Adult-onset mitochondrial PEO remains predominantly caused by mtDNA point mutations or a single, large scale deletion. Sixteen nuclear-encoded genes were identified that are
associated with adult-onset PEO and mtDNA instability, leading to a broad spectrum of clinical features affecting multiple body systems (Table 3.2). There were 667 patients described in 188 published articles with confirmed genetic diagnoses (Table 3.1). Twelve genes were identified systematically; SPG7, AFG3L2, DNM2 and RNASEH1 variants were identified with additional searches, using the initial search terms employed.
Gene Musc le NS Psychi at ri c C ardi ova sc ul ar E nd ocr in e D iges ti v e R es pir a tor y R eproduct ive U ri nary POLG ++ ++ + + + + - + - TWNK ++ + ++ + + + - + - OPA1 ++ ++ + - - + - - - TYMP ++ ++ + - - ++ - - - RRM2B ++ ++ + + - + + - + SLC25A4 ++ + + - + - - - - SPG7 ++ ++ + - - - - - + RNASEH1 ++ ++ - + - - ++ - - TK2 ++ + - - - - + - - MGME1 ++ - + + - - ++ - + POLG2 ++ ++ - - - + + - - AFG3L2 ++ ++ - - - - - - - DGUOK ++ - - - - ++ - - - MPV17 ++ ++ ++ - ++ ++ - - - DNA2 ++ - - - - - - - - DNM2 ++ ++ ++ ++ - - - - -
Table 3.2 Body Systems Affected in Adult-Onset PEO and mtDNA Instability Disorders. Summary of the body systems affected in adult-onset PEO and mtDNA instability due to nuclear-gene defects. NS – nervous system. ‘++’ - frequently involved. ‘+’ - rarely involved. ‘-‘ – not involved. Adopted and amended from Sommerville et al. (2014).
3.5.1 Influence of Publications on Systematic Review Quality
Systematic reviews are greatly influenced by the quality of the papers describing the case studies. With 188 papers reporting patients from a period greater than 10 years, there was vast variation in the quality of reporting. Several patients identified from the literature were
initially described without a confirmed genetic diagnosis, particularly before 1999, with molecular and genetic analyses of the same patients reported in later articles. For the purpose of this review, articles that described patients in the greatest detail were considered of a high quality. This included a full case report for each patient; containing the age of onset, age at clinical examination, a complete description of the phenotype, and full molecular and genetic analyses. This was notable in recent articles, but earlier papers and those describing large patient cohorts were poor. Age of onset was a key detail for this review, but was not described
in some earlier papers. It was challenging to determine if some patients should be included in the review. Ultimately, such patients were included if a dominant aetiology with multiple mtDNA deletions were confirmed, which was more likely to suggest onset of symptoms in adult-life. Articles reporting ‘juvenile’ patients were excluded, while ‘young adults’ were included. Therefore, it was not feasible to perform meta-analyses or statistical comparisons.
3.5.2 Broad Phenotypic Spectrum of Adult-Onset PEO with Multiple mtDNA Deletions Patients with adult-onset PEO and mtDNA instability presented a broad spectrum of clinical features ranging from indolent or isolated PEO to fatal multisystem phenotypes. The broadest features were observed in patients harbouring POLG and TWNK variants, comprising over 65% of all described patients in the literature who met the review criteria. It should be noted though that the prevalence of mutations in each gene identified from the literature may not be representative of the wider population (Gorman et al., 2015b). It was also not uncommon for the same pathogenic heterozygous variants of either POLG or TWNK to cause divergent phenotypes between patients. Psychiatric features such as depression or psychosis were particularly prevalent in patients with POLG and TWNK variants compared to other associated genes. POF was also confined to patients with either POLG or TWNK variants only. RRM2B variants also showed a diverse phenotypic spectrum, but were uncommon compared to POLG and TWNK variants. Nonetheless TWNK, RRM2B and SLC25A4 variants were more frequently associated with indolent or mild PEO phenotypes. POLG2 mutations were also associated with mild PEO and ptosis, with all patients also presenting proximal muscle weakness. Multisystem phenotypes were commonly associated with dominant or recessive POLG variants. Sensory ataxia, neuronopathy and Parkinsonism were also indicative of POLG variants.
