rs142967670 — GCDH R88C

Pathogenic missense variant in glutaryl-CoA dehydrogenase; homozygosity causes glutaric acidemia type 1, an organic acidemia leading to striatal necrosis and movement disorders if untreated; heterozygotes are unaffected carriers relevant for family planning

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GCDH R88C — The Glutaric Acidemia Type 1 Carrier Variant

Glutaryl-CoA dehydrogenase (GCDH) is a mitochondrial enzyme responsible for breaking down three amino acids — lysine, hydroxylysine, and tryptophan — in the final steps of their catabolism. When GCDH fails, its toxic substrates (glutaric acid and 3-hydroxyglutaric acid) accumulate and cause striatal necrosis11 striatal necrosis
destruction of the caudate nucleus and putamen, the brain's movement-coordination centers, triggering a severe movement disorder that resembles dyskinetic cerebral palsy.

The rs142967670 C>T transition creates the p.Arg88Cys substitution — replacing a positively charged arginine with a cysteine at position 88 of the mature protein. Schmiesing et al. 201722 Schmiesing et al. 2017 showed that R88C disrupts mitochondrial ultrastructure (forming stacked cristae and partially dissolving the outer mitochondrial membrane) and destabilizes the GCDH homotetramer, resulting in complete loss of enzymatic activity. Two copies of this variant cause glutaric acidemia type 1 (GA1), a rare but devastating organic acidemia. One copy produces an unaffected carrier.

The Mechanism

The Arg88 residue sits on the surface of the GCDH subunit interface. Mutating it to cysteine undermines the quaternary assembly of the enzyme into its active homotetramer. The result is twofold: reduced protein stability and aberrant binding to electron transfer flavoprotein beta33 electron transfer flavoprotein beta
ETFβ, the redox partner that accepts electrons from GCDH during amino acid oxidation. Without functional GCDH, lysine catabolism stalls, and glutarylcarnitine accumulates in blood — the biomarker used in newborn screening. In brain tissue, 3-hydroxyglutaric acid acts as an endogenous neurotoxin that selectively injures the striatum during metabolic stress (febrile illness, fasting, surgery), causing irreversible encephalopathic crises.

The Evidence

GA1 is an autosomal recessive condition: only homozygotes or compound heterozygotes (two different pathogenic GCDH variants) develop disease. Christensen et al. 200444 Christensen et al. 2004 studied 215 GA1 patients and found that more than half had complete absence of GCDH activity, with 34% retaining residual activity up to 5%. No reliable genotype-phenotype correlation for clinical outcome was established — outcome depends primarily on whether an encephalopathic crisis occurs, not which specific mutation is present.

The impact of early detection is stark. Strauss et al. 202055 Strauss et al. 2020 followed 168 GA1 patients across three treatment cohorts spanning 31 years: striatal degeneration occurred in 90% of unscreened patients, 47% of screened patients on protein restriction only, and just 7% of screened patients on specialized lysine-free formula with emergency IV treatment during febrile episodes. No neurological injuries occurred after 19 months of age, identifying the first two years of life as the critical intervention window.

The 2023 international guidelines66 The 2023 international guidelines — the third revision led by Boy et al. across European and North American metabolic centers — summarize current best practice: newborn screening via acylcarnitine profiling (glutarylcarnitine elevation), low-lysine diet from diagnosis, L-carnitine supplementation to correct secondary carnitine depletion, and an intensified emergency protocol during any catabolic stress. Dietary restriction can typically be relaxed after age 6, when the brain's striatum is no longer in the vulnerability window.

The R88C allele (c.262C>T) is classified Pathogenic in ClinVar (VCV000189150, 2-star review status, 10 concordant submitters) and listed as OMIM allelic variant 608801.0001. The allele is ultra-rare globally (~5 per 100,000 chromosomes in gnomAD non-Finnish European), consistent with the estimated GA1 birth incidence of 1 in 30,000–100,000 live births across most populations.

Practical Actions

For carriers (one copy, CT genotype): no clinical management of GA1 is required — carriers have one functional GCDH gene and maintain adequate enzyme activity. The practical implication is reproductive: each child of two carriers has a 25% chance of inheriting two pathogenic alleles. Genetic counseling and partner testing are the key actions.

For affected individuals (TT genotype — extremely rare to appear in a standard report): confirmed GA1 requires immediate referral to a metabolic medicine specialist. The cornerstone of treatment is a low-lysine diet (typically using lysine-free amino acid formula), L-carnitine supplementation (50–100 mg/kg/day in children), and an emergency protocol card authorizing IV glucose and L-carnitine during any febrile illness, which is the trigger for the catastrophic striatal crises.

