Introduction

The branched-chain organic acid 3-methylglutaconic acid (3-MGA) is an intermediate of the mitochondrial leucine catabolism. In the urine of healthy individuals, 3-MGA is found only in traces (<20 mmol/mol creatinine); in young infants it can be higher (up to 30 mmol/mol creatinine) as the creatinine is relatively lower due to lower muscle mass.

In patients with inborn errors with 3-methylglutaconic aciduria as a discriminative feature (3-MGA-IEM), urinary 3-MGA concentrations can (intermittently) rise above 1000 mmol/mol creatinine (Wortmann et al. 2013a, b).

The leucine pathway shows the metabolic pathway of leucine. 3-MGA, 3-methylglutaric acid (3-MG), and 3-hydroxyisovaleric acid (3-HIVA) accumulate when the conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA by the enzyme 3-methylglutaconyl-CoA hydratase (3-MGH, EC 4.2.1.18 encoded by AUH) is disturbed (Fig. 70.1) (Wortmann et al. 2010). This is the primary 3-methylglutaconic aciduria (3-MGA-uria) or AUH-defect, formerly known as 3-MGA-uria type I. The urinary excretion of 3-MGA is generally higher in primary 3-MGA-IEM, AUH defect, than in all other (secondary) 3-MGA-IEM. Patients with AUH defect excrete even higher amounts of urinary 3-MGA after a leucine-rich, or in general a protein-rich, meal (Table 70.12) (Wortmann et al. 2014). This is not the case in all other patients with 3-MGA-uria underlining that the excreted 3-MGA does not originate from leucine degradation. Another distinctive feature between primary and secondary 3-MGA-IEM is the elevation of 3-HIVA which is only seen in the AUH defect.

3-MGA-uria can be frequently seen (3% of all urine samples of patients with suspected IEM) in association with several IEM, such as organic acidurias, glycogen storage disorders, fatty acid oxidation disorders, and urea cycle disorders (Fig. 70.1 classification updated from) (Wortmann et al. 2013a, b). Therefore it is important to repeat urinary organic acid analysis in patients with 3-MGA-uria and to carefully interpret the other general clinical chemistry (blood gas analysis, glucose, lactate, ammonia, full blood counts, etc.) and metabolic screening tests (serum amino acids, acylcarnitines in dried blood spot, oligosaccharides in urine). This will allow to confirm that 3-MGA-uria is only an accompanying finding.

In another group of patients, 3-MGA-uria is only slightly and/or intermittently elevated, and 3-MGA-uria is a minor finding. The majority of patients in this group are patients with mitochondrial disorders where it is detected in about 11% of all patients. It is more frequently seen in ATPase-related disorders, with mitochondrial DNA depletion or deletion (e.g., Pearson syndrome), but not in patients with single respiratory chain complex deficiencies with exception of ATPase-related disorders (Wortmann et al. 2013a, b). As 3-MGA-uria is not found in all of these patients with the mentioned specific mitochondrial disorders, these disorders are discussed and not here.

Once 3-MGA-uria has been proven to be an isolated and consistently present finding, 3-MGA-uria as a major finding, the diagnosis of a 3-MGA-IEM can be made. One subgroup is formed by the disorders involving defective phospholipid biosynthesis (TAZ, SERAC1, AGK) (Clarke SL et al. 2013; Thiels C et al. 2016; Mass RR et al. 2017; Roeben B et al. 2018; Wortmann SB et al. 2015; Wortmann SB et al. 2012; Haghighi A et al. 2014; Mayr JA et al. 2012), all other 3-MGA-IEM share mitochondrial (membrane) dysfunction (OPA3, DNAJC19, CLPB, HTRA2, TIMM50, TMEM70, MIC13, Fig. 70.2) (Anikster et al. 2006; Ucar SK et al. 2017; Davey KM et al. 2006; Pronicka E et al. 2017; Wortmann SB et al. 2015; Kovacs-Nagy R et al. 2018; Shahrour MA et al. 2017; Magner M et al. 2015; Kishita Y et al. 2020). There are no additional (metabolic) clues that can help to further distinguish between the different types of 3-MGA-IEM with exception of the clinical features (see table on differential diagnosis at the section signs and symptoms). All 3-MGA-IEM show a distinctive pattern of signs and symptoms which allows to distinguish between them; however patients affected by the different 3-MGA-IEM show a spectrum within their subtype (Fig. 70.1).

