Table 1:

Clinical symptoms and signs, morphological and biochemical findings, and serum FGF-21 concentrations in adults with mitochondrial disorders and adult disease controls, listed by participants’ numbers

	Sex	Age at onset (years)	Age at serum sampling (years)	Age at death (years)	BMI (kg/m²)	Main clinical features	Lactate (mmol/L)	Pyruvate (μmol/L)	Lactate: pyruvate	CK (U/L)	Liver dys-function^*	Muscle histology	Biochemical analysis	DNA diagnosis	FGF-21 (pg/mL)

Muscle-manifesting mitochondrial disorders
1	F	42	55	Alive	18.3	Cardiomyopathy, diabetes mellitus, hearing impairment	2.4	97^†	25	140	No	30% COX-neg	CI+CIV 60%	mtDNA, tRNA-Leu, 3243A→G, 82% muscle	1762^†
2	F	31	47	Alive	24.0	Diabetes mellitus, hearing impairment, GI, myalgia	2.3	ND	ND	67	ND	ND	ND	mtDNA, tRNA-Leu, 3243A→G	641^†
3	F	NA	79	Alive	18.3	Deafness, myalgia, cataract	1.6	ND	ND	130	ND	5% COX-neg	ND	mtDNA, tRNA-Leu, 3243A→G	624^†
4	M	40	46	Alive	20.4	Diabetes mellitus, hearing impairment, epilepsy, myopathy	5.7^†	ND	ND	408^†	ND	4% COX-neg	ND	mtDNA, tRNA-Leu, 3243A→G, 31% blood	580^†
5	F	31	47	Alive	17.1	Short stature, PEO, myopathy, diabetes mellitus, GI	1.3	ND	ND	45	ND	ND	ND	mtDNA, tRNA-Leu, 3243A→G	572^†
6	M	48	53	Alive	25.1	Cardiomyopathy, myopathy, hearing impairment, diabetes mellitus, RR	1.6	72^†	22	143	No	ND	ND	mtDNA, tRNA-Leu, 3243A→G, 17% blood	562^†
7	F	NA	67	Alive	18.9	Diabetes mellitus, hearing impairment	2.5^†	97^†	26	62	No	ND	ND	mtDNA, tRNA-Leu, 3243A→G, in son	395^†
8	M	35	40	Alive	21.2	Hearing impairment, epilepsy, ataxia, strokes, cardiomyopathy, myopathy, neuropathy	5.6^†	ND	ND	2546^†	ND	20% COX-neg	ND	mtDNA, tRNA-Leu, 3243A→G	289^†
9	M	30	52	Alive	21.0	Diabetes mellitus, hearing impairment, ataxia, ptosis	3.9^†	136^†	29	65	No	7% COX-neg	ND	mtDNA, tRNA-Leu, 3243A→G, 77% urine	289^†
10	M	38	39	Alive	22.6	Mildly affected exercise-related myalgia, mild hearing impairment	1.0	ND	ND	129	ND	ND	ND	mtDNA, tRNA-Leu, 3243A→G	219^†
11	M	37	39	Alive	21.0	Headaches	1.1	ND	ND	120	No	∼2% COX-neg	ND	mtDNA, tRNA-Leu, 3243A→G 90% in urine	88
12	M	13	43	Alive	NA	Exercise-induced muscle pain, aercise intolerance	1.6	ND	ND	331	ND	Myopathic, COX-intensity variable	Partial CI	mtDNA, tRNA mutation	2125^†
13	F	50	65	Alive	NA	Ptosis and restricted eye movements	0.5	ND	ND	106	No	3% COX-neg	ND	mtDNA, tRNA mutation	1283^†
14	F	34	50	Alive	21.9	PEO, myopathy	1.5	50	30	471^†	No	11% COX-neg	Partial CI+CIV	TWINKLE^‡- dominant, 13dupAA	659^†
15	M	30	49	Alive	28.8	PEO, myopathy, fatty liver	1.5	78^†	19	715^†	Yes	8% COX-neg	Partial CI+CIV	TWINKLE^‡- dominant, 13dupAA	586^†
16	M	25	51	Alive	23.0	PEO, myopathy	1.2	54	22	1300^†	No	12% COX-neg	Partial CI+CIV	TWINKLE^‡- dominant, 13dupAA	570^†