Interactions

GCDH R88C most commonly causes GA1 as a homozygote or in compound heterozygosity with a second pathogenic GCDH variant. Other well-characterized GA1 alleles include R402W (the most common European mutation, ~40% of German alleles), R227P, A421V (the Old Order Amish founder allele), and numerous others across the gene's 11 exons. Compound heterozygotes (R88C on one chromosome, another pathogenic variant on the other) have the same clinical syndrome as R88C homozygotes — the critical variable is whether any residual GCDH activity is preserved.

Secondary carnitine deficiency occurs in all untreated GA1 patients because excess glutaric acid is conjugated to carnitine and excreted as glutarylcarnitine, depleting free carnitine. L-carnitine supplementation directly addresses this mechanism-specific depletion.

Nutrient Interactions

lysine altered_metabolism
tryptophan altered_metabolism
carnitine increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-carrier Normal

Common sequence — no GCDH R88C variant

Glutaric acidemia type 1 is caused by loss-of-function variants in GCDH (glutaryl-CoA dehydrogenase). The R88C variant is one of more than 200 known pathogenic alleles spread across GCDH's 11 exons. Carrying CC at rs142967670 rules out this particular variant but does not exclude other GA1-causing mutations. If you have a family history of GA1 or a metabolic disorder consistent with organic acidemia, comprehensive GCDH sequencing is the appropriate test.

CT Carrier Carrier

Carrier of one R88C allele — unaffected but relevant for family planning

The GCDH R88C variant (c.262C>T) is classified Pathogenic by ClinVar (VCV000189150, 2-star review status, 10 concordant submitters) and is listed as OMIM allelic variant 608801.0001. As a missense change replacing a surface arginine with cysteine, it disrupts the mitochondrial architecture and enzyme quaternary structure, causing complete loss of GCDH activity in homozygotes. In heterozygotes, the remaining wild-type allele provides sufficient activity — no biochemical or clinical abnormalities are expected.

Glutaric acidemia type 1 (GA1) is an autosomal recessive condition (OMIM 231670) with an estimated birth incidence of approximately 1 in 30,000 to 1 in 100,000, varying by population. GA1 is included in newborn screening programs in most high-income countries via acylcarnitine profiling (glutarylcarnitine elevation on tandem mass spectrometry), and early-detected cases managed with low-lysine diet and L-carnitine supplementation have excellent neurological outcomes. This underscores the importance of knowing carrier status before conception.

TT Homozygous Homozygous

Two copies of R88C — complete GCDH loss of function, glutaric acidemia type 1

GA1 is clinically characterized by macrocephaly (often present from birth), a symptom-free period in infancy, and then one or more acute encephalopathic crises typically triggered by febrile illness between 3 months and 6 years of age. These crises produce acute bilateral striatal necrosis — destruction of the caudate nucleus and putamen — resulting in dystonia and dyskinesia that can be profoundly disabling.

Treatment initiated before the first crisis (via newborn screening) dramatically changes outcome. Strauss et al. 2020 followed 168 GA1 patients for 31 years: in the cohort managed from birth with lysine-free amino acid formula and emergency IV glucose/carnitine during fever, only 7% experienced striatal degeneration. In unscreened patients, the rate was 90%.

Two biochemical mechanisms drive treatment: (1) Low-lysine diet restricts the substrate that produces toxic glutaric acid and 3-hydroxyglutaric acid — this is the primary intervention and is typically maintained strictly through age 6, then relaxed. (2) L-carnitine supplementation corrects secondary carnitine deficiency, because excess glutaric acid is excreted as glutarylcarnitine, depleting free carnitine needed for fatty acid oxidation.

The emergency protocol — providing IV 10% glucose (8–10 mg/kg/min) plus IV L-carnitine during any febrile illness — prevents the metabolic surge that triggers striatal crises. Every GA1 patient should carry an emergency letter authorizing this treatment before a diagnosis can be confirmed in an unfamiliar emergency department.

R88C specifically causes complete loss of GCDH activity (Schmiesing et al. 2017 demonstrated disrupted mitochondrial ultrastructure and unstable homotetramer formation). No genotype-phenotype correlation for clinical outcome has been established in GA1 — crisis prevention, not genotype, determines neurological prognosis.