Single mtDNA Deletion Syndromes (Kearns–Sayre, CPEO, Pearson) and CPEO of Nuclear Origin

Single large-scale mitochondrial DNA deletion syndromes (SLSMDS), progressive external ophthalmoplegia due to multiple deletions of nuclear origin, ophthalmoplegia with neuropathy (TWNK/POLG) and NAXE deficiency

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

Table 0.1 brings together the entities caused by a single mitochondrial DNA (mtDNA) deletion, which form a continuous clinical spectrum, and Table 0.2 the forms of progressive external ophthalmoplegia (PEO) of nuclear origin, ophthalmoplegia with peripheral neuropathy and NAD(P)HX epimerase deficiency, grouped because they share a differential diagnosis entry. SLSMD denotes a single large-scale mtDNA deletion and SLSMDS the syndromes it causes; OMIM numbers are those of the Online Mendelian Inheritance in Man catalogue; 95% CI is the 95% confidence interval.

Table 0.1 — Single large-scale mitochondrial DNA deletion syndromes (SLSMDS)

Table 0.2 — PEO of nuclear origin (multiple mtDNA deletions) and the “ophthalmoplegia with peripheral neuropathy” entry

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; PEOA and PEOB, autosomal dominant and recessive PEO in OMIM nomenclature; adPEO and arPEO, autosomal dominant and recessive PEO; SANDO, sensory ataxic neuropathy with dysarthria and ophthalmoparesis; IOSCA, infantile-onset spinocerebellar ataxia; MTDPS, mtDNA depletion syndrome; PEBEL1, progressive early-onset encephalopathy with brain oedema and/or leukoencephalopathy type 1.

Prevalence of nuclear forms: in north-eastern England, adult mitochondrial disease due to nuclear genes has a minimum prevalence of 2.9/100,000 (95% CI 2.2–3.7), with dominant TWNK at 0.7/100,000 and dominant RRM2B at 0.2/100,000; POLG was identified in almost half of patients with autosomal dominant PEO in an Italian cohort [13, 27]. Specific treatment: none authorised for adult-onset PEO of nuclear origin; ERN: EURO-NMD [26]. Related entities: mitochondrial diseases in general, MELAS and the m.3243A>G spectrum, MERRF (myoclonic epilepsy with ragged red fibres, including the MERRF/KSS overlap), POLG-related disorders and mtDNA depletion syndromes.

1. Introduction

1.1. Foundational Clinical Descriptions

In 1958, Thomas Kearns and George Sayre, from the Mayo Clinic, described two patients with retinitis pigmentosa, external ophthalmoplegia and complete heart block, one with a histological study, and proposed that the association constituted a distinct syndrome [45, 46]. The chapter of the Atlas of Inherited Metabolic Diseases devoted to the syndrome prints the year 1995 for this description, but the reference it cites is the 1958 article in the Archives of Ophthalmology, so the correct date is 1958 [3]. In the following decades, debate centred on whether “ophthalmoplegia-plus” was an entity distinct from Kearns–Sayre syndrome (KSS) or the same process with variable expression: in 1977, Berenberg and colleagues framed the question in terms of lumping or splitting, and the age threshold of 20 years was eventually adopted as an operational criterion, although the Atlas authors consider it artificial because patients with later onset share the same deletions and may develop any multisystem manifestation of KSS [3].

In 1979, Howard Pearson and colleagues described four unrelated children with severe transfusion-dependent macrocytic anaemia from the first year of life, variable neutropenia and thrombocytopenia, normally cellular marrow with marked vacuolation of erythroid and myeloid precursors, haemosiderosis and ring sideroblasts, and exocrine pancreatic dysfunction; two autopsies showed extensive pancreatic fibrosis and two showed splenic atrophy, and the authors distinguished the new syndrome from Shwachman syndrome [4]. One of these patients spontaneously recovered from anaemia and later developed typical KSS, an observation that anticipated the concept of a continuous spectrum between the two syndromes [47, 48].

1.2. Milestones in Molecular Discovery

In 1988, Holt, Harding and Morgan-Hughes, in London, found two mtDNA populations in muscle from 9 of 25 patients with mitochondrial myopathy, one with deletions of up to 7 kb, without abnormalities in leucocyte DNA; this was the first demonstration of mtDNA heteroplasmy in humans and of disease associated with a mitochondrial genome defect [49]. In the same year, Zeviani and colleagues, at Columbia University, identified large-scale muscle mtDNA deletions in 7 of 7 patients with KSS, measuring 2.0 to 7.0 kb and with proportions of deleted genomes between 45 and 75%, absent in 10 patients with other mitochondrial myopathies [50]. Moraes and colleagues used Southern blotting to study muscle mtDNA from 123 patients with mitochondrial myopathies or encephalomyopathies and found deletions in 32, all with pure ocular PEO or KSS, measuring 1.3 to 7.6 kb, with an identical 4.9-kb deletion in 11 of them [51]. In 1989, Schon and colleagues showed that this approximately 5-kb deletion, present in more than one-third of patients, is flanked by a perfect 13-base-pair (bp) direct repeat that acts as a recombination hotspot [52].

The link between Pearson syndrome (PS) and mtDNA followed a parallel course: in 1988, Rötig and colleagues described a blood mtDNA deletion in an infant with pancytopenia and, in 1989, formally associated the deletion with the marrow-pancreas syndrome [53, 54]. In 1990, the same group characterised PS as a multisystem mitochondrial disease of childhood [55], and in 1992, the development of KSS in a boy who had survived PS caused by an mtDNA deletion was published [48].

Identification of the nuclear causes of PEO with multiple mtDNA deletions began in 2000, when Kaukonen and colleagues described heterozygous variants in adenine nucleotide translocator 1 (ANT1, now SLC25A4) in five families and one sporadic patient with autosomal dominant PEO (adPEO), the first dominant mechanism of mtDNA maintenance disease [32]. In 2001, variants were described in POLG, the catalytic subunit of polymerase gamma, in a Belgian family with adPEO [56], and in TWNK (formerly C10orf2 or PEO1), encoding the Twinkle helicase, in 12 families of various origins [30]. These were followed by POLG2 in 2006 [34], RRM2B in 2009 [57], DNA2 in 2013 [37] and RNASEH1 in 2017 [38].

1.3. Nomenclature, Reclassifications and Definitions

GeneReviews groups the overlapping phenotypes of KSS, KSS spectrum, PS, CPEO and CPEO-plus and, rarely, Leigh syndrome (subacute necrotising encephalomyelopathy) under the designation single large-scale mtDNA deletion syndromes (SLSMDS) [1]. The designations “KSS spectrum” and “CPEO-plus” were introduced in 2015 by Mancuso and colleagues, based on an Italian cohort of 228 patients, to classify patients who do not meet the classical criteria for KSS or pure CPEO [1, 2]. Current operational definitions are as follows [1, 17]: KSS is a progressive multisystem disease with onset before 20 years, characterised by the triad of pigmentary retinopathy, CPEO (including ptosis) and cardiac conduction disturbance, or, under the classical criteria, by PEO and pigmentary retinopathy with onset before 20 years and at least one of heart block, cerebellar ataxia or CSF protein above 1 g/L (100 mg/dL); KSS spectrum corresponds to ptosis and/or ophthalmoparesis with at least one of retinopathy, ataxia, conduction defect, hearing loss, growth deficiency, cognitive impairment, tremor or cardiomyopathy, with greater muscle involvement and a worse prognosis than CPEO-plus; CPEO consists of ptosis, ophthalmoplegia, oropharyngeal weakness and variable proximal weakness and/or exercise intolerance; CPEO-plus adds neuropathy, diabetes, migraine, hypothyroidism, neuropsychiatric manifestations or optic neuropathy without meeting KSS spectrum criteria; PS is marrow failure with refractory sideroblastic anaemia and variable exocrine pancreatic insufficiency, usually beginning in the first year. Pigmentary retinopathy is the feature distinguishing KSS from CPEO, and CPEO-plus with pigmentary retinopathy is reclassified as KSS spectrum [1].

Nuclear gene nomenclature has changed over time, and older clinical sources use symbols no longer approved by the HUGO Gene Nomenclature Committee: PEO1 and C10orf2 correspond to TWNK, ANT1 to SLC25A4, POLG1 to POLG, TP to TYMP and PABP2 to PABPN1; the Atlas also prints “RRM1B” instead of RRM2B [58, 59]. The term “progressive external ophthalmoplegia” denotes the clinical sign, shared by single deletions, multiple deletions of nuclear origin, some mtDNA point variants and non-mitochondrial causes [60]. The group of mtDNA maintenance disorders, previously divided into depletion syndromes (severe, childhood-onset) and multiple deletion syndromes (adult-onset, milder, with CPEO and myopathy), is now understood as a phenotypic continuum [28].

1.4. Scope and Grouped Entities

The single mtDNA deletion is the central entity, with four presentations (PS, KSS and KSS spectrum, CPEO and CPEO-plus, and Leigh syndrome due to a single deletion). Autosomal dominant and recessive PEO due to nuclear mtDNA maintenance genes is included as a nuclear cause of CPEO and an essential differential diagnosis, including POLG disease and the depletion syndromes. The entity “ophthalmoplegia with peripheral neuropathy” involves two genes with different mechanisms: the TWNK/POLG component corresponds to PEO with neuropathy and the ataxia–neuropathy spectrum, including SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoparesis), and is covered in the subsections on nuclear causes; the NAXE component corresponds to a fever-triggered metabolite repair encephalopathy, treatable with vitamin B3, which may include ophthalmoplegia but is neither an mtDNA deletion syndrome nor PEO, and is described in short subsections and in the differential diagnosis [41, 42, 61]. The general approach to mitochondrial diseases and the MERRF/KSS overlap complete the framework.

2. Molecular Genetics and Pathophysiology

2.1. The Mitochondrial Genome, Heteroplasmy and the Threshold Effect

Human mtDNA is a circular molecule of 16,569 bp encoding 2 ribosomal RNAs, 22 transfer RNAs (tRNAs) and 13 polypeptides of the oxidative phosphorylation (OXPHOS) system; the remaining 70 of the 83 OXPHOS polypeptides are encoded in the nucleus [62]. Each cell contains hundreds to thousands of copies, the mutation rate is 10 to 20 times higher than that of nuclear DNA, and variants may coexist with normal molecules in variable proportions (heteroplasmy), which differ between tissues and change over time [62]. Biochemical expression requires the proportion of mutated genomes to exceed a threshold specific to the tissue and variant: for common point variants, the threshold typically lies between 80 and 95%, whereas for large deletions it is often 50 to 70% deleted mtDNA [17]. The GeneReviews on POLG disease prints 15,569 bp for genome size and calls the proofreading function of polymerase gamma an endonuclease, although it is an exonuclease; both formulations are incorrect [27].

2.2. Origin, Structure and Classes of Single Deletions

Single deletions measure between 1.1 and 10 kb, the range used in the current diagnostic criterion; earlier sources gave ranges of 1.3 to 7.6 kb or 1.3 to 8.8 kb, reflecting only the series available at the time [1, 3, 63]. More than 150 different deletions have been associated with KSS, and the MitoBreak database, developed in Porto, catalogues the breakpoints of mtDNA rearrangements [1, 64]. Deletions are almost always located in the major arc between the heavy-strand (OH) and light-strand (OL) origins of replication, sparing both, and remove structural genes and at least one tRNA gene; transcription persists, but the transcript is not translated, and larger deletions also remove messenger RNAs of complexes I, III, IV or V, resulting in combined respiratory chain deficiency [1, 17, 47]. A patient with PS and a 7767-bp deletion had deficient oxygen consumption with NAD-linked substrates and deficiency of all complexes [47].