17	M	30	60	Alive	NA	PEO, proximal muscle weakness in lower extremities sensory polyneuropathy	4.2^†	ND	ND	234	No	5% COX-neg	ND	POLG-dominant, P.Y955C	347^†
18	M	35	56	Alive	34.9	PEO, myopathy	1.2	ND	ND	147	Yes	5% COX-neg	ND	TWINKLE^‡- dominant, 13dupAA	338^†
19	M	25	38	Alive	26.7	PEO, myopathy	1.2	ND	ND	196	No	5% COX-neg	Partial CI+IV	TWINKLE^‡- dominant, 13dupAA	237^†
21	F	15	18	18	10.1	Severe MNGIE	4.8^†	290^†	17	ND	ND	ND	TP 1%	TYMP homozygous, c.112G→T	3738^†
22	M	18	21	21	13.3	Severe MNGIE	6.1^†	210^†	29	ND	ND	Normal at age 18 years	TP 4%	TYMP homozygous, c.854T→C	3771^†
23	M	22	24	24	NA	Severe MNGIE	5.0^†	ND	ND	<20	ND	ND	Elevated P-thymidine	TYMP homozygous, c.457G→A	3750^†
24	M	31	32	Alive	13.9	Severe MNGIE	1.3	6	ND	ND	ND	RRFs, COX-neg	TP 0%	TYMP homozygous, c.893G→A	2323^†
25	M	na	22	24	NA	Moderate MNGIE	ND	ND	ND	ND	ND	ND	TP 9.5%	TYMP homozygous, c.1327-1346del	317^†
26	M	22	29	Alive	13.5	Moderate MNGIE	4.1^†	40	103^†	46	ND	ND	TP 0%	TYMP homozygous, c.433G→A	283^†
27	F	15	47	49	16.3	Moderate MNGIE, diabetes mellitus	ND	ND	ND	ND	ND	RRF	TP 2%	TYMP IVS5+1G→A c715G→A	281^†
28	M	NA	16	Alive	NA	Moderate MNGIE	ND	ND	ND	ND	ND	ND	TP 4%	TYMP c.1319insG, c.1311G→A	266^†
29	M	7	11	Alive	13.3	Moderate MNGIE	ND	ND	ND	ND	ND	ND	TP 3%	TYMP c.433G>A, IVS4-1G→A	65
Mitochondrial disease with nervous system involvement
30	F	16	24	24	NA	MIRAS, epilepsy, terminal status epilepticus	ND	ND	ND	234^†	ND	Normal at age 19	ND	POLG homozygous, p.W748S	4374^†
31	M	>40	51	Alive	31.3	MIRAS	1.7	69	25	89	No	ND	ND	POLG homozygous, p.W748S+E1143G	537^†
32	F	21	31	Alive	NA	MIRAS	1.8	ND	ND	115	ND	ND	ND	POLG homozygous, p.A467T	357^†
33	M	27	43	Alive	33.4	MIRAS	2.1	98^†	21	96	No	4.5% COX-neg	ND	POLG homozygous, p.W748S+E1143G	291^†
34	M	32	51	Alive	25.6	MIRAS, hearing impairment	2.0	119^†	17	188	No	ND	ND	POLG homozygous, p.W748S+E1143G	246^†
35	F	20	22	Alive	22.5	MIRAS, epilepsy, migraine, liver transplant	1.2	121^†	10	38	No	ND	ND	POLG homozygous, p.W748S+E1143G	173
36	M	20	38	Alive	32.0	MIRAS	3.0^†	130^†	23	172	No	0.4% COX-neg	ND	POLG homozygous, p.W748S+E1143G	149
37	M	13	30	Alive	38.7	MIRAS	1.9	94^†	20	263	No	ND	ND	POLG homozygous, p.W748S+E1143G	131
38	M	44	52	Alive	25.0	MIRAS	0.9	47^†	19	103	No	5.4% COX-neg	ND	POLG homozygous, p.W748S+E1143G	116
39	M	38	49	Alive	21.7	MIRAS	1.6	82^†	20	318	No	3.7% COX-neg	ND	POLG homozygous, p.W748S+E1143G	54
40	F	19	25	Alive	28.0	MIRAS	1.3	ND	ND	102	No	ND	ND	POLG homozygous, p.W748S+E1143G	50
41	M	28	41	Alive	28.6	MIRAS	2.2	104^†	21	571^†	No	0.5% COX-neg	ND	POLG homozygous, p.W748S+E1143G	25
Other disorders affecting muscle
42	F	NA	57	Alive	NA	Myotonic dystrophy type 2	ND	ND	ND	1095^†	No	ND	ND	Expansion in ZNF9^§	701^†
43	M	2	40	Alive	NA	Spinal muscular atrophy type 2	ND	ND	ND	36	No	ND	ND	Homozygotic deletion in SMN1	436^†
