August 01, 2019
Years published: 1987, 1990, 1994, 2004, 2019
NORD gratefully acknowledges Bridget McClain and Ashby Martin, NORD Editorial Interns from the University of Notre Dame; Barb Calhoun, MSN, RN, NP, Nurse Practitioner and Outreach Coordinator, Boler-Parseghian Center for Rare and Neglected Diseases at the University of Notre Dame; and Nikolas Boy, MD, Metabolic Pediatrician, Centre for Child and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine, Heidelberg University Hospital, for assistance in the preparation of this report.
Glutaric aciduria type I (GA1) is a rare hereditary metabolic disorder caused by a deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). It is in the group of disorders known as cerebral organic acidemias. Individuals with this condition have deficiency or absence of GCDH enzyme that is involved in the lysine metabolism. GCDH deficiency results in increased concentrations of potentially neurotoxic metabolites, glutaric acid (GA), 3-hydroxy glutaric acid (3-OH-GA) and glutaconic acid within body tissues, especially within the brain. Two arbitrary biochemical subtypes have been defined, high (HE) and low excretors (LE), depending on the amount of GA in the urine. Newborns may show unspecific clinical signs like enlarged head circumference (macrocephaly) or decreased muscle tone (hypotonia). Without treatment, most affected children develop an acute encephalopathic crisis following febrile illness episodes or other catabolic conditions resulting in bilateral striatal injury and consequently, dystonic movement disorder. Cognitive outcome has not been systematically studied, but severe cognitive dysfunction is rarely seen. Sometimes babies with GA1 have been mistaken to have been abused because they present with subdural and/or retinal hemorrhages. GA1 is included in the newborn screening panel in a growing number of countries which is essential for early intervention. Importantly, patients with the low excreting phenotype may be missed by newborn screening.
Babies with GA1 are born healthy and may only present with unspecific signs like macrocephaly at birth. Macrocephaly is one of the earliest signs of GA1 so newborns with an enlarged head circumference should be evaluated for GA1. Especially during the age of 3 months until 3 years, most affected babies develop an acute encephalopathic crisis which is triggered by catabolic conditions such as febrile infections, febrile reactions to vaccinations or surgery. These crises result in striatal injury and a complex, mostly dystonic, irreversible and severe movement disorder which is associated with high morbidity and mortality. These babies can experience several symptoms resembling those of cerebral palsy, such as frequently assuming odd positions due to disordered muscle tone (dystonia), involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs. Controlling the movement of hands, arms, feet, legs, head, and neck may become very hard and muscle spasms may occur. Repeated stress on the body (such as infection and fever) can cause symptoms to worsen, but in some children, brain damage will occur without a triggering fever. Mild to moderate intellectual disabilities may also accompany these symptoms, but some studies have shown that the intellectual ability of a person with GA1, even if untreated, is not or only mildly affected.
In recent years, also other neurologic disease manifestations have been reported such as chronic kidney disease.
For 80-90% of people with GA1, motor symptom development is preventable, but this requires early diagnosis by newborn screening and treatment from birth on. Treatment consists of a low lysine diet and oral carnitine supplementation as well as intermittent emergency treatment during episodes that are likely to induce catabolism. If treatment is delayed or inadequate, motor symptoms begin to manifest acutely or insidiously during infancy or early childhood (before the age of 6) and are often highly variable. A minority of GA1 patients is diagnosed lately in adolescence or even adult age, following the diagnostic work-up of unspecific neurologic symptoms.
If GA1 is not treated, most patients experience an “acute encephalopathic crisis” following preceding trigger symptoms such as:
Possible irreversible neurologic symptoms of an acute encephalopathic crisis are
Other possible symptoms noted:
GA1 is caused by changes (mutations) in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase or GCDH. This enzyme is responsible for metabolizing the amino acids lysine, hydroxylysine, and tryptophan. Mutations in the GCDH gene prevent production of the enzyme resulting in abnormal levels of glutaric, 3-hydroxyglutaric and (to a lesser extent) glutaconic acids These products accumulate and cause damage to an area of the brain called the basal ganglia that regulates motor movement.
GA1 is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. Both parents of a patient are carriers in autosomal-recessive conditions. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
GA1 is a rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 patients with this type of organic aciduria in the United States. GA1 occurs in approximately 1 of every 100,000 births. Five genetic isolates are known with a high carrier frequency (up to 1:10) and incidence (up to 1:250 newborns): the Old Order Amish Community in Lancaster County, Pennsylvania, United States, the Oji-Cree First Nations in Manitoba and Western Ontario, Canada, the Irish Travelers in the Republic of Ireland and United Kingdom, the Lumbee in North Carolina, United States and the Xhosa in South Africa.
The characteristic metabolites GA, 3-OH-GA, glutaconic acid and glutarylcarnitine (C5DC) can be detected in body fluids (urine, plasma, CSF) and tissues using gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS). As neonatal diagnosis and start of treatment significantly improves neurologic outcome. This condition has been included in MS/MS based newborn screening disease panels in many countries
Abnormal newborn screening results should be confirmed by quantitative analysis of GA and 3-OH-GA in urine and/or blood with GC/MS, mutation analysis of the GCDH gene and/or GCDH enzyme analysis in leukocytes or fibroblasts. The diagnosis is confirmed by significantly reduced enzyme activity and/or detection of two disease-causing GCDH gene mutations.
Today, GA-I is considered to be a treatable condition. Metabolic treatment consists of a low lysine diet with supplementation of a lysine-free, trytophane-reduced, amino acid mixture, oral supplementation of L-carnitine and an intensified emergency treatment during episodes of intercurrent illness or surgical interventions. It has been recommended by an international guideline group for all patients up to 6 year.
Children with GA1 can develop normally if a thorough treatment plan is followed properly, but treatment must begin from a very early age (from the newborn period before symptoms occur and onwards). If not promptly and properly treated, GA1 will typically cause serious, irreversible, neurologic damage that can permanently affect control of voluntary muscle movement and can severely impact life and shorten life expectancy, especially if damage occurs before the age of 6.
Long-term outcome is still incompletely understood, neurologic disease or extracerebral manifestation like chronic kidney disease may occur in adulthood and variable extrastriatal MRI changes may progress after age 6 years. Therefore, protein control using natural protein with a low lysine content and avoidance of lysine-rich food is advisable after age 6 years.
Genetic counseling is recommended for families of children with GA1.
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