The common 4977-bp deletion extends from MT-ATP8 to MT-ND5 and is flanked by a 13-bp direct repeat (positions 8470–8482 and 13447–13459) [3, 52]. The historical nomenclature, used by GeneReviews and most of the literature, is NC_012920.1:m.8470_13446del4977; under the Human Genome Variation Society (HGVS) 3' alignment rule, VariantValidator normalises this description to NC_012920.1:m.8483_13459del, with the same size, and ClinVar records the variant as pathogenic (VCV000430680) [1, 6, 7]. The notation m.8483_13459del4977 in Inborn Metabolic Diseases matches the normalised form, whereas the Atlas gives coordinates 8488–13460 on one page and 8482–13460 on another; the difference results solely from the position assigned to the 13-bp repeat [17, 47]. The frequency of the common deletion varies by series: approximately half of patients with KSS according to the Atlas, more than one-third according to Schon, approximately one-third of SLSMDS according to GeneReviews and 40–50% of patients with PS [1, 3, 8, 52]. In a cohort of 30 patients from Philadelphia, the deleted region involved MT-ND5 in 96%, irrespective of phenotype [65].

Deletions are classified by the nature of their flanking sequences: class I deletions are flanked by perfect direct repeats and are attributed to homologous recombination or slipped mispairing during replication; class II deletions have no homologous sequences at their boundaries [1, 3]. In a review cited by Grigalionienė and colleagues, 60–69% of deletions are flanked by perfect repeats of 4 to 13 bp, approximately 30% by imperfect repeats, and the remainder have no repeat [66]. In some patients, duplications (molecules containing a normal genome and a deleted genome in tandem) and deletion dimers coexist; clinical features generally overlap, some children with duplications had tubulopathy or hypoparathyroidism and hearing loss, duplication size is inversely proportional to deletion size, and the presence of duplications is associated with a higher recurrence risk than an isolated deletion [3, 47, 62]. In a pair of patients studied by Jacobs in 2004, the patient with a linear 25-kb duplication had a milder course and died at 10 years, while the patient with a deletion dimer died at 39 months with lactate of 28 mmol/L; the hypothesis that more dimers signify greater severity rests on very few cases [47].

2.3. Clonal Expansion, Tissue Segregation and Phenotype

Within an individual, the deletion has a uniform size, indicating clonal expansion of a single deleted molecule arising during oogenesis or in the early embryo [1]. Depending on the timing and lineage in which it arises, the molecule may be distributed across all three embryonic germ layers (KSS, with the deletion detectable in all tissues), segregate predominantly in the haematopoietic lineage (PS), or remain confined to skeletal muscle (CPEO) [1]. Expressivity therefore depends on three factors: heteroplasmic load, tissue distribution and each tissue's vulnerability, which defines the threshold [1].

The time course differs between dividing and postmitotic tissues. In PS blood, heteroplasmy is generally above 70% at diagnosis, and autopsies show more than 70–80% deleted mtDNA in all tissues [8]. Spontaneous haematological recovery is attributed to selection of haematopoietic stem cells with a low load, and the blood and marrow load falls as anaemia improves [8, 47]. In muscle and brain, conversely, deleted molecules have a replicative advantage and accumulate: in repeated biopsies from patients with KSS, muscle load rose from 50–60% to more than 80%, explaining the transition from PS to KSS and the progression of myopathy [8, 62]. The proportion of deleted genomes in muscle ranges between 27 and 85% in older series and generally increases with age, in parallel with clinical deterioration [3]. Blood poorly reflects the load in affected tissues in mtDNA rearrangements, particularly in adults [62].

2.4. Genotype–Phenotype Correlations and Penetrance

Correlations between deletion characteristics and phenotype are statistically detectable but weak and inconsistent between cohorts. In 87 patients from Newcastle, with validation in 256 published cases, deletion size, skeletal muscle heteroplasmy and genomic location (deletions including MT-CYB and cytochrome c oxidase genes) correlated with the density of cytochrome c oxidase (COX)-deficient fibres, age at onset and progression measured by the NMDAS (Newcastle Mitochondrial Disease Adult Scale); because the predictors are interrelated, multiple regression was required [1, 67]. In the Italian cohort of 228 patients, deletions were larger in KSS spectrum than in CPEO, and heteroplasmy was inversely related to age at onset [2]. In 111 Canadian adults with CPEO, smaller deletions (r² = 0.12) and higher heteroplasmy (r² = 0.25) were associated with earlier onset, without a relationship to severity [19]. Conversely, in 47 Czech patients and 34 British children, no correlation was found between severity and heteroplasmy, deletion size or respiratory chain activity [1, 68]. In the Philadelphia cohort, higher blood heteroplasmy was associated with earlier onset [65]. These correlations have population-level value and do not allow prediction of an individual patient's course [1, 47].

Penetrance is a function of the proportion of deleted mtDNA; the GeneReviews authors are not aware of non-penetrant individuals, and patients with muscle heteroplasmy of 25–33% are symptomatic [1]. No other known phenotype is associated with large single mtDNA deletions, and there are no allelic disorders in the classical sense [1]. A child with a single deletion and an overlapping presentation of PS, KSS and Leigh syndrome was described who also had a de novo variant in SSBP1, the gene encoding mitochondrial single-stranded DNA-binding protein, raising the possibility of nuclear modifiers [69].

2.5. mtDNA Maintenance and Multiple Deletions of Nuclear Origin

mtDNA maintenance depends on nuclear proteins that ensure mtDNA synthesis (the replisome), the supply of deoxynucleotides within mitochondria and mitochondrial fusion dynamics; synthesis is continuous and is not regulated by the cell cycle [28]. Pathogenic variants in approximately 20 nuclear genes cause depletion (a quantitative reduction in copy number), multiple deletions (a qualitative alteration), or both: genes involved in mtDNA synthesis (POLG, POLG2, TWNK, TFAM, RNASEH1, MGME1, DNA2), the nucleotide salvage pathway (TK2, DGUOK, SUCLA2, SUCLG1, ABAT), cytosolic nucleotide metabolism (TYMP, RRM2B), nucleotide import (SLC25A4, AGK, MPV17) and fusion (OPA1, MFN2, FBXL4) [17, 28]. The proposed mechanism is replication fork stalling, with formation of deletions that subsequently expand clonally in muscle and cause progressive respiratory chain deficiency [57, 60]. Multiple deletions of different sizes within the same tissue point to a nuclear maintenance gene as the primary cause and warrant sequencing of these genes [1, 18].

Polymerase gamma is a heterotrimer comprising the catalytic subunit, encoded by POLG, and two accessory subunits encoded by POLG2; Twinkle (TWNK) is the hexameric 5'→3' replicative helicase that acts with polymerase gamma and single-stranded DNA-binding protein [27, 30]. adPEO variants in POLG cluster in the polymerase active-site region [27]; adPEO TWNK variants cluster in the intersubunit interaction region [30]. RRM2B encodes p53R2, the p53-inducible small subunit of ribonucleotide reductase, which ensures de novo deoxynucleotide synthesis in non-dividing cells; in RRM2B-related adPEO, truncating variants in the last exon escape nonsense-mediated decay (NMD) and produce a truncated protein with a dominant-negative effect or gain of function, whereas the same variants in the biallelic state cause more severe presentations [36, 57]. SLC25A4 encodes the muscle and heart ADP/ATP translocator; the familial adPEO variant replaces a conserved alanine with proline, and the analogous mutation in yeast causes a respiratory defect [32]. The dominant de novo variants p.(Arg80His) and p.(Arg235Gly) cause a severe neonatal form with mtDNA depletion and cardiomyopathy, and the prognosis of depletion forms is worse than that of multiple deletion forms [33, 70]. Few likely causal POLG2 variants have been described (12 variants in 19 patients in a 2024 review) [35]. RNASEH1 was the fourth cause of adult Mendelian PEO with multiple deletions, after POLG, RRM2B and TWNK, in a British referral cohort of 74 probands (variants in 3 families), which measures diagnostic yield in that cohort rather than prevalence [38].

Table 2.1 — Representative variants of PEO of nuclear origin and the common deletion, normalised in VariantValidator (GRCh38, MANE Select transcript, Matched Annotation from NCBI and EMBL-EBI) and ClinVar (accessed 10 October 2026)

The p.(Ala467Thr) variant retains approximately 4% of polymerase gamma activity, p.(Gly848Ser) less than 1%, and the variants p.(Thr251Ile) and p.(Pro587Leu), each reducing activity by approximately 30%, reduce activity to approximately 5% when in cis; determining the phase of these two variants in an individual patient requires parental testing [27]. The SLC25A4 variant c.703C>G received no response from VariantValidator and was confirmed only in ClinVar; the novel deletion in the case in section 10 (m.6069_11956del) was described by the authors from its breakpoints and has no independent normalisation [7, 66].

2.6. Allelic Disorders of Nuclear Genes

Nuclear PEO genes have broad allelic spectra that depend on zygosity [17, 28]. In addition to adPEO and arPEO, POLG causes Alpers–Huttenlocher syndrome, myoclonic epilepsy with myopathy and sensory ataxia (MEMSA), the ataxia–neuropathy spectrum (including mitochondrial recessive ataxia syndrome, MIRAS, and SANDO) and a form resembling mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); the current classification divides them by age at onset into early (<12 years), juvenile or adult (12–40 years) and late (>40 years), the latter with PEO and a better prognosis [27]. In the biallelic state, TWNK causes infantile-onset spinocerebellar ataxia (IOSCA), encephalohepatopathy with depletion and Perrault syndrome type 5 [28, 31]. RRM2B causes a severe infantile depletion encephalomyopathy (often fatal, with tubulopathy), an MNGIE-like form and arPEO with a KSS-like presentation [36, 40]. SLC25A4 causes the dominant de novo neonatal form and recessive hypertrophic cardiomyopathy with myopathy [28, 33]. POLG2 has recessive depletion forms, hepatic and neuro-ophthalmic, provisionally classified [35]. In the biallelic state, DNA2 causes Seckel syndrome type 8 and Rothmund–Thomson syndrome type 4 [1, 37]. TK2 predominantly causes childhood-onset depletion myopathy, and DGUOK a neonatal hepatocerebral syndrome [28, 40].

2.7. NAD(P)HX Epimerase Deficiency (NAXE)

NADH and NADPH undergo spontaneous hydration at high temperatures or through the action of glyceraldehyde-3-phosphate dehydrogenase, generating NAD(P)HX, inactive forms; the epimerase encoded by NAXE converts the S form to the R form, which the dehydratase encoded by NAXD repairs [61]. Biallelic NAXE variants make the protein undetectable in fibroblasts and increase cyclic NADHX, and affected children decompensate during febrile infections [41]; in NAXD deficiency, fibroblasts accumulate S-, R- and cyclic NADHX, corrected by expression of the normal enzyme, and show mitochondrial dysfunction, as does muscle [71]. In a murine Naxd model, a low-vitamin B3 diet accelerated pathology and supplementation prolonged survival more than 40-fold, supporting niacin or nicotinamide therapy (preclinical evidence) [72]. Inborn Metabolic Diseases erroneously refers to “vitamin D3 (nicotinamide)”; nicotinamide is a form of vitamin B3 [61]. The mechanism does not involve mtDNA or its maintenance, distinguishing this entity from the others in the group.

3. Clinical Spectrum and Manifestations by System

3.1. A Continuous Spectrum That Evolves with Age

PS, KSS, KSS spectrum, CPEO and CPEO-plus form a continuum, and the same patient may change category over a lifetime: PS progresses to KSS in survivors, CPEO may acquire multisystem manifestations, and the paediatric phenotype rarely remains stable [1, 16, 65]. Phenotypic distribution depends on the recruitment age of each cohort, as Table 3.1 shows: paediatric series have more PS and KSS, whereas adult or mixed series are dominated by CPEO.

Table 3.1 — Cohorts of patients with a single mtDNA deletion: phenotypic composition and main findings

In the Broomfield cohort, the median age at presentation ranged from 1 week to 3 months in PS and was 6 years in the other phenotypes [1]. Several features associated with KSS in the Italian cohort, such as hearing loss, poor weight gain, short stature, cognitive impairment, tremor and cardiomyopathy, are absent from the classical criteria [1, 2].

Table 3.2 — Frequency of manifestations in two paediatric cohorts (34 British children and 42 children in the Champ Foundation registry) and a mixed Italian cohort (228 patients), according to GeneReviews

The frequencies in Table 3.2 derive from different populations and methods, and the Champ Foundation registry is based on patient- and caregiver-reported outcomes; in the registry, 69% of children had at least one neurological manifestation and 92% at least one endocrine manifestation, and all children with haematological manifestations had PS [1, 75].

