Glutaric Acidemia Type 1

Clinical characteristics.

The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease – i.e., after age 6 years). Of note, the GA-1 phenotype can vary widely between untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to six years in infantile-onset GA-1 and after age six years in later-onset GA-1. Characteristically these crises result in acute bilateral striatal injury and subsequent complex movement disorders. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic; however, they may be at increased risk for other manifestations (e.g., renal disease) that are becoming apparent as the understanding of the natural history of treated GA-1 continues to evolve.

Diagnosis/testing.

Because the early initiation of treatment dramatically improved the outcome for persons with GA-1, an international guideline group has recommended NBS. The diagnosis of GA-1 in a proband with a positive NBS result or suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GCDH or, when molecular genetic test results are uncertain, by detection of significantly reduced activity of the enzyme glutaryl-CoA dehydrogenase (GCDH) in cultured fibroblasts or leukocytes.

Management.

Prevention of primary manifestations: When GA-1 is suspected during the diagnostic evaluation of a newborn with an elevated concentration of 3-OH-GA in plasma or urine, metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach by experienced subspecialists from a specialized metabolic center. The main principles of treatment are to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA. Combined metabolic therapy includes low-lysine diet, carnitine supplementation, and emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts.

Surveillance: Regular evaluations by a metabolic specialist and metabolic dietician; routine evaluation of growth parameters and head circumference, developmental progress and educational needs, clinical signs and symptoms of movement disorders, biochemical parameters, and renal function (in adolescents and adults).

Agents/circumstances to avoid: Excessive dietary protein or protein malnutrition inducing catabolic state, prolonged fasting, catabolic illness (intercurrent infection; brief febrile illness post vaccination), inadequate caloric provision during other stressors (e.g., surgery or procedure requiring fasting/anesthesia).

Evaluation of relatives at risk: Testing of all at-risk sibs of any age to allow for early diagnosis and treatment. For at-risk newborn sibs when prenatal testing was not performed: in parallel with NBS either test for the familial GCDH pathogenic variants or measure urine organic acids, plasma amino acids, and acylcarnitine profile.

Pregnancy management: It is recommended that care for a pregnant woman with GA-1 be provided by a multidisciplinary team including the treating obstetrician, a metabolic physician, and a specialist metabolic dietician.

Genetic counseling.

GA-1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GCDH pathogenic variants in an affected family member are known, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Establishing the Diagnosis

The diagnosis of GA-1 in a proband with suggestive biochemical and/or clinical findings is confirmed by identification of biallelic pathogenic variants in GCDH (Table 1) or, when molecular genetic test results are uncertain, by detection of significantly reduced activity of the enzyme glutaryl-CoA dehydrogenase in cultured fibroblasts or leukocytes.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing or use of a multigene panel) and comprehensive genomic testing (typically exome sequencing) depending on the indications for testing. Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.

• Infants with positive newborn screening and follow-up testing (see Scenario 1) are likely to be diagnosed using gene-targeted testing.
• Symptomatic individuals with nonspecific clinical and imaging findings in whom the diagnosis of GA-1 has not been considered (see Scenario 2) are more likely to be diagnosed using comprehensive genomic testing [Marti-Masso et al 2012].

Scenario 2

When the diagnosis of GA-1 has not been considered, either a multigene panel or comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) are options.

• A multigene panel that includes GCDH and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) includes exome sequencing (most commonly used) and genome sequencing. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of GA-1.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Glutaric Acidemia Type 1

Quantification of glutaryl-CoA dehydrogenase enzyme activity in cultured fibroblasts or leukocytes by a clinical laboratory may help confirm the diagnosis of GA-1 in newborns with positive NBS results when GCDH sequencing is equivocal (e.g., only 1 or no detectable pathogenic variants, variants of unknown significance) or glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) levels in blood and/or urine are equivocal.

Shortcomings of enzymatic testing on fibroblast cultures or leukocytes include the following:

• Difficulty distinguishing carriers (i.e., heterozygotes for one GCDH pathogenic variant) – who by definition are not affected – from affected individuals (i.e., those with biallelic GCDH pathogenic variants) [Goodman & Kohlhoff 1975, Goodman et al 1975]. This is particularly true for the dominant negative variant (c.553_570del18) [Bross et al 2012].
• The relatively large blood volumes (3-5 mL) required to reliably perform the leukocyte assay
• The limited number of clinical laboratories offering enzymatic testing on leukocytes

Clinical Description

The phenotypic spectrum of untreated glutaric acidemia type 1 (GA-1) ranges from the more common form (infantile-onset disease) to the less common form (later-onset disease after age 6 years). Of note, the GA-1 phenotype can vary widely among untreated family members with the same genotype, primarily as a function of the age at which the first acute encephalopathic crisis occurred: three months to three years in infantile-onset GA-1 and after age six years in later-onset GA-1 [López-Laso et al 2007, Wang et al 2014]. Characteristically these crises result in acute bilateral striatal injury and subsequent complex movement disorders. Patients may also develop insidious-onset basal ganglia injury in the absence of an identified acute encephalopathic crisis.

