Clinical Description
Single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) predominantly comprise overlapping phenotypes including Kearns-Sayre syndrome (KSS), KSS spectrum, Pearson syndrome (PS), chronic progressive external ophthalmoplegia (CPEO), and CPEO-plus (see Table 2). Leigh syndrome is rarely a manifestation of a single large-scale mitochondrial DNA deletion (SLSMD).
Table 2.
Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Phenotypes
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| Phenotype | Cohort of 34 Children 1 | Cohort of 228 Adults & Children 2 |
|---|
|
KSS
| 29% | 7% |
|
KSS spectrum
| 0% | 25% |
|
PS
| 32% | 3% |
|
CPEO
| 9% | 57%-64% 3 |
|
CPEO-plus
| 21% | |
|
No phenotype assigned
| 9% | |
CPEO = chronic progressive external ophthalmoplegia; KSS = Kearns-Sayre syndrome; PS = Pearson syndrome
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Using classic criteria for CPEO (ptosis, ophthalmoplegia, dysphagia, proximal limb weakness, exercise intolerance), 57% met criteria for CPEO.
Onset. In a cohort of 34 children with an SLSMDS, the most common initial manifestation was isolated ptosis (47%); the second most common presenting feature was transfusion-dependent anemia (32%) [Broomfield et al 2015]. In children identified with an SLSMDS, the median age at presentation was age one week to three months for those with PS and age six years for the other phenotypes.
Although individuals with an SLSMDS may be assigned a clinical diagnosis based on features at the time of presentation, the phenotypes comprise a continuous spectrum of disease, and features evolve with time (see Table 3). In addition, several features strongly associated with the development of KSS are not included in the clinical criteria (e.g., sensorineural hearing loss, poor weight gain, short stature, cognitive impairment, tremor, cardiomyopathy) [Mancuso et al 2015].
Table 3.
Single Large-Scale Mitochondrial DNA Deletion Syndromes: Frequency of Select Features
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| Feature | Two Cohorts of 34 1 & 42 Children 2 | Cohort of 228 Children & Adults 3 | Comment |
|---|
|
Neurologic
| Dysautonomia | 86% | | 69% of children w/SLSMDSs were reported to have ≥1 neurologic manifestation. 2 |
| Exercise intolerance | 77% | 20% |
| Muscle weakness | 26%-71% | 47% |
| Sensorineural hearing loss | 31%-67% | 18% |
| Ataxia | 6%-69% | 12% |
| Migraine headaches | 37% | 4% |
| Dysarthria | 34% | |
| Gross motor delays | 26% | |
| Hypotonia | 24% | 8% |
| Cognitive impairment | 23% | 4% |
| Muscle wasting | | 18% |
| Dysphagia | | 15% |
| Increased CK | | 15% |
| Muscle pain | | 6% |
| Seizures | 6%-9% | |
| Neuropathy | | 4% |
| Tremor | 3% | 3% |
|
Ocular
| Ptosis | 54%-64% | 92% | |
| Retinopathy | 34%-38% | 11% |
| Ophthalmoparesis | 26% | 84% |
| Corneal thickening | 9% | |
| Recurrent uveitis | 3% | |
|
Cardiac
| Conduction defects | 45%-66% | 5% | Right bundle branch block, arrhythmia, complete heart block |
| Cardiomyopathy | ~10% | 3% | |
|
Endocrine
| Short stature | 9%-76% | 10% | 92% of children w/SLSMDSs were reported to have ≥1 endocrine manifestation. 2 |
| Diabetes mellitus | 24%-26% | 9% |
| Hypoparathyroidism | 9%-57% | |
| Adrenal insufficiency | 9% | 3% |
| Hypothyroidism | 3% | |
|
Hematologic
| Neutropenia | 91% | 2% | All children w/hematologic manifestations had PS. |
| Thrombocytopenia | 73% | |
| Anemia | 32%-77% | 5% |
|
Other
| Renal manifestations | 80%-85% | 2% | Tubular &/or glomerular dysfunction |
| Psychiatric manifestations | 69% | 3% | |
| Poor weight gain | 63%-89% | | |
| Increased liver enzymes | 31% | 5% | |
| Insomnia | 29% | | |
CK = creatine kinase; SLSMDSs = single large-scale mitochondrial DNA deletion syndromes
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Kearns-Sayre Syndrome (KSS) and KSS Spectrum
KSS is a multisystem disorder with onset before age 20 years, defined by a classic clinical triad of pigmentary retinopathy (sometimes referred to as retinitis pigmentosa), CPEO, and cardiac conduction defect. KSS predominantly affects the central nervous system, skeletal muscle, and heart. Onset is usually in childhood, with ptosis, ophthalmoplegia, or both. Exercise intolerance and impaired night vision (nyctalopia) may be early symptoms. Additional findings may include cerebellar ataxia, tremor, elevated cerebrospinal fluid protein, dysphagia, cricopharyngeal achalasia, sensorineural hearing loss, endocrinopathies (diabetes mellitus, growth hormone deficiency, hypoparathyroidism, adrenal insufficiency), renal involvement, learning disability, cognitive decline/dementia, abnormal brain MRI, poor weight gain, short stature, and cardiomyopathy. KSS may progress to death by young adulthood.
