Reversible Infantile Respiratory Chain Deficiency

Class of mitochondrial disorders of intramitochondrial translation with severe presentation in the first months of life and spontaneous recovery: myopathic form due to the homoplasmic variants m.14674T>C and m.14674T>G in MT-TE and hepatic form due to autosomal recessive TRMU deficiency.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Reversible infantile respiratory chain deficiency denotes a group of mitochondrial disorders in which a defect of intramitochondrial translation manifests severely in the first months of life and then regresses spontaneously, without targeted treatment, if the child survives the acute phase. It may present as a myopathy or as a hepatopathy [16]. The myopathic form is due to the homoplasmic variants m.14674T>C and m.14674T>G in the mitochondrial gene MT-TE, which encodes the tRNA for glutamate, and the hepatic form to autosomal recessive deficiency of TRMU, the enzyme that thiolates the wobble-position uridine of the mitochondrial tRNAs for glutamate, lysine and glutamine [6, 16]. Orphanet defines the myopathic form as a genetic disorder of oxidative phosphorylation (OXPHOS) with severe, potentially fatal myopathy from the neonatal period to early childhood, followed by marked spontaneous improvement of muscle function in infancy, with lactic acidosis and a transient decrease in respiratory chain activity [2]. The molecular mechanism of remission has not been elucidated [16].

The class comprises the myopathic form, with its variants and nuclear modifiers, and the TRMU-related hepatic form, a member of the family of reversible infantile mitochondrial diseases. The other monogenic forms of neonatal and infantile ALF, such as the vesicular trafficking disorders due to NBAS, RINT1 and SCYL1, belong to the class of recurrent and neonatal acute liver failure of monogenic cause, which also includes TRMU deficiency [24, 25]. Disorders with only partial reversibility, such as EARS2 and MTO1 deficiencies, fall within the differential diagnosis [26, 27].

1.2. First descriptions

The earliest description collected by OMIM is that of Jerusalem and colleagues, in 1973, of a girl with profound weakness and hypotonia of all muscles except the ocular muscles in the first months of life, hyporeflexia, hepatomegaly, macroglossia and mild elevation of muscle enzymes, whose biopsy showed a slight increase in glycogen and a marked increase in lipids and mitochondria; the child had normal intellectual development and motor delay, and the macroglossia disappeared [1, 28]. In 1983, DiMauro and colleagues described a 2-week-old boy with profound generalised weakness, hypotonia, hyporeflexia, macroglossia and severe lactic acidosis, who improved without specific treatment: he achieved head control at 4.5 months, rolled over at 7 and walked at 16 months, being left at 33 months with mild proximal weakness; lactate normalised at 14 months [29]. This patient's three biopsies, at 1, 7 and 36 months, showed COX staining in fewer than 5%, about 60% and all of the fibres, and COX activity rose from 8% of the lowest control to 47% and then to supranormal values, in contrast with the fatal infantile form of COX deficiency [29]. The condition was named benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase deficiency, after an initial communication in 1981 [9, 29].

Isolated reports or reports of small sibships followed. Zeviani and colleagues described in 1987 a 6-week-old boy ventilated until 15 months, with COX activity of 11% and 57% in biopsies at 4 and 11 months and severe fibrosis in the second [1]. Salo and colleagues described in 1992 two siblings, born to non-consanguineous parents, with sucking and breathing difficulties in the first weeks, profound hypotonia, hepatomegaly, raised creatine kinase (CK) and lactic acidosis, free of clinical signs at 4 years and at 28 months, and stressed that early diagnosis is what allows intensive treatment to be maintained until spontaneous improvement [30]. In 1989, Suzuki and colleagues used the designation benign and reversible muscle COX deficiency [15].

1.3. Molecular discovery and reclassification

In 2009, Horvath and colleagues identified the maternally inherited homoplasmic variant m.14674T>C in MT-TE in 17 patients from 12 families, including the cases of DiMauro, Zeviani and Salo, and demonstrated a reduction of the glutamate tRNA in affected muscle [9]. In 2010, Mimaki and colleagues described 8 Japanese patients, identified a second substitution at the same nucleotide, m.14674T>G, and demonstrated the pathogenicity of m.14674T>C in cybrids, with deficiency of COX and other complexes [10]. In 2011, Uusimaa and colleagues demonstrated genetic heterogeneity, with m.14674T>C in 4 of 7 families and TRMU variants in others, and proposed replacing "benign COX deficiency" with "reversible infantile respiratory chain deficiency", because the biochemical defect extends beyond complex IV [3]. In 2020, Hathazi and colleagues showed that most patients carrying m.14674T>C also have heterozygous nuclear variants in genes that interact with the glutamate tRNA, mainly EARS2 and TRMU, and proposed digenic inheritance [13].

The hepatic form followed a parallel course. Lev and colleagues described in 2002 a female infant born to unrelated Yemenite Jewish parents with fulminant neonatal lactic acidosis and progressive liver failure from 9 weeks, with jaundice, ascites, hypersplenism, coagulopathy and pancreatic failure; transplantation was proposed, but liver function and acidosis improved spontaneously, and complex IV activity was 12% in the liver only [4]. In 2009, Zeharia and colleagues described 13 unrelated infants with ALF and lactic acidaemia and normal mtDNA content, of whom 4 died during crises and the survivors had no recurrence over up to 14 years of follow-up; homozygosity mapping identified variants in TRMU, with a marked reduction in 2-thiouridylation of mitochondrial tRNAs, and the authors proposed that limited sulphur availability in the neonatal period defines a temporal window of risk [23]. The convergence of the two forms on the same tRNA, that for glutamate, supported the hypothesis of a common mechanism of reversibility [26].

1.4. Current classifications

OMIM distinguishes transient infantile mitochondrial myopathy (#500009, also entitled transient infantile respiratory chain deficiency) from transient infantile liver failure (#613070), and cross-refers each to the other as a similar disorder [1, 4]. Orphanet assigns separate codes to myopathy with reversible COX deficiency (ORPHA:254864) and to infantile ALF due to a synthesis defect of mtDNA-encoded proteins (ORPHA:217371) [2, 5]. In the functional classification of mitochondrial translation defects used by Rahman and Mayr, MT-TE belongs to the group of the 22 mtDNA-encoded tRNAs and TRMU to the autosomal recessive group of tRNA modification genes (with ERAL1, GTPBP3, MRM2, MTO1, NSUN3, PNPT1, PUS1, THG1L, TRIT1, TRMT5, TRMT10C and TRNT1); both produce combined deficiency of complexes I, III, IV and V [16]. The review by Boczonadi and colleagues groups under the name reversible infantile mitochondrial diseases the myopathic form due to m.14674T>C/G, the hepatic form due to TRMU and the partial recoveries observed in deficiencies of mitochondrial tRNA synthetases and tRNA-modifying enzymes [27].

2. Molecular Genetics and Pathophysiology

2.1. Intramitochondrial translation and the glutamate tRNA

mtDNA encodes 13 respiratory chain subunits (seven of complex I, one of complex III, three of complex IV or COX and two of complex V), the 12S and 16S rRNAs and the 22 tRNAs required for protein synthesis within the mitochondrion; there are thousands of copies per cell, identical at birth in most people (homoplasmy) or mixed when normal and mutant molecules coexist (heteroplasmy) [14]. In heteroplasmic variants, the mutant proportion has to exceed a tissue threshold for a biochemical deficiency to appear; in homoplasmic variants, all copies carry the variant and expression depends on other factors [9, 14]. Defects of mtDNA tRNAs, of tRNA modification and of aminoacylation produce a pattern of combined deficiency of complexes I, III, IV and V, with preservation of complex II, which is entirely nuclear-encoded [16].

The MT-TE gene occupies nucleotides 14674 to 14742 and is transcribed from the L-strand [7]. Position 14674 corresponds to the discriminator base, the last base at the 3′ end of the tRNA, immediately before the CCA sequence to which glutamate is attached; no pathogenic variant had been described at this position in any of the other 21 mitochondrial tRNAs [9]. The six pathogenic MT-TE variants known in 2009 reached high levels of heteroplasmy or homoplasmy in muscle, always involved skeletal muscle and none had a reversible phenotype, so reversibility is specific to position 14674 and not a general property of glutamate tRNA variants [9].

2.2. TRMU and 2-thiouridylation of the wobble position

The uridine at the first anticodon position (U34, the wobble position) occurs only in the mitochondrial tRNAs for glutamate, lysine and glutamine, and is modified at carbon 5 (taurinomethyl derivative, τm5) and at carbon 2 by thiolation (s2), giving rise to 5-taurinomethyl-2-thiouridine [26, 31]. TRMU (also called MTU1 or MTO2) catalyses 2-thiolation and uses cysteine as the sulphur donor [6, 23]. The 2-thio group gives conformational rigidity to the anticodon, ensures stable and accurate pairing with the codon and is required for efficient recognition of the glutamate tRNA by its synthetase [26]. Cystathionase (cystathionine γ-lyase), which synthesises cysteine from methionine, has physiologically low activity in the first months of life, making cysteine a conditionally essential amino acid during this period; the coincidence of this nadir with the severe reduction of thiolated tRNAs explains decompensation, mainly hepatic, and its resolution when endogenous cysteine synthesis increases [6, 18]. The direct substrate of thiouridylation includes the taurinomethyl group, and taurine supplementation has a theoretical rationale without published clinical data [6].

The experimental data are not uniform. In fibroblasts from a patient with no detectable TRMU protein, mitochondrial translation was normal despite a marked reduction in 2-thiolation, and the only abnormality was the accumulation of a complex II assembly intermediate, which led Sasarman and colleagues to conclude that the enzyme is dispensable for translation when tRNA levels are normal and may have another function in sulphur trafficking [32]. Skin is therefore not suitable for diagnosis [6]. In trmu-null zebrafish, loss of τm5s2U altered the conformation, stability and aminoacylation of the three tRNAs differently in each tissue, with greater vulnerability of the liver, greater impairment of hepatic complexes I, III and IV, steatosis and hepatomegaly; the liver showed the highest complex I to complex II ratio, which the authors interpret as a hepatic preference for electron flow through complex I [31]. These data are preclinical.

2.3. Variants of the myopathic form and normalisation

The difference in ClinVar classification between m.14674T>C and m.14674T>G reflects the number of families and functional data available for each substitution, and not a demonstrated clinical difference between them [10, 33]. In the original study, m.14674T>C was not found in 200 German controls and appeared in 3 of 2704 sequences in mtDB and MITOMAP as a polymorphism, but retrospective review showed that these individuals had the disease phenotype [9].

2.4. Penetrance and digenic inheritance

The penetrance of m.14674T>C is low. In the three multigenerational families studied in 2009, 7 of 22 homoplasmic maternal relatives had severe hypotonia, and most carriers never had weakness [9]. In published families, about 30% of homoplasmic carriers develop symptoms in the first year [13, 26]. At population scale, penetrance is much lower: with a carrier frequency of 0.01% and a penetrance of 30%, one would expect a prevalence of the order of 1/30,000 and more than 2000 patients in the United Kingdom alone, whereas fewer than 100 patients had been described worldwide; in the UK Biobank, 11 of 358,916 unrelated Europeans were homoplasmic for m.14674T>C, with no evidence of mitochondrial disease [13]. The study abstract estimates that only about 1 in 100 carriers develops the disease [13].