In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed manifestations of either infantile-onset or later-onset GA-1 remain asymptomatic.

Infantile-onset GA-1. If untreated, 80%-90% of children with infantile-onset GA-1 will experience an acute encephalopathic crisis, 95% of which occur in the first 24 months of life. These crises can be precipitated by intercurrent febrile illness, febrile reaction to vaccinations, or fasting and catabolic stressors associated with anesthesia and surgical procedures [Kölker et al 2006, Boy et al 2017b]. Characteristically these crises result in acute bilateral striatal injury and are followed (typically between ages 3 months and 3 years; in rare cases, between ages 3 and 6 years) by progressive complex neurologic movement disorders. Disability and mortality are high after acute crises [Kyllerman et al 2004, Kölker et al 2006].

Dietary treatment and intense emergency treatment during intercurrent illness (see Management) have reduced the frequency of acute encephalopathic crises and movement disorders to 10%-20%.

Subdural hemorrhages, a rare manifestation of GA-1, may develop even in individuals diagnosed on NBS, managed appropriately, and without macrocephaly [Zielonka et al 2015, Ishige et al 2017]. Subdural hemorrhages may appear spontaneously or following mild head trauma in GA-1; they can also resolve spontaneously. Isolated subdural hemorrhage without other features of GA-1 on brain MRI is extremely uncommon [Vester et al 2015, Vester et al 2016].

Seizures are reported in 7% of individuals with GA-1 [Kölker et al 2015a]. While self-limited seizures may accompany the acute encephalopathic crisis, in other instances they may be the presenting manifestation [McClelland et al 2009]. Infantile spasms have been reported in some [Young-Lin et al 2013, Liu et al 2015].

When GA-1 is diagnosed after the onset of neurologic manifestations, outcome is poor and the therapeutic effect of the usual interventions is more limited [Hoffmann et al 1996, Bjugstad et al 2000, Busquets et al 2000a, Kyllerman et al 2004, Kölker et al 2006, Kamate et al 2012, Wang et al 2014]. Nonetheless, therapeutic intervention may prevent additional progressive neurologic deterioration in some [Hoffmann et al 1996, Bjugstad et al 2000, Kölker et al 2006, Badve et al 2015, Fraidakis et al 2015].

With early diagnosis and adherence to treatment, 80%-90% of individuals with GA-1 remain largely asymptomatic [Strauss et al 2011, Viau et al 2012, Couce et al 2013, Lee et al 2013, Boy et al 2018].

Insidious onset of manifestations was previously seen in an estimated 10%-20% of symptomatic individuals [Kölker et al 2006]; it now appears to be more common because early diagnosis and treatment of GA-1 have reduced the incidence of acute encephalopathic crises [Boy et al 2018].

Individuals who adhere to maintenance and emergency treatments rarely develop dystonia; those who do not are at high risk of developing a movement disorder [Kölker et al 2007, Heringer et al 2010, Strauss et al 2011, Kölker et al 2012, Boy et al 2018]. Those who have insidious onset generally have less severe movement disorders and less extensive lesions on brain MRI than those with acute encephalopathic crisis [Boy et al 2019]. The insidious phenotype may correlate with lack of adherence to chronic dietary treatment [Boy et al 2018].

Late-onset GA-1. Late-onset GA-1 is defined as onset of manifestations after age six years. Some individuals with late-onset GA-1 (e.g., mothers diagnosed due to the birth of a child with an abnormal NBS result) are entirely asymptomatic. Others have a variety of neurologic findings. Among eight symptomatic individuals ages eight to 71 years, the following were observed: chronic headaches (4), macrocephaly (4), epilepsy (2), tremor (2), and dementia (2). All had MRI evidence of frontotemporal hypoplasia and abnormal signal of the white matter; five had subependymal nodules. All showed the high excreting phenotype [Boy et al 2017a]. Others have reported clinical and neuroimaging findings [Külkens et al 2005, Pierson et al 2015, Zhang & Luo 2017].

