Glutaric aciduria type 1

Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down 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), 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. Intellectual disability may occur. GA1 is an autosomal recessive disorder caused by deficiency of the enzyme glutaryl-CoA dehydrogenase (GCDH), encoded by the GCDH gene.

Signs and symptoms

The severity of glutaric acidemia type 1 varies widely; some individuals are only mildly affected, while others suffer severe problems. GA1 can be defined as two clinical entities: GA-1 diagnosed at birth or pre-birth and managed through dietary restrictions, and GA-1 diagnosed after an encephalopathic crisis. A crisis may occur under both headings, but the care of individuals diagnosed before a crisis can be managed to avoid most or all injury.

GA1 without 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, given the importance of the early diagnosis of GA1. 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 an 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). GA, in patients who have suffered a crisis, 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 their own excessive postural muscle tone to their own advantage.

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.

Genetics The condition is inherited in an autosomal recessive pattern: mutated copies of the gene GCDH must be provided by both parents to cause GA1. The GCDH gene encodes the enzyme glutaryl-CoA dehydrogenase. 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. GA1 occurs in approximately 1 of every 30,000 to 40,000 births. As a result of founder effect, 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 low GCDH activity: in an early study of GA1, GCDH activity was found to be 38%, 42%, and 42% in three of the four unaffected relatives tested, a pattern consistent with the 50% level that would be expected in heterozygous carriers. Those levels are close to those found in some heavily symptomatic GA1-affected children.

Pathophysiology

Glutaryl-CoA dehydrogenase participates in the degradation of the amino acids, specifically lysine, hydroxylysine and tryptophan. This enzyme catalyzes following reaction:

Glutaryl − CoA + FAD ⟶ Crotonyl − CoA + FADH 2 + CO 2 {\displaystyle {\ce {Glutaryl-CoA + FAD -> Crotonyl-CoA + FADH2 + CO2}}}

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 GA1. Glutaric acid (GA) can block Na+-dependent glutamate uptake by causing oxidative stress. Na+/K+-ATPase also gets inhibited by GA which hampers astrocyte re-uptake of glutamate, and worsens excitotoxicity; inhibition of Na+/K+-ATPase causes edema of neurons which capilaries, and causes dilatation of deep venous system, due to lack of valves, flow would be decreased in striatum and thalamus. Due to metabolic dysfunction, alpha-ketoglutarate gets depleted which hampers HIF1a degradation and upregulates VEGF; this upregulation causes weak blood vessels (without junction proteins) to form, an these vessels tend to cause hemorrhages. Oxidative stress gets induced by glutaric acid which in turn damages lipids, proteins and DNA. GA also activates astrocytes, can cause microgliosis which in turn causes inflammatory proceses and disrupts myelination. Another substartes that geet inhibited are mitochondrial respiraotry chain complexes (I, II, and III gets inhibited). 3-Hydroxyglutaric Acid (3HGA) like GA can cause oxidative stress, inhibition of mitochondrial complex II, and astrogliosis. 3HGA can inhibit glutamate decarboxylase which participates in synthesis of GABA, and it can account for decreased GABA.

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