Hathazi and colleagues studied 42 homoplasmic individuals (27 affected and 15 unaffected) from 19 families and found, in 24 of the 27 affected, rare and potentially damaging heterozygous variants in nuclear genes that aminoacylate or modify the glutamate tRNA or take part in glutamate and glutamine metabolism, absent in healthy carriers [13]. Six variants of EARS2 (mitochondrial glutamyl-tRNA synthetase) cosegregated with the disease in 9 patients from 6 families, three of them already described in compound heterozygosity in leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL); the common TRMU variant c.28G>T p.(Ala10Ser) was present in 9 patients from 8 families; the rare variant TRMU c.902A>G p.(Tyr301Cys) cosegregated in one family; and there were also variants in QRSL1, GOT2, GLS and MSS51 [13]. The probability of combining m.14674T>C with a damaging EARS2 variant was estimated at about 1.35 × 10⁻⁶, and that of combining m.14674T>C with TRMU p.(Ala10Ser) at about 1 × 10⁻⁵, values compatible with the rarity of the disease [13]. In the review of 55 patients published in 2026, modifier screening was performed in 34 and found pathogenic heterozygous variants in 24, mainly in EARS2 (9) and TRMU (6) [15]. One of the new cases in that series had maternally inherited m.14674T>C and a paternally inherited EARS2 frameshift variant, NM_001083614.2:c.412_427dup p.(Ser143LeufsTer27), and his brother, carrying only the mitochondrial variant, was healthy [15]. Two Brazilian patients had heterozygous variants in QRSL1 and EARS2 [36].

2.5. Mechanism of presentation and recovery

In the symptomatic phase, the glutamate tRNA in muscle falls to 16–30% of the value in age-matched controls; after recovery, and in the muscle of healthy carrier mothers, it rises only to 30–60%, and patients' myoblasts have normal mitochondrial translation despite levels of about 50% [9]. Complete clinical recovery with a modest increase in the tRNA indicates that mechanisms downstream of the tRNA itself are at work [9]. Cybrids with m.14674T>C show deficiency of complexes I, III and IV, but undifferentiated myoblasts have normal activity, which points to nuclear factors that become manifest during muscle proliferation or differentiation; the aminoacylation ratio of the glutamate tRNA was normal [1, 10].

Three lines of evidence support the role of thiolation and amino acid supply. First, muscle from two patients in the symptomatic phase had very low thiolation of the glutamate tRNA, which increased by about 20% after recovery, whereas in normal muscle the thiolated proportion does not vary with age; experimental reduction of TRMU worsened thiolation and caused a translation defect in myoblasts with m.14674T>C, but not in controls or in cells with the MELAS and MERRF variants, and the addition of 5 mM L-cysteine to the medium corrected complex I and IV activity [26]. Second, transcriptomics and proteomics of muscle from six patients showed an integrated mitochondrial stress response, with increased FGF21 and GDF15, activation of GCN2, ATF4 and ATF5, increased amino acid transporters, serine synthesis, one-carbon metabolism, fatty acid oxidation and the Krebs cycle, and reduced glycolysis, followed by mTOR activation, increased PGC1α and mitochondrial biogenesis; muscle mtDNA copy number was more than double that of age-matched infants in the symptomatic phase and increased 4- to 40-fold after recovery [13]. Third, cysteine depletion in the medium reduced complexes I and IV in fibroblasts, especially those of m.14674T>C carriers, and glutamine and glutamate depletion reduced COX subunits in cells with an additional EARS2 variant [13]. The authors propose three phases: a stress response with metabolic remodelling, mTOR activation with biogenesis, and recovery with a fall in stress markers [13]. Skeletal muscle is the largest reservoir of glutamate and cysteine, which may explain the muscle selectivity of the MT-TE form [13].

Uusimaa and colleagues observed selective loss of COX-negative oxidative type 1 fibres and type 2 fibre predominance in late biopsies, and proposed that recovery is accompanied by the disappearance of this subpopulation [3]. The hypothesis of a physiological increase in mtDNA copy number with age was not confirmed in the 2009 series, which found no changes between successive biopsies [9], whereas the 2020 series found a compensatory increase; the difference may depend on the methods and the patients studied.

2.6. Genetics of TRMU deficiency

Forty-seven pathogenic or likely pathogenic variants, 17 of them novel, and one intragenic deletion of more than one exon have been described in 62 individuals; the first version of the article counted 48 variants and was retracted and republished by the authors with corrected variant classification, without substantial change in the results [11]. Variants are distributed throughout the gene, with greater density in the catalytic domain, near the site of interaction with the tRNA base, and in the β-barrel; the most frequent are c.835G>A p.(Val279Met), in 16 individuals, and c.229T>C p.(Tyr77His), in 13 [11]. According to HGMD data collected in GeneReviews, sequencing detected 26 of 28 variants and targeted deletion/duplication analysis 2 of 28 [6]. There is no consensus on genotype–phenotype correlations, but loss-of-function variants are associated with shorter survival: in the corrected version of the cohort, 23 individuals had at least one loss-of-function variant and its presence reduced overall survival (P=0.0089 in Kaplan–Meier analysis), with no difference between having the variant on one or both alleles (P=0.6) [11]. GeneReviews, based on the same patients, reports the death of 10 of 20 children with loss-of-function variants and of 10 of 42 with other variants (p=0.022), and a mean follow-up of 78 months in children with two missense variants or in-frame indels and of 38 months in those with at least one nonsense, frameshift or splicing variant [6]. The Yemenite Jewish founder variant p.(Tyr77His) was homozygous in 8 infants and in compound heterozygosity with a splicing variant in 1, and no homozygote died; the start-loss variant c.2T>A, observed in several ethnic groups, is associated with early mortality, with at least five known deaths [6].

The variants in the table were normalised in VariantValidator on the MANE transcript; those in GeneReviews were provided by the authors without independent verification of classification [6, 12]. The designation p.Met1Lys used in databases for c.2T>A is not the correct HGVS description, which is p.(Met1?) [12].

2.7. Allelic disorders and tissue expression

In MT-TE, other variants cause disorders without reversibility: m.14709T>C is associated with myopathy with diabetes, maternally inherited diabetes and deafness and, in some families, congenital myopathy with intellectual disability and ataxia, with heteroplasmy load correlating with severity in one Tunisian family but not in another; m.14692A>G, homoplasmic, is associated with maternally inherited diabetes and deafness [7, 35]. In TRMU, the variant c.28G>T p.(Ala10Ser) aggravates aminoglycoside-associated deafness in carriers of MT-RNR1 m.1555A>G, described in Chinese, Israeli Arab, and Italian and Spanish populations [6, 38]. This modifier function concerns a different group of people and should not be confused with TRMU deficiency [6].

The MT-TE form is selective for skeletal muscle: the COX reaction is absent in almost all muscle fibres in the acute phase, but present in muscle spindles and intramuscular vessels [9]. TRMU deficiency is predominantly hepatic, but not exclusively so: there is reduced complex IV activity in muscle even with normal muscle histology, reduced thiolation in muscle and cases with transient hypotonia, cardiomyopathy and Leigh syndrome [3, 6, 26]. These tissue differences, and the fact that both forms converge on the glutamate tRNA and on cysteine availability, explain why the class is treated together [13, 26].

3. Clinical Spectrum and Manifestations by System

3.1. Myopathic form: acute presentation

The disease affects skeletal muscle selectively and within a narrow age window: all patients in the 2009 series had profound hypotonia and respiratory and feeding difficulties in the first days or weeks of life, with markedly raised serum lactate [9]. Even when presentation is later, careful review of the history finds subtle hypotonia and feeding difficulties from birth, and acute deterioration is often triggered by a viral infection [3]. The myopathy is rapidly progressive in the first weeks, with profound weakness, nasogastric tube or gastrostomy feeding and, in some infants, ventilation until 12–18 months [16]. There may be facial weakness, a high-arched palate and macroglossia [1, 29]. In the review of 55 patients, the initial presentations were feeding difficulties (22), hypotonia (12), dyspnoea (11), developmental delay (7) and lethargy or altered consciousness (3); one patient presented at 4 years with gait unsteadiness [15].

In the 2026 review, muscle involvement occurred in 47 of the 55 patients (85%; the article states 85.55%), gastrointestinal involvement (feeding difficulties, dysphagia, vomiting) in 80.00% and respiratory involvement (recurrent infections, dyspnoea, respiratory failure) in 47.27% [15]. The cohort figures overlap, because the 2026 review and the 2020 study include patients published in 2009 and 2011, and they do not measure the same thing: the older series describe patients with the classic picture selected by biopsy, while the 2026 one pools heterogeneous reports [13, 15].

3.2. Laboratory and histological findings in the acute phase

Lactate is raised at presentation (3.2–16.4 mmol/L in the 2011 series; raised in 35 of 41 patients, between 2.27 and 13.44 mmol/L, in the 2026 review) and normalises with recovery; when measured late it may already be normal [3, 15]. Cerebrospinal fluid (CSF) lactate was raised in 7 of 8 patients tested [15]. CK ranges from normal to moderately raised (266–900 U/L in 5 patients in 2011; raised in 25 of 36, between 203 and 1402 U/L, in 2026), and there was low carnitine in several patients in the 2009 series [3, 9, 15]. Transient transaminase elevations have been described in 9 patients and signs of myocardial injury in 5 [15]. Hyperammonaemia may be the presentation, as in a 4-week-old girl with hypotonia and faltering growth [39].

The acute-phase muscle biopsy is essentially identical to that of the fatal mitochondrial myopathies: numerous ragged-red fibres (RRF), even more numerous COX-negative fibres, increased lipid and glycogen and, on electron microscopy, giant mitochondria with multilamellar paracrystalline inclusions [9]. In the 2026 review, RRF were present in 33 of 36 biopsies (median age 3 months), lipid or glycogen accumulation in 32 of 36, COX-negative fibres in 12 of 36 and degenerated mitochondria in 18 of 36 [15]. Muscle COX activity ranged from 3% to 52% of normal in the 2009 series, frequently with associated complex I deficiency, and activities returned to normal or supranormal values on recovery [9]. Enzymology showed isolated complex IV deficiency in 12 of 25 patients and combined complex I and IV deficiency in 13 of 25, with normalisation in all 5 reassessed [15]. Muscle magnetic resonance imaging (MRI) may show mild or severe fatty replacement, mainly in the posterior leg muscles [36].

3.3. Myopathic form: medium- and long-term course

Clinical recovery usually begins at around 6 months and is completed over months [16]. In the review of 50 patients with prognostic data, symptom resolution occurred at 6.42 ± 2.82 months, head control at 11.1 ± 8.25 months, independent walking at 21.73 ± 8.17 months and age-appropriate development at 22.31 ± 7.61 months [15]. A minority have a long symptomatic phase: one patient in the Newcastle series remained symptomatic until at least 7 years of age [26].