Nomenclature

No.

Disorder_name

Alternative name

Gene symbol

Chromosomal location

Mode of Inheritance

Affected protein

OMIM No.

70.1

AUH deficiency

3-methylglutaconic aciduria type 1

AUH

9q22.31

AR

3-methylglutaconyl-CoA hydratase

600529

70.2

TAZ deficiency

Barth syndrome; Taffazin deficiency

TAZ

Xq28

XLR

Taffazin

300394

70.3

SERAC1 deficiency

3-methylglutaconic aciduria with dystonia, deafness, hepatopathy, encephalopathy, and Leigh-like syndrome (MEGDHEL)

SERAC1

6q25.3

AR

Serine active site-containing protein 1

614725

70.4

AGK deficiency

Sengers syndrome

AGK

7q34

AR

Acylglycerokinase

212350

70.5

OPA3 deficiency

Optic atrophy type 3 (dominant); 3-methylglutaconic aciduria type 3, Costeff syndrome (recessive)

OPA3

19q13.2–13.3

AD, AR

 

606580

70.6

DNAJC19 deficiency

Dilated cardiomyopathy with ataxia (DCMA syndrome); 3-methylglutaconic aciduria type 5

DNAJC19

3q26.33

AR

- DNAJ/HSP40 homolog, subfamily C, member 19

608977

70.7

CLPB deficiency

3-methylglutaconic aciduria type 7, with cataracts, neurologic involvement and neutropenia

CLPB

11q13.4

AR

- Caseinolytic peptidase B

616254

70.8

HTRA2 deficiency

3-methylglutaconic aciduria type 8

HTRA2

2p13.1

AR

- HTRA serine peptidase 2

606441

70.9

TIMM50 deficiency

3-methylglutaconic aciduria type 9

TIMM50

19q13.2

AR

Translocase of inner mitochondrial membrane 50

607381

70.10

TMEM70 deficiency

Transmembrane protein 70 deficiency

TMEM70

8q21.11

AR

Complex V assembly protein

612418

70.11

MICOS13 deficiency

MICOS complex subunit MIC13 deficiency

MICOS13

19p13.3

AR

MICOS complex, 13-KD subunit

618329

Metabolic Pathways

Fig. 70.1
figure 1

Inborn errors with 3-methylglutaconic aciduria as discriminative feature (3-MGA-IEM). (Updated from Wortmann et al. 2013a, b)

Full size image
Fig. 70.2
figure 2

Leucine metabolism (Updated from Wortmann et al. 2013a, b)

Full size image

Signs and Symptoms

 

AUH-def.

TAZ-def.

SERAC1-def.

AGK-def.

OPA3-def.

DNAJC19-def

CLPB-def.

HTRA2-def.

TIMM50-def.

TMEM70-def.

MIC13-defect

MIM #

250950

302060

614739

212350

258501

610198

616271

617248

617698

614052

618329

Gene

AUH

TAZ

SERAC1

AGK

OPA3

DNAJC19

CLPB

HTRA2

TIMM50

TMEM70

MIC13

3-MGA-uria

x

x

x

x

x

x

x

x

x

x

x

Mode of inheritence

AR

XLR

AR

AR

AR

AR

AR

AR

AR

AR

AR

Typical age at onset

4-5th decade

Neonatal

Neonatal- first year

Childhood

Childhood

Childhood

Neonatal

Neonatal

Neonatal

Neonatal

Neonatal

Developmental delay

 

(x)

x

(x)

x

x

x

x

x

x

x

Intellectual disability

  

x

  

x

x

x

x

x

x

Movement disorder

x

 

x

 

x

x

x

x

  

x

Central hypopnea

      

x

x

   

Optic atrophy

  

(x)

 

x

      