3.2. Kearns–Sayre Syndrome and KSS Spectrum

Children with KSS are normal at birth and develop appropriately in early childhood; signs emerge in later childhood or adolescence, and the earliest manifestation is often restricted eye movements or ptosis [3, 63]. Exercise intolerance and night blindness may occur early, and the disease may progress to death in young adulthood [1].

Eye. Ptosis is usually asymmetric and worsens with fatigue, whereas the oculomotor deficit is usually symmetric and progresses to complete ophthalmoplegia; diplopia is uncommon and blurred vision may occur [1, 3]. Pigmentary retinopathy has an atypical “salt-and-pepper” or bone-spicule appearance, compromises low-light vision more than acuity, and the electroretinogram (ERG) shows rod and cone dystrophy, with delayed a-waves even without symptoms or fundus abnormalities; visual loss may be the presenting complaint, and optic atrophy and a choroideraemia-like pattern have been described [1, 3]. Corneal thickening (9%) and recurrent uveitis (3%) have been reported [1].

Muscle and swallowing. Skeletal myopathy causes proximal more than distal weakness, exercise intolerance and reduced reflexes, sometimes with scoliosis; oropharyngeal weakness, cricopharyngeal achalasia and oesophageal dysfunction cause dysphagia [1, 3, 63].

Central nervous system. Cerebellar ataxia (broad-based gait, dysmetria, intention tremor) is frequent, and focal neuropsychological deficits (visuospatial perception and executive functions), spasticity, hypotonia and, in late stages, dementia may develop [3, 63]. MRI shows leukoencephalopathy with a centripetal pattern (affected U-fibres and relatively spared periventricular white matter), bilateral lesions of the globus pallidus, thalamus and brainstem, and cerebral and cerebellar atrophy, while computed tomography (CT) shows basal ganglia calcification [3, 17, 76]. Spinal cord lesions involving H-shaped grey matter and the posterior columns, or the spinal trigeminal nuclei, have been described in four patients [76]. In children, initial MRI shows selective lesions of the upper brainstem tegmentum, progressing to other brainstem and white matter regions [74]. Stroke-like episodes are rare in KSS, unlike MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes), and occurred in 9% of the Nordic cohort [1, 73]. Cerebral folate deficiency has been described, with low CSF 5-methyltetrahydrofolate (5-MTHF) [1, 18].

Heart. Conduction disease is the dominant cardiac manifestation and involves the distal conduction system (prolonged HV interval): right bundle branch block, left anterior fascicular block, bifascicular block, PR interval prolongation and, finally, complete atrioventricular block (AVB) [1, 3, 77]. In the prospective Rome series, all 15 children with KSS had an intraventricular conduction defect (bifascicular block in 11), left anterior fascicular block preceded right bundle branch block in most, and 6 progressed to AVB [78]. Complete AVB has been described in children aged 5 to 13 years, progression may be rapid and asymptomatic, and the initial manifestation may be a seizure or syncope caused by AVB [1, 3, 77]. A systematic review estimated that 50% of patients with KSS develop cardiac complications and described bradycardia-dependent polymorphic ventricular tachycardia [79]. Hypertrophic or dilated cardiomyopathy, ventricular pre-excitation and atrial fibrillation have been described, and cardiac MRI detects subclinical involvement [79, 80]. In the American inpatient database for 2016–2019 (640 KSS admissions), ventricular arrhythmia or cardiac arrest occurred in 2.3%, and none of the admissions with this event had a pacemaker [81].

Endocrine system. Endocrinopathies are frequent: mitochondrial diabetes (due to insulin deficiency and resistance, with higher glycated haemoglobin, lower body mass index, less ketoacidosis and less diabetic retinopathy than type 1 or 2 diabetes), hypoparathyroidism with severe hypocalcaemia and tetany, growth hormone (GH) deficiency, hypogonadism (delayed puberty, amenorrhoea), hypothyroidism and adrenal insufficiency [1, 3, 82]. Four children with KSS and duplications initially presented with hypoparathyroidism and hearing loss, and tetany was controlled with low doses of calcitriol [3]. In a Rome study of 18 patients with SLSMD, basal adrenocortical function was abnormal in 39%, the response to corticotropin (ACTH) stimulation was insufficient in 25% of patients with KSS (subclinical insufficiency) and 66% of patients with PS, and 44% had symptomatic adrenal insufficiency [83]. Non-autoimmune Addison disease has been described in a patient with the 4.9-kb deletion [3].

Kidney and electrolytes. The kidney is the organ most frequently affected during paediatric disease (tubular or glomerular dysfunction in 85%), and renal tubular acidosis may be the presenting feature [1, 16]. Fanconi syndrome, chronic tubulointerstitial nephritis, cystic kidney disease, glomerular disease, presentations resembling Bartter, Gitelman or Lowe syndromes, hypomagnesaemia due to renal wasting, and progression to chronic kidney disease occur [3, 63, 84]. Potassium, phosphate, chloride, sodium and magnesium losses worsen during acute illness [1].

Other systems. Bilateral sensorineural hearing loss is frequent and may not be fully corrected by hearing aids [1, 63]. Short stature, poor weight gain and exocrine pancreatic insufficiency may coexist [1]. Psychiatric manifestations are frequent in paediatric cohorts, and physical disability was associated with cognitive decline in the Mayo Clinic series [1, 46].

3.3. Pearson Syndrome

Anaemia is frequently the only initial symptom: it develops in the first weeks or months of life, at a median of 5 months (0–31) in a German–Austrian cohort of 25 patients, and some cases have prenatal onset, with hydrops fetalis or intrauterine growth restriction (approximately 10%) [1, 8, 85]; the Oxford Desk Reference lists PS, because of fetal anaemia, among the metabolic diseases that may present with hydrops fetalis [86]. Pregnancy and delivery are generally uncomplicated [8]. Other cases begin later than classically described [85].

Haematology. Anaemia is macrocytic or normocytic and hyporegenerative, frequently with elevated fetal haemoglobin and erythropoietin; neutropenia (80%) and thrombocytopenia (72%) accompany it or develop shortly afterwards [8]. Marrow is normocellular or hypocellular, with multilineage dysplasia, vacuolation of erythroid and myeloid precursors in almost all patients, and ring sideroblasts in 70–85%; these findings may be absent in the first months [8, 47]. Prednisone, vitamin B12, folate and oxymetholone had no effect in the original series [47]. Red cell and often platelet transfusion dependence resolves spontaneously in approximately two-thirds of patients, generally between 1 and 3 years (66% in the German–Austrian cohort), without predictive factors, and haematological recovery does not indicate less severe non-haematological manifestations [8, 17]. Clonal evolution and myeloid neoplasia have been described: 7q deletion at 2 years, transient monosomy 7, myelodysplastic syndrome with excess blasts and a somatic RUNX1 variant; in the Champ Foundation registry, 9% had myeloid neoplasia [8].

Pancreas, liver and kidney. Exocrine pancreatic insufficiency due to fibrosis (steatorrhoea, malabsorption, chronic diarrhoea) occurs in 27–62% and was absent in up to 73% of patients with PS in an Italian cohort [1, 8]. Liver disease develops early (before 2 years), with hepatomegaly in 30–70%, steatosis, elevated transaminases and, in fatal cases, liver failure [8, 47]. Proximal tubulopathy (Fanconi syndrome, renal tubular acidosis, hypokalaemia, hypomagnesaemia) develops predominantly between 2 and 4 years, and some patients progress to chronic kidney disease [1, 8, 17].

Metabolism and other systems. Lactic acidosis (sometimes intermittent, with a lactate/pyruvate ratio generally above 20) and infection-triggered metabolic crises are frequent causes of death [8]. Insulin-dependent diabetes (including neonatal diabetes), GH deficiency, hypothyroidism, hypoparathyroidism and adrenal insufficiency may develop at any age [8, 87]. Ptosis, pigmentary retinopathy, cataract and conduction defects occur late [8]. Motor and language delay is generally mild, cognitive impairment is not typical, and psychiatric problems were reported in 69% in the Champ Foundation registry [8]. Poikiloderma, splenic atrophy, microcephaly and Leigh syndrome have been described [1, 8].

Table 3.3 — Frequency and age at onset of non-haematological complications of Pearson syndrome

Table 3.3 reproduces Table 1 from the review by Yoshimi and colleagues, which compiles published series; percentages from the Reynolds registry include 8 children with KSS and are based on caregiver-reported outcomes [8, 75].

Transition to KSS. Survivors develop progressive multisystem disease and, eventually, the neurological manifestations of KSS [17, 62]. In an Italian cohort of 11 patients, 64% developed neurological symptoms (weakness, exercise intolerance, ataxia) and KSS manifestations [1, 14]. Pearson's original patient became transfusion-independent at 11 months, developed progressive short stature with GH deficiency, and at 12 years had disabling tremor, stuttering and moderate lactic acidosis, with an intelligence quotient of 109 [47]. Síndromes Genéticas: Reconhecer para Tratar places the transition “at around 20 years”, but the figure has no source and contradicts the series, in which KSS develops in childhood after marrow recovery [1, 74, 87].

3.4. CPEO and CPEO-plus Due to a Single Deletion

CPEO due to a single deletion is predominantly myopathic, with progressive ptosis and ophthalmoplegia typically beginning in adulthood (mean age 26 years), variable oropharyngeal and proximal weakness, and normal life expectancy [1]. Usual presentation is in adolescence or young adulthood, with little involvement of other organs, and most patients have no family history [62]. In 116 Canadian adults with CPEO, knee extension strength was 37% lower than in controls, and smoking reduced strength only in women [88]. In 23 Dutch patients with confirmed CPEO, expiratory (76.8% of predicted) and inspiratory (79.5%) muscle strength were reduced, particularly in patients with girdle weakness, without a relationship to respiratory complaints, disease severity or duration [89]. In CPEO-plus, brain MRI is typically normal [1]. In the Madrid series, muscle biopsies showed mitochondrial abnormalities in 95%, and there was no genotype–phenotype correlation [15]. Childhood onset of progressive ptosis and ophthalmoplegia is more typical of KSS spectrum, and young adults with CPEO-plus may be better classified as KSS spectrum [1].

3.5. Leigh Syndrome Due to a Single Deletion

Leigh syndrome due to a single deletion is rare (fewer than 5% of Leigh cases, which have more than 111 monogenic causes) and presents with stress-associated psychomotor regression, elevated lactate and T2 lesions in the basal ganglia and brainstem; deletions predominantly involve the globus pallidus, whereas other causes of Leigh affect the caudate and putamen [1]. Leigh-like MRI and neuropathology have been described in PS, with diffuse hyperintensity of the globus pallidus, pons and white matter [47].

3.6. PEO of Nuclear Origin

POLG-related PEO. In adPEO, the universal manifestation is progressive weakness of the extraocular muscles with ptosis and strabismus; most patients have generalised myopathy (early fatigue, exercise intolerance), and some have sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, premature ovarian failure and cataracts, with cardiomyopathy and gastrointestinal dysmotility less frequent [27, 58]. In arPEO, progressive PEO may initially occur in isolation, but many patients develop other manifestations over years or decades because the same variants cause the ataxia–neuropathy spectrum [27]. Exercise intolerance with fatigue or myalgia disproportionate to weakness, associated with PEO, suggests POLG or another mtDNA deletion syndrome [90].

TWNK-related PEO. In 25 Spanish patients with TWNK-related adPEO or PEO-plus, the mean age at onset was 43 years and at diagnosis 63 years; 22 had a positive family history; ptosis 92%, PEO 80%, weakness (proximal, neck, bulbar) 48%, exercise intolerance 28%, cardiac involvement 24%, neuropathy 8%, ataxia 4%, parkinsonism 4%, mild hyperCKaemia 28%; 19 of 19 biopsies showed mitochondrial dysfunction; 56% had received a previous misdiagnosis (myasthenia gravis 36%, oculopharyngeal muscular dystrophy 20%) [29]. GeneReviews also lists onset between 20 and 40 years, progressive hearing loss, cataracts, cardiomyopathy, dysphagia, sensory ataxia, cognitive decline, diabetes, infertility and mood disorders [1].