Patients followed into adulthood show that not all abnormalities are transient. In the 2011 series, with a median age of 14 years (2–35), functional difficulties were minor, but marked fatigability and severe myalgia were almost constant and sometimes disabling; examination ranged from normal to mild weakness of the pelvic girdle and of ankle dorsiflexion, with muscle hypertrophy and Achilles tendon contractures, and facial weakness, ptosis and a myopathic facies (long face and chin, flat midface, narrow upslanting palpebral fissures) became more evident with age [3]. Clinical geneticists distinguished carriers from non-carriers by facies with better-than-chance accuracy (p=0.025) [3]. Late biopsy shows marked improvement but rarely complete normalisation, with fibrosis, fibre atrophy and mild myopathy; in the 2026 review, 9 of 14 post-recovery biopsies (median 5 years) had residual RRF or variation in fibre size and 5 of 14 were normal [9, 15].

3.4. Extramuscular and atypical manifestations of the myopathic form

Mild, reversible hepatic and cardiac involvement occurs mainly in the most severe metabolic crises: 3 of 17 patients in the 2009 series had hepatic involvement, 2 of 8 in the 2011 series had transient cardiac impairment, and 5 patients in the 2026 review had signs of myocardial injury [3, 9, 15]. In a girl from Taiwan, mild septal hypertrophy normalised at 1 year and 2 months and mild left ventricular hypertrophy appeared at 4 years, coinciding with a new rise in CK [40]. The central nervous system is spared in most: cognition and peripheral nerves were normal in the initial phase in all 2009 patients, although one later developed epilepsy, and brain MRI abnormalities are rare (2 of 14 patients studied, with basal ganglia hyperintensity; 2 Japanese siblings with caudate and putamen lesions) [9, 10, 15].

Other findings described include hypothyroidism in 2 patients and in the mother of one of them, more evident extraocular involvement in patients without m.14674T>C and, in the family with m.14701C>T, lipomas on the back in 5 relatives and ataxia in one adult [3, 22]. In the 2026 Chinese series, a boy who recovered from the myopathy developed language stagnation and autism spectrum traits at 2 years and 8 months, attributed to a likely pathogenic variant in CLCN4 (Raynaud–Claes syndrome, X-linked dominant) and not to RIRCD, which illustrates the possibility of a second diagnosis [15]. Some homoplasmic carriers without a neonatal phase, mostly mothers, have mild myopathy, myalgia or exercise intolerance in adulthood [3, 13, 15].

3.5. Hepatic form (TRMU deficiency): presentation

Infants with untreated TRMU deficiency become symptomatic between 2 and 4 months with acute liver dysfunction (raised transaminases and γ-glutamyltransferase, synthetic failure, hepatomegaly), metabolic abnormalities (severe persistent lactic acidosis, hypoglycaemia, hyperammonaemia) and faltering growth [6]. In the Yemenite Jewish series, the children had been born at term, were healthy in the neonatal period and were admitted at 2–4 months with irritability, poor feeding and vomiting, with pale grey skin, jaundice, abdominal distension, hepatomegaly and coagulopathy, low albumin, direct hyperbilirubinaemia, metabolic acidosis, hyperlactataemia, lactic aciduria and raised alpha-fetoprotein [4]. Vomiting is often the first manifestation, and lactic acidosis probably precedes liver dysfunction [6]. The presentation may mimic glycogen storage disease type Ia, organic acidaemias and defects of beta-oxidation and of pyruvate metabolism [18].

In the international cohort, first symptoms appeared at a median of 2 months and genetic diagnosis at a median of 6 months (2 prenatal and 9 post-mortem diagnoses); transaminase elevation was the most common hepatic finding (52 of 62), and ALF, defined by consensus prothrombin time or INR criteria, occurred in 43 of the 62, the earliest at 2 weeks, peaking between 1 and 5 months and none after the first year; 33 of the 43 had a single episode, there was hepatic encephalopathy in 13, and in the 31 liver biopsies fibrosis or cirrhosis (62%), microvesicular steatosis (43%), macrovesicular steatosis (41%) and cholestatic changes (41%) predominated [11]. In 23% of children there were recurrent episodes of ALF in the first year, mainly in the first 5 months; the maximum was 5 episodes, in two children, one transplanted and followed up to 13 years and the other with spontaneous resolution and a native liver at 17 years [6]. In the Yemenite series, improvement began after 2 to 3 weeks of support, liver function normalised in 3 to 4 months and liver size between 3 months and 3 years [4]. Hypoglycaemia may persist after hepatic recovery and require tube feeding or gastrostomy to maintain glucose delivery [6]. Liver disease may progress to fibrosis, micronodular cirrhosis, steatosis and persistent nodules, and variceal haemorrhage has been described [6].

3.6. TRMU deficiency: extrahepatic manifestations

Acute respiratory failure may result from insufficient respiratory effort due to hypotonia, and there is evidence of central apnoea [6]. Leigh syndrome has been described in two infants with ALF, severe hypotonia, acute encephalopathy and regression, and the experience of the GeneReviews authors suggests that neurologically near-normal infants may have MRI compatible with Leigh syndrome, so this phenotype may be underestimated [6, 41]. MRI may show lesions of the thalamus, putamen, basal ganglia, pontine tracts, superior cerebellar peduncles, subthalamic nuclei and brainstem, which may normalise after recovery [6]. An Irish girl with biallelic TRMU variants had early hypotonia and feeding difficulties, ALF with fulminant lactic acidosis, profound COX deficiency in muscle and liver and right thalamic hyperintensity with a lactate peak on spectroscopy, both resolved by 1 year; she recovered, with slightly delayed walking, axial weakness and bulbar involvement [3, 4]. There was dilated cardiomyopathy with reduced contractility in 5 infants, transient nephromegaly and proteinuria in one infant, dysphagia before hepatic decompensation and language delay [6]. A transplanted child had chronic respiratory failure with tracheostomy and symmetrical deep white matter changes, interpreted as an extrahepatic expression of the mitochondrial disease [18]. Saudubray and García-Cazorla include TRMU deficiency among the metabolic causes of macrophage activation syndrome [24].

3.7. TRMU deficiency: mortality and neurodevelopment

Of the 60 infants symptomatic at first assessment collected in GeneReviews, 20 died: 8 from complications of ALF (one from variceal haemorrhage), 8 from multiorgan failure, 3 from cardiorespiratory failure and 1 from sepsis; the median age at death was 3 months [6]. In the international cohort, 42 of the 62 were alive at a median age of 6.8 years (0.6–22) after a median follow-up of 3.6 years; the 20 deaths occurred at a median age of 3 months, mainly from multiorgan failure (8) or liver failure (8) [11]. A recent fatal case in Lebanon combined homozygosity for c.262G>A with concomitant cytomegalovirus infection, with death on day 35 of admission [37]. In the full text of the international cohort, neurodevelopmental delay was recorded in 26 of the 62 individuals (9 without data): it resolved in 11, persisted in 4 (severe in 3 and motor only in 1), 9 died and 2 were lost to follow-up; the abstract of the same article reports 11 individuals with delay and 4 with persistence, and the authors could not distinguish whether the delay is primary or a consequence of ALF [11]. In the same cohort there was encephalopathy in 6, seizures in 4 and cardiomyopathy in 5 individuals, of which one resolved, one progressed to mild left ventricular dilatation and three occurred in children who died [11]. In a retrospective study of 25 children, 9 recovered from their delays some months after hepatic recovery, 5 retained delays and 11 were lost to follow-up or died; GeneReviews reports complete attainment of milestones in 60% of children with delay [6].

3.8. Natural history and treated disease

The data on both forms mainly describe disease without targeted treatment. In the myopathic form, 87.27% of the 55 pooled patients received support only, and the remainder received coenzyme Q10, carnitine or vitamins without demonstrable effect, so the published course corresponds to natural history under intensive care [15]. In TRMU deficiency, natural history with support coexists with observational data on cysteine supplementation: two siblings treated before symptoms (one with maternal L-cysteine in the third trimester and supplementation from birth, the other with cysteine from birth) had less severe acidosis and liver dysfunction and fewer admissions than their older siblings, but one of them was placed on the transplant list and developed stage 4 micronodular cirrhosis at 26 months [6, 18]. In the international cohort, 25 of the 62 patients (40%) received an oral source of cysteine, and supplementation was associated with longer survival (P=0.0052), with no effect on native liver survival (P=0.24) [6, 11].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the myopathic form

The myopathic form should be considered in any hypotonic infant with suspected mitochondrial myopathy, especially when severe hypotonia appears between birth and 2 months with lactic acidosis and a need for intensive care and nutritional support [9, 24]. Saudubray and García-Cazorla recommend screening for the glutamate tRNA variant in hypotonic infants with suspected mitochondrial myopathy, and include reversible myopathy due to glutamate tRNA variants in the table of metabolic causes of severe hypotonia with hyperlactataemia [24]. Uusimaa and colleagues consider it mandatory to think of this disease in all early-onset cases, because of the difference in prognosis compared with the other infantile mitochondrial diseases [3].

The features that point to this form are: profound hypotonia with a relatively expressive face or with facial weakness, sucking and swallowing difficulty, respiratory difficulty, macroglossia, hepatomegaly in some cases, normal or moderately raised CK, raised lactate in blood and CSF, absence of brain involvement on MRI in most, and a muscle biopsy with RRF and COX-negative fibres [9, 15, 29]. A maternal history of hypotonia in infancy, of mild myopathy or of fatigue, or siblings or maternal relatives with a similar picture, strengthens the hypothesis, but the absence of a family history is the rule, given the low penetrance [3, 13, 40]. In the general approach to the hypotonic infant, central hypotonia is much more frequent than peripheral hypotonia; an alert, responsive infant with hypotonia stable over hours or days suggests a peripheral neuromuscular cause, and a lethargic infant deteriorating over hours or days suggests a central or metabolic cause [42]. RIRCD has features of both: it is a myopathy, but with lactic acidosis and sometimes rapid deterioration [9].

4.2. When to suspect TRMU deficiency

Between 2 and 4 months, the combination of acute liver dysfunction with raised γ-glutamyltransferase and transaminases, hyperammonaemia, conjugated hyperbilirubinaemia, severe persistent lactic acidosis, persistent hypoglycaemia, poor feeding and failure to gain weight should raise suspicion of TRMU deficiency [6]. Murali and colleagues propose considering the diagnosis in every infant with lactic acidosis and hypoglycaemia of unknown cause, with or without liver disease, and starting cysteine supplementation until it is excluded [18]. The 2026 systematic review of recurrent paediatric ALF associates the triad of lactic acidosis, hypoglycaemia and ALF in the infant with TRMU deficiency, and marked hyperammonaemia with urea cycle disorders [25]. After 4 months, in a child who recovered spontaneously from ALF with symptomatic care, a Leigh-like syndrome, cardiomyopathy, hepatomegaly, poor weight gain or persistent lactic acidosis should prompt testing for TRMU [6]. Saudubray and García-Cazorla also include respiratory chain defects, especially TRMU deficiency, among the metabolic causes of isolated transaminase elevation and of steatosis in children [24]. Consanguinity, affected siblings and Yemenite Jewish ancestry increase the probability, but the absence of a family history does not exclude the diagnosis [6].

