Table 1. Clinical characteristics and response to sildenafil therapy in off-label compassionate studies in in six patients with LS carrying MT-ATP6 variants.

Patient [sex]	Variant [mtDNA haplogroup] (heteroplasmy)	mtDNA variant on the protein level	Phenotype [manifestation age]	[HPO number] symptoms	cMRI features [at age in years]	Initiation of sildenafil treatment [years] (dosage)	Effect of sildenafil treatment
1 [male]	m.9176T>G [K1b2a3] (99.4%)	MT-ATP6 p.L217R	LEIGH [2 years]	[HPO:1250] epilepsy [HPO:1260] dysarthria [HPO:1270] motor developmental delay [HPO:1639] cardiomyopathy [HPO:2093] respiratory insufficiency [HPO:3477] demyelinating neuropathy [HPO:6789] encephlopathy [HPO:7240] ataxia	Increased T2-signal intensities at the Putamen, Nucleus caudatus on both sides and at the perisylvian gray matter. [16.5 years]	December 2018 ongoing [16 years] (2.0 mg/kg/day)	Improvements: independent breathing (tracheostoma could be closed), motor abilities (can sit, walk with support, maneuver wheel-chair), seizures stopped, independent eating and swallowing, cardiomyopathy improved. No change: neuropathy, dysarthria
2 [male]	m.8993T>G [U5a1b3] (87.7%)	MT-ATP6 p.L156R	LEIGH [2.5 years]	[HPO:1270] motor developmental delay [HPO:2381] transient aphasia [HPO:4911] metabolic crises [HPO:7021] pain insensitivity [HPO:7240] ataxia	Increased T2- and FLAIR-signal intensities at the Putamen and Nucleus caudatus on both sides. [2.2 years]	October 2019 ongoing [15 years] (1.2 mg/kg/day)	Improvements: no metabolic crises during febrile illness, improvement of exercise tolerance (free walking distance improved from 500 to >5000 meters), no daytime sleepiness, ataxia improved, SARA score improved from 15.5 to 11 points. No change: mild intellectual disability
3 [female]	m.9185T>C [T2b] (100.0%)	MT-ATP6 p.L220P	LEIGH [5 years]	[HPO:0544] horizontal ophthalmoplegia [HPO:1256] mild intellectual disability [HPO:1270] motor developmental delay [HPO:2355] loss of ambulation [HPO:3477] axonal neuropathy [HPO:3752] episodic muscle weakness	Increased T2-signal intensities at the Putamen on both sides [5 years], which had spontaneously disappeared by the age of 14 years.	May 2019 until November 2021 [21 years] (2.9 mg/kg/day)	Improvements: reduction of episodes of muscle weakness, improvement of exercise intolerance. No change: neuropathy. Comments: After stopping sildenafil due to a delayed drug reaction (skin rash), the disease symptoms reappeared.
4 [male]	m.8993T>G [R0a1a] (96.7%)	MT-ATP6 p.L156R	LEIGH [2-3 years]	[HPO:0365] deafness [HPO:1249] intellectual developmental delay [HPO:1270] motor developmental delay [HPO:2123] myoclonic seizures [HPO:2421] loss of head control [HPO:3546] exercise intolerance [HPO:7240] ataxia	Increased FLAIR-signal intensities at the Nuclei caudati on both sides and enlargement of the internal and external CSF spaces due to diffuse brain atrophy. [35 years]	May 2022 ongoing [38 years] (1.5 mg/kg/day)	Improvements: increased muscle strengh (keeping his head position, ability to sit and walk), dysphagia, hyposthenia, slight improvement of in cognitive abilities. No change: deafness, ataxia. Comments: While the patient had to discontinue sildenafil for the time of an operation, the symptoms reoccurred after a short time and disappeared again after reinitiation of sildenafil.
5 [male]	m.8570T>C [H4] (98.5%)	MT-ATP6 p.L15P MT-ATP8 p.X68Q+26AS*	NARP [2 months]	[HPO:1639] hypertrophic cardiomyopathy [HPO:1903] anemia [HPO:2015] dysphagia [HPO:4911] multiple metabolic crises [HPO:8947] floppy infant	Delayed myelination, frontal brain atrophy. Increased T2-signal intensities in the brain stem affecting the Fasciculus longitudinalis and the Substantia nigra on both sides. [2.2 years]	September 2019 ongoing [9 months] (1.5 mg/kg/day)	Improvements: dysphagia, did not have a metabolic crisis after initiation of sildenafil therapy (before nearly one crisis every month with ICU admission), cardiomyopathy stable. No change: intellectual disability, delayed motor and cognitive development
6 [female]	m.8993T>C [T2a1a] (100.0%)	MT-ATP6 p.L156R	LEIGH [7 years]	[HPO:1258] spastic paraplegia [HPO:1268] intellectual decline [HPO:1290] muscular hypotonia [HPO:1332] dystonia [HPO:2015] dysphagia [HPO:2371] loss of speech [HPO:2421] loss of head control [HPO:4911] metabolic crisis [HPO:6789] encephalopathy	Increased T2-signal intensities at the Putamen, Pallidum, and Nucleus caudatus on both sides and within the cortical gray matter. [7.5 years]	June 2024 ongoing (7 years] (1.8 mg/kg/day)	Improvements: sitting with support and standing with assistance, consciousness normalized, normal language perception, slow improvement of muscle tone and movement disorder. No change: still wheel-chair dependent due to profound dystonia

NARP: Neuropathy, Ataxia, Retinitis pigmentosa; HPO: Human Phenotype Ontology; cMRI: cranial Magnetic Resonance Imaging; FLAIR: Fluid Attenuated Inversion Recovery; CSF: cerebrospinal fluid; SARA: Scale for the Assessment and Rating of Ataxia