RRM2B-related PEO. RRM2B-related adPEO has a mean onset at 46 years and is the most multisystemic form of dominant PEO; arPEO has a mean onset at 7 years, a predominantly myopathic phenotype and greater severity, and two patients with a KSS-like syndrome beginning before 20 years have been described (PEO, pigmentary retinopathy, hearing loss and elevated CSF protein in one, tubulopathy in the other) [36]. A 42-year-old woman with biallelic missense variants and depletion had 12 years of progressive ptosis, ophthalmoplegia, gastrointestinal dysmotility, cachexia and neuropathy, an MNGIE-like presentation [36].

Table 3.4 — Manifestations of RRM2B-related adPEO (n = 42, series by Pitceathly 2012 and Sommerville 2014, according to GeneReviews)

PEO due to SLC25A4, POLG2, DNA2, RNASEH1, TK2, DGUOK and MGME1. SLC25A4-related adPEO has adult onset, ptosis and ophthalmoplegia, sometimes axial or proximal myopathy, and a relatively benign course; GeneReviews also mentions cardiomyopathy and encephalopathy [1, 32, 70]. In POLG2 disease, heterozygotes have PEO and cerebellar ataxia as core features, and ataxia, neuropathy, tremor, parkinsonism, seizures and cognitive decline have been described in a Belgian family [34, 35]. DNA2-related PEO progresses slowly, with onset from childhood to adulthood, proximal myopathy predominantly affecting the lower limbs with cramps, myalgia and elevated creatine kinase (CK), a slender build, facial weakness, exertional dyspnoea and obstructive sleep apnoea [1, 37]. RNASEH1 disease combines PEO, ptosis, ataxia and dysphagia in young adulthood [28, 38]. The adult-onset form of TK2 disease presents with facial and limb weakness, ptosis, dysphagia, dysarthria and respiratory failure, with multiple deletions and ragged-red fibres [28]. Adult-onset DGUOK forms combine myopathy, ptosis and ophthalmoplegia, and, in one report, parkinsonism [28, 40]. MGME1 disease combines PEO, myopathy and emaciation [28].

3.7. Ophthalmoplegia with Peripheral Neuropathy: SANDO and the Ataxia–Neuropathy Spectrum

PEO associated with peripheral neuropathy suggests a nuclear mtDNA maintenance gene [91]. The ataxia–neuropathy spectrum (ANS), including SANDO, is caused predominantly by biallelic POLG and also by TWNK and OPA1; it combines sensory ataxia due to neuronopathy, neuropathy, dysarthria and ophthalmoparesis, with juvenile or adult onset (12–40 years), seizures and stroke-like episodes in some patients, and PEO emerging with long survival [17, 27]. TWNK-related adPEO may also include axonal sensory neuropathy and ataxia [1, 29]. In mitochondrial disease generally, neuropathy is more frequent in POLG, TYMP, MPV17 and SURF1 disorders and with the m.8993T>G/C variant [84].

3.8. NAD(P)HX Epimerase Deficiency (PEBEL1)

The disease manifests after initially normal development, generally in the second year of life, with acute or subacute fever-triggered episodes: ataxia with cerebellar oedema, myelopathy, skin lesions, regression, hypotonia, seizures and respiratory failure [41, 44]. In the original cohort, CSF lactate was elevated in all patients, and the course progressed to coma, global cerebral atrophy and death [41]. In a review of 59 patients (45 with NAXE and 14 with NAXD), overall mortality was 66.7%, and respiratory failure was the most common cause of death [42]. Ophthalmoplegia and ptosis have been described in some cases, including a milder form in a man followed for more than 20 years with chronic ataxia, nystagmus, ptosis and mild spasticity, but they are not cardinal features [43]. NAXD deficiency (PEBEL2) is almost identical and may also present with cardiac dysfunction triggered by intercurrent illness, including after COVID-19 [71, 92].

4. Clinical Recognition and Warning Signs

4.1. When to Suspect, by Age

Newborn and infant. PS should be suspected in transfusion-dependent hyporegenerative macrocytic or normocytic anaemia in the first year, particularly if accompanied by neutropenia or thrombocytopenia, lactic acidosis, growth delay, chronic diarrhoea with steatorrhoea, liver disease or tubulopathy [1, 8]. Non-haematological symptoms are often absent at presentation, so PS enters the differential diagnosis of any isolated hyporegenerative anaemia in infancy [8]. PS was found in 2.2% of 362 patients with a clinical diagnosis of Diamond–Blackfan anaemia (DBA) and in 4.6% (8/173) of patients referred for DBA testing without a genetic diagnosis, only 2 of whom had been clinically recognised as PS [93, 94]. Other contexts that should prompt consideration of PS are non-immune hydrops fetalis, pancreatic insufficiency associated with neutropenia or pancytopenia, pancytopenia with abnormal marrow precursors and neonatal lactic acidosis, acute pancreatitis and neonatal diabetes [87, 91].

Childhood. In British children, isolated ptosis was the most frequent initial manifestation (47%) [16]. Progressive ptosis in childhood, particularly when asymmetric and associated with short stature, hearing loss, endocrinopathy (hypoparathyroidism, diabetes, GH deficiency), tubulopathy or retinopathy, should prompt mtDNA deletion testing [1, 91]. Other paediatric clues are AVB with syncope (KSS and PRKAG2 syndrome), very low CSF folate (KSS, POLG disease, FOLR1-related folate receptor alpha deficiency, severe methylenetetrahydrofolate reductase deficiency and dihydrofolate reductase deficiency), basal ganglia calcification (KSS, MELAS), pigmentary retinitis of mitochondrial origin (KSS, mtDNA deletions and neuropathy, ataxia and retinitis pigmentosa syndrome, NARP), and hearing loss beginning in later childhood or adolescence (KSS and myoclonic epilepsy with ragged-red fibres, MERRF) [91].

Adolescent and adult. Progressive ptosis and ophthalmoplegia, symmetric in eye movement and asymmetric in the eyelids, without marked daily fluctuation and rarely with diplopia, suggest CPEO; the presence of pigmentary retinopathy before 20 years converts the presentation to KSS or KSS spectrum [1]. A family history compatible with autosomal dominant transmission, peripheral neuropathy, sensory ataxia, parkinsonism, premature ovarian failure or cataract point to a nuclear cause [27, 29, 91]. General clues to mitochondrial disease include myopathy, ptosis, external ophthalmoplegia, pigmentary retinopathy, sensorineural hearing loss, cardiomyopathy, conduction defects, diabetes, Fanconi syndrome and sideroblastic anaemia; any of these with lactic acidosis, or the combination of diabetes and hearing loss, is highly suggestive [62].

4.2. Warning Signs and Emergencies

Table 4.1 — Warning signs and emergencies

Conduction disease may advance without symptoms, and low-output symptoms (dyspnoea, fatigue) tend to be attributed to myopathy [77, 95]. Apart from an abnormal ECG, there is no biomarker that predicts progression [77].

4.3. Newborn Screening

None of the entities in this group is included in newborn screening programmes; PS is recognised through haematological and metabolic signs in the first months [8]. The consulted sources describe no validated newborn screening markers for mtDNA deletions.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical Criteria

Table 5.1 — Criteria and operational definitions of SLSMDS

The diagnosis of any SLSMDS is established in a patient with suggestive manifestations by identifying a single mtDNA deletion of 1.1 to 10 kb [1]. The diagnostic algorithm proposed by Gorman and colleagues in 2016 integrates clinical features, tissue and the testing method [1, 96].

5.2. Biochemical Tests and Biomarkers

Table 5.2 — Biomarkers and laboratory findings

5.3. Genetic Testing: Tissue, Methods and Limitations

Tissue selection. In children, the single deletion was identified in blood (leucocytes) and/or urinary sediment in all tested patients, so muscle biopsy is not necessary in the paediatric age group [1, 16]. In KSS, the deletion is present in all tissues (blood, buccal mucosa, urinary sediment), but in older patients muscle may be necessary if blood and urine are negative [1]. In PS, the deletion is most abundant in blood, rarely detectable only in marrow, and is generally also present in buccal mucosa and urinary cells [1, 8]. In CPEO, the deletion is typically confined to muscle, which should be tested by open or percutaneous needle biopsy; in 111 Canadian adults with CPEO, all those tested in muscle had at least one deletion [1, 19]. In the Czech series, identifying patients required combined and repeated analysis of buccal mucosa and urinary cells [68]. The Mitochondrial Medicine Society (MMS) recommends testing another tissue when suspicion is strong and blood is negative, and states that urine may be more informative than blood [18].

Methods. Next-generation sequencing (NGS) of the complete mitochondrial genome is the MMS-preferred method because it detects deletions and duplications, identifies breakpoints and quantifies heteroplasmy; it detects low heteroplasmy, down to 5–10% or even 1–2%, depending on the platform [1, 18]. Long-range PCR detects the deletion but does not quantify heteroplasmy or define breakpoints; quantitative PCR and droplet digital PCR (ddPCR) quantify heteroplasmy [1, 66]. Southern blotting, the historical method, is less sensitive for low heteroplasmy and may not distinguish a single deletion from multiple deletions in the same region [1, 18]. Multiplex ligation-dependent probe amplification (MLPA) is less sensitive than PCR and may miss deletions with heteroplasmy below 40%; in the case in section 10, MLPA was normal with three different DNA amounts despite a 5888-bp deletion visible on long-range PCR [66]. Long-read sequencing is being developed to identify deletions [98].

Limitations. A negative blood result does not exclude the disease in an adult, and a negative muscle result depends on the method and detection threshold [1, 18]. Hybridisation-dependent assays require caution because of homology with mtDNA segments inserted into the nuclear genome (NUMTs) [1]. A small single deletion detected only by PCR requires caution before attributing primary disease to it [18]. Occasional COX-negative fibres are a normal variant after 40 years, but never exceed 5% of fibres [62]. Blood heteroplasmy does not predict severity in an individual patient [1, 68].

Multiple deletions and nuclear genes. Detection of multiple deletions requires sequencing of nuclear mtDNA maintenance and biosynthesis genes by multigene panel, exome or genome, preferably as a trio, with intragenic deletion and duplication analysis; quantification of tissue mtDNA copy number identifies depletion [18, 28, 80]. Leucocyte DNA is the first material for nuclear genes, and tissue is needed only if the result is equivocal [28]. In RRM2B-related adPEO, sequencing detects approximately 97% and deletion/duplication analysis approximately 3% of known pathogenic variants; this proportion describes the variants detectable by each method rather than the clinical sensitivity of the test [36]. Exome sequencing is now the standard for nuclear screening, but screening for large mtDNA rearrangements requires dedicated techniques (long-range PCR, real-time PCR or ddPCR) in a relevant tissue [17]. NGS panels for congenital anaemia and marrow failure generally do not include mtDNA, so deletion testing must be explicitly requested when PS or undiagnosed DBA is suspected [8, 93].

Report content. For an mtDNA deletion, the report should state the reference sequence (NC_012920.1), breakpoints in normalised HGVS nomenclature and size, heteroplasmy and the tissue analysed, the method and its detection threshold, the presence of duplications and the distinction between a single deletion and multiple deletions [1, 18]. For a nuclear gene, it should state the gene, the MANE transcript with version, the HGVS variant, zygosity, classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, and segregation analysis [36]. A variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis; familial segregation and demonstration of multiple deletions or depletion in muscle contribute to reclassification [18, 36].

5.4. Muscle Biopsy and Biochemical Studies

Muscle biopsy shows ragged-red fibres on modified Gomori trichrome staining, succinate dehydrogenase (SDH)-hyperactive fibres, and COX-negative and SDH-positive (“ragged-blue”) fibres on sequential COX/SDH histochemistry, in a mosaic pattern reflecting the heteroplasmy of each fibre; electron microscopy shows abnormal mitochondria with paracrystalline inclusions and lipid accumulation [1, 17, 63]. The MMS recommends COX, SDH, NADH-tetrazolium reductase and combined SDH/COX staining, with electron microscopy strongly recommended in children, vastus lateralis biopsy and rapid freezing in liquid nitrogen [18]. Enzymology shows combined deficiency of complexes with mtDNA-encoded subunits (I, III and IV), particularly when corrected for citrate synthase, but may be normal depending on the load and, in deletion and depletion syndromes, particularly in early stages [1, 18]. Biopsy remains the single most useful test in an adult with CPEO, allows microdissection of individual fibres to quantify the load, and should be processed at a specialist centre [17, 62]. The Madrid series proposes muscle biopsy as the first step in adult PEO and complete mtDNA sequencing when no deletions are found [15]. Biopsy is not mandatory in RRM2B disease [36].