Other reported manifestations of late-onset GA-1 include the following:

• Peripheral neuropathy (1 adult) [Herskovitz et al 2013]
• Brain neoplasms (in several adults and children) [Korman et al 2007, Burlina et al 2012, Herskovitz et al 2013, Pierson et al 2015, Serrano Russi et al 2018]. This finding has led to an as-yet unsubstantiated speculation about possible increased susceptibility to brain neoplasms in adults.

Non-neurologic disease manifestations observed in individuals in GA-1 regardless of age of onset. Chronic kidney disease may occur in those with GA-1, even with adherence to treatment, and may be an extracerebral manifestation in adults with GA-1 [Kölker et al 2015b].

Note: Infants with biochemical findings consistent with GA-1 on NBS, but normal blood levels of GA and 3-OH-GA and only one identifiable GCDH pathogenic variant, may warrant close clinical follow up. However, given the high sensitivity of GCDH molecular genetic testing, the chances that an infant with these findings is affected and at risk of developing acute striatal necrosis are low.

Genotype-Phenotype Correlations

Most GCDH variants reported to date are missense variants [Schmiesing et al 2017].

GA-1 biochemical (excreter) subtypes. GA-1 was originally divided into two arbitrarily defined biochemical subtypes: high excreters of urinary glutaric acid (GA) and low excreters of urinary GA [Baric et al 1999]. High excreters and low excreters are at the same risk for striatal injury [Christensen et al 2004, Kölker et al 2006]. While excreter status has no clear correlation with the clinical phenotype in childhood, evidence suggests that high excreters have higher concentrations of GA and 3-OH-GA in the CNS and have increased prevalence of progressive white matter lesions on MRI [Boy et al 2017a].

• High excreters have no or very low glutaryl-CoA dehydrogenase activity (0%-3%) [Goodman et al 1998, Baric et al 1999, Busquets et al 2000b]. NBS sensitivity for the high excreter biochemical phenotype is 100% [Boy et al 2018].
• Low excreters have up to 30% residual glutaryl-CoA dehydrogenase activity [Goodman et al 1998, Busquets et al 2000b]. They have biallelic GCDH pathogenic variants, at least one of which is a hypomorphic missense variant. NBS sensitivity for the low excreter biochemical phenotype is 84% [Boy et al 2018]. See Table 10 for details on variants associated with low excreter status.

Prevalence

Well over 500 individuals with GA-1 have been reported to date [Boy et al 2017b]. Prevalence estimates for GA-1 vary between 1:30,000 and 1:100,000-110,000 [Kyllerman & Steen 1980, Lindner et al 2004, Tsai et al 2017].

Details on founder variants reported in Ojibway-Cree First Nation Canadians of Manitoba and Ontario, South African Xhosa peoples, Pennsylvania Amish, Lumbee Native Americans of North Carolina, and Irish Traveler communities in the Republic of Ireland are included in Table 10.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual following diagnosis of GA-1, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis of GA-1

Treatment of Manifestations

All children with GA-1 and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing diet in GA-1. German (D)-Austrian (A)-Swiss (CH) (DACH) recommendations have been used in several clinical trials and have resulted in positive outcomes [Kölker et al 2007, Heringer et al 2010, Kölker et al 2012, Boy et al 2013].

The main principles of treatment are to reduce lysine oxidation and enhance physiologic detoxification of glutaryl-CoA. Combined metabolic therapy includes the following [Boy et al 2013]:

• Low-lysine diet
• Carnitine supplementation
• Emergency treatment during episodes with the goal of averting catabolism and minimizing CNS exposure to lysine and its toxic metabolic byproducts

Table 4.

Routine Daily Treatment in Individuals with Glutaric Aciduria Type 1

Notes: (1) Riboflavin supplementation is not recommended currently as standard therapy for GA-1 [Boy et al 2017a]. (2) To date, there is no robust evidence that use of other medications, such as phenobarbitone, N-acetylcysteine, creatine monohydrate, topiramate, glutamate receptor antagonists, and antioxidants, is beneficial in GA-1 [Greenberg et al 2002, Kyllerman et al 2004, Boy et al 2017a]. (3) Arginine supplementation is not currently recommended in acute or chronic settings [Boy et al 2017b].

Table 5.

