3‐Methylglutaconyl‐CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis

Abstract

3‐Methylglutaconyl‐CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3‐methylglutaconate, with or without 3‐hydroxyisovalerate and 3‐methylglutarate. It is an ultra‐rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood‐onset clinical phenotype associated with this disorder. Some patients have non‐specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow‐up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer‐term follow‐up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult‐onset leukoencephalopathy.

Counting Conditions on Newborn Bloodspot Screening Panels in Australia and New Zealand

“…As per the Wilson and Jungner criteria, part of the decision matrix should include the capacity of clinical services to deliver care to true positive cases and rapidly distinguish false positive and indeterminate cases [ 8 ]. In some cases, especially for rare scenarios, patients can be followed up for many years before it is clear whether they are affected or not [ 26 ]. The availability of cost-effective interventions, acceptable to society, should remain as a guiding ethical and policy principle.…”

Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases

“…Whilst there are some similar cases of 3-methylcrotonyl-CoA carboxylase (3MCCC) and 3-methylglutaconyl-CoA hydratase deficient patients, there are equally many asymptomatic individuals with these biochemical conditions. As a consequence, the role of 3-HMG, 3-MGL, and 3-HIVA in the pathophysiology of these disorders must be better defined [ 8 , 31 , 34 , 35 ]. Traditionally, the hyperammonemia in organic acidemias has been thought to arise from inhibition of N-acetylglutamate synthase but may also arise from insufficiency of Krebs cycle intermediates, favoring α-ketoglutarate production from glutamate [ 36 , 37 , 38 ].…”

Organic Acidemias: Clinical Presentation in Neonates

“…The clinical spectrum ranges from asymptomatic newborns identified in NBS to adults with advanced neurodegeneration. 124 Management: Restricted leucine and L-carnitine supplementation. 124 Prognosis: Guarded.…”