In PS, marrow aspirate examination at peak anaemia shows marked vacuolation of erythroid and myeloid precursors (vacuoles that do not stain with Giemsa, haematoxylin and eosin, Sudan black or periodic acid–Schiff and lack a limiting membrane on electron microscopy), increased haemosiderin and ring sideroblasts [8, 47]. Marrow cytogenetics at diagnosis detects clonal evolution [8].

5.5. Additional Assessments at Diagnosis

A 12-lead ECG, echocardiogram and Holter monitoring are part of the initial assessment: the ECG is abnormal in 68% of primary mitochondrial diseases, and CPEO and KSS typically show right bundle branch block with T-wave inversion [77, 80]. Cardiac MRI is the reference examination for fibrosis (late gadolinium enhancement) and subclinical involvement [79, 80]. Brain MRI should be performed before cochlear implant or pacemaker placement [1]. Ophthalmological assessment includes acuity, visual fields, motility, documentation of ptosis, fundoscopy, ERG and optical coherence tomography (OCT) [1, 84]. Audiometry, endocrine assessment (growth, thyroid-stimulating hormone, free thyroxine, parathyroid hormone, calcium, magnesium, glucose, glycated haemoglobin, fructosamine, morning cortisol), renal assessment (urea, creatinine, glomerular filtration rate, cystatin C, N-acetylglucosaminidase, urinary amino acids and electrolytes), full blood count with ferritin, faecal elastase, swallowing and nutritional assessment, respiratory function tests and a sleep study complete the assessment [1, 84].

5.6. Practical Algorithm

Table 5.3 — Diagnostic sequence by presentation

5.7. Prenatal and Preimplantation Diagnosis

Prenatal diagnosis and preimplantation genetic testing for single deletions are scientifically possible but technically prohibitive and not clinically available, because NGS does not accurately quantify deletion heteroplasmy and ddPCR does not reliably detect heteroplasmy below 10%, and because the proportion in amniocytes or chorionic villi does not predict that in fetal or adult tissues [1, 47]. In nuclear forms, both are possible after identification of the familial variants [28, 36]. Corresponding counselling is in section 8.

6. Differential Diagnosis

6.1. Differential Diagnosis of Progressive Ptosis and Ophthalmoplegia

Table 6.1 — Differential diagnosis of CPEO and KSS

Ptosis in SLSMDS is typically asymmetric, whereas in other causes it tends to be more symmetric and fluctuating [1]. Myasthenia gravis is the most frequent misdiagnosis: 36% of Spanish patients with TWNK-related PEO had received that diagnosis and 20% a diagnosis of OPMD [29]. GeneReviews lists “absence of anti-AChR and anti-MuSK antibodies” as a feature of myasthenia in its differential diagnosis table, a formulation that appears reversed because these antibodies are usually present in myasthenia gravis and only the seronegative form lacks them [1]. Distinguishing CPEO due to a single deletion from PEO of nuclear origin is not possible clinically, because the Madrid series found no genotype–phenotype correlation; the distinction is made by the type of muscle deletion and nuclear testing [15, 18]. Christianson syndrome and SPG7-related spastic paraplegia have also been described with external ophthalmoplegia [91].

6.2. Differential Diagnosis of Pearson Syndrome

Table 6.2 — Differential diagnosis of PS

PS is distinguished from DBA and Shwachman–Diamond syndrome by marrow cytology (vacuoles and ring sideroblasts) and bi- or pancytopenia, contrasting with the isolated cytopenia of the other two; reticulocytes are frequently normal in PS and low in DBA [8]. The presence of mtDNA deletions in 2.2% of a DBA cohort led Alter to propose deletion testing in the initial genetic evaluation of every suspected DBA case [93]. Other differential diagnoses of PS are neonatal diabetes, childhood liver failure and non-immune hydrops fetalis [87, 91].

6.3. Cardiac Differential Diagnosis

The conduction disease and cardiomyopathy of KSS enter the differential diagnosis with sarcomeric hypertrophic cardiomyopathy, fatty acid beta-oxidation defects (long-chain 3-hydroxyacyl-CoA dehydrogenase and very-long-chain acyl-CoA dehydrogenase deficiencies), Pompe disease, Danon disease, PRKAG2 syndrome (hypertrophic cardiomyopathy, pre-excitation and high-grade AVB), congenital disorders of glycosylation, myotonic dystrophy and other neuromuscular disorders [77, 80]. KSS and maternally inherited diabetes and deafness (MIDD) are listed among mitochondrial causes of dilated cardiomyopathy with extracardiac manifestations [99], and left ventricular non-compaction was described in 13% of 113 children with mitochondrial disease [100].

6.4. Differential Diagnosis of NAXE Deficiency

NAXE deficiency is distinguished from SLSMDS by age (second year of life), acute fever-triggered decompensations, cerebellar oedema and myelopathy, skin lesions and autosomal recessive inheritance [41, 42, 61]. NAXD deficiency is clinically almost identical and additionally includes cardiomyopathy triggered by intercurrent illness [71, 92]. MRI findings are frequently subtle, and elevated CSF lactate was constant in the original cohort [41, 43].

7. Treatments and Risk Management Strategies

7.1. General Principles

There is no curative treatment or authorised drug for SLSMDS or adult-onset PEO of nuclear origin; management rests on early detection and treatment of each organ's complications, prevention of metabolic decompensation and rehabilitation, delivered by a multidisciplinary team with a coordinator [1, 17, 75]. The MMS recommends care at a tertiary centre with metabolic and cardiological experience, and the 2022 Heart Rhythm Society (HRS) consensus recommends coordinated care at a centre with neurological, cardiac, arrhythmic, pulmonary and genetic expertise (class of recommendation 1, level B-NR) [77, 84]. Patients should have a summary document updated at every visit, a written emergency plan and a medical alert bracelet [18, 84].

Exercise is recommended by the MMS because it induces mitochondrial biogenesis: supervised, progressive programmes combining resistance and endurance training, starting at low intensity after cardiac screening; high-intensity interval training has not been adequately studied [18]. Nutrition should be optimised, with prevention of prolonged fasting [1, 18].

7.2. Conduction Disease and the Heart

Conduction disturbances are a cause of mortality in KSS that timely pacemaker placement can prevent [101]. Guidelines agree that advanced AVB and symptomatic bradycardia require a pacemaker, but differ on the threshold for prophylactic pacing, as Table 7.1 shows.

Table 7.1 — Recommendations for pacing and implantable cardioverter-defibrillators (ICDs) in KSS and mitochondrial myopathies

The divergence results from scarce data: recommendations are based on series and consensus (level C or B-NR), the pacing threshold is undefined, there is no marker beyond the ECG to predict progression, and CRT has not been specifically studied in this population [20, 77]. Arguments for early pacing are rapid and sometimes asymptomatic progression to complete AVB and asystole, documented in an asymptomatic young woman who, after a prophylactic pacemaker for abnormal conduction without advanced AVB, rapidly progressed to complete AVB with 100% ventricular pacing [1, 103]. In the Rome series, 11 of the 15 children received an endocardial pacemaker (6 for AVB and 5 for bifascicular block), and none of the 4 deaths was sudden [78]. HRS recommendations apply “if consistent with goals of care”, including individual consideration in patients with advanced multisystem disease [77].

Device selection has particular considerations. Block in KSS is typically infra-Hisian, and right ventricular apical pacing may induce dyssynchrony; in patients with AVB and LVEF ≤50%, CRT may be considered, extrapolating from the BLOCK-HF trial, or conduction system pacing, whose efficacy depends on the level of block [95]. Sudden death due to bradycardia-dependent polymorphic ventricular tachycardia and torsade de pointes after pacemaker implantation explain why some authors propose a preventive ICD [79, 80]. In a middle-aged population with genetically confirmed mitochondrial disease, sudden death of unknown cause accounted for 6% of deaths (1.5 per 1000 person-years), and there are no studies of ICDs for primary or secondary prevention [77]. In the Mayo Clinic series, the 4 deaths among 35 patients were sudden and cardiac in origin, and the authors suggest considering electrophysiological testing and a prophylactic ICD [46]. Atrial fibrillation, observed predominantly in CPEO, should receive anticoagulation according to general guidelines (class 1, B-NR) [77].

Cardiomyopathy is treated according to general guidelines (diuretics, angiotensin-converting enzyme inhibitors, beta-blockers) [80]. Lipophilic beta-blockers inhibit mitochondrial function in vitro (propranolol is the most inhibitory in rat muscle), and Blank and colleagues consider atenolol, which has low lipophilicity, the first choice [80]. The 2020 Delphi consensus considers beta-blockers, amiodarone and enalapril safe [104]. Heart transplantation may be considered in end-stage heart failure, taking comorbidities and natural history into account, and has been performed in a patient with incomplete KSS [84, 101]. The European hypertrophic cardiomyopathy sudden death risk calculator is not validated below 16 years or in metabolic or syndromic cardiomyopathy [80]. Exercise testing or stress echocardiography should be performed with close monitoring and not in every patient, because of the risk of decompensation, and physical activity should be prescribed by cardiology [84].

Recommended cardiac surveillance for KSS is: ECG every 6–12 months, echocardiography every 6–12 months (at least annually), 24–48-hour Holter monitoring every 3–6 months in mtDNA deletions (and every 1–2 years in other high-risk patients), and pacemaker interrogation at visits; in the Rome paediatric series, ECG, Holter monitoring and interrogation were performed twice yearly [1, 78, 84]. Table 11.1 summarises these intervals.

7.3. Ptosis, Ophthalmoplegia and the Retina

Ptosis surgery, for symptomatic or cosmetic purposes, is indicated in patients with good residual orbicularis strength and should be performed by a surgeon experienced in mitochondrial disease; Bell's phenomenon and the tear film determine the risk of exposure keratopathy [23, 36, 84]. In a prospective study of 24 eyelids in 12 patients with CPEO and a normal tear film (mean age 45 years), levator resection (levator function >4 mm, 16 eyelids) and silicone frontalis suspension (poorer function, 8 eyelids) increased margin-reflex distance from −0.54 ± 1.03 to 2.42 ± 0.60 mm and reduced chin elevation angle from 21.6° to 3.3°, with mild to moderate exposure keratopathy in 4 eyes, treated medically, over a mean follow-up of 34 months [23]. The authors recommend prophylactic lubrication, close follow-up and assessment of tear break-up time and the Schirmer test [23]. Ocular lubrication is indicated with ptosis and after correction [1, 84].

As a non-surgical alternative for severe ptosis (not specific to CPEO), a randomised crossover trial of 16 patients compared a magnetic levator prosthesis with frontalis sling tape and placebo: the interpalpebral fissure during spontaneous blinking was 2.4 mm with the prosthesis, 4.1 mm with the tape and 1.1 mm with placebo (p < 0.001), and incomplete closure during voluntary blinking occurred in 6.7%, 35.6% and 2.2%, respectively [105]. An eyelid sling is another option described for severe ptosis [1].

CPEO strabismus is typically a large-angle exotropia (mean 47 prism dioptres, with a vertical deviation in half) and causes diplopia or cosmetic concern [24]. In a British series of 28 patients, prisms (3), occlusion (3), botulinum toxin (7) and surgery (8) were used; the most effective technique was maximal bilateral lateral rectus recession with medial rectus resection and adjustable sutures, submaximal corrections were always undercorrected, and recurrence was frequent because of disease progression [24]. Prisms are useful for diplopia [1]. For pigmentary retinopathy, lutein and acetylcysteine have been used without demonstrated efficacy, and cataract is managed by ophthalmology [1, 21]. Low vision warrants referral [84].

7.4. Endocrinopathies, Kidney, Gastrointestinal Tract, Hearing and Respiration

Endocrinology. Hormone replacement follows standard practice: insulin (mitochondrial diabetes may require it because of deficiency and resistance), levothyroxine, hydrocortisone, GH for documented deficiency, calcitriol and calcium for hypoparathyroidism [1, 17, 84]. Metformin should be used cautiously according to the MMS and is considered safe by the 2020 international consensus (see 7.8) [84, 104]. In vasopressor-refractory hypotension, stress-dose corticosteroids should be given empirically, sampling ACTH and cortisol beforehand without delaying treatment [84]. The authors of the Rome adrenal study propose early and regular basal and post-stimulation assessment [83]. Fall prevention, calcium and vitamin D, and bone densitometry in encephalopathy or immobility form part of care [84].