4.3. Warning and emergency signs

In the myopathic form, the emergency signs are respiratory failure due to muscle weakness, aspiration, recurrent respiratory infections and malnutrition; the only death in the 2009 series was from pneumonia at 39 days in the setting of severe hypotonia, and the two deaths in the 2026 review were from respiratory failure [9, 15]. In TRMU deficiency, the emergency signs are coagulopathy, hepatic encephalopathy with hyperammonaemia, lactic acidosis that worsens with increased glucose delivery, refractory hypoglycaemia, ascites, gastrointestinal bleeding and respiratory failure [6, 18]. Lactic acidosis that worsens when glucose delivery is increased, as in a girl initially treated as having glycogen storage disease type Ia, should steer away from a diagnosis of glycogen storage disease and suggest mitochondrial disease [18].

4.4. The problem of limitation of care

The central clinical reason for recognising this class is to avoid early decisions to limit or withdraw support. Acute-phase muscle biopsies do not distinguish the reversible form from the fatal mitochondrial myopathies, and a severe mitochondrial myopathy early in life is as a rule irreversible, which leads clinicians and parents to consider end-of-life decisions [9]. For this reason, the authors of the molecular description argue that support should not be withdrawn early from these children and that genetic testing determines prognosis and management [9]. Molecular diagnosis makes it possible to select the children with an excellent prognosis in order to maintain respiratory support, and patients should receive intensive supportive care during the first 6 months [3, 36]. In TRMU deficiency, the transient nature of ALF alters the transplantation decision: spontaneous recovery with support is possible, and transplantation did not improve overall survival in the 11 recipients described [6, 25].

4.5. Newborn screening

The sources consulted do not describe newborn screening for either form; in TRMU deficiency, one patient's newborn screening was normal, despite hypoglycaemia, acidosis and hyperammonaemia in the first days [18]. In siblings of a patient with known TRMU variants, prenatal diagnosis or immediate molecular testing after birth allows supplementation to be started before symptoms [6].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria for either form [6]. The diagnosis of the myopathic form is established in an infant with the picture described and the homoplasmic variant m.14674T>C or m.14674T>G in MT-TE; that of TRMU deficiency, in a patient with suggestive findings and biallelic pathogenic or likely pathogenic variants in TRMU [6, 9, 10]. Two variants of uncertain significance in TRMU, or one pathogenic variant and one of uncertain significance, neither confirm nor exclude the diagnosis [6]. No non-molecular test confirms the MT-TE form; muscle histochemistry serves to guide genetic testing [9, 17].

5.2. Initial biochemical assessment

The Mitochondrial Medicine Society (MMS) recommends, when mitochondrial disease is suspected, full blood count, CK, transaminases, albumin, lactate and pyruvate, plasma amino acids and acylcarnitines and urinary organic acids; postprandial lactate is more sensitive than fasting lactate, the lactate/pyruvate ratio is only of value when lactate is raised, and in CSF lactate, pyruvate, amino acids and 5-methyltetrahydrofolate should be requested [17]. The GeneReviews chapter on mitochondrial disorders considers that a fasting plasma lactate above 3 mmol/L and a CSF lactate above 1.5 mmol/L support the diagnosis, but that normal values do not exclude it [14]. In the myopathic form, lactate and CK should be measured at presentation, because they normalise with recovery [3]. In TRMU deficiency, hyperalaninaemia and lactic aciduria help distinguish chronic lactic acidosis from acidosis secondary to ALF or critical illness [6]. During paediatric ALF, neither lactate nor the lactate/pyruvate ratio is specific for mitochondrial disease [25]. The 2022 position statement of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) specifies that, in the Pediatric Acute Liver Failure Study Group cohort, neither lactate ≥2.5 mmol/L nor a raised lactate/pyruvate ratio (>25 mol/mol) was specific for mitochondrial disease or predicted outcome, so neither the diagnosis nor the transplantation decision should rest on these values alone [43]. Growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) have been proposed as follow-up markers, without validation for clinical decision-making [13, 17, 18].

5.3. Genetic testing

For the myopathic form, the MMS recommends massively parallel sequencing of the whole mitochondrial genome rather than testing for a few point variants [17]. The m.14674T>C variant can also be tested in a targeted way, for example by PCR with a mismatched primer and BccI digestion, which produces fragments of 108 and 74 base pairs on the normal allele and of 108, 46 and 28 base pairs on the mutant allele [9]. As the variant is homoplasmic, blood is an adequate sample, and homoplasmy can be confirmed in blood and urine from maternal relatives [9, 15]. A negative result for m.14674T>C/G should lead to sequencing of TRMU and, more broadly, of nuclear genes, because the same picture may have other causes [3]. Trio exome or genome sequencing allows a search for modifiers (EARS2, TRMU, QRSL1, GOT2, GLS, MSS51) and additional diagnoses, and targeted reanalysis may find them years after a first negative result [13, 15].

For TRMU deficiency, GeneReviews proposes a mitochondrial disease, cholestasis or infantile ALF panel that includes TRMU, or an exome, more commonly used, or a genome [6]. The 2023 UK guideline recommends the hepatic presentation panels in infants with ALF and suspected mitochondrial disease, and includes TRMU in that group [44]. The MMS prefers next-generation panels with complete coverage of nuclear mitochondrial genes to single-gene testing, and the exome when the panel is negative [17]. NASPGHAN considers rapid exome sequencing the most accurate tool for diagnosing mitochondrial hepatopathy in ALF, with variable geographical availability [43]. In an international multicentre study of 260 children with ALF of indeterminate cause, recruited in 19 countries between 2011 and 2022, the exome established the diagnosis in 37% (97 of 260), in 41% of children with ALF in the first year of life and in 64% of those with recurrent ALF; mitochondrial diseases were the most frequent group (45% of diagnoses), and in 68% of them ALF occurred in the first 6 months [45]. A recent Indian report of transient infantile ALF due to TRMU focuses on the role of rapid exome sequencing [46].

5.4. Limits of testing

The proportion of variants detected by each method is not equivalent to the clinical sensitivity of the test. In TRMU deficiency, sequencing detected 26 of 28 variants and targeted deletion/duplication analysis 2 of 28 [6]. In one patient, a trio exome with mitochondrial genome sequencing was initially negative, and only targeted reanalysis, two years later, identified a missense variant and a deletion of one and a half exons of TRMU [18]. Apparent homozygosity should prompt consideration of a deletion of one or more exons not detected by sequencing or of uniparental isodisomy, and the absence of one of the variants in both parents, with confirmed parentage, a de novo variant or parental mosaicism [6]. Splicing variants close to the acceptor, such as c.1102-3C>G, may require RNA studies for interpretation [3]. The exome has limited coverage of some regions and does not reliably detect large deletions and duplications, repeat expansions or epigenetic changes [14]. The classification of published TRMU variants also has limits: in a letter to the editor about the international cohort, Kulseth pointed out that several missense variants were classified as likely pathogenic or pathogenic solely on the basis of rarity (PM2), in silico prediction (PP3) and phenotype (PP4, weighted as strong evidence), that the phase of the two variants was not documented in a large proportion of the 31 compound heterozygotes, and that two siblings with the same variants do not meet the cosegregation criterion; faced with a rare TRMU variant in a new patient, classification should be redone with current criteria and with parental testing [11, 47].

For mtDNA, the interpretation of homoplasmic variants has a specific difficulty: according to the UK guideline, a homoplasmic variant inherited from a clinically unaffected homoplasmic mother is in principle unlikely to be pathogenic, and a frequency of 1/1000 or more in MITOMAP or gnomAD without disease association also argues against pathogenicity, but there are homoplasmic pathogenic variants with variable penetrance that constitute exceptions [44]. m.14674T>C is one such case: the mothers are as a rule healthy homoplasmic carriers, and the variant was once listed as a polymorphism [9, 15]. The report should state the homoplasmy or the heteroplasmy level [44]. The absence of identified nuclear modifiers does not exclude the contribution of other genetic or environmental factors [13].

5.5. Muscle and liver biopsy

The MMS recommends muscle or liver biopsy when the diagnosis is not confirmed by DNA, with histochemistry for COX, succinate dehydrogenase (SDH), NADH-tetrazolium reductase and combined COX/SDH, electron microscopy (strongly recommended in paediatrics), and enzymology of complexes I to IV in frozen tissue or fresh mitochondria, normalised to citrate synthase or complex II [17]. Sampling should include fresh tissue on wet ice for mitochondrial respiration, tissue frozen on dry ice for enzymology, histochemistry, Western blot and blue native gel electrophoresis (BN-PAGE), and fixed tissue for electron microscopy [16]. In the myopathic form, the acute-phase biopsy shows RRF, COX-negative fibres, increased lipid and glycogen and COX deficiency, isolated or combined with complex I deficiency [9, 15]. Two interpretive cautions apply: enzymology normalises with recovery, so a normal late biopsy does not refute an earlier diagnosis, and the deficiency is absent in undifferentiated myoblasts even when present in mature muscle, so fibroblasts and myoblasts cannot be used to exclude it [9, 10]. The MMS warns that enzymology may be falsely normal depending on the timing of the assay and the tissue studied [17].

In TRMU deficiency, biopsies are not necessary for diagnosis [6]. When performed, the liver shows bridging, portal and perisinusoidal fibrosis, focal eosinophilic ground-glass appearance, micronodular cirrhosis, necrosis, mitochondrial proliferation, micro- and macrovesicular steatosis, canalicular cholestasis, ductular proliferation, ballooning degeneration, increased iron and oncocytic hepatocytes; enzymology is variable, but complex IV is uniformly decreased, and BN-PAGE shows abnormal assembly mainly of complexes I and IV [6]. In muscle there may be variation in fibre size, lipid, RRF and deficiency of complexes I, III and IV [6]. Skin biopsy is of no use [6]. Abdominal ultrasound may be normal or show an enlarged, hyperechoic liver, diffuse steatosis and persistent nodules, and MR spectroscopy may show a lactate peak in the acute phase [6].

When an infant dies without a diagnosis and metabolic disease is suspected, samples collected immediately after death allow the investigation to continue and support counselling on recurrence risk and prenatal diagnosis in a subsequent pregnancy: frozen heparinised plasma, blood on a Guthrie card for acylcarnitines, frozen urine, EDTA blood for DNA extraction and storage, skin for fibroblast culture and fragments of liver and muscle frozen immediately for histochemistry and enzymology [48]. In the international TRMU deficiency cohort, 9 of the 62 diagnoses were made post mortem [11].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

In TRMU deficiency, once the familial variants have been identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible; prenatal diagnosis has been used to guide maternal L-cysteine supplementation and to start supplementation at birth [6]. In the MT-TE form, the UK guideline considers that prenatal diagnosis is generally not appropriate for homoplasmic variants, because all children of a homoplasmic mother inherit the variant and the result does not predict clinical expression [44]. For the same reason, preimplantation testing, which selects embryos with a low mutant load for heteroplasmic variants, does not apply to a homoplasmic variant [44].

