Table 1 Phenotypic comparison of the case presented in this study and those previously published to assess the phenotypic spectrum associated with the MT-TL1: m.3291T > C variant (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C).
Reference | Age of onset (years) | M/F | Phenotype | % heteroplasmy (tissue) | Biochemical–Lactate levels | Other biochemical and/or histochemical evidence | Remarks |
|---|---|---|---|---|---|---|---|
Goto et al. [9] | 7 | M | MELAS; episodic headaches and vomiting, partial and generalized seizures, transient visual and auditory disturbances followed by headaches, cerebral infarctions, mild ID, muscle weakness | 86% (muscle), 30% (whole blood), 20% (EBV-transformed lymphocytes) | Elevated (serum and cerebrospinal fluid) | No definite deficiencies of respiratory chain enzymes. RRFs, succinate dehydrogenase reactive vessels | Variant absent in unaffected mother and sister |
Uziel et al. [14] | 6 | F | Mild myopathy: proximal and axial muscle weakness and wasting, normal IQ, impaired growth (weight and length <p3), fatigue | 87% (muscle), 45% (lymphocyte), 50% (fibroblast) | Elevated (serum and urine) | Reduction complex I, III, and IV. RRFs and COX-negative fibers, hypotrophic type II fibers, increased lipid content | Mother (below average height, otherwise unaffected) and unaffected brother had heteroplasmy levels of 19% and 6%, respectively |
Valente et al. 2009 [18] | 51 | NA | Myopathy | NA | NA | Normal biochemical parameters. RRFs and COX-negative fibers | |
Valente et al. [18] | 12 | NA | Deafness, cognitive impairment | NA | NA | Reduction complex I. RRFs | |
Salsano et al. [19] | Puberty | F | Slowly progressive cognitive decline, behavioral disturbances, Wolff-Parkinson-White syndrome, hearing loss, weight loss, hyperkinesia (myoclonic jerks and tics), cerebellar symptoms and cortical and cerebellar atrophy | 95% (muscle), 40% (blood) | Elevated (serum), normal at re-evaluation (serum) | Reduction complex I. RRFs and COX-negative fibers | Variant absent in unaffected mother and sister (blood and urine). Schizophrenia and Wolff-Parkinson-White syndrome are reported for maternal aunts |
Sunami et al. [10] | 45 | F | Severe cerebellar ataxia, myopathy, mild ophthalmoparesis, hearing loss, and asymptomatic EEG abnormality | 11% (peripheral leukocytes), 74% (muscle) | Normal (sample not specified) | RRFs, succinate dehydrogenase reactive vessels, COX-negative fibers | Family of 5 affected individuals in 4 generations |
Sunami et al. [10] | NA | F | Hearing loss and glaucoma | NA | NA | NA | Family of 5 affected individuals in 4 generations |
Sunami et al. [10] | 14 | F | Palindromic rheumatism, recurrent migraine. Multiple small hyperintense areas in subcortical white matter of cerebrum on T2 MRI | NA | NA | NA | Family of 5 affected individuals in 4 generations |
Sunami et al. [10] | 36 | F | Photo-induced myoclonus, atrophy of cerebellum, absence of tendon reflexes, truncal ataxia, normal mental status | 16% (peripheral leukocytes) | NA | NA | Family of 5 affected individuals in 4 generations |
Sunami et al. [10] | 15 | F | Generalized seizures, myoclonic jerks, slight cognitive decline, absence of tendon reflexes | 27% (peripheral leukocytes) | NA | NA | Family of 5 affected individuals in 4 generations |
Emmanuele et al. [13] | 43 | M | Progressive myoclonus epilepsy, cerebellar ataxia, cortical and cerebellar atrophy, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy, bifascicular heart block, premature graying (20 years) | 92% (muscle) | Elevated (serum) | Normal respiratory chain enzymes. RRFs and succinate dehydrogenase reactive vessels | |
Yarham et al. [8] | 51 | M | Bilateral sensorineural deafness, falls, speech disturbance, weight loss, diabetes mellitus, macroglossia with fatty infiltration, dysarthria, bilateral pes cavus, lipoma, low tendon reflexes, dysmetria, generalized brain atrophy | 39% (muscle) | Elevated (cerebrospinal fluid) | Dystrophic changes and lipid infiltrates, RRFs, COX-negative fibers, succinate dehydrogenase reactive vessels | Unaffected sister shows heteroplasmy levels of 6% in both urine and blood |
Liu et al. [11] | 14 | F | Progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, nystagmus, basal ganglia calcification, brain atrophy, and stroke-like lesions | 93% (muscle), 67% (blood), 62% (fibroblasts) | Elevated (serum) | RRF, COX-negative fibers, succinate dehydrogenase reactive vessels | Mother of proband (phenotype: emaciation and short stature) and asymptomatic sister of proband have heteroplasmy levels of 46% and 50%, respectively |
Keilland et al. [12] | 15 | F | Status epilepticus (age 15 years), but in retrospect longstanding history of fatigability, weakness, low body weight (<p3). Ptosis, external ophthalmoplegia, eyelid myoclonia, distal polymyoclonus, stroke-like episodes, gastroparesis, poor gut mobility, constipation, brain abnormalities (old infarction, high signal in parenchym) | 75% (muscle), 35% (urine), 30% (blood), 25% (cultured primary skin fibroblast) | Elevated (serum) | Reduction complex I and III. RRFs, succinate dehydrogenase reactive vessels, COX-negative fibers | Mother history of migraine headaches (heteroplasmy in lymphocytes 11%), also headaches in maternal grandmother and maternal great aunt. Brother of proband easily fatigued (heteroplasmy in lymphocytes 14%), sister of proband has headaches (heteroplasmy in lymphocytes 5%) |
This publication | 23 | M | Severe intellectual disability, brain imaging abnormalities (pachygyria, polymicrogyria, white matter abnormalities, in retrospect signs of stroke on brain CT), spastic tetraparesis, oral dystonia and dystonia of hands and feet, epilepsy, episodic headaches with nausea and emesis, adverse drug reactions, feeding difficulties, secondary microcephaly in childhood, low body weight, drooling, severe progressive neuromuscular scoliosis and congenital hip dysplasia, dental and gingival abnormalities, facial dysmorphisms | 23% (blood), 58% (urine) | Normal (serum 1.8 mmol/l; age 20 years; and cerebrospinal fluid 1.0 mmol/l, age 15 months) | Not tested | Heteroplasmy levels in the mother: 4% (blood), 17% (urine). The variant was observed in one of the sisters with heteroplasmy levels of 4% (blood) and 9% (urine), but undetectable in blood and urine of the other sister |