Kidney and electrolytes. Tubulopathy requires large-volume electrolyte supplements (bicarbonate, potassium, phosphate, magnesium), often with early gastrostomy, and doses should be increased rapidly during fever or vomiting [1, 84]. Renally eliminated drugs should be adjusted; in end-stage kidney disease, dialysis and kidney transplantation are options after multidisciplinary review, with survival similar to national averages in most cases [1, 84].

Swallowing, nutrition and the gastrointestinal tract. Dysphagia requires feeding therapy, a low threshold for videofluoroscopy and gastrostomy for persistent problems, choking or aspiration, with attention to refeeding syndrome risk; cricopharyngeal achalasia may benefit from upper oesophageal sphincter dilatation [1]. Pancreatic enzymes are indicated for exocrine pancreatic insufficiency in PS and KSS and may improve diarrhoea and weight gain [1, 47]. Weight should be measured at least every 6 months, and growth failure or diarrhoea should prompt assessment for pancreatic insufficiency using faecal elastase [84]. Dysmotility is managed with diet, laxatives and percutaneous gastrostomy or jejunostomy when indicated, with parenteral nutrition rarely required [28, 36].

Hearing. Formal audiometry is performed at diagnosis and every 1–2 years; digital hearing aids are used for moderate to severe loss and cochlear implantation for profound loss, preceded by brain MRI; excessive noise should be avoided and aminoglycosides used cautiously [1, 84].

Respiration and sleep. Respiratory muscle weakness, documented in CPEO, warrants baseline and periodic respiratory assessment (seated and supine spirometry, oximetry) and polysomnography; pre- and postoperative non-invasive ventilation and chest physiotherapy are indicated in neuromuscular weakness, and respiratory infections should be treated early [28, 84, 89]. Drying agents for hypersalivation and airway clearance techniques are useful in severe dysphagia [1].

Neurology and mental health. Epilepsy is treated with standard antiseizure medications; levetiracetam and clobazam appear most effective in mitochondrial epilepsy [1, 17]. Physiotherapy, occupational therapy, fall-prevention equipment and adapted sport maintain function; anxiety and depression are managed conventionally, with standardised screening [1, 84]. Educational support, social services and palliative or home nursing care complete the plan [1].

7.5. Cerebral Folate Deficiency and Folinic Acid

Folinic acid (calcium folinate; leucovorin) is indicated off-label in KSS with low CSF 5-MTHF or white matter abnormalities on MRI [1, 21]. The dose suggested by GeneReviews and the Children's Hospital of Philadelphia dosing review is 1.5–5 mg/kg/day orally, divided into 2 to 3 doses, with a maximum of 100 mg/day; an intravenous leucovorin formulation is approved by the Food and Drug Administration (FDA) for other indications [1, 21]. Folinic acid is preferred to folic acid because of better central nervous system penetration; reported adverse effects are rare (tics, agitation, hypersensitivity) [21]. The MMS recommends considering it in patients with central nervous system manifestations and administering it routinely in documented CSF deficiency or associated disorders such as KSS [18].

The evidence is observational. In a Spanish study of 8 patients with KSS, 6 received oral folinic acid (1 mg/kg/day in 4 and 3 mg/kg/day in 2) for 1 to 8 years; CSF 5-MTHF was low in all at baseline and normalised in the 3 who underwent repeat lumbar puncture, without adverse effects, but only 2 improved neurologically and 4 progressed clinically and radiologically; one patient treated early at a high dose had white matter improvement, and the authors concluded that early high-dose treatment appears advisable [106]. In a patient described by Pineda, folinic acid at 2.5 mg/kg/day enabled recovery of ataxic walking after loss of ambulation, with normal CSF 5-MTHF and improved myelination on MRI after one year [3]. Folinic acid also improves seizures and neurological problems associated with cerebral folate deficiency [17]. Efficacy has not been demonstrated in a trial, but treatment has been adopted as standard practice in mitochondrial medicine [1].

7.6. Supplements and Cofactors

By consensus and without trials, the MMS considers that coenzyme Q10 should be offered to most patients (ubiquinol, which is more bioavailable, with dose adjustment according to plasma or leucocyte levels), that alpha-lipoic acid and riboflavin should be offered, and that L-carnitine is justified only with documented deficiency and monitoring [18]. The 2012 Cochrane review found no evidence supporting or refuting vitamin supplements in mitochondrial diseases [17]. In KSS, the only specific evidence is a 1985 report in which coenzyme Q10 at 60–120 mg/day for 3 months normalised lactate and pyruvate and improved 1st-degree AVB and eye movements, without affecting the QRS [3, 97]. The coenzyme Q10 dose of ≥30 mg/kg/day in childhood and up to 3 g/day in adults refers to primary coenzyme Q10 biosynthesis deficiency and does not apply to deletions [17]. L-carnitine is no longer used routinely because of its association with atherosclerosis through trimethylamine N-oxide, and vitamin C has not demonstrated antioxidant efficacy [21].

Table 7.2 — Doses of supplements used in mitochondrial medicine (off-label use; Children's Hospital of Philadelphia expert review, not a formal guideline)

Source: Tables 1 and 2 of Barcelos and colleagues [21]; none of these products is authorised for SLSMDS, and the doses derive from clinical practice rather than trials. For pigmentary retinopathy, the same review also mentions vitamin A palmitate 15,000 IU/day [21]. Intravenous arginine is an emergency treatment for MELAS stroke-like episodes, not a specific recommendation for deletions; metabolic episodes are very rare in SLSMDS, and a patient with a single deletion treated with intravenous arginine for worsening ophthalmoplegia and ataxia and new atonic episodes had partial improvement of the atonic episodes [1, 18, 107].

7.7. Treatment of Pearson Syndrome

Haematology. Anaemia is treated with red cell transfusions and, if necessary, platelet transfusions; erythropoietin and eltrombopag have limited effects, and granulocyte colony-stimulating factor (G-CSF) may correct neutropenia [8, 47, 84]. Iron chelation may be necessary, but the indication weighs the spontaneous resolution rate, short life expectancy and toxicity, with unknown benefit; sedated cardiac and liver MRI for iron quantification is usually unnecessary because transfusion dependence generally lasts less than 2 years [1, 8]. HSCT corrected haematological abnormalities and metabolic acidosis in one patient who died of neoplasia; of the 6 patients with PS who underwent transplantation in the literature, 4 died (pulmonary haemorrhage and acidosis; recipient-derived acute myeloid leukaemia with 7q deletion and trisomy 8 after a second transplant; two of unspecified causes) and 2 were alive 3 years and 20 months after cord blood transplantation, both with a pre-existing chromosome 7 aberration [8, 47]. HSCT is not recommended before 3–4 years because spontaneous resolution is frequent, its role in non-haematological complications is uncertain, and it is the only curative treatment for PS with myeloid neoplasia [8].

Metabolism, nutrition and organs. Prevention of catabolic decompensation (fasting, fever, surgery, injury, dehydration) is central; sodium bicarbonate treats persistent acidosis, electrolytes are corrected, and pancreatic enzyme and hormone replacement are frequently required [8]. Tube feeding, gastrostomy or parenteral nutrition is often necessary [8]. Infection prevention (vaccination), antipyretics and early antibiotic therapy are part of the emergency protocol; with recurrent or severe infections, immunity should be investigated (immunoglobulins, vaccine titres, lymphocyte subsets), and antibiotic prophylaxis, immunoglobulin or G-CSF considered [8, 84]. Conduction defects are treated with ablation or a pacemaker [8]. Coenzyme Q10, L-carnitine and vitamins are used with limited evidence [8].

7.8. Drugs, Anaesthesia and Stressful Situations

Drug recommendations have changed. Older lists, still reproduced in reference sources, advised avoiding or cautiously using numerous drugs (valproate, barbiturates, aminoglycosides, linezolid, tetracyclines, chloramphenicol, macrolides, ciprofloxacin, metformin, statins, high-dose paracetamol, topiramate, vigabatrin, propofol, lipophilic beta-blockers, amiodarone, zidovudine) [18, 62, 80, 84]. The 2020 international Delphi consensus (16 experts from 6 countries, evidence level 4) concluded that drugs without clear in vivo evidence of mitochondrial toxicity can be used with monitoring during the first days (adverse effects and lactate), and considered most of these drugs safe [104]. Table 7.3 summarises the positions.

Table 7.3 — Drug safety: 2020 Delphi consensus and MMS positions

The divergence between the MMS (2015 and 2017, with North American panels) and the 2020 international consensus is resolved in favour of the more recent source, with individual risk–benefit assessment by the physician managing the mitochondrial disease; valproate remains contraindicated in POLG disease, requiring exclusion of this cause in PEO of nuclear origin before prescribing it [1, 27, 104]. International Mito Patients maintains a list of potentially harmful drugs, used as the starting point in the Delphi process [104, 108].

Anaesthesia and surgery. Adverse events with general anaesthesia are exceptionally rare, but the risk of metabolic decompensation during and after anaesthesia, surgery or intercurrent illness warrants minimising preoperative fasting and administering dextrose-containing fluids before, during and after the procedure (except with a ketogenic diet, pyruvate metabolism defects or an adverse response to glucose), with sufficient glucose to maintain normoglycaemia [18, 36, 80]. There is no established link with malignant hyperthermia, and local anaesthetics are well tolerated [18]. Brain MRI should precede cochlear implant and pacemaker placement [1]. If peripheral oxygen saturation is below 95%, blood gas analysis should be performed, and pre- and postoperative non-invasive ventilation is indicated in neuromuscular weakness, limiting opioids [84].

Acute illness. The emergency plan includes avoiding prolonged fasting, dextrose-containing fluids, assessment of electrolytes, glucose, transaminases and lactate, repeat neuroimaging with an acute neurological change, and nutrition within the first 48 hours in intensive care [18, 84]. Physical stressors (infection, fever, dehydration, anorexia) may cause sudden deterioration [27]. Frequent meals and uncooked cornstarch are useful in patients with hypoglycaemia [28].

7.9. Pregnancy, Lactation and Transition

Women with mitochondrial disease have a variable course during pregnancy, with increased risks of cardiac deterioration, preterm delivery, pre-eclampsia and magnesium sulphate toxicity [80]. The MMS recommends high-risk obstetric surveillance, early and late oral glucose tolerance testing and preconception counselling; the quantitative figures in that recommendation (25% preterm delivery, 12% pre-eclampsia, 11% gestational diabetes in 96 pregnancies) refer to the m.3243A>G variant and should not be extrapolated to deletions [84]. Premature ovarian insufficiency in some nuclear forms (POLG, TWNK) may lead to medically assisted reproduction [27, 84]. No pregnancy data are available for Kygevvi® [39]. The consulted sources describe no lactation data specific to supplements used in SLSMDS.

During transition from paediatric to adult care, recommended measures are coordination by a specialist, care at a centre with multidisciplinary expertise, and a summary document updated at every visit; the consulted sources describe no SLSMDS-specific transition protocols [75, 77, 84].

7.10. Regulatory Status

No medicine is authorised for SLSMDS, CPEO due to a single deletion or adult-onset PEO of nuclear origin [1, 39]. Two recent medicines are relevant to differential diagnosis and expectation management, and neither applies to single deletions.

Table 7.4 — Regulatory status of related therapies

Kygevvi® dosing (FDA label). Powder for oral solution in sachets containing 2 g doxecitine and 2 g doxribtimine, reconstituted with the dedicated kit and administered in 3 equal doses approximately 6 hours apart (±2 hours), with food: start at 260 mg/kg/day (130 mg/kg of each component), increase to 520 mg/kg/day and maintain at 800 mg/kg/day (400 mg/kg of each component), with titration after a minimum of 2 weeks at each level according to tolerability; the maximum recommended dose is 400 mg/kg/day of each component, and the solution should be discarded 16 hours after reconstitution [39]. Adverse effects in the main trial (n = 47, ages 0.7 to 74 years) were diarrhoea (72%), abdominal pain (23%), vomiting (21%; 28% in children and 7% in adults), and elevated alanine aminotransferase (21%) and aspartate aminotransferase (17%); 9% discontinued because of an adverse effect and 22% reduced the dose. Transaminases and bilirubin should be measured before treatment and annually, and diarrhoea or vomiting requires dose reduction or interruption and electrolyte replacement [39]. EU doses were not verified in the SmPC [109].

