Table 2.

Clinical and pathological findings in individuals with POLRMT variants.

ID	Clinical features and relevant clinical investigations	Muscle biopsy findings	Biochemical and laboratory findings
Family 1 Patient 1a female	GA: 36 weeks, birth weight 4100 grams, birth length 50 cm, OFC 38 cm; Genu varum around age 1 year; proximal tubulopathy or renal Fanconi syndrome with hypophosphatemic rickets; mild developmental delays and hypotonia; short stature; BMI 27 kg/m2; elevated lactate; enuresis; normal pubertal development; stage 3 chronic kidney disease; white matter volume loss with mild ventriculomegaly and thinning of the corpus callosum	Increased lipid in the myofibres	Mild combined CI + CIII respiratory chain defect in fibroblasts. CI deficiency and milder loss of CIII activity in skeletal muscle mtDNA testing for point mutations, deletions and CI gene sequencing normal
Family 2 Patient 2a,b female	Intellectual disability; high frequency hearing loss; BMI 28.4 kg/m2; developmental delay; mild hypotonia; bilateral ptosis; left eye exotropia; constipation; normal lactate and pyruvate levels; several foci of FLAIR high signal in subcortical white matter of the frontal lobes bilaterally; mild increase in lactate on MRS in the left insular cortex and thalamus	Mitochondrial aggregates on EM, normal biopsy histologically	Mild combined CI + CIII respiratory chain defects in fibroblasts and skeletal muscle No evidence of mtDNA depletion, single or multiple mtDNA deletions in muscle
Family 3 Patient 3a,c male	Indolent PEO phenotype; bilateral ptosis; brain MRI is normal; an uncle was reported to have PEO but this was never clinically-confirmed	25% COX-deficient muscle fibres, some ragged-red fibres	Mild CI and CIV defects in skeletal muscle No evidence of mtDNA copy number abnormality, mtDNA rearrangements or mtDNA point mutations
Family 4 Patient 4a male	Birth weight 3315 grams, length 52 cm, OFC 36.5 cm; at the age 3.5 y: OFC 51 cm (75th centile), height 83 cm (<3rd centile), weight 12.3 kg (10th centile); global, mild developmental delay; hypotonia; expressive-receptive language difficulties (20 words at 3.5 years); short stature; low phosphorous; medullary nephrocalcinosis; one episode of anaemia requiring a blood	Not determined	Respiratory chain studies not undertaken Renal hypomagnesemia: 0.6 mg/dl (normal range 1.7–2.4 mg/dl) Elevated lactate: 2.4 to 3.8 mmol/l (normal range 0.7–2.1 mmol/l) Normal creatine kinase levels
Family 5 Patient 5a male	GA: 39 weeks, weight 2800 grams, length 48 cm, OFC 31 cm; profound intellectual disability (IQ 20); microcephaly; severe global developmental delay (head control:13 m, sitting: 4 y, walking 8 y); short stature; strabismus; no speech; generalised myopathy; walking with assistance	Not determined	Respiratory chain studies not undertaken
Family 6 Patient 6a female	GA: 37 weeks, weight 2690 grams (−1 SD), length 47 cm (−1 SD), OFC 32 cm (−1.5 SD); bilateral club foot; epicanthal folds; strabismus; hypotelorism; blue scleras; low nasal bridge; upturned nose; opened mouth appearance; high palate; dysmorphic ears; bilateral simian crease; no sucking reflex in infancy; moderate intellectual disability; microcephaly; global developmental delay; short stature; strabismus; no speech; focal epilepsy; muscular hypotonia; iron deficient anaemia and thrombocytopenia; secondary carnitine deficiency; low folate; MRI brain: ventriculus septi pellucidi	Not determined	Unspecific organic aciduria (increased excretion of Krebs cycle metabolites and methylmalonate) Lactate/pyruvate ratio: 70 (normal range <25)
Family 7 Patient 7a male	Predominant muscle weakness, accompanied by muscle atrophy	Myopathic findings on electromyography - type 2 fibre predominance, rare “nuclear bags”, some COX-deficient fibres, mitochondrial abnormalities on EM	Respiratory chain enzymes and coenzyme Q10 levels normal in skeletal muscle Elevated creatine kinase levels: 873 U/L (normal range 175 U/L)
Family 7 Patient 8a male	Proximal muscle weakness, neurological examination is notable for right exotropia	Myopathic findings on electromyography	Mildly elevated creatine kinase levels: 307 U/L (normal 175 U/L)

^ainvestigated by whole-exome sequencing;

^binvestigated by mitochondrial gene panel;

^cinvestigated by whole-genome sequencing; GA gestational age; OFC occipital frontal circumference; BMI body mass index; MRI magnetic resonance imaging; MRS magnetic resonance spectroscopy; CI Complex I; CIII Complex III; EM electron microscopy, n/a not applicable.