6. Differential Diagnosis

6.1. Comparative table

6.2. Myopathic form: differential of the hypotonic infant with mitochondrial myopathy

The most difficult differential is with the irreversible mitochondrial myopathies and encephalomyopathies, because the clinical picture, lactate and acute-phase biopsy overlap; only the course and molecular testing distinguish them [9, 40]. Uusimaa and colleagues group the COX deficiencies of infancy into generalised encephalomyopathy (Leigh syndrome, mainly due to SURF1) and two muscle forms, fatal and reversible, separated by their course [3]. In disorders with partial reversibility, such as EARS2-related LTBL and MTO1-related cardiomyopathy, recovery is incomplete and brain or cardiac involvement predominates [16, 26]. Outside the mitochondrial diseases, the differential of the hypotonic infant includes congenital myotonic dystrophy, the most frequent neonatal neuromuscular cause, neonatal myasthenia, congenital muscular dystrophies, congenital myopathies, spinal muscular atrophy, Prader–Willi syndrome and Pompe disease [42]. Lactic acidosis and mitochondrial histology rule out most of these hypotheses, but Menkes disease and spinal muscular atrophy were excluded by specific tests in one of the published cases [40]. Primary coenzyme Q10 deficiency is treatable and should be considered when enzymology shows combined deficiency of complexes I+III and II+III [16].

6.3. Hepatic form: differential of infantile ALF with lactic acidosis

TRMU deficiency shares with the mtDNA depletion syndromes the age, the metabolic profile and ALF, but in the latter the course is progressive and hepatic mtDNA content is reduced; in TRMU deficiency the content is normal and deficiency of complexes I, III and IV coexists with preserved complex II [4, 6]. mtDNA depletion is a more severe and permanent disease, and valproate is associated with fulminant ALF in POLG-related disease [4, 16]; in DGUOK-related disease there is often cirrhosis already at presentation, with no reversible phenotype [11]. Liver mtDNA copy number nevertheless has limits as a discriminating test: in a consecutive series of 39 infants with ALF in Birmingham (2009–2011), 5 had genetically confirmed mtDNA depletion (DGUOK 2, POLG 2, MPV17 1), and 8 of the 15 patients without genetic mitochondrial disease with a measurement available had low or borderline hepatic copy number, which indicates that depletion may be secondary to ALF itself [50]. Disorders with infantile ALF and their own biochemical marker (galactosaemia, tyrosinaemia type 1, urea cycle disorders, beta-oxidation defects) are excluded by first-line metabolic tests [24, 25]. While these results are awaited, Saudubray and colleagues recommend excluding galactose, fructose and protein from the diet, with normal intake of the other nutrients, and starting nitisinone (NTBC) if tyrosinaemia type 1 is suspected [49]. In recurrent ALF, marked hyperammonaemia suggests ornithine transcarbamylase deficiency or HHH syndrome, lactic acidosis with hypoglycaemia suggests TRMU or dihydrolipoamide dehydrogenase deficiency, and microcytic anaemia, hypoalbuminaemia and hypotonia suggest LARS1 deficiency [25]. The vesicular trafficking disorders with fever-triggered recurrent ALF (NBAS, RINT1, SCYL1) have repeated crises throughout childhood, unlike TRMU deficiency, which is limited to the first year [11, 24]. Infantile ALF due to TRMU may coexist with infections, such as cytomegalovirus infection, which worsen the picture [37].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no curative therapy or specific guideline for either form; the applicable recommendations come from the MMS consensus statements on primary mitochondrial disease (2015 and 2017), the GeneReviews chapter on TRMU deficiency and case series [6, 17, 51]. GeneReviews explicitly states that no clinical practice guidelines have been published for TRMU deficiency [6]. The principle that distinguishes this class from the other infantile mitochondrial diseases is that recovery is the expected outcome, so ventilatory and nutritional support should be maintained during the acute phase and not withdrawn, and it is the molecular diagnosis that underpins this decision [3, 9, 16]. Saudubray and colleagues summarise that surveillance for RIRCD is associated with good outcomes, although some patients with myopathy need prolonged ventilation, up to 18 months, and some with TRMU-related ALF need liver transplantation [16].

7.2. Myopathic form: support in the acute phase

Treatment of the MT-TE form is supportive: invasive or non-invasive ventilation for as long as the weakness requires, nasogastric tube or gastrostomy feeding, correction of lactic acidosis by conventional means, prevention and early treatment of respiratory infections and aspiration, and physiotherapy [3, 9, 16]. In the 2011 series, most patients needed only intermittent nasogastric tube feeding, one kept a gastrostomy in childhood and another needed a temporary tracheostomy; in the 2026 review, 43.63% needed mechanical ventilation and 70.91% a tube or gastrostomy [3, 15]. Prolonged non-invasive ventilation may be associated with maxillary hypoplasia [3]. In the general MMS recommendations for mitochondrial patients in intensive care, ventilatory assessment should include aspiration, atelectasis and infection, taking hypotonia and myopathy into account; lactate and pyruvate may rise acutely during the introduction of feeding or weaning from respiratory support; nutritional support should begin, if possible, within the first 48 hours; and patients should have a summary document with the underlying disease, nutritional needs, medication and contraindicated therapies, updated at each visit [51].

Decisions on gastrostomy should be made with gastroenterology and, in some cases, with palliative care [51]. In a disease with expected recovery, palliative care involvement does not mean limitation of care, but support for the family during an admission that may last months [6, 9]. Amino acid intake appears relevant to recovery: the myopathic form is associated with activation of amino acid deprivation response pathways, and cysteine and glutamate depletion worsens the deficiency in patient cells, but there are no clinical studies of nutritional intervention in the MT-TE form [13].

7.3. TRMU deficiency: treatment of the acute phase

Symptomatic treatment of the liver disease includes correction of hypoglycaemia, lactic acidosis, coagulopathy and hyperammonaemia [6]. Glucose should be given with caution: in the acute phase, hepatic oxidation is limited and high dextrose concentrations increase lactate and may cause or worsen metabolic acidosis, so euglycaemia has to be balanced against acid–base balance [6]. In the emergency treatment of primary hyperlactataemia of the newborn, Saudubray and colleagues note that sustained hyperlactataemia may be due to a glucose-rich infusion and be corrected with 5% or even 2.5% dextrose [49]. This guidance contrasts with that of NASPGHAN for paediatric ALF in general, which proposes 10% dextrose with half-normal saline and 15 mEq/L potassium, at about 90% of maintenance, and glucose delivery rates of up to 10–15 mg/kg/min to keep blood glucose between 90 and 120 mg/dL; in TRMU deficiency, the rate has to be adjusted to lactate and blood glucose [6, 43]. One of Murali's patients needed very high intravenous glucose delivery rates and enteral bicarbonate, and lactic acidosis worsened as the glucose delivery rate increased [18]. Oral bicarbonate and sodium citrate/citric acid were used in the published series, with very variable doses between patients, and in one infant bicarbonate, at 1.2 mEq/kg/day, was stopped because of metabolic alkalosis [18]. Hyperammonaemia was treated with lactulose and, in one infant, with intravenous ammonia scavengers [18]. In paediatric ALF, NASPGHAN considers ammonia >100 µmol/L on admission an independent risk factor for high-grade encephalopathy and >200 µmol/L strongly associated with cerebral herniation, allows protein restriction to 1 g/kg/day in parenteral nutrition if there is hyperammonaemia, advises against lipids when mitochondrial or fatty acid oxidation disease is suspected, and recommends subcutaneous vitamin K (1 mg in infants) without prophylactic correction of coagulation with plasma [43]. The recommendation on lipids diverges from that of the MMS, which allows their use in acute mitochondrial decompensation [17]. GeneReviews recommends a multidisciplinary team with hepatology, neurology and medical genetics, and respiratory support as needed, with tracheostomy if there is central apnoea; after diagnosis, it proposes assessing liver function and coagulation, nutritional status, swallowing and the need for gastrostomy, motor, adaptive, cognitive and language development (with early intervention), neurology if there is persistent delay or seizures, physical medicine and rehabilitation, cardiology with electrocardiogram and echocardiogram, genetic counselling and social support for the family [6].

The 2026 systematic review of recurrent paediatric ALF recommends measures common to all genetic causes: immediate treatment of hypoglycaemia, avoidance of fasting and catabolism, early treatment of infection and timely involvement of the metabolic, hepatology, intensive care and transplant teams [25]. The same review considers that suspected TRMU deficiency justifies early supplementation with a source of cysteine, and that routine acetylcysteine in all paediatric ALF not caused by paracetamol is not supported by randomised evidence and should not replace aetiological treatment or transplant assessment [25]. NASPGHAN reserves acetylcysteine for confirmed or highly probable paracetamol poisoning, because its broad administration in paediatric ALF not caused by paracetamol showed no benefit [43]. The authors of the international TRMU deficiency cohort propose, on the contrary, considering acetylcysteine in all cases of suspected mitochondrial ALF until TRMU deficiency has been excluded [11]. The two positions are not mutually exclusive: that of NASPGHAN addresses paediatric ALF in general, and that of the cohort authors the infant with suspected mitochondrial disease, in whom TRMU deficiency is in the differential diagnosis.

7.4. TRMU deficiency: L-cysteine and acetylcysteine supplementation

Supplementation with L-cysteine, with or without acetylcysteine, should begin as soon as TRMU deficiency is suspected, before molecular confirmation [6, 18]. The rationale is that cysteine is the sulphur donor of the TRMU reaction and its endogenous synthesis is low in the first months; acetylcysteine is also a precursor of reduced glutathione and may improve the redox potential in mitochondrial diseases [6, 18]. There is no consensus on the best way to provide cysteine; limited evidence suggests that acetylcysteine should be combined with L-cysteine, especially in the first year, and Murali and colleagues consider acetylcysteine alone insufficient, after one of their six patients died and another needed transplantation [6, 18]. Infant formulas enriched in L-cysteine may be used to reach the target; in one infant a methionine-free formula intended for homocystinuria was used, later replaced by L-cysteine powder when plasma methionine fell [6, 18, 52]. Supplementation should be maintained at least throughout the first year [6].

The efficacy data are observational. In the international cohort of 62 patients, 25 (40%) received an oral source of cysteine, mainly acetylcysteine (19 of 25), at a median dose of 150 mg/kg/day (interquartile range 62.5); overall survival was longer in those supplemented (P=0.0052), especially in the subgroup of 22 patients with loss-of-function variants (P=0.0033), and the probability of survival in the first year was 90% with supplementation and 50% without it [11]. GeneReviews summarises the same cohort as survival beyond the acute decompensation phase of 84% in supplemented children and 61% in non-supplemented children [6]. The cohort authors grade the recommendation to supplement at least throughout the first year as level 1c of the Centre for Evidence-Based Medicine and propose acetylcysteine as the main source, because of its antioxidant effect in the liver, but acknowledge that the data do not allow the best source, dose or duration to be defined [11]. This preference diverges from that of Murali and colleagues, for whom acetylcysteine alone is insufficient, and from that of GeneReviews, which advises combining it with L-cysteine [6, 18]. Supplementation did not alter native liver survival, because hepatic necrosis already established does not improve once it is started [6]. Two siblings treated before symptoms had a milder course than their affected siblings, but the evidence does not allow the conclusion that supplementation prevents liver dysfunction [6]. The 2026 systematic review does not propose doses, because of heterogeneity of formulations, routes, monitoring and doses in the patients treated, and recommends individualisation by a metabolic disease specialist, with monitoring for the adverse effects of each formulation [25]. Taurine supplementation has no published data and should not be offered outside research [6].