Note: Individuals with KSS spectrum have ptosis and/or ophthalmoparesis and at least one of the following: retinopathy, ataxia, cardiac conduction defects, hearing loss, growth deficiency, cognitive impairment, tremor, and/or cardiomyopathy.
Central nervous system involvement manifests as sensorineural hearing loss, cerebellar ataxia, impaired intellect (intellectual disability and/or dementia), and tremor.
Brain MRI may show leukoencephalopathy often associated with cerebral and cerebellar atrophy, basal ganglia lesions (typically involving the globus pallidus), and midbrain / brain stem lesions, similar to those seen in individuals with Leigh syndrome [Broomfield et al 2015, Moscatelli et al 2022]. A secondary cerebral folate deficiency has been reported in individuals with KSS; supplementation with folinic acid can be beneficial [Quijada-Fraile et al 2014] and may reverse white matter abnormalities seen on imaging with corresponding subjective improvement in coordination.
Compared to other mitochondrial encephalomyopathies (e.g., MELAS, MERRF, NARP), individuals with KSS only very rarely have metabolic strokes. In a recent retrospective analysis of metabolic stroke, one individual had an SLSMD and received intravenous arginine therapy for worsening ophthalmoplegia and ataxia together with new onset of atonic episodes. After intravenous arginine administration, partial improvement was seen in atonic episodes. MRI revealed bilateral symmetric basal ganglia and white matter lesions [Ganetzky & Falk 2018].
Ophthalmologic manifestations. Pigmentary retinopathy of KSS affects low-light vision more prominently than visual acuity, leading affected individuals to report impaired night vision (nyctalopia). Fundoscopy reveals an atypical "salt-and-pepper" retinopathy. Electroretinogram often reveals rod-cone retinal dystrophy. Visual field testing reveals normal visual fields. Peripheral vision may be compromised by ptosis. Vision generally deteriorates insidiously, making age at onset difficult to discern.
Skeletal muscle involvement is progressive and manifests as ptosis, extraocular muscle paralysis (ophthalmoplegia), oropharyngeal and esophageal dysfunction, exercise intolerance, fatigue, and limb muscle weakness (proximal > distal). The defect of extraocular movement is usually symmetric but may cause blurred or double vision. Ptosis is usually asymmetric and exacerbated by fatigue.
Heart involvement is most commonly characterized by conduction (bundle branch) block, which can be progressive and quickly lead to complete heart block. Complete heart block has been reported in children ages five to 13 years. [Broomfield et al 2015]. Cardiomyopathy has been reported in several individuals [Broomfield et al 2015]. Cardiac MRI is an emerging tool used to detect subclinical cardiac involvement [Kabunga et al 2015]. Prophylactic pacemaker is advised, as the conduction block may rapidly progress to complete heart block and asystole [Trivedi et al 2018].
Endocrinopathies are common in individuals with KSS and include mitochondrial diabetes mellitus, hypoparathyroidism, growth hormone deficiency, adrenal insufficiency, and irregular menses [Al-Gadi et al 2018]. Mitochondrial diabetes mellitus may be caused by both insulin deficiency and insulin resistance, and is associated with higher hemoglobin A1c, lower body mass index, lower rates of diabetic ketoacidosis, higher associated neuropathy and nephropathy rates, and less diabetic ophthalmologic involvement. Individuals may present with extreme hypocalcemia and tetany due to hypoparathyroidism [Katsanos et al 2001, Al-Gadi et al 2018]. Short stature may be the result of growth hormone deficiency, poor weight gain, and/or exocrine pancreatic enzyme deficiencies.
