Acute Encephalopathic Presentation of 3-Methylglutaconic Aciduria Type I With a Novel Mutation in AUH Gene

Dudipala, Sai Chandar; Prashanthi, M; B, Krishna Chaithanya; Chenalla, Laxman Kumar

doi:10.7759/cureus.11951

Cited by 4 publications

(5 citation statements)

References 10 publications

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“…Engelke et al 8 proposed this mechanism, citing evidence of raised CSF/plasma ratios of 3‐HIVA in an adult patient with MGA1 and progressive leukoencephalopathy, but also in other conditions affecting leucine degradation where neurological abnormalities occur (such as biotinidase deficiency) 15 . However, there are reports of patients with normal MRIs, who are still excreting 3‐HIVA 12,16 . Additionally, another disorder with raised 3‐HIVA, 3‐methylcrotonyl‐CoA carboxylase (3‐MCC) deficiency, does not result in neurological or developmental abnormalities in at least 57% of patients 17 .…”

Section: Discussionmentioning

confidence: 99%

“… 15 However, there are reports of patients with normal MRIs, who are still excreting 3‐HIVA. 12 , 16 Additionally, another disorder with raised 3‐HIVA, 3‐methylcrotonyl‐CoA carboxylase (3‐MCC) deficiency, does not result in neurological or developmental abnormalities in at least 57% of patients. 17 3‐HIVA is also excreted in isovaleric acidaemia and HMGCL deficiency, neither of which have the same reported phenotype as MGA1.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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“…Methylglutaconic aciduria type I causes symptoms of acute encephalitis and dilated cardiomyopathy. 31 Moreover, several OAs present in the neonatal or infantile period with a wide anion gap, metabolic acidosis and hyperammonemia. 15 Of the 17 known OAs, around half are known to cause cardiac dysfunction (Organic Acidemia Association, 2020).…”

Section: Removal Of the Toxinsmentioning

confidence: 99%

Closing the gap: an urgent need for newborn screening of organic acid disorders in developing countries

Vankwani,

Wasim,

Mirza

et al. 2024

J Pak Med Assoc

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Organic acid disorders are rare inherited metabolic disorders of key metabolic pathways. For the identification of specific organic acids, investigation of urinary metabolites and genetic testing are required through newborn screening programmes. Delayed diagnosis leads to complications, such as cardiac attacks, respiratory problems, neuro-developmental disorders, intellectual disability, and even premature death. The burden of such inherited disorders is quite high in developing countries of South Asia due to high rate of consanguinity in the region. Unfortunately, such disorders are left untreated due to the lack of screening facilities in such countries. The current narrative review was planned to highlight the urgent need for closing this gap and implementing effective newborn screening programmes for organic acid disorders in developing countries. ---Continue

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“…MGCA1 has been diagnosed in 19 subjects described in the literature (Tables 1 and 2). Patients affected by this disease manifest a wide range of clinical signs, ranging from no or mild symptoms [8,9] to mild neurological impairment [10,11], acute encephalopathy [12][13][14], severe encephalopathy with basal ganglia involvement [15,16], and slowly MGH catalyses the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-coenzyme A (3-MG-CoA) to 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA). MGH deficiency results in 3-MG-CoA accumulation within the mitochondrial matrix [5,6], which in turn is converted to 3-methylglutaconic acid by coenzyme A thioester bond hydrolytic cleavage, followed by export of 3-methylglutaconic acid from the mitochondrion [7].…”

Section: Introductionmentioning

confidence: 99%

“…MGCA1 has been diagnosed in 19 subjects described in the literature (Tables 1 and 2). Patients affected by this disease manifest a wide range of clinical signs, ranging from no or mild symptoms [8,9] to mild neurological impairment [10,11], acute encephalopathy [12][13][14], severe encephalopathy with basal ganglia involvement [15,16], and slowly progressive leukoencephalopathy presenting in adulthood [17][18][19][20]. Dilated cardiomyopathy [21], central precocious puberty, attention deficient hyperactivity disorder, learning disability, and white matter alterations on magnetic resonance imaging [22] have also been described.…”

Section: Introductionmentioning

confidence: 99%

3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature

Nardecchia

Caciotti

Giovanniello

et al. 2022

IJMS

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3-Methylglutaconic aciduria type I (MGCA1) is an inborn error of the leucine degradation pathway caused by pathogenic variants in the AUH gene, which encodes 3-methylglutaconyl-coenzyme A hydratase (MGH). To date, MGCA1 has been diagnosed in 19 subjects and has been associated with a variable clinical picture, ranging from no symptoms to severe encephalopathy with basal ganglia involvement. We report the case of a 31-month-old female child referred to our center after the detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid. A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis. To further investigate the strong biochemical indication, we measured MGH activity, which was markedly decreased. Finally, single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis. The patient was then supplemented with levocarnitine and protein intake was slowly decreased. At the last examination, the patient showed mild clumsiness and an expressive language disorder. This case exemplifies the importance of the biochemical phenotype in the differential diagnosis of metabolic diseases and the importance of collaboration between clinicians, biochemists, and geneticists for an accurate diagnosis.

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Acute Encephalopathic Presentation of 3-Methylglutaconic Aciduria Type I With a Novel Mutation in AUH Gene

Cited by 4 publications

References 10 publications

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

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

Closing the gap: an urgent need for newborn screening of organic acid disorders in developing countries

3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature

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