The genetics of Leigh syndrome and its implications for clinical practice and risk management

Figures & data

Table 1 Clinical manifestations seen with Leigh syndrome patients

Symptoms
Gastrointestinal
Dysmotility
Constipation
Acid reflux
Vomiting
Anorexia
Dysphagia
Failure to thrive (gain weight)
Pulmonary
Abnormal respiration
Hypoxia
Cardiac
Hypertrophic cardiomyopathy
Asymmetric septal hypertrophy
Ventricular septal defects
Neurologic
Seizures
Cognitive impairment
Hypotonia
Dystonia
Neuropathy
Generalized weakness
Hyporeflexia
Ataxia
Chorea
Spasticity
Central apnea
Stroke (metabolic)
Tremor
Dermatologic
Abnormal odor of skin
Hyperpigmented skin eruptions
Hypertrichosis
Metabolic/renal
Lactic acidosis
Tubulopathy
Nephrotic syndrome
Fanconi syndrome
Endocrine
Diabetes
Thyroid dysfunction
Audiologic
Sensorineural hearing loss
Auditory neuropathy
Immunologic
Impaired immunity
Ophthalmologic
Nystagmus
Ophthalmoparesis
Retinitis pigmentosa
Failure to acquire smooth pursuit
Musculoskeletal
Muscle weakness
Ptosis
Pes cavus

Table 2 Genes known to be associated with Leigh syndrome

Gene	Defect	Location	Reference
BCS1L	Complex III	Nuclear	Morán et al, 2010^Citation78
C12ORF65	Complex I	Nuclear	Antonicka et al, 2010^Citation79
COX10	Complex IV	Nuclear	Böhm et al, 2006;^Citation32 Antonicka et al, 2003^Citation31
COX11	Complex IV	Nuclear	Böhm et al, 2006^Citation32
COX15	Complex IV	Nuclear	Böhm et al, 2006^Citation32
FOXRED1	Complex I	Nuclear	Calvo et al, 2010^Citation80
GFM1	Mitochondrial translation defect	Nuclear	Genetics Home Reference, 2011^Citation2
LRPPRC	Complex IV	Nuclear	Debray et al, 2011^Citation37
MT-ATP6	Complex V	Mitochondrial	Saneto and Singh, 2010;^Citation6 Kucharczyk et al, 2009;^Citation41 Baracca et al, 2007;^Citation39 Santorelli et al, 1993^Citation9
MT-ND1	Complex I	Mitochondrial	Lenaz et al, 2004^Citation81
MT-ND2	Complex I	Mitochondrial	Genetics Home Reference, 2011^Citation2
MT-ND3	Complex I	Mitochondrial	Leng et al, 2014;^Citation52 Gerards et al, 2013;^Citation20 Levy et al, 2013^Citation82
MT-ND4	Complex I	Mitochondrial	Mitchell et al, 2004^Citation83
MT-ND5	Complex I	Mitochondrial	Kirby et al, 2003^Citation84
MT-ND6	Complex I	Mitochondrial	Kirby et al, 2000^Citation85
MT-TK	Complex I	Mitochondrial	Rahman et al, 1996^Citation12
MT-TL1	Complex I	Mitochondrial	Rahman et al, 1996^Citation12
MT-TV	Complex I	Mitochondrial	Rahman et al, 1996^Citation12
MT-TW	Complex I	Mitochondrial	Rahman et al, 1996^Citation12
NDUFA1	Complex I	X-linked	Fernandez-Moreira et al, 2007^Citation86
NDUFA2	Complex I	Nuclear	Hoefs et al, 2008^Citation87
NDUFA4	Complex IV	Nuclear	Pitceathly et al, 2013^Citation88
NDUFA9	Complex I	Nuclear	van den Bosch et al, 2012^Citation88
NDUFA10	Complex I	Nuclear	Hoefs et al, 2011^Citation90
NDUFA11	Complex I	Nuclear	Bénit et al, 2004^Citation91
NDUFA12	Complex I	Nuclear	Ostergaard et al, 2010^Citation91
NDUFAF2	Complex I	Nuclear	Hoefs et al, 2009^Citation93
NDUFAF5	Complex I	Nuclear	Chol et al, 2003^Citation10
NDUFAF6	Complex I	Nuclear	Genetics Home Reference, 2011^Citation2
NDUFS1	Complex I	Nuclear	Bénit et al, 2001;^Citation94 Martín et al, 2005^Citation93
NDUFS2	Complex I	Nuclear	Tuppen et al, 2010^Citation96
NDUFS3	Complex I	Nuclear	Bénit et al, 2001^Citation94
NDUFS4	Complex I	Nuclear	Quintana et al, 2010;^Citation97 Anderson et al, 2008;^Citation98 Leshinsky-Silver et al, 2009^Citation99
NDUFS7	Complex I	Nuclear	Lebon et al, 2007^Citation100,Citation101
NDUFS8	Complex I	Nuclear	Marina et al, 2013^Citation102
NDUFV1	Complex I	Nuclear	Bénit et al, 2001^Citation94
PDHA1	Pyruvate dehydrogenase deficiency	X-linked	Lissens et al, 2000;^Citation103 Rahman et al, 1996^Citation12
PDHB	Pyruvate dehydrogenase deficiency	X-linked	Quintana et al, 2009^Citation104
PDHX	Pyruvate dehydrogenase deficiency	X-linked	Schiff et al, 2006^Citation105
PDSS2	Ubiquinone deficiency	Nuclear	López et al, 2006^Citation21
PET100	Complex IV	Nuclear	Lim et al, 2014^Citation106
SCO2	Complex IV	Nuclear	Joost et al, 2010^Citation107
SDHA	Complex II	Nuclear	Pagnamenta et al, 2006^Citation108
SDHAF1	Complex II	Nuclear	Ohlenbusch et al, 2012^Citation109
SLC19A3	Thiamine transport defect	Nuclear	Gerards et al, 2013^Citation20
SUCLA2	Mitochondrial DNA depletion	Nuclear	Carrozzo et al, 2007;^Citation3 Ostergaard et al, 2007^Citation110
SUCLG1	Mitochondrial DNA depletion	Nuclear	Ostergaard et al, 2010^Citation92
SURF1	Complex IV	Nuclear	Rossi et al, 2003^Citation34
TACO1	Complex IV	Nuclear	Weraarpachai et al, 2009^Citation111
TTC19	Complex III	Nuclear	Atwal, 2013^Citation112
UQCRQ	Complex III	Nuclear	Barel et al, 2008^Citation113