In the absence of an approved dose for the condition, the reference dose is that of GeneReviews, based on the experience of two institutions, and the labels serve only for comparison [6, 18]. The adverse effects described in the oral acetylcysteine labels are nausea, vomiting and other gastrointestinal symptoms, especially with the high doses of the antidote regimen, and rare rash; with the intravenous formulation, flushing and erythema in the first 30 to 60 minutes and hypersensitivity reactions, with monitoring of asthmatic patients [57, 58]. The cysteine hydrochloride injection label warns of acid–base imbalance, including metabolic acidosis in preterm infants, hyperammonaemia in infants (with frequent ammonia measurement), increased urea and pulmonary vascular precipitates in parenteral nutrition, and contraindicates it in inborn errors of amino acid metabolism [54]. In an infant on a cysteine-rich, methionine-poor formula, plasma methionine fell, which required a change of formulation; the plasma amino acid profile is therefore useful in monitoring [18, 52]. The authors of the 2021 series propose GDF15, FGF21, blood cysteine and the resolution of hyperlactataemia and ALF as possible markers of response, without having evaluated them systematically [18].

In the myopathic form there are no clinical data on cysteine supplementation. The in vitro correction of complex I and IV deficiency by L-cysteine in myoblasts from patients with m.14674T>C, and partial correction by L-cysteine (but not by acetylcysteine) in fibroblasts with NC_012920.1:m.3243A>G (MT-TL1) and NC_012920.1:m.8344A>G (MT-TK), are preclinical data that justify studies, not routine treatment [26, 60].

7.5. TRMU deficiency: liver transplantation

Orthotopic liver transplantation was performed in 11 children with TRMU deficiency when the liver disease did not respond to medical treatment, at a median age of 4 months: 4 during the first episode of ALF, 6 after recurrent episodes and 1 at 11 years for hepatoblastoma, the only one described in this disease [6]. Transplantation did not improve overall survival, and there were two post-transplant deaths, one from variceal haemorrhage and the other from multiorgan failure [6]. The decision is therefore individual, and the 2026 review recommends reserving transplantation for irreversible deterioration despite support and supplementation, taking into account the genotype and extrahepatic disease [6, 25]. GeneReviews allows transplantation to be considered before a therapeutic trial in patients with the p.(Met1?) variant, who appear to respond less to cysteine [6]. The TRMU variant does not affect the graft [6]. The first transplanted patient described had a course complicated by acute cellular rejection, Epstein–Barr virus-associated post-transplant lymphoproliferative disorder treated with rituximab and hypogammaglobulinaemia, in addition to chronic respiratory failure and white matter changes characteristic of the mitochondrial disease [18]. In mitochondrial liver disease in general, the MMS considers transplantation an option in ALF, to be decided according to comorbidities and the natural history of the specific disease, with additional caution in POLG-related disease [51]. NASPGHAN adds that patients with mitochondrial disease, excluding POLG-related disease, tolerate solid organ transplantation with survival similar to that of other patients, but that extrahepatic disease may not be apparent at the time of transplantation, and that valproate-associated ALF in unsuspected mitochondrial disease should contraindicate transplantation [43]. In TRMU deficiency, extrahepatic involvement is uncommon and the neurological prognosis is as a rule favourable, which distinguishes this disease from the multisystem mitochondrial diseases [11, 45]. In the international cohort, transplantation did not alter overall survival (P=0.079), and the authors point out that no ALF occurred after the first year, a fact to be weighed in the decision, although progression of established ALF and worsening hepatic encephalopathy eventually make transplantation unavoidable [11].

7.6. Vitamins and cofactors

The MMS recommends offering coenzyme Q10 to most patients with mitochondrial disease, and not only to those with primary deficiency, considers ubiquinol the most bioavailable form, recommends offering alpha-lipoic acid and riboflavin, folinic acid when there is central nervous system involvement and levocarnitine when there is documented deficiency, and advises introducing supplements one at a time [17]. The same statement acknowledges that few trials have evaluated these treatments and that a Cochrane review found little evidence in favour of any vitamin or cofactor [17, 61]. Saudubray and colleagues, from a European perspective, consider that there is no evidence base to support or refute so-called vitamin and cofactor cocktails and do not detail them [16]. This divergence between the North American statement and the European textbook is one of emphasis and not of data. None of these sources proposes specific doses for RIRCD; when the decision is made to use them, the reference doses for primary mitochondrial disease in general are those of the Philadelphia group's mitochondrial medicine guide, as daily doses divided into 2 or 3 doses: ubiquinol 2–8 mg/kg/day in children and 50–600 mg/day in adults, with a maximum of 1200 mg/day (ubidecarenone up to 2400 mg/day), with insomnia and nausea as adverse effects; riboflavin 50–400 mg/day, maximum 1200 mg/day; alpha-lipoic acid 50–600 mg/day, maximum 1800 mg/day; vitamin E 1–2 IU/kg/day in children, maximum 5500 IU/day; thiamine 150 mg/day under 3 years and 300 mg/day above, maximum 900 mg/day [53]. The same guide no longer recommends routine levocarnitine, because of the association of chronic use with atherosclerosis in the general population, and found no preclinical efficacy of vitamin C as an antioxidant [53]. Saudubray's textbook gives coenzyme Q10 at 30 mg/kg/day (up to 3 g/day in adults) for primary biosynthesis deficiencies, with benefit not demonstrated in other mitochondrial diseases, and levocarnitine at 100–200 mg/kg/day only in documented carnitine deficiency; in acute congenital lactic acidaemia it recommends a trial of thiamine, riboflavin and biotin, and describes dichloroacetate (50 mg/kg/day in 1 or 2 doses in the emergency chapter, 25 mg/kg/day orally in 2 doses in the drug table, with no maximum dose defined in the source), which lowers lactate with little clinical effect beyond reduction of tachypnoea and causes reversible peripheral neuropathy with chronic use [49, 62]. The review of 55 patients with the myopathic form and the GeneReviews chapter on TRMU deficiency do not describe the use of dichloroacetate [6, 15]. In the myopathic form, 7 of the 55 pooled patients received coenzyme Q10, carnitine or vitamins, and the rest support only, with no documented difference in course [15]. In a girl from Taiwan, CK rose again at 4 years, 17 months after ubidecarenone (5 mg twice daily) and pyridoxine (25 mg daily) had been stopped, and fell after their reintroduction; this is an isolated observation, in a setting in which CK normalises spontaneously with recovery [40]. In TRMU deficiency, some patients also received ubiquinol, citrulline, levocarnitine, thiamine, riboflavin, biotin, selenium (15 µg/day) and vitamins C (25 mg/day) and E (200 IU/day), without evaluation of their contribution [18].

7.7. Agents and circumstances to avoid

In TRMU deficiency, GeneReviews recommends avoiding drugs that increase metabolic demand, such as corticosteroids, or that inhibit mitochondrial function, such as valproic acid and prolonged propofol infusion, and avoiding fasting, which increases metabolic demand and may worsen hypoglycaemia [6]. Corticosteroids increase lactate by stimulating glycogenolysis and gluconeogenesis and, if indicated, should be given under the guidance of a metabolic disease specialist; paracetamol may be avoided during liver dysfunction because of a theoretical risk of oxidative stress [6]. In mitochondrial disease in general, the MMS advises avoiding whenever possible, or using with caution, valproic acid, statins, metformin, high-dose paracetamol and some antibiotics (aminoglycosides, linezolid, tetracycline, azithromycin and erythromycin) [17]. The 2017 MMS statement stresses that hepatocerebral involvement is frequent in infantile mitochondrial disease and that valproate should be avoided in seizure control, because of the risk of fulminant ALF [51]. Saudubray and colleagues indicate levetiracetam and clobazam as the antiepileptic drugs that appear most effective in mitochondrial epilepsy and acknowledge that, apart from valproate, there is no evidence to exclude other drugs in most patients [16]. Corticosteroids, metformin, statins and antiretrovirals may worsen a mitochondrial myopathy [51]. The Oxford Desk Reference also lists barbiturates, gentamicin (deafness), ciprofloxacin, chloramphenicol and tetracycline (inhibitors of mitochondrial replication or translation), metformin and zidovudine [63].

These lists were reviewed in an international Delphi consensus of 16 experts from six countries (2020), which considered the 46 drugs or groups studied generally safe in primary mitochondrial disease, with restrictions linked to specific molecular defects and clinical situations: valproic acid should be avoided in POLG-related disease, in known liver disease and when POLG-related disease is clinically suspected, and may be used in refractory epilepsy in other patients without liver disease; aminoglycosides should be avoided in carriers of mtDNA variants that predispose to ototoxicity (NC_012920.1:m.1555A>G and m.1494C>T, in MT-RNR1), which should be tested for before prolonged elective treatments, but should not be withheld in an emergency; linezolid may be used with lactate monitoring, especially in children with pre-existing lactic acidaemia; paracetamol, corticosteroids in the acutely ill patient, metformin, statins (with CK monitoring), tetracyclines, quinolones, volatile and local anaesthetics, barbiturates in general anaesthesia and propofol for induction were considered safe, and propofol infusions of up to 48 hours acceptable in refractory status epilepticus; antibiotics for less than 7 days are rarely a problem, and infection is a greater risk than the antibiotic [64]. The consensus has level of evidence 4 (expert opinion) and stresses that the decision should be individual [64]. In practice, the more restrictive GeneReviews list for TRMU deficiency applies to the infant with active liver disease, in whom valproate, prolonged propofol infusion and fasting remain inadvisable, and the Delphi consensus avoids withholding necessary drugs for purely theoretical reasons [6, 64].

There is an apparent divergence on corticosteroids: the GeneReviews chapter on TRMU deficiency advises against them because they increase metabolic demand and lactate, whereas the MMS recommends considering stress-dose corticosteroids in mitochondrial patients in vasopressor-refractory shock, and the Delphi consensus considers them safe in the acutely ill patient [6, 51, 64]. The two recommendations apply to different situations; in refractory shock, the life-saving indication prevails, with lactate monitoring.

7.8. Intercurrent illness, anaesthesia and the perioperative period

The MMS recommends that patients have a written emergency plan and a medical alert bracelet, that they avoid prolonged fasting and that they receive dextrose-containing fluids before, during and after procedures, except in defects of pyruvate metabolism, on a ketogenic diet or with a documented adverse reaction to glucose [17]. In acute decompensation, dextrose-containing fluids should be given, potentially toxic drugs stopped, metabolic abnormalities corrected and usual therapies maintained; lipids may be used [17]. In TRMU deficiency, the dextrose recommendation has to be reconciled with the rise in lactate caused by high-concentration glucose in the acute phase [6].