Deafness

  

x

        

Epilepsy

  

(x)

   

(x)

 

x

 

x

Cataracts

   

x

  

x

x

   

Cardiomyopathy

 

x

 

x

 

x

   

x

 

Neutropenia

 

x

    

x

x

   

Growth failure

 

x

x

x

x

x

x

x

x

x

x

Liver involvement

  

x

       

x

Table 70.1 AUH deficiency
Full size table
Table 70.2 TAZ deficiency
Full size table
Table 70.3 SERAC1 deficiency
Full size table
Table 70.4 AGK deficiency
Full size table
Table 70.5 OPA3 deficiency
Full size table
Table 70.6 DNAJC19 deficiency
Full size table
Table 70.7 CLPB deficiency
Full size table
Table 70.8 HTRA2 deficiency
Full size table
Table 70.9 TMEM70 deficiency
Full size table
Table 70.10 TIMM50 deficiency
Full size table
Table 70.11 MICOS13 deficiency
Full size table

Reference Values

Metabolite

Reference value

3-Hydroxyisovaleric acid (U)

0–25 mmol/mol creatinine (0–2 month)

0–50 mmol/mol creatinine (2 months–2 years)

0–45 mmol/mol creatinine (2–10 years)

0–15 mmol/mol creatinine (10–18 years)

0–20 mmol/mol creatinine (> 18 years)

(GCMS, TML laboratory, Radboud university, Nijmegen, NL)

3-Methylglutaconic acid (U)

0–20 mmol/mol creatinine (0–2 month)

0–15 mmol/mol creatinine (2 months–2 years)

0–10 mmol/mol creatinine (>2 years)

(GCMS, TML laboratory, Radboud university, Nijmegen, NL)

3-Methylglutaric acid (U)

Absent, if present not quantified (GCMS, TML lab, Radboud University, Nijmegen, NL)

Pathological Values

Metabolite

Pathological value

3-Methylglutaconic acid (U)

20–40 mmol/mol creatinine: Suggestive for mitochondrial dysfunction as it can be seen in numerous inborn errors of metabolism

> 40 mmol/mol creatinine: Suggestive for inborn error of metabolism with 3-methylglutaconic aciduria as discriminative feature

Leucine Loading Test

Indication: To distinguish between primary and secondary 3-methylglutaconic aciduria.

Procedure: Collect a urine portion for urinary organic acid analysis and a venous blood sample for serum amino acids. Give 100 mg/kg (max. 6 g) leucine powder orally, and repeat listed investigations 1 h after the leucine gift. Collect a 24-h urine sample for another urinary organic acid analysis.

Interpretation: Table below lists the typical findings before and after leucine loading in several 3-methylglutaconic acidurias. Only in primary 3-MGA_uria due to AU deficiency a clear increase in urinary 3-MGA occurs.

Table 16 Results of the leucine loading tests in different 3-methylglutaconic acidurias
Full size table

Specimen Collection

Urine for organic acid analysis should be analyzed immediately or frozen at –20 °C.

DNA Testing

All 3-MGA-IEM show a distinctive pattern of signs and symptoms which justifies single gene testing. In less clear presentations, the whole exome or genome sequencing (WES/WGS) is the method of choice. As both point mutations and deletion(s) in the mitochondrial DNA can cause disorders with unspecific 3-methylglutaconic aciduria, one should inquire at the genetic lab and make sure that the genetic test chosen covers these. Leucocyte-derived DNA from 3–5 ml EDTA blood (children, adults) will be enough for all mentioned genetic tests, and WGS can be performed in much less blood even from a dried blood spot.

Treatment Summary

AUH defect is a disorder of leucine catabolism. Acute deteriorations in relation to catabolism as in other intoxication-type IEM has not been described. The clinical manifestation is an adult-onset (fourth decade onwards) slowly progressive leukoencephalopathy with ataxia and spasticity (Wortmann et al. 2010). A leucine-restricted diet or a protein-defined (vegetarian) diet could be considered; data on this are lacking and will be difficult to obtain. In general, only a supportive treatment is available for all 3-MGA-IEM.