the encephalopathic crisis.

GA1 before the encephalopathic crisis

Macrocephaly

Babies with glutaric acidemia type 1 often are born with unusually large heads (macrocephaly). Macrocephaly is amongst the earliest signs of GA1. It is thus important to investigate all cases of macrocephaly of unknown origins for GCDH deficiency^[2][3], given the importance of the early diagnosis of GA1^[4]. Macrocephaly is a "pivotal clinical sign" of many neurological diseases. Physicians and parents should be aware of the benefits of investigating for an underlying neurological disorder, particularly a neurometabolic one, in children with head circumferences in the highest percentiles.

GA1 after the encephalopathic crisis

Neuromotor aspects

 Affected individuals may have difficulty moving and may experience spasms, jerking, rigidity or decreased muscle tone and muscle weakness (which may be the result of secondary carnitine deficiency). Glutaric aciduria type 1, in many cases, can be defined as a cerebral palsy of genetic origins.

Occupational therapy

 A common way to manage striatal necrosis is to provide special seating. These special wheelchairs are designed to limit abnormal movements. However, spasticity can be worsened by constraint.

Parents and caregivers can provide a more interactive occupational therapy by enabling the child to use his or her own excessive postural muscle tone to his ir her own advantage (see picture; note the care with which minimal pressure is applied while ensuring safety).

The excessive tone can also be managed with "jolly jumpers" and other aids to the upright stance that do not constrain the child but help him or her gradually tone down the rigidity.

Bleeding abnormalities

Some individuals with glutaric acidemia have developed bleeding in the brain or eyes that could be mistaken for the effects of child abuse.

Treatment

Correction of secondary carnitine depletion

Like many other organic acidemias, GA1 causes carnitine depletion^[5]. Whole-blood carnitine can be raised by oral supplementation. However, this does not significantly change blood concentrations of glutarylcarnitine or esterified carnitine,^[4] suggesting that oral supplementation is suboptimal in raising tissue levels of carnitine. In the field of clinical nutrition, researchers come to the same conclusion, that oral carnitine raises plasma levels but doesn't affect muscle carnitine, where most of it is stored and used.^[6]

• In contrast, regular intravenous infusions of carnitine caused distinct clinical improvements : "decreased frequency of decompensations, improved growth, improved muscle strength and decreased reliance on medical foods with liberalization of protein intake."^[5]
• Choline increases carnitine uptake and retention^[7]. Choline supplements are inexpensive, safe (probably even in all children requiring anticholinergics) and can provide spectacular evidence of the suboptimal efficiency of carnitine supplementation by increasing exercise tolerance, truncal tone and general well-being.

Precursor restriction

Dietary control may help limit progression of the neurological damage.

Selective precursor restriction

Tryptophan

Formulas such as XLys, XTrp Analog, XLys, XTrp Maxamaid, XLys, XTrp Maxamum or Glutarex 1 are designed to provide amino acids other than lysine and tryptophan, in order to tentatively prevent protein malnutrition.

The entry of tryptophan to the brain is crucial in the proper synthesis of the neurotransmitter serotonin in the brain. One way to acutely cause depression or bulimia or anxiety in humans, in order to assess an individual's vulnerability to those disorders, is to supplement with a formula with all or most amino acids except tryptophan. The protein synthesis elicited by the amino acids leads circulating amino acids, including tryptophan, to be incorporated into proteins. Tryptophan thus lowers in the brain as a result of the protein synthesis enhancement (causing circulating tryptophan to lower more than other amino acids) (Young, 1993), and perhaps also competition of large neutral amino acids for transport across the blood-brain barrier through the large neutral amino acid transporter 1 (LNAA1). The consequence is acute tryptophan depletion (ATD) in the brain and a consecutive lowering of serotonin synthesis. ATD, which is basically a diagnostic procedure, is not a treatment for GA1.

In the Amish community, where GA1 is overrepresented (Morton, 2003), patients with GA1 did not and still don't receive tryptophan-free formulas, neither as the sole source of amino acids, nor as a supplement to protein restriction. Doctor D. Holmes Morton, the 1993 Albert Schweitzer Prize for Humanitarianism laureate, is taking care of patients affected with GA1 and other metabolic diseases in this community in his Clinic for Special Children.

5-hydroxytryptophan, the precursor of serotonin that is not metabolized to glutaryl-CoA, glutaric acid and secondary metabolites, could be used as an adjunct to selective tryptophan restriction, considering the risks associated with the procedure. However, the evidence in favour of selective tryptophan restriction remains insufficient and the consensus evolves towards the restriction of lysine only (Kolker & al. 2006).

Lysine

Lysine restriction, as well as carnitine supplementation, are considered the best predictors of a good prognosis for GA1 (Kolker & al., 2006). This excludes, however, patients who already suffered an encephalopathic crisis, for whom the prognosis is more related to the treatment of their acquired disorder (striatal necrosis, frontotemporal atrophy).

Protein restriction

Vegetarian diets and, for younger children, breastfeeding^[8]are common ways to limit protein intake without endangering tryptophan transport to the brain.

Enhancement of precursor's anabolic pathway

Lysine and hydroxylysine anabolic pathway enhancement

A possible way to prevent the build-up of metabolites is to limit lysine and hydroxylysine degradation, as lysine is one of the most abundant amino acids and tryptophan is one the least abundant amino acids.