In anaesthesia, the MMS considers that mitochondrial patients are at increased risk of complications, recommends minimising preoperative fasting and adding glucose to fluids, using volatile anaesthetics and muscle relaxants with caution in patients with myopathy or reduced respiratory drive, avoiding propofol or limiting it to short procedures because of the risk of propofol infusion syndrome, titrating anaesthetics slowly, and considers local anaesthetics well tolerated, with no established link to malignant hyperthermia [17]. In patients with neuromuscular weakness, preoperative respiratory assessment with oximetry (and blood gases if saturation is below 95%) should be performed, non-invasive ventilation before and after surgery considered, narcotics limited and atelectasis actively treated [51]. These recommendations apply to both forms, particularly during the weakness phase of the myopathic form and in the child with residual liver disease.

7.9. Pregnancy, lactation and transition

In one case of prenatal diagnosis of TRMU deficiency, the mother received 500 mg of L-cysteine twice daily in the third trimester, with the aim of ensuring cysteine for the fetus for the postnatal period; the son had a milder course than his affected sister [6, 18]. This is a single pregnancy, without systematic safety data. The cysteine hydrochloride injection label does not anticipate malformations or risks to the pregnancy or to the breastfed infant with appropriate administration, with no animal reproduction studies [54]. The people with TRMU deficiency described are still young and there are no reports of reproduction [6]. In the myopathic form, adult homoplasmic female carriers may have mild myopathy, which should be taken into account in the monitoring of pregnancy and delivery; the sources consulted do not describe specific obstetric complications [3, 13]. For women with mitochondrial disease, the MMS recommends closer monitoring by specialists, follow-up by high-risk obstetrics (risk of preterm delivery and pre-eclampsia described mainly in carriers of m.3243A>G), a glucose tolerance test early and later in pregnancy, review of medication and preconception genetic counselling [51].

Transition to adult care is relevant mainly in the myopathic form, because fatigability, myalgia, facial weakness, ptosis, contractures and hypothyroidism persist or appear in adolescence and adulthood [3]. In TRMU deficiency, transition should include liver surveillance (fibrosis, cirrhosis, nodules and the theoretical risk of liver tumours) and follow-up of neurodevelopment [6].

7.10. Regulatory status

There is no authorised medicine for either form of RIRCD in the USA, the EU or Brazil, according to the databases consulted (Drugs@FDA/openFDA, the EMA medicines list, Infomed and ANVISA open data) [54–56, 58].

7.11. Available evidence and trials

There are no randomised or controlled trials in either form. Searches of ClinicalTrials.gov for TRMU, reversible infantile respiratory chain deficiency, MT-TE, transient infantile liver failure and cysteine in mitochondrial disease found no studies directed at this class; the closest study evaluates acetylcysteine in carriers of m.3243A>G with low brain glutathione (NCT05241262, phase 1) [65]. A negative search of a registry does not prove that no studies exist. The comparison between supplemented and non-supplemented patients in the 2023 cohort, which the authors acknowledge is limited by heterogeneity, sample size and design, is retrospective, with non-randomised treatment, different eras and possible survival bias (patients who live longer have more opportunity to be diagnosed and treated), and the frequent spontaneous recovery makes it difficult to attribute effects to treatment [11, 25]. The survival difference should be read in absolute terms, in a disease in which mortality without treatment is around one third of symptomatic patients [6].

7.12. Developments in the last 12 months

Between November 2025 and October 2026, the literature brought data of four types. At the level of clinical series and case review, Li and colleagues published in July 2026 three Chinese cases and a review of 55 patients with genetically confirmed RIRCD, with the first familial demonstration of a paternally inherited EARS2 frameshift variant as a modifier of the penetrance of m.14674T>C and a case of a second diagnosis (CLCN4) [15]. At the level of systematic review, Lipiński and colleagues published in 2026 a review of the genetic causes of recurrent paediatric ALF, with recommendations on TRMU deficiency, acetylcysteine and transplantation [25]. At the preclinical level, He and colleagues showed in trmu-null zebrafish a specific hepatic vulnerability to loss of τm5s2U, linked to the predominance of electron flow through complex I [31]. At the level of case reports, a fatal Lebanese case of TRMU deficiency aggravated by cytomegalovirus and an Indian case diagnosed by rapid exome sequencing were published [37, 46]. There were no marketing authorisation applications, regulatory opinions or authorisations for this class in the sources consulted [54, 65].

8. Reproductive Options and Family Counselling

8.1. Myopathic form: maternal inheritance of a homoplasmic variant

mtDNA point variants are transmitted only through the maternal line; the father of a patient is not at risk, and the children of a male carrier do not inherit the variant [14]. As m.14674T>C and m.14674T>G are homoplasmic, all children of a carrier mother inherit the variant, and the counselling question is no longer the proportion transmitted, as in heteroplasmic variants, but penetrance [9, 44]. In the family of patient 14 in the 2009 series, the variant was homoplasmic in all maternal relatives and absent in the parents [9]. In the 2026 review, homoplasmic maternal transmission was documented in 45 of 46 cases studied, and only 6 of 39 mothers had a history of recurrent respiratory infections or malnutrition in childhood and mild exercise intolerance in adulthood [15].

The estimate of disease risk in a child of a female carrier is uncertain. In families with patients, about 30% of homoplasmic carriers manifested disease in the first year, but in the families of the 2009 cohort it was 7 of 22 maternal relatives, and in the general population penetrance is much lower, of the order of 1 in 100 or less [9, 13, 26]. The digenic contribution changes the reasoning: in the 2020 cohort, 24 of 27 patients had additional heterozygous nuclear variants, absent in healthy carriers, and in the 2026 Chinese case the EARS2 variant came from the father, while the brother, carrying only the mitochondrial variant, was healthy [13, 15]. Thus, the recurrence risk also depends on the nuclear variants inherited from both parents, and identification of the modifier in the family may refine counselling, although there are no validated risk models [13, 15]. One family without m.14674T>C or TRMU variants, with a mother with subtle myopathy, suggested dominant transmission of an unknown cause [3].

8.2. Myopathic form: reproductive options

The 2023 UK guideline considers that prenatal diagnosis is generally not appropriate for homoplasmic variants, and that mitochondrial donation (maternal spindle transfer or pronuclear transfer) may be offered to women with pathogenic mtDNA variants when other options are not viable, for example for homoplasmic variants, in countries where it is legal, such as the United Kingdom [44]. In the United Kingdom, 2015 legislation authorised both techniques and the regulatory authority licensed the first clinic in March 2017; each case has to be approved [16]. Oocyte donation also avoids transmission [16]. The severity of the disease, the low penetrance and the favourable prognosis with intensive care make these options disproportionate in most families with RIRCD; the practical aim of counselling is above all to prepare for early recognition and support in a future affected child [9, 15]. Testing of maternal relatives (mother, siblings and maternal aunts and uncles) is done on blood or urine [9, 15]. The Oxford Desk Reference points out that predictive testing may be offered to maternal relatives, but that the main difficulty in mtDNA diseases is predicting phenotype from genotype, with high uncertainty even with specialist counselling, and that prenatal diagnosis should only be undertaken with a centre experienced in mitochondrial genetics [63]. For a homoplasmic variant with low penetrance, this uncertainty is maximal, because the result is known in advance and does not inform on expression [13, 44].

8.3. TRMU deficiency: autosomal recessive inheritance

The parents of a patient are presumed heterozygous and should be tested to confirm carrier status and allow a reliable calculation of risk [6]. When both are carriers, each sibling has, at conception, a 25% risk of being affected, 50% of being an asymptomatic carrier and 25% of inheriting neither variant; carriers are not at risk of disease [6]. The children of a patient are obligate carriers, unless the other parent is a carrier or affected, and each sibling of the patient's parents has a 50% risk of being a carrier [6]. Apparent homozygosity requires consideration of an undetected deletion or uniparental isodisomy, and a variant absent in both parents requires consideration of a de novo mutation or parental mosaicism [6]. Carrier testing of the partners of known carriers should be considered, especially in Yemenite Jewish ancestry, where the p.(Tyr77His) variant is a founder variant [6].

8.4. TRMU deficiency: prenatal and preimplantation diagnosis and the at-risk newborn

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss them is before pregnancy [6]. Prenatal diagnosis here also has a therapeutic function: it allowed maternal L-cysteine to be started in the third trimester in one pregnancy and supplementation from birth in two siblings [6, 18]. If there is no prenatal testing, a newborn sibling of a patient should receive L-cysteine, with or without acetylcysteine, until targeted molecular testing has been completed [6]. The approach to prenatal diagnosis is a personal decision for the family [6].

8.5. Testing of minors and content of counselling

In the MT-TE form, testing of asymptomatic minor siblings of a patient has no therapeutic consequence, because all children of the carrier mother have the variant and expression depends on modifiers; it is of value only to prepare surveillance for a possible neonatal presentation in a future child of these individuals and should be discussed with the family [9, 44]. In TRMU deficiency, testing of a newborn sibling is urgent and therapeutic, and genetic counselling, including the risks for offspring and reproductive options, should be offered to young adults who are affected, carriers or at risk of being carriers [6]. Counselling should include the nature of the disease, the recurrence risk, the favourable prognosis of those who survive the acute phase, the importance of not limiting care early in a future affected child, and referral to clinical genetics or a service specialising in mitochondrial diseases [6, 9, 44].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: what each figure measures

There are no population estimates of prevalence or incidence for either form; the available figures count published patients or variant carriers, and measure different things [6, 13]. For the myopathic form, fewer than 100 patients had been described worldwide in 2020, and the 2026 review pooled 55 genetically confirmed cases from 43 families [13, 15]. The carrier frequency of m.14674T>C is 0.01% in the healthy population according to HmtDB and 3 × 10⁻⁵ in the UK Biobank (11 of 358,916 unrelated Europeans), and reaches 0.2% in Oceania, associated with haplogroup M27b1, with no data on disease prevalence in that region [13]. In 2011, a frequency of about 0.1% and 60,000 potential carriers in the United Kingdom were estimated from mtDB and MITOMAP, a figure that later population databases revised downwards [3, 13]. The discrepancy between the expected number of patients, calculated from carrier frequency and penetrance in families, and the observed number is the main argument in favour of digenic inheritance [13]. Orphanet has no prevalence figure for ORPHA:254864 [2].

For TRMU deficiency, GeneReviews pools 62 individuals from 56 families, living in 18 countries according to the original article, and Orphanet records 32 cases or families, with a prevalence class below 1/1,000,000 [5, 6, 11]. The European series of infantile ALF give an order of magnitude for the contribution of mitochondrial diseases, not of TRMU deficiency: among 39 consecutive infants with ALF at a Birmingham centre (2009–2011), 5 had genetically confirmed mitochondrial disease, all due to mtDNA depletion, and no TRMU deficiency was identified, in a series in which systematic sequencing focused on the mtDNA depletion genes and 12 cases remained undiagnosed [50]; in the multicentre study of 260 children with ALF of indeterminate cause, mitochondrial diseases accounted for 45% of the 97 diagnoses, and NBAS (20), MPV17 (8) and DGUOK (7) were the most frequent genes [45]. Brazil has no estimates of its own in the sources consulted. In Portugal, the national cohort of 450 patients with suspected mitochondrial disease studied at the Instituto Nacional de Saúde Doutor Ricardo Jorge with a 213-gene nuclear panel and mtDNA sequencing does not report m.14674T>C among the homoplasmic variants identified, and EARS2 was the nuclear gene with the most pathogenic or likely pathogenic variants (9%); the absence of cases in a cohort does not demonstrate absence of the disease in the country [66].