7.11. Clinical Trials and Investigational Therapies

Table 7.5 — Trials and studies with relevant results or status

Results in Table 7.5 are not mutually comparable: populations, endpoints and durations differ, and open-label, uncontrolled or compassionate-use studies do not allow observed changes to be attributed to treatment. The only randomised phase 3 trial including patients with a single deletion (MMPOWER-3) was negative, and the subgroup analysis that prompted NuPower is post hoc and hypothesis-generating [113, 114]. Negative or terminated trials (mavodelpar, bocidelpar, EPI-743 in PS) form part of the overall picture, and none of the identified randomised trials showed benefit on the primary endpoint in patients with an mtDNA deletion [113, 119, 124, 125]. Natural history studies are under way (Champ Foundation, NCT05029843; PS, NCT02327364, completed in 2020) to provide external controls [126, 127].

7.12. Developments in the Last 6–12 Months

Table 7.6 — Developments between October 2025 and October 2026, with evidence level

Shortly before the 12-month window, two paediatric natural history cohorts were published, one on longitudinal neuroimaging and another on phenotypic evolution with elevated GDF15 in all patients (retrospective observational studies) [65, 74]. Also before the window, and still without journal-published results, Minovia announced in 2025 FDA Fast Track and rare paediatric disease designations for MNV-201 in PS (designations that are not equivalent to approval) and interim phase 2 data from 3 of the 6 planned patients and 2 compassionate-use patients, without related serious adverse events and with a “preliminary signal” in growth, without numerical disclosure [129, 130]. The search conducted on 10 October 2026 found no 2026 announcements about MNV-201, which does not prove that none exist.

7.13. NAXE Deficiency: Treatment with Vitamin B3

High-dose niacin (nicotinic acid) or nicotinamide supplementation is the proposed treatment, without formal authorisation for this indication [42, 61]. In the Beijing series, 7 patients treated with nicotinamide 180–500 mg/day were all alive at a median follow-up of 3.9 years, 3 attended school normally, and there were no significant adverse reactions; in the combined review with the literature, 17 of 21 patients treated with niacin or nicotinamide survived (81.0%), whereas 85.5% of untreated patients died within 2 years of onset [42]. Four patients with NAXD deficiency treated with high-dose niacin survived repeated febrile episodes [92]. Only a transient response was described in one patient with NAXE treated with high-dose niacin [131]. The treated versus untreated comparison is observational, retrospective and subject to era and selection bias, and urticaria and flushing are known effects of niacin [21, 42, 43].

7.14. Ophthalmoplegia with Neuropathy (POLG/TWNK Spectrum)

In PEO with neuropathy due to POLG or TWNK, management follows that of other PEO forms (ptosis surgery, prisms, physiotherapy, speech therapy, nutrition) and adds treatment of neuropathic pain (amitriptyline, nortriptyline, gabapentin) and sensory ataxia [28, 36]. The contraindication to valproate in POLG disease is the principal safety issue [27, 104].

7.15. Summary of Guideline Recommendations

Table 7.7 — Guideline and consensus recommendations and differences

8. Reproductive Options and Family Counselling

8.1. Single Deletion: Origin and Recurrence Risks

SLSMDS are almost never inherited: the deletion arises de novo in maternal oocytes during germline development or in the early embryo [1]. The proband's mother is usually unaffected, and testing her somatic tissues generally does not detect the deletion, although it does not exclude germline mosaicism [1]. Generic counselling for mtDNA diseases, according to which a woman transmits the variant to all children at a variable load, does not apply to single deletions, contrary to what the Brazilian reference source suggests [1, 63]. In the case in section 10, the deletion was not detected in the healthy mother's blood [66].

Table 8.1 — Recurrence risks by scenario

The Oxford Desk Reference gives a “very low, <1–5%” risk for women with a single deletion and for PS, compatible with the confidence interval of Chinnery and colleagues [9, 62]. Maternal transmission to more than one child has never been described, and unaffected mothers are unlikely to have more than one affected child [1, 9]. Exceptional transmissions have been published from a mother with PEO or ocular myopathy to a child with PS, with an identical deletion in both (including the “5355” deletion), and from mother to child with KSS; in one such family, the daughter was unaffected [3, 47, 132, 133]. A mother with clinical PEO therefore has a risk of having a child with PS, and only one of the mothers with an affected child in Chinnery's series had a muscle mtDNA duplication [9, 47]. The bottleneck between oocyte and embryo allows only a few hundred to a few thousand mtDNA molecules through, making offspring heteroplasmy unpredictable [1, 8].

8.2. Prenatal Diagnosis, Preimplantation Testing and Other Options

Prenatal diagnosis and preimplantation genetic testing for single deletions are technically prohibitive and not clinically available: NGS does not accurately quantify deletion heteroplasmy, ddPCR does not reliably detect heteroplasmy below 10%, and mitotic segregation means that the proportion in amniocytes or chorionic villi does not predict that in fetal tissues; rearrangements also disappear in cell culture without uridine [1, 47]. The Oxford Desk Reference, which addresses mtDNA diseases collectively, allows prenatal diagnosis in low-risk women at specialist centres, and the cardiogenetic review mentions transfer of embryos below a load threshold (generally 18%) for point variants; neither proposal has been validated for deletions, and the GeneReviews position takes precedence [1, 62, 80]. The MMS recommends prenatal diagnosis “when feasible”, which for deletions refers back to the same limitations [84].

Oocyte donation avoids transmission [62, 80]. Mitochondrial donation (pronuclear and spindle transfer) was legislated in the United Kingdom in 2015, and the Human Fertilisation and Embryology Authority (HFEA) licensed the first clinic in March 2017; the first birth after spindle transfer occurred in Mexico for the m.8993T>G variant [17]. These techniques are intended predominantly for maternally inherited variants, and their relevance to a woman affected by a single deletion, whose transmission risk is approximately 4%, should be considered during counselling [9, 17]. The guidance from the 243rd European Neuromuscular Centre (ENMC) workshop on reproductive options in maternally inherited mtDNA diseases was not consulted in full text [134].

8.3. Pearson Syndrome

PS follows the same rules: almost all cases are sporadic, due to a mutational event early in embryonic development, and the few reports of mothers with CPEO and children with PS are exceptional [8, 132, 133]. The sibling risk is the same as in Table 8.1, and a clinically normal mother could have more than one affected child only through germline mosaicism, an unquantified situation [1, 47].

8.4. Nuclear Forms: Autosomal Dominant and Recessive Inheritance

In autosomal dominant forms (POLG, TWNK, SLC25A4, POLG2, RRM2B, DNA2), most patients have an affected parent, the proportion of de novo cases is unknown (probably <1% in POLG-related adPEO), and an affected individual's offspring have a 50% risk [27, 28, 36]. If the variant is not detected in the parents, the sibling risk is approximately 1% because of theoretical germline mosaicism, although no case of germline mosaicism has been described in these genes [28, 36]. Age at onset and severity vary greatly between generations and within a family, and a heterozygous parent may have reduced penetrance; penetrance data for POLG-related adPEO are unavailable [27, 36]. Parental assessment should focus on ophthalmoplegia, myopathy, ataxia and neuropathy because isolated migraine, depression, fatigue and seizures are common in the population and provide little information [27]. Family history may appear negative because of non-recognition, early death or late onset [28].

In autosomal recessive forms (POLG, RNASEH1, TK2, DGUOK, MGME1, RRM2B), parents are obligate carriers and each sibling's risk is 25% [28, 36]. The same applies to NAXE deficiency [41]. In nuclear forms, prenatal diagnosis and preimplantation genetic testing are possible once the familial variants have been identified, and counselling should take place before pregnancy [28, 36].

8.5. Cascade Testing, Minors and Counselling Content

In a single deletion, cascade testing of relatives is not useful because the risk to relatives is extremely low; clinical screening of first-degree relatives is justified only when the molecular cause has not been identified [1, 80]. In dominant nuclear forms, testing at-risk relatives identifies presymptomatic carriers, with an immediate practical implication in valproate avoidance by carriers of POLG variants [27, 104]. The consulted sources do not define an age for predictive testing of asymptomatic minors in adult-onset nuclear forms. Prepregnancy counselling should be offered to affected young adults [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and What Each Figure Measures

Table 9.1 — Frequency estimates

Síndromes Genéticas: Reconhecer para Tratar gives a prevalence of 1–9/100,000 for KSS and a frequency of 1/1,000,000 live births for PS, without an explicit primary source, and the GeneGuidance database gives 1–9/1,000,000 for KSS in an older field; current Orphadata figures take precedence [10, 63, 87]. Prevalence by phenotype depends on the age of the population studied: paediatric series record 21–32% PS, whereas mixed or adult series record 57–64% CPEO (Table 3.1) [2, 16, 73]. The absence of estimates for CPEO due to a single deletion results from population studies aggregating all phenotypes.

9.2. Nuclear Forms, Founder Variants and Populations

POLG was identified in almost 50% of patients with adPEO in an Italian cohort and is probably the most frequent cause of adPEO; in north-eastern England, however, POLG occurred only with recessive disease (6 manifest patients), and dominant TWNK was the most frequent nuclear cause of PEO [13, 27]. In Madrid, multiple deletions accounted for 26% of 89 mitochondrial PEO cases, with TWNK (8) ahead of POLG (7), TK2 (6) and RRM2B (2); in Canada, pathogenic nuclear variants accounted for 7.6% of 111 adults with CPEO, with POLG the most frequent [15, 19]. Carrier frequencies of recessive POLG variants vary by region: p.(Ala467Thr) 0.6% in Belgium, 0.17–0.69% in Europe, 0.69% in the United Kingdom and 0% in Italy; p.(Trp748Ser) 0.8% in Finland, where it is a founder variant, and 0% in Italy; p.(Gly848Ser) 0.016%, probably of European origin; the complex allele p.[Thr251Ile;Pro587Leu] 1% in Italy [27].

9.3. Portugal and Brazil

The consulted sources include no epidemiological data from Portugal or Brazil for SLSMDS or PEO of nuclear origin. The MitoBreak database, which collects mtDNA deletion breakpoints from around the world, was developed in Porto [64]. The Brazilian reference textbook describes KSS and PS and cites cases published in Brazilian journals (two KSS cases and two mitochondrial myopathy cases in Arquivos Brasileiros de Oftalmologia, one KSS case in a heart failure journal) and a Portuguese PS case in Acta Pediátrica Portuguesa in 2007, which were not read [63, 87]. A case of progressive conduction disease in mitochondrial myopathy with PEO and pigmentary retinopathy was published in 2026 from Luanda, Angola, without a molecular diagnosis [128]. The absence of data in the consulted sources does not demonstrate the absence of published studies.

9.4. Special Populations

Infants and children. PS is the infantile presentation, with the highest mortality in the group (section 11), and KSS is a paediatric disease by definition [1, 8]. The European hypertrophic cardiomyopathy sudden death risk calculator is not validated below 16 years [80]. The HRS notes an absence of evidence on anticoagulation in children with atrial fibrillation in these disorders [77].

Pregnant women. See section 7.9; there are no quantitative data specific to deletions [80, 84].

Older adults. PEO of nuclear origin often manifests after 40 years, and the mean age at diagnosis of TWNK-related PEO was 63 years in Spain; dementia has been described in a 74-year-old woman with SLC25A4-related adPEO [27, 29, 135].

Athletes and exertion. Physical activity should be prescribed by cardiology after cardiac screening [18, 84].

Altitude and air travel. Patients with cardiomyopathy or respiratory weakness should have saturation monitoring and access to oxygen [84].