Interaction of GCDH deficiency with GLO deficiency

While GCDH deficiency is a rare disease, GLO deficiency is the most common of metabolic diseases affecting Humanity, limiting ascorbic acid biosynthesis to a minute fraction of what other non-primate species synthecize. It was thus called by OMIM (Online Mendeleian Inheritance in Man) a "public" error of metabolism. The nutrient ascorbic acid (which is often called "Vitamin C") is a necessary cofactor for the utilization of lysine in collagen synthesis. Collagen, the most abundant protein in the human body, requires great amounts of lysine, the most abundant amino acids in proteins. Ascorbic acid, the main hydroxyl radical quencher, works as the cofactor providing the hydroxyl radical required to collagen cross-linking; lysine thus becomes hydroxylysine.

GA1 worsens during stresses and catabolic episodes, such as fasts and infections. Endogenous catabolism of proteins could be an important route for glutaric acid production. It thus follows that collagen breakdown (and protein breakdown in general) should be prevented by all possible means.

Ascorbic acid is used to prevent multiple organ failure and to lessen mortality and morbidity in intensive care units. It thus appears reasonable to include sufficient doses of ascorbic acid to the treatment protocol during stresses and other challenges to growth in order to stimulate collagen synthesis and thus prevent lysine breakdown (all required citations will be submitted).

Tryptophan anabolic pathway enhancement

The conversion of tryptophan to serotonin and other metabolites depends on vitamin B6^[9]. If tryptophan catabolism has any impact on brain glutaric acid and other catabolite levels, vitamin B6 levels should be routinely assayed and normalized in the course of the treatment of GA1.

Management of intercurrent illnesses

Stress caused by infection, fever or other demands on the body may lead to worsening of the signs and symptoms, with only partial recovery.

Genetics

The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause glutaric acidemia type 1. The GCDH gene encodes the enzyme glutaryl-CoA dehydrogenase. This enzyme is involved in degrading the amino acids lysine, hydroxylysine and tryptophan. Mutations in the GCDH' gene prevent production of the enzyme or result in the production of a defective enzyme with very low residual activity, or an enzyme with relatively high residual activity but still phenotypic consequences^[10][11]. This enzyme deficiency allows glutaric acid, 3-hydroxyglutaric acid and (to a lesser extent) glutaconic acid to build up to abnormal levels, especially at times when the body is under stress. These intermediate breakdown products are particularly prone to affect the basal ganglia, causing many of the signs and symptoms of glutaric acidemia type 1.

Glutaric acidemia type 1 occurs in approximately 1 of every 30,000 to 40,000 births. It is much more common in the Amish community and in the Ojibway population of Canada, where up to 1 in 300 newborns may be affected.

Relatives of children with GA1 can have very low GCDH activity: in an early study of GA1, GCDH activity was found to be 38%, 42%, and 42% of controls in three of the four relatives tested^[12]. Those levels are close to those found by Christensen & al^[13] in some heavily symptomatic GA1-affected children.

This article incorporates public domain text from The U.S. National Library of Medicine

Epistemology

GA1 can be described as a metabolic disease, a neurometabolic disease, a cerebral palsy or a basal ganglia disorder (it is also misdiagnosed as shaken baby syndrome). Depending on the paradigm adopted, GA1 will mostly be managed with precursor restriction or with neurorehabilitation (or with incarceration of the parents in the case of presumed shaken baby syndrome).

So-called "orphan diseases", such as GA1, can be adopted into wider groups of diseases (such as carnitine deficiency diseases, cerebral palsies of diverse origins, basal ganglia disorders, and others); Morton at al. (2003b) emphacize that acute striatal necrosis is a distinctive pathologic feature of at least 20 other disorders of very different etiologies (e.g. HIV encephalopathy-AIDS dementia complex, pneumococcal meningitis, hypoadrenal crisis, methylmalonic acidemia, propionic acidemia, middle cerebral artery occlusion, hypertensive vasculopathy, acute mycoplasma pneumoniae infection, 3-nitropropionic acid intoxication, late onset familial dystonia, cerebrovascular abrupt and severe neonatal asphyxia ("selective neuronal necrosis")).

Amongst 279 patients who had been reported to have GA1, 185 were symptomatic (two thirds); being symptomatic was seen as an indication of "low treatment efficacy". High risk screening, neonatal screening and a diagnosis of macrocephaly were the ways to identify bearers of the GCDH' defective gene who weren't frankly symptomatic. Macrocephaly remains the main sign of GA1 for those who aren't related to GA1 in any way or benefit from no screening program. GA1 was considered as a "treatable disease"^[14]. GA1 is thus the cause of a disease that is currently not treatable, but it is treatable.

Two thirds of the patients who have GA1 will receive little benefit from the treatment for GA1 but can benefit from treatments given to victims of middle cerebral artery occlusion, AIDS dementia and other basal ganglia disorders : brain implants, stem cell neurorestauration, growth factors, monoaminergic agents, and many other neurorehabilitation strategies.

References

• Mahfoud A,Dominguez CL,Rizzo C, Ribes A. (2004) "In utero macrocephaly as clinical manifestation of glutaric aciduria type I. Report of a novel mutation." Rev Neurol. 2004 Nov 16-30;39(10):939-42.
• Martinez Granero MA, Garcia Perez A, Martinez-Pardo M, Parra E. 2005. "Macrocephaly the first manifestation of glutaric aciduria type I: the importance of early diagnosis." Neurologia. 2005 Jun;20(5):255-60.
• Morton DH, Robinson DL, Puffenberger EG, Strauss KA. 2003. "Type I glutaric aciduria, part 1: natural history of 77 patients." Am J Med Genet C Semin Med Genet. 2003 Aug 15;121(1):38-52.
• Young SN. (1993) "The use of diet and dietary components in the study of factors controlling affect in humans: a review." J Psychiatry Neurosci. 1993 November; 18(5): 235–244.