Nutritional Requirements for L-lysine, L-Carnitine, Calories, and Natural Protein for Infants and Children with GA-1

If an affected individual is clinically well despite an intercurrent infectious illness or febrile reaction to vaccinations, emergency outpatient management may be considered (see Table 6). If outpatient emergency treatment can be performed adequately and safely and if the child does not develop concerning symptoms during the illness, maintenance treatment and diet should be reintroduced stepwise over the next 48 (-72) hours (see Table 4).

Table 6.

Emergency Outpatient Treatment in Individuals with Glutaric Aciduria Type 1

Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma), often occurring in the setting of intercurrent illness and/or inadequate caloric intake, should be managed symptomatically and with generous caloric support in a hospital setting, with aggressive treatment and supportive care of any identified or clinically suspected acute conditions (see Table 7).

Table 7.

Acute In-Patient Treatment in Individuals with Glutaric Aciduria Type 1

Transitional care from pediatric to adult-centered multidisciplinary care settings. As GA-1 is a lifelong disorder with varying implications according to age, smooth transition of care from the pediatric setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Standardized procedures for transitional care do not exist for GA-1 due to the absence of multidisciplinary outpatient departments.

• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with GA-1 together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• In puberty and early adulthood, deficits in adherence to treatment may occur due to deteriorating compliance or other unknown factors, resulting in negative impact on outcomes [Watson 2000].
• As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential.

Prevention of Primary Manifestations

Dietary restriction of lysine intake remains the cornerstone of GA-1 treatment. Although management of any given affected individual is nuanced and managed on a case-by-case basis, minor illnesses, where caloric needs are increased or provision of adequate calories is compromised, should be observed closely and promptly treated with a low threshold for hospital admission (see Treatment of Manifestations).

Prevention of Secondary Complications

One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see also Tables 6 and 7).

Table 8.

Prevention of Secondary Manifestations in Individuals with Glutaric Aciduria Type 1

Surveillance

Regular evaluations by a metabolic specialist and metabolic dietician are appropriate. See Table 9 for additional recommended surveillance.

Table 9.

Recommended Surveillance for Individuals with Glutaric Aciduria Type 1

Note:

• Because C5DC acylcarnitine values are likely to reflect carnitine concentrations in plasma and not dietary lysine intake, they have no role in biochemical surveillance or ongoing care of persons with GA-1 [Chace et al 2003, Lindner et al 2004].
• Because urinary or plasma concentrations of GA or 3-OH-GA do not correlate with clinical parameters or outcomes [Christensen et al 2004, Kölker et al 2006, Boy et al 2013], they have no role in clinical surveillance or for guidance of ongoing care of persons with GA-1.

Agents/Circumstances to Avoid

Avoid the following:

• Excessive dietary protein or protein malnutrition inducing catabolic state
• Prolonged fasting
• Catabolic illness (intercurrent infection; brief febrile illness post-vaccination)
• Inadequate caloric provision during other stressors, especially when fasting is involved (surgery or procedure requiring fasting/anesthesia)

Although there are no data on which to base such a recommendation, given the increased risk of subdural hemorrhage in individuals with GA-1, avoidance or extreme caution with contact sports and physical activities that involve high risk for minor head injuries would appear to be a sensible precaution.

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment. For at-risk newborn sibs when prenatal testing was not performed: in parallel with NBS, either test for the familial GCDH pathogenic variants or measure urine organic acids, plasma amino acids, and acylcarnitine profile.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although there are no formal published recommendations for dietary or medical management for pregnant women with GA-1, it is recommended that care be provided by a multidisciplinary team including the treating obstetrician, a metabolic physician, and a specialist metabolic dietician. Because the perinatal period is a time of high catabolic stress for women with GA-1, most metabolic physicians would agree that emergency management and close observation are required; however, evidence and/or sufficient clinical data regarding efficacy or necessity of emergency treatment for GA-1 during the peripartum period are not available. Uneventful clinical courses for affected mothers (and their babies) has been reported for women receiving emergency treatment during the peripartum period [Ituk et al 2013], as well as for women who did not receive any specific therapy [Garcia et al 2008].

While to date no specific guidelines are available for surgical procedures and other perinatal stressors, usual perioperative/perianesthetic precautions are likely to be clinically relevant (see Prevention of Secondary Complications).

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Glutaric acidemia type 1 (GA-1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one GCDH pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical features of the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Note: Phenotype of GA-1 can vary widely among untreated family members who have the same genotype.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the clinical features of the disorder.

Offspring of a proband. Unless an individual's reproductive partner also has GA-1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in GCDH.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a GCDH pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the GCDH pathogenic variants in the family.

