Glutaric Acidaemia

Synonyms: GA, Glutaric aciduria, Glutaryl-CoA dehydrogenase deficiency (Type I GA), Electron transport flavoprotein deficiency and electron transport flavoprotein oxoreductase deficiency (both Type II GA), Multiple Acyl-CoA dehydrogenase deficiency (MADD – synonymous with Type II GA), Glutaryl-CoA oxidase deficiency (Type III GA)

These are rare inborn errors of metabolism. They are caused by a heterogeneous group of mutations that impair either mitochondrial (Type I and II) or peroxisomal (Type III) metabolism. Glutaryl-CoA dehydrogenase (deficient in Type I GA) plays a key role in the metabolism of lysine, hydryoxylysine, and tryptophan. The affected enzymes in Type II GA are intimately involved in fatty acid, amino acid and choline metabolism. Peroxisomes are ubiquitous single-membrane organelles responsible for the sequestration and activity of key metabolic enzymes, present in nearly all eukaryotic cells. They play an important role in the metabolism of long- and very-long-chain fatty acids, the biosynthesis of plasmalogens, cholesterol synthesis, bile acid synthesis, amino acid metabolism and purine metabolism.¹

• Type I – Very rare. In The Republic of Ireland there were 21 patients identified in the country over a 16-year period.² High incidence in Amish community in USA (carrier frequency approximately 10%).³
• Type II – Incredibly rare. No reliable population-based figures.
• Type III – Exceedingly rare. A handful of reported cases.

Type I⁴ The earliest presentation in neonates is microencephalic macrocephaly (small brain in big head), which causes disruption of intracerebral bridging veins; this may lead to subdural haematoma and retinal haemorrhage in newborns. Failure to thrive, hypotonia and hypoglycaemia are other features. It may damage the basal ganglia. Acute striatal necrosis in infancy is the main cause of morbidity associated with the condition. The damage is stroke-like in its sudden evolution and CT appearance. It leads to severe dystonia and progressive athetosis that may cause oromotor, gastro-oesophageal, skeletal, and respiratory complications. Where the putamen is damaged it causes abrupt onset behavioural arrest. Spastic diplegia and cerebral palsy are possible modes of presentation. Episodes of encephalopathy may be associated with acute illness. Although it is commonly a disease of infancy there are patients who appear to have milder forms of the disease that present in later childhood. Exercise intolerance, hypoglycemia, and seizures can be features of illness in older patients.

Type II May cause severe or fatal neonatal acidosis with mustiness of the breath, often described as being akin to the smell of sweaty feet. There is usually a propensity to episodic hypoglycaemia in infancy and childhood, with muscular hypotonia and/or respiratory distress. Fatty infiltration of, and damage to the liver is often present. May present as dysmorphia or with renal/cardiac anomalies. There is a great degree of variability in severity and some patients may not have symptoms until they are in their teenage years, when muscular problems such as proximal myopathy are the usual mode of presentation.⁵

Type III Presents in a variable fashion depending upon the particular cause of the genetic problem (the condition seems to be caused by chromosomal abnormalities and may co-exist with other diseases such as thalassaemia). Failure to thrive, dysmorphia, bowel disorders and thyroid axis abnormalities are some of the possible modes of presentation of this incredibly rare disease.

A large number of other inborn or acquired errors of metabolism may cause similar symptoms and biochemical derangement. Specialist analysis of biochemical and genetic information is needed to distinguish between the numerous possibilities. Child abuse may initially be suspected in some cases of Type I GA due to the presence of intracerebral bleeding, causing a suspicion of shaken-baby syndrome. Metabolic abnormalities that mimic child abuse should always be borne in mind and form part of the investigation of suspected mistreatment of children.

Blood and urine levels of glutarate and 3-hydroxyglutarate are grossly elevated in all types of GA, as detected by direct assay or gas-liquid chromatography. There are also low blood levels of carnitine and acylcarnitine. In Type II GA there are a range of abnormal organic acids in the blood and urine. Biopsy of muscle and liver may be required. The biochemical response to riboflavin and carnitine or lysine loading may help in making the diagnosis. Estimation of enzyme activity in cultured fibroblasts may be employed.⁶

The mainstays of ameliorative therapy are careful dietary manipulation, treatment with riboflavin and supplementation of L-carnitine. This helps to enhance enzymatic function and overcome the sequelae of the secondary carnitine deficiency. Early identification, particularly of Type I GA, is crucial so that this therapy can be given before neurological damage occurs, which is irreversible. Careful highly-specialist management of episodes of illness or anaesthesia is necessary in Type I GA to prevent acute neurological damage or encephalopathic crises.

• Hypoglycaemia
• Muscular weakness or dystonia
• Basal ganglia damage
• Spastic diplegia and cerebral palsy
• Fluid and blood collections in the cranium due to bridging vein disruption
• Acute or chronic metabolic acidosis
• Liver damage
• Episodic encephalopathy
• Severe illness and death

For Type I GA the overall long-term outlook is fairly poor with death or severe disability a likely outcome before adulthood in most cases. Individual outcomes are highly variable depending on the degree of phenotypic expression of the heterogeneous genetic abnormalities. Earlier recognition of the disease, particularly in high-risk groups such as The Amish, combined with advanced specialist treatment is improving the situation in terms of survival and disability. The outlook in Type II GA is poor in those affected in childhood, but some cases have responded well to riboflavin therapy. Type III GA carries a grave prognosis with death during neonatal period or infancy being the usual outcome.

It is possible to screen newborns for the Type I form of the disease using tandem-mass-spectrometry analysis of heel-prick blood that is routinely taken to screen for other inborn errors of metabolism. This technique is being employed in high-risk populations such as The Amish, and may help to reduce the burden of neurological disease caused by the condition, through the institution of early dietary manipulation and supplementation.⁷ Population-based screening is not currently employed due to the rarity of the condition.