9.2. Geography, ancestry and founder effect

The myopathic form has been described on several continents and in different mitochondrial haplogroups, which shows that m.14674T>C arose independently several times [9, 13]. In the 2009 series, the patients were Caucasians of American, Swedish, German, Brazilian and Italian origin; in the 2020 cohort, the families came from the United Kingdom, Germany, Sweden, Estonia, Italy, the USA, Canada and Brazil [9, 13]. In the 2026 review, 38.98% of cases were European, 25.42% Asian, 8.47% from the USA, 6.78% Brazilian (4 cases) and 16.95% Caucasian of unspecified origin [15]. Japanese, Chinese and Taiwanese patients, a Turkish Cypriot girl and Danish families with the m.14701C>T variant have been described [3, 10, 15, 22, 40]. From Brazil, in addition to the cases included in the cohorts, there is a description of two patients with muscle fatty replacement and modifiers in QRSL1 and EARS2 [36].

TRMU deficiency has a founder effect in Yemenite Jews, through the variant c.229T>C p.(Tyr77His): the 2009 series included 7 unrelated Yemenite families [4, 6]. The c.2T>A variant has been observed in several ethnic groups [6]. Among the sources read, there are patients described in France, Spain, Ireland, the USA, Lebanon and India, and the 2023 international cohort pooled patients from 56 families living in 18 countries, with MetabERN support [3, 11, 18, 37, 41, 46, 67]. The variant c.835G>A p.(Val279Met), the most frequent in that cohort, has been described in patients of various origins, including the Irish girl and French patients [3, 11, 67]. Taken together, these reports do not allow frequencies to be estimated by country.

9.3. Special populations

Preterm infants may be more vulnerable to cysteine deficiency, because hepatic cystathionase increases with postnatal age and cysteine is conditionally essential in the neonatal period, especially in premature infants [18]. In infants on parenteral nutrition with severe liver disease, the cysteine hydrochloride injection label provides for its addition to amino acid solutions, with monitoring of acid–base balance and ammonia [54]. Female homoplasmic carriers of m.14674T>C may have mild late-onset myopathy without a neonatal phase [3, 13].

9.4. Reference networks and patient organisations

In Europe, the myopathic form falls within EURO-NMD (rare neuromuscular diseases) and MetabERN (hereditary metabolic disorders, which includes mitochondrial diseases), and TRMU deficiency within MetabERN and ERN RARE-LIVER (rare liver diseases) [19–21]. Patient organisations with information on mitochondrial diseases include the United Mitochondrial Disease Foundation (USA), The Lily Foundation (United Kingdom) and the Mito Foundation (Australia); the GeneReviews chapter on TRMU deficiency also lists the American Liver Foundation, the Childhood Liver Disease Research Network, Liver Canada, Liver UK and the contact registry of the North American Mitochondrial Disease Consortium [6, 68–70].

10. Illustrative Clinical Case

Li and colleagues described in 2026 a Chinese girl, the second child of healthy non-consanguineous parents, born at term weighing 3.0 kg [15]. At 10 days she had feeding difficulties and dyspnoea, treated as pneumonia; at 1.5 months she was readmitted with bronchopneumonia and malnutrition and needed a nasogastric tube for some time. CK was 307 U/L (reference 26–192), alanine aminotransferase 190 U/L and aspartate aminotransferase 171 U/L, with normal lactate, ammonia, homocysteine and urinary metabolic screening. Motor development was delayed: she achieved head control at 5 months, rolled over at 8 and sat unsupported at 11 months. At that age she was referred to the authors' centre because she could not stand and was dependent on the tube; she weighed 7.5 kg and measured 68 cm (both below the 3rd centile) and had generalised hypotonia, reduced strength and hyporeflexia, with age-appropriate cognition and language. Biochemistry had already normalised, and electromyography, cardiac assessment and cranial imaging were normal. A maternal aunt had died at 7 days of life with feeding difficulties [15].

Whole mtDNA sequencing at 11 months identified homoplasmic m.14674T>C in blood, and homoplasmy was confirmed in the blood and urine of asymptomatic maternal relatives; the initial trio exome found no pathogenic variants [15]. Biopsy of the right biceps, performed at 1 year and 3 months, showed variation in fibre size with increased endomysial connective tissue, diffuse RRF without rimmed vacuoles, SDH-positive "ragged-blue" fibres, focal hyperactivity on the NADH reaction, increased lipid and glycogen and, on electron microscopy, myofibrillar degeneration with sarcomeric disorganisation, lipid and collagen (figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13559098/figure/f2/); the biopsy of her 11-year-old brother, an asymptomatic carrier, was normal, and respiratory chain enzymology was postponed until clinical stabilisation [15]. At 7 years, targeted reanalysis of the exome identified in EARS2 a frameshift variant, classified as likely pathogenic, inherited from the father and absent in the mother and brother [15]. The article describes it as an insertion c.427_428ins of 15 nucleotides in the text and of 16 nucleotides (insTACCCCTGTTTCTGCT) in the legend of figure 3; only the 16-nucleotide version produces the reported frameshift, and it is normalised on the MANE transcript as NM_001083614.2:c.412_427dup p.(Ser143LeufsTer27), a 16-nucleotide duplication [12, 15].

The child received vitamins and coenzyme Q10 for a prolonged period, without evidence that they altered the course [15, 17]. She stood and came off the tube at 1.2 years, walked at 1.5 years and began running and jumping at 2 years, with mild weakness. At the last assessment, at 7 years and 9 months, she measured 125 cm (25th centile), weighed 22 kg (10th–25th centile), was attending the first year of school with good performance and took part in physical education, but tired easily [15].

The case brings together the characteristic features of the class: onset in the first weeks with feeding and respiratory difficulties, extensive mitochondrial abnormalities on biopsy, spontaneous recovery after the first year, residual fatigue and a digenic combination that explains why the same mitochondrial variant did not cause disease in the brother [13, 15]. The vitamin supplementation used does not correspond to a specific recommendation for this disease; what the sources recommend is nutritional and respiratory support until recovery [3, 9]. The acute-phase and recovery-phase histochemistry of another patient, with abundant COX-negative fibres at 3 months, partial improvement at 9 years and few COX-negative fibres in the muscle of the asymptomatic mother, is illustrated in figure 2 of Horvath and colleagues (https://pmc.ncbi.nlm.nih.gov/articles/PMC2768660/figure/F2/) [9].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis of the myopathic form

The prognosis of those who survive the acute phase is favourable, but it does not always equate to normality. In the 2026 review, 32.00% of patients recovered completely and 58.00% were left with mild residual myopathy (exercise intolerance, subtle weakness, ptosis); there were 2 deaths from respiratory failure (at 39 days and 3 months after onset) and 3 patients with a poor prognosis [15]. In the 2009 series, 1 of 17 patients died, and many of the rest retained mild residual myopathy; one later developed epilepsy [9]. In patients followed up to 35 years of age, fatigability and myalgia were the most disabling long-term complaints, and facial weakness, ptosis, contractures and hypothyroidism appeared or became more marked with age [3]. The course also depends on modifiers or second diagnoses, as in the patient with a CLCN4 variant and language disorder [15].

11.2. Prognosis of TRMU deficiency

Mortality among symptomatic infants was 20 of 60, with a median age at death of 3 months, and loss-of-function variants are associated with poorer survival [6]. Of the 62 patients in the international cohort, 42 were alive at a median age of 6.8 years; the authors conclude that ALF was transient and reversible in 40 of the 62 (65%) and fatal in more than one third [11]. Survivors in the original series had no recurrence of ALF over up to 14 years of follow-up, but 23% of children in later series had recurrent episodes in the first year, and some survivors were left with cirrhosis, liver nodules or persistent hepatomegaly [6, 18, 23]. The risk of liver cancer in childhood is theoretically increased, as in other mitochondrial hepatopathies, and there is one case of hepatoblastoma at 11 years [6]. Neurodevelopment is normal or near-normal in most survivors, with persistent delay in a minority [11, 18]. Lactate may remain raised for years in asymptomatic children [6, 18].

11.3. Surveillance

The MMS recommendations for cardiac, endocrine, auditory and respiratory surveillance were written for primary mitochondrial disease in general and not for this class, which has a favourable course; they should be adapted to the severity of each patient [51]. In TRMU deficiency, follow-up also serves to monitor the response to L-cysteine and acetylcysteine and to detect new developmental problems or seizures, and the authors of the international cohort advise that the first year be spent under a specialist centre with paediatric hepatology and mitochondrial disease expertise [6, 11]. In the myopathic form, one case report proposes clinical examination, CK and echocardiography at least every 6 months, a frequency that reflects the authors' opinion and not a consensus recommendation [40].

12. Summary and Final Considerations

Reversible infantile respiratory chain deficiency brings together disorders of mitochondrial translation that manifest severely in the first months and regress spontaneously. The myopathic form is due to the homoplasmic variants m.14674T>C and m.14674T>G at the discriminator base of the glutamate tRNA, maternally inherited, with very low penetrance explained largely by heterozygous nuclear variants in EARS2, TRMU and other genes of glutamate and glutamine metabolism; the hepatic form is due to biallelic variants in TRMU, the enzyme that uses cysteine to thiolate the wobble position of the tRNAs for glutamate, lysine and glutamine. Both converge on the glutamate tRNA and on cysteine availability during the period when cystathionase is physiologically of low activity.

In the myopathic form, the infant has profound hypotonia, feeding and respiratory difficulties and lactic acidosis, with a muscle biopsy indistinguishable from the fatal mitochondrial myopathies, and recovers at around 6 months if given ventilatory and nutritional support; many are left with mild myopathy, fatigue and myalgia. In the hepatic form, the infant aged 2 to 4 months has ALF with lactic acidosis, hypoglycaemia and hyperammonaemia, with a mortality of about one third without targeted treatment; early supplementation with L-cysteine and acetylcysteine, started as soon as the diagnosis is suspected, is associated with longer survival in observational data, and liver transplantation is reserved for irreversible deterioration.

The diagnosis is molecular: mtDNA sequencing identifies the myopathic form, panels or the exome identify TRMU, and reanalysis and testing for deletions resolve some initially negative cases. The main clinical consequence of the diagnosis is to avoid early limitation of care in a child who has a high probability of recovering, and to guide counselling: maternal inheritance with uncertain penetrance and a digenic contribution in the myopathic form, autosomal recessive inheritance with the possibility of prenatal diagnosis and supplementation from birth in the hepatic form.

13. References

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