Though defining the genotype-phenotype correlations remains challenging, it was possible to delineate distinct phenotypes due to pathogenic OPA1, TYMP and SPG7 variants. Dominant, heterozygous OPA1 mutations caused optic atrophy with varying severity of visual loss in childhood, followed by ophthalmoparesis and mitochondrial myopathy in adult-life (Payne et
al., 2004). Hence, it was vital to provide an exemption of the review criteria for OPA1 to
allow inclusion this review. Similarly, recessive TYMP variants cause MNGIE with patients typically presenting gastrointestinal dysmotility of varying severity, encephalopathy, PEO and sensorimotor neuropathy (Nishino et al., 1999a). Unlike other associated nuclear-encoded genes, TYMP variants were frequently associated with mtDNA depletion in the skeletal muscle; multiple mtDNA deletions were uncommon. For patients with dominant and
recessive SPG7 variants, spastic ataxia was the prominent feature, in addition to PEO (Pfeffer
et al., 2014; Wedding et al., 2014).
Delineating the genotype-phenotype correlation for the remaining associated nuclear-encoded genes was not possible. This was due the inherent lack of patients who met the review criteria or because few patients were reported. Nonetheless, discrete features may direct targeted gene screening in undiagnosed patients. Respiratory insufficiency and myopathy were prominent in patients with recessive TK2, MGME1 or RNASEH1 variants. Also, patients with TK2 and
MGME1 variants had generalised muscle wasting. However, onset in TK2 patients was
typically later than those with MGME1 or RNASEH1 variants. Liver involvement in adult- onset PEO was unmistakably rare, except for adults homozygous for the POLG p.Ala467Thr variant (Neeve et al., 2012), one adult patient with recessive DGUOK variants (Ronchi et al., 2012b) and one adult patient with recessive MPV17 variants (Garone et al., 2012).
Mendelian adult-onset, mitochondrial PEO was predominantly associated with multiple mtDNA deletions in the skeletal muscle. The exception was TYMP, which was generally association with mtDNA depletion. POLG variants were also associated with mtDNA depletion in adults harbouring recessive variants, particularly the frequently occurring p.Ala467Thr, p.Thr251Ile, p.Pro587Leu and p.Trp748Ser variants. Additional patients identified with depletion included one with a heterozygous TWNK variant (Jeppesen et al., 2008) and one with compound heterozygous RRM2B variants that phenocopied MNGIE (Shaibani et al., 2009). Furthermore, disturbed mtDNA maintenance was not confirmed in a significant number of patients, which may be due to unavailable skeletal muscle for analysis.
Inheritance of adult-onset Mendelian PEO was overwhelmingly due to autosomal dominant, heterozygous variants that were inherited or occurred de novo. POLG, RRM2B, and SPG7 were associated with both dominant and recessively inherited PEO. TYMP, RNASEH1, TK2,
MGME1, DGUOK and MPV17 variants were also associated with recessively inherited PEO
only. Although rare, digenic inheritance of variants in nuclear-encoded genes associated with adult-onset PEO and mtDNA maintenance occurred more frequently than would perhaps be expected (Van Goethem et al., 2003a; Galassi et al., 2008; Nakhro et al., 2011; Da Pozzo et
al., 2015), suggesting that it may be an under-recognised pathological mechanism.
3.5.3 Concluding Remarks
PEO is the most prominent feature of Mendelian mtDNA maintenance disorders, due to defects of nuclear-encoded genes essential for mtDNA integrity. Adult-onset Mendelian PEO
with multiple mtDNA deletions has been historically described in the literature (Zeviani et al., 1989), though it was not until the discovery of TYMP variants using linkage analysis that the underlying genetic aetiology began to be deciphered (Nishino et al., 1999a). Although there are overlapping clinical features shared between mutations of different nuclear genes, there are some discrete features that can direct targeted gene sequencing of undiagnosed patients. Nonetheless, the phenotypic spectrum is broad and for several genes there are currently few patients reported to allow a complete delineation of phenotypes and progression. As further patients are reported in the literature, continued revision of the clinical spectrum of adult- onset Mendelian PEO and mtDNA instability with further serve both clinicians and patients, providing crucial guidance on disease progression, treatment options and the development of therapeutic strategies.