Note: References listed are only a sample of published literature.

Figure 1 Axial MRI scan (A) and MRS spectrum (B) of a 9-year old boy with Leigh syndrome due to a mutation in the mtDNA.

Notes: (A) Axial fluid-attenuated inversion recovery image from a 3 T scanner (Siemens Trio) of a 9-year-old boy with Leigh syndrome resulting from a mitochondrial DNA mutation (m.11487 C>T). There is T2/fluid-attenuated inversion recovery hyperintensity in the bilateral caudate and putamen. Ex vacuo dilation of the frontal horns and bodies of the lateral ventricles is well visualized. (B) Summed spectrum from central gray nuclei in the same patient using the point-resolved spectroscopy pulse sequence (3 T Siemens Trio; time to echo (TE), 288 ms; time to relaxation (TR), 1,700 ms; 16×16 acquisition, interpolated to 32×32, 16 cm). The region of interest is the outlined region in the right putamen. An elevated lactate doublet peak (the lactate peak is upward at this TE time) is found at the echo time of 135 ms. N-acetylaspartate (NAA), choline-containing compounds (Cho), creatine + phosphocreatine (Cr), and second creatine (Cr2) peaks are also shown.

Figure 2 Axial MRI scan (A) and MRS spectrum (B) of a 17-year old male with Leigh syndrome due to a mutation in the mtDNA.

Notes: (A) Axial fluid-attenuated inversion recovery image from a 3 T scanner (Siemens Trio) of a 17-year-old teenage boy with Leigh syndrome resulting from a mitochondrial DNA mutation (m.3700 G>A). There is a T2/fluid-attenuated inversion recovery hyperintensity in the caudal pons. Not shown is the hyperintensity that extends to the cervicomedullary junction. There were no abnormalities noted in the basal ganglia. (B) Summed spectrum from the caudal pons in the same patient using the point-resolved spectroscopy pulse sequence (3 T Siemens Trio; TE, 135 ms; TR, 5,180; 16×16 acquisition, interpolated to 32×32 cm). The region of interest is the outlined region of the caudal pons. An elevated lactate doublet peak is found at the echo time of 135 ms (peak is downward at this TE time). There is a reduced N-acetylaspartate (NAA) peak suggesting loss of neuronal integrity in the same region. Choline-containing compounds (Cho), creatine + phosphocreatine (Cr), and second creatine (Cr2) peaks are also shown.

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