Carriers are asymptomatic and are not at risk of developing clinical features of the disorder.

Quantification of glutaryl-CoA dehydrogenase enzyme activity in fibroblasts or leukocytes is not useful in determining carrier status.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the GCDH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Biochemical testing for prenatal diagnosis of GA-1 is not recommended; molecular genetic testing is preferred.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Glutaryl-CoA dehydrogenase (GCDH) plays an integral role in degradative metabolism of L-lysine, L-hydroxylysine, and L-tryptophan [Greenberg et al 1995, Fu et al 2004]. Glutaric acidemia type 1 (GA-1) is caused by insufficiency or absence of functional glutaryl-CoA dehydrogenase (GCDH), resulting from biallelic GCDH pathogenic variants. Enzymatic insufficiency or absence results in the accumulation of upstream byproducts of L-lysine, L-hydroxylysine, and L-tryptophan degradation: glutaric acid, 3-hydroxyglutaric acid, glutarylcarnitine (C5DC acylcarnitine), and glutaconic acid.

Accumulation of glutaric acid and 3-OH-glutaric acid causes neurotoxicity (especially striatal injury).

Gene structure. GCDH comprises 11 exons and spans approximately 7 kb of genomic DNA. Human GCDH cDNA encodes a 438-amino acid precursor protein and a 394-amino acid mature protein with a molecular mass of 43.3 kd. Alternative splicing between exons 10 and 11 produces two GCDH mRNA transcripts, only one of which is enzymatically active. The precursor protein undergoes cleavage by mitochondrial processing peptidase to form the mature GCDH subunit [Goodman et al 1995].

Pathogenic variants. More than 200 (confirmed or likely) pathogenic GCDH variants have been reported to date [Stenson et al 2014]. Most GCDH variants reported to date are missense variants. It is possible that many of these pathogenic variants affect stability and, hence, heteromeric glutaryl-CoA dehydrogenase enzyme complex formation, and are disruptive to mitochondrial architecture.

Of note, c.91+5G>T (the Ojibway-Cree First Nation founder variant) as well as p.Arg227Pro, p.Val400Met, and p.Met405Val are associated with a low-excreter phenotype and may be more difficult to detect conclusively with biochemical testing (and on NBS utilizing C5DC acylcarnitine). Homozygous p.Arg227Pro and p.Val400Met are both associated with 8%-10% residual enzyme activity [Christensen et al 2004].

The c.553_570del18 (p.Gly185_Ser190del) deletion, a suspected dominant-negative allele, is associated with enzyme activity much lower than 50% [Bross et al 2012]. An individual heterozygous for the deletion did not – to the authors' knowledge – manifest any clinical features of GA-1 [Author, personal observation].

Table 10.

Notable GCDH Pathogenic Variants

Normal gene product. GCDH encodes the flavin adenine dinucleotide-dependent mitochondrial matrix protein GCDH, which forms homotetramers and oxidizes and decarboxylates glutaryl-CoA. GCDH cDNA encodes a 438-amino acid precursor protein and a 394-amino acid mature protein, with a 44-amino acid mitochondrial targeting sequence at the N terminal [Goodman et al 1998].

Abnormal gene product. GA-1 results from loss of GCDH function, with a mechanism attributed to abnormal surface residues causing impaired stability and impaired GCDH protein interactions and heteromeric complex formation [Schmiesing et al 2017].

Glutaric acid probably derives from hydrolysis of the accumulated enzyme substrate (glutaryl-CoA), but the origin of 3-hydroxyglutaric acid remains unknown. These putative toxins do not cross the blood-brain barrier and thus are probably synthesized within the brain from accumulated glutaryl-CoA, but the reasons why one or both of them preferentially affect the striatum and why there is a period of heightened striatal vulnerability in infancy and early childhood remain a mystery.

Author History

Austin Larson, MD (2019-present)
Steve Goodman, MD, FACMG (2019-present)
James Weisfeld-Adams, MB ChB, FAAP, FACMG (See Author Notes.)

Author Notes

Dr James Weisfeld-Adams contributed extensively to the early drafts of this GeneReview. He died of renal cancer in April 2018. He is survived by his wife and two sons. A biochemical geneticist, Dr Weisfeld-Adams served on the faculties of the University of Colorado School of Medicine and the Mount Sinai School of Medicine. James was a devoted father and husband as well as a compassionate and skilled clinician.

Revision History

• 19 September 2019 (bp) Review posted live
• 16 October 2017 (jwa/al) Original submission

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