44	F	50	71	Alive	NA	Inclusion body myositis	ND	ND	ND	555^†	No	Myositis, <1% COX-neg	ND	Unknown	392^†
45	F	67	76	Alive	NA	Inclusion body myositis	ND	ND	ND	310^†	No	Myositis, 8% COX-neg	ND	Unknown	253^†
46	F	NA	77	Alive	NA	Oculopharyngeal muscular dystrophy	ND	ND	ND	38	Yes	<1% COX-neg	ND	PABPN1 (GCG)₆ expanded to (GCG)₉	251^†
47	M	60	65	Alive	NA	Motoneuron disease	ND	ND	ND	1760^†	No	Denervation myopathy, 2% COX-neg	ND	Unknown	190
48	F	40	54	Alive	NA	Myotonic dystrophy type 1	ND	ND	ND	330^†	No	ND	ND	1500 CTG repeats in DMPK	162
49	F	2	40	Alive	NA	Spinal muscular atrophy type 3	ND	ND	ND	137	No	ND	ND	Unknown	135
50	F	44	51	Alive	NA	Myotonic dystrophy type 2	0.6	ND	ND	7794^†	No	Dystrophy	ND	CCTG ecpansion in ZNF9^§	131
51	M	6	39	Alive	NA	Becker’s muscle dystrophy	ND	ND	ND	3725^†	No	ND	ND	ND	114
52	F	50	68	Alive	NA	Cardiomyopathy, muscle weakness of lower limbs	1.2	ND	ND	42	Yes	<1% COX-neg	ND	LMNA mutation	98
53	F	30	54	Alive	NA	Muscle weakness	ND	ND	ND	937^†	ND	Dystrophy	ND	CAPN3 compound heterozygous, p.F454S; p.Y745X	81
54	M	83	85	Alive	NA	Inclusion body myositis	1.3	ND	ND	650^†	Yes	Myositis 8% COX-neg	ND	Unknown	68
55	F	40	55	Alive	NA	Myotonic dystrophy type 2	ND	ND	ND	310^†	No	Dystrophy	ND	CCTG expansion in ZNF9^§	56
56	M	NA	65	Alive	NA	Inclusion body myositis	ND	ND	ND	321	Yes	Myositis <1% COX-neg	ND	Unknown	46
57	F	NA	48	Alive	NA	Myotonic dystrophy type 2	0.8	ND	ND	175	No	ND	ND	CCTG expansion in ZNF9^§	42
58	F	58	71	Alive	NA	Inclusion body myositis	0.4	ND	ND	283^†	No	Myositis 3% COX-neg	ND	Unknown	40
59	F	NA	57	Alive	NA	Welander’s muscular dystrophy	ND	ND	ND	254^†	No	ND	ND	Founder haplotype of Welander’s disease	24
60	F	37	48	Alive	NA	Myotonic dystrophy type 1	0.5	ND	ND	155	No	ND	ND	300 CTG repeats in DMPK	24
61	F	15	23	Alive	NA	Late-onset Pompe’s disease	0.6	ND	ND	1807^†	Yes	Gtycogen increase	ND	α-l,4-glucosidase mutations	18
62	F	13	41	Alive	NA	Myotonic dystrophy type 1	ND	ND	ND	740^†	No	Dystrophy	ND	1300 CTG repeats in DMPK	17
63	M	49	58	Alive	NA	Inclusion body myositis	0.4	ND	ND	2114^†	No	Myositis <1% COX-neg	ND	Unknown	17

BMI=body-mass index. CK=creatine kinase. F=female. COX-neg=cytochrome-c-oxidase-negative muscle fibres. CI=respiratory chain complex IV deficiency. CIV=respiratory chain complex IV deficiency. mtDNA=mitochondrial DNA. tRNA=transfer RNA. ND=not determined. GI=gastrointestinal. NA=not available. M=male. RR=increased blood pressure. PEO=progressive external ophthalmoplegia. MNGIE=mitochondrial neurogastrointestinal encephalomyopathy. TP=thymidine phosphorylase. RRF=ragged red fibre. MIRAS=mitochondrial recessive ataxia syndrome.

For liver function test results see webappendix p2.

^†

Abnormal biomarker values.

^‡

Also known as C10orf2.

^§

Also known as CNBP.