9.5. European Reference Networks and Patient Associations

MetabERN, the European Reference Network for hereditary metabolic diseases, includes the PM-MD subnetwork (disorders of pyruvate metabolism, the Krebs cycle, oxidative phosphorylation, and thiamine transport and metabolism) and the U-IMD registry, and is the appropriate network for PS and paediatric multisystem KSS [25]. ERN EURO-NMD, for rare neuromuscular diseases, includes mitochondrial diseases and is the appropriate network for PEO and mitochondrial myopathy [26]. Patient associations with information and their own registries are The Champ Foundation, dedicated to SLSMDS and PS and sponsoring a natural history study [126, 136], the United Mitochondrial Disease Foundation in the USA [137], The Lily Foundation in the United Kingdom [138], International Mito Patients [108], the Mito Foundation in Australia [139] and MitoCanada [140]. GeneReviews also cites MitoAction, the Charlie Gard Foundation, the Foundation Fighting Blindness, the Muscular Dystrophy Association, the eyeGENE and Monogenic Diabetes Registry (including deletion-related mitochondrial diabetes) registries, and the North American Mitochondrial Disease Consortium (NAMDC) [1]. The consulted sources identify no Portuguese or Brazilian associations specific to these disorders.

10. Illustrative Clinical Case

In 2023, Grigalionienė and colleagues, in Vilnius, described a 20-year-old man with classical KSS referred to clinical genetics for molecular confirmation [66]. Since 3 years of age, he had photophobia and nystagmus with slow visual deterioration, and pigmentary retinopathy was diagnosed at 8 years. At 6 years, he developed 3rd-degree AVB and, one year later, after two syncopal episodes in the same week, a pacemaker was implanted; sensorineural hearing impairment was diagnosed around the same time. He had poor appetite, low weight and exercise intolerance. At 12 years, tremor and progressive cerebellar ataxia developed, and he had been wheelchair-dependent since 14 years. Hypocalcaemia, hypokalaemia, hypogonadism and low vitamin D had been identified in early childhood, and there were no similar cases in the family [66].

On examination, he had a thin build, short stature, bilateral ophthalmoplegia, ptosis, nystagmus and torticollis, symmetric lower limb weakness (grade 2 on the Medical Research Council scale) with almost normal upper limb strength, reduced reflexes with absent ankle jerks, and normal sensation [66]. Blood lactate was recurrently elevated (between 1.7 and 6.8 mmol/L; normal 0.7–2.6), CK was 247 U/L (normal 25–195), and amino acids were normal. T2-weighted MRI showed symmetric hyperintensities in the basal ganglia, cerebellar dentate nuclei and subcortical white matter, a pattern consistent with that described for KSS (section 3.2) [1, 66].

Molecular testing of peripheral blood DNA illustrates the limitations of the methods. Long-range PCR with two primer pairs revealed a heteroplasmic deletion of approximately 6 kb (Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9834195/figure/mgg32059-fig-0001/); MLPA (SALSA P125 kit) was normal even when repeated with 1, 4 and 10 ng DNA (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC9834195/figure/mgg32059-fig-0002/); only primer walking with Sanger sequencing identified the breakpoints of a novel 5888-bp deletion, NC_012920.1:m.6069_11956del, with breakpoints in MT-CO1 and MT-ND4 flanked by a CAAC repeat, removing MT-CO2, MT-ATP8, MT-ATP6, MT-CO3, MT-ND3 and MT-ND4L and the tRNA genes MT-TS1, MT-TD, MT-TK, MT-TG and MT-TR (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC9834195/figure/mgg32059-fig-0003/) [66]. The article calls the deletion “heterozygous”, an inappropriate term for mtDNA; the deletion is heteroplasmic, and heteroplasmy was not quantified. The deletion was not detected in the healthy mother, consistent with the usual de novo origin [1, 66]. The patient died shortly afterwards during pneumonia with respiratory failure [66].

The case combines the complete triad with onset well before 20 years, childhood conduction disease requiring a pacemaker after syncope, hearing loss, ataxia and endocrinopathies, and shows that clinical diagnosis may precede molecular confirmation by several years. Diagnostically, it demonstrates that normal MLPA does not exclude a single deletion and that long-range PCR detects but does not define the deletion, consistent with the current recommendation for complete mitochondrial genome sequencing [18, 66]. The article does not describe endocrine management, supplements or cardiac surveillance after pacemaker placement, so care cannot be compared with recommendations; guidelines recommend periodic respiratory assessment and early antibiotic treatment of respiratory infections in patients with neuromuscular weakness [28, 84].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

KSS and KSS spectrum. KSS is life-limiting, unlike CPEO, and may progress to death in young adulthood [1, 62]. In the Nordic and Dutch cohort of 80 patients with onset before 16 years, median time from onset to death was 11.5 years [73]. In the Mayo Clinic series, 4 of 35 patients (11%) died, all from sudden cardiac events [46]. In the Rome paediatric series, 4 of the 15 children died (mean age 14.7 years), none suddenly, with 11 carrying pacemakers [78]. KSS sudden death percentages circulating in secondary sources (approximately 10% as an extracardiac manifestation and up to 20% as sudden cardiac death in a review table; heart block responsible for 20% of deaths) lack an explicit denominator and do not replace cohort figures [63, 80]. In the Italian cohort, retinopathy was associated with more hearing loss, ataxia and growth deficiency; ataxia with more hearing loss, retinopathy, growth deficiency, cognitive involvement and tremor; and conduction defects with more hearing loss and cardiomyopathy [1, 2]. Physical disability was associated with cognitive decline [46], and in the Philadelphia cohort fatigue increased and quality of life declined with age [65].

Cardiac risk in adults with mitochondrial disease. Among 260 French adults with genetic mitochondrial disease (109 with a single deletion), followed for a median of 7 years, major adverse cardiac events (sudden death, death from heart failure, resuscitated cardiac arrest, 3rd-degree AVB, sinus node dysfunction, transplantation or heart failure admission) occurred in 27 (10%), with a higher incidence in single deletions and m.3243A>G; independent predictors were intraventricular conduction block (hazard ratio, HR, 16.9; 95% CI 7.2–39.4), diabetes (HR 7.0; 95% CI 2.9–16.7), ventricular ectopics (HR 3.6; 95% CI 1.4–9.2) and left ventricular hypertrophy (HR 2.5; 95% CI 1.1–5.8), and event incidence was 1.7%, 15% and 42% with 0, 1 and ≥2 factors [101, 141]. In paediatric mitochondrial diseases generally, cardiomyopathy was associated with mortality of 71% versus 26% without cardiomyopathy, and survival at 16 years was 16% versus 95%; these figures are not specific to deletions [80].

Pearson syndrome. Mortality is high in the first years: approximately half of patients in the literature die by 3 years, and Rötig's French series recorded death before 3 years in 62% [8, 47]. In the German–Austrian cohort (n = 25), overall survival at 5 years was 58%, without a plateau, with a median age at death of 49 months, and few patients reach 15 years; no prognostic factors have been identified [8]. In the Czech series, PS survival was 60%, and in the mixed Italian cohort 4 of 6 patients with PS had died during follow-up [1, 68]. Causes of death are metabolic crisis with severe lactic acidosis, infections (sepsis with neutropenia), hepatic or multiorgan failure and, in older patients, arrhythmia [1, 8]. Survival is poorer in PS than in the other phenotypes in the British and Philadelphia cohorts [16, 65]. Síndromes Genéticas: Reconhecer para Tratar reports death of more than 50% before 4 years, a figure compatible with the series [87].

CPEO. Pure CPEO due to a single deletion is compatible with normal life expectancy and usually has a benign course, but may acquire multisystem manifestations, and respiratory weakness and dysphagia determine morbidity [1, 62, 89].

Nuclear forms. Late-onset POLG-related PEO has the best prognosis within the POLG spectrum [27]. TWNK-related PEO has a slow course, with diagnosis often decades after onset [29]. SLC25A4 forms with multiple deletions have a better prognosis than depletion forms [70]. Natural history varies greatly even for the same defect [17].

NAXE deficiency. Without treatment, mortality is approximately two-thirds, with 85.5% of untreated patients dead within 2 years of onset; with vitamin B3, 81% of reported treated patients survived in observational series [42].

11.2. Surveillance

Table 11.1 — Surveillance in SLSMDS and PEO of nuclear origin

The RRM2B GeneReviews gives a frequency of “biannually” for neurological assessment, physiotherapy, blood gas analysis and gastrointestinal examination, an ambiguous English term (twice yearly or every two years), so these intervals are left to the clinician's judgement [36]. The Newcastle progression prediction tool for single deletions estimates progression from deletion size, location and heteroplasmy, with population-level value [1, 67].

11.3. Prognosis with Treatment

A pacemaker prevents death from asystole in patients with conduction disease, and the Rome paediatric series, with liberal pacing, recorded no sudden deaths [78, 101]. Folinic acid may stabilise or improve white matter abnormalities in some patients with cerebral folate deficiency, without a demonstrated effect on overall progression [106]. In PS, spontaneous haematological recovery does not imply less severe non-haematological disease, and the role of HSCT in non-haematological complications is uncertain [8].

12. Summary and Final Considerations

Single mtDNA deletion syndromes result from a deletion of 1.1 to 10 kb arising de novo in the maternal germline or early embryo, expanding clonally and distributing differently across tissues. Tissue distribution defines the initial phenotype: marrow and blood in Pearson syndrome, all tissues in Kearns–Sayre syndrome, skeletal muscle in CPEO. Negative selection in haematopoietic cells and accumulation in postmitotic tissues explain spontaneous haematological recovery in PS and its progression to KSS, as well as myopathy progression. PS, KSS, KSS spectrum, CPEO and CPEO-plus form a continuum, and the 2015 classifications allow patients who do not meet classical criteria to be categorised. The common 4977-bp deletion, historically described as m.8470_13446del4977, is written in normalised notation as NC_012920.1:m.8483_13459del and is present in approximately one-third of patients.

Diagnosis rests on deletion testing in the appropriate tissue: blood and urine in children, muscle in adults and in CPEO. Complete mitochondrial genome sequencing is the preferred method; MLPA and Southern blotting may miss deletions with low heteroplasmy, and a negative blood result in an adult does not exclude the disease. Detection of multiple muscle deletions shifts the diagnosis towards nuclear mtDNA maintenance genes, among which TWNK and POLG are most frequent in European and North American series, with autosomal dominant or recessive inheritance. In suspected Diamond–Blackfan anaemia without a genetic diagnosis, mtDNA deletion testing identifies PS in 2–5% of cases.

Prognosis depends mainly on three factors: distal conduction disease in KSS, which may progress without symptoms to complete AVB and sudden death; metabolic and infectious decompensations in PS, with approximately 58% survival at 5 years; and neuromuscular, respiratory and bulbar weakness in long-standing forms. Pure CPEO is compatible with normal life expectancy. There is no disease-modifying treatment: a pacemaker is indicated with conduction disturbance (ESC class IIa; HRS class 2a when progressive), folinic acid (1.5–5 mg/kg/day, maximum 100 mg/day, off-label) treats cerebral folate deficiency, and hormone, electrolyte, nutritional and transfusion replacement, ptosis and strabismus surgery, and rehabilitation constitute the remainder of treatment. Surveillance includes ECG and echocardiography every 6–12 months, Holter monitoring every 3–6 months in deletions, and annual endocrine, renal, hearing and ophthalmological screening.

Drug recommendations were revised by the 2020 international consensus, which considers most previously avoided drugs safe with monitoring; valproate remains contraindicated in POLG disease, requiring clarification of the cause of nuclear PEO before prescribing it. The recurrence risk of a single deletion is very low for siblings (≤1%) and approximately 4% for the offspring of an affected woman, and prenatal diagnosis is unreliable. Nuclear forms follow Mendelian rules.

No randomised trial has shown benefit in mtDNA deletions; MMPOWER-3 with elamipretide was negative, and NuPower in nuclear forms has no published results. Mitochondrial augmentation therapy with haematopoietic stem cells is in a phase 2 trial in PS. Kygevvi®, approved by the FDA in 2025 and authorised in the EU in 2026, is restricted to TK2 deficiency with onset up to 12 years and does not cover adult-onset PEO. NAXE deficiency, grouped with these entities because of occasional ophthalmoplegia, is a fever-triggered metabolite repair encephalopathy distinct from mtDNA deletions, in which vitamin B3 was associated with greater survival in observational series.

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