Kidney disease. Renal tubular acidosis occurs in individuals with KSS and may be the presenting feature [Eviatar et al 1990, Broomfield et al 2015]. The kidney is the most frequently affected organ over the course of disease, with tubular or glomerular dysfunction occurring in 85% (17/20) [Broomfield et al 2015]. Impaired kidney function can be determined by decreased glomerular filtration rate (GFR) or abnormal elevation of urinary tubulopathy markers such as retinol-binding protein (RBP) [Bernard et al 1987] or N-acetyl-3-glucosaminidase (NAG) [Vaidya et al 2008] – potentially useful screening biomarkers in presymptomatic individuals [Herget-Rosenthal et al 2004]. Electrolyte abnormalities such as hypokalemia, hypophosphatemia, hypochloremia, acidosis, hyponatremia, and/or hypomagnesemia may be present at baseline or occur during acute illness and require monitoring and replacement therapies.
Prognosis. One study investigated whether the presence of a specific clinical manifestation could predict other features, a common question from individuals with SLSMDSs. Those with retinopathy had statistically significant increased incidence of hearing loss, ataxia, and poor growth. Those with ataxia had statistically significant increased incidence of hearing loss, retinopathy, poor growth, cognitive involvement, and tremor. Those with cardiac conduction defects had statistically significant increased incidence of hearing loss and cardiomyopathy [Mancuso et al 2015].
Pearson Syndrome (PS)
PS manifests clinically with bone marrow failure resulting in pancytopenia, severe refractory, transfusion-dependent sideroblastic anemia, and variable exocrine pancreatic insufficiency. In one study, age of onset for PS was 0.3 ± 0.8 years [Mancuso et al 2015]. In addition, multisystem involvement results in poor weight gain, hypotonia, and metabolic derangements including lactic acidosis. PS features are variable and progressive.
Pancytopenia. PS is associated with variable neutropenia, thrombocytopenia, and transfusion-dependent macrocytic, sideroblastic anemia with normocellular or hypocellular bone marrow.
Sideroblastic anemia. Anemia typically appears in the first year of life and may be the initial manifestation of bone marrow failure or accompanied by pancytopenia. Sideroblastic anemia is defined by the presence of anemia and ringed sideroblasts in the bone marrow. Ringed sideroblasts are normoblasts (precursors to mature red blood cells) with excessive deposits of iron in the mitochondria and are detected by iron stains of bone marrow. In addition, there is striking vacuolization of the hematopoietic progenitor cells and hemosiderosis.
Exocrine pancreatic dysfunction due to pancreatic fibrosis is manifest clinically by poor weight gain, growth deficiency, malabsorption, chronic diarrhea, and excessive fat excretion in the stools (steatorrhea), which can be identified by Sudan staining of the feces or measurement of fecal fat and/or fecal elastase. The gold standard is the secretin stimulation test, which requires placing a catheter in the duodenum and is technically difficult to perform in infants. Exocrine pancreatic dysfunction is a variable feature that is not seen in up to 73% of individuals with PS [Farruggia et al 2016].
Renal tubular defects. Renal Fanconi syndrome with resultant electrolyte disturbances is seen in individuals with PS. Renal tubular acidosis results in elevation of several urinary amino acids, metabolic acidosis that may require bicarbonate replacement, and electrolyte disturbances (hypokalemia, hypomagnesemia) that may require replacement therapy.
Additional features may include hydrops fetalis, hepatic involvement with elevated transaminases and steatosis, microcephaly, endocrinopathies (growth hormone deficiency, hypothyroidism, hypoparathyroidism, diabetes mellitus, and adrenal insufficiency), skin findings (poikiloderma), splenic atrophy, impaired cardiac function, and acute metabolic decompensations during intercurrent illness. One study including six individuals with PS reported the following frequency of findings: elevated liver enzymes (67%), poor weight gain (50%), hypotonia (33%), CPEO (33%), diabetes mellitus (33%), renal manifestations (33%), and lactic acidosis (67%) [Mancuso et al 2015].
Prognosis. Death may occur in early infancy or childhood due to metabolic decompensation, liver failure, or sepsis due to neutropenia. Four of six individuals with PS had died at follow up (about four to six years later) in one study [Mancuso et al 2015]. Survival and spontaneous recovery from bone marrow dysfunction after several years is possible, with a transition to clinical manifestations of KSS. In an Italian cohort of 11 individuals with PS, 64% developed neurologic symptoms (weakness, exercise intolerance, ataxia) and clinical manifestations of KSS [Manea et al 2009, Morel et al 2009, Williams et al 2012, Crippa et al 2015, Farruggia et al 2016].
Chronic Progressive External Ophthalmoplegia (CPEO) and CPEO-Plus
CPEO is predominantly a myopathic disorder characterized by progressive ptosis and extraocular muscle paralysis (ophthalmoplegia) typically presenting in adulthood. The mean age of onset is 26 years. CPEO variably also includes severe oropharyngeal and proximal limb weakness. The disorder is compatible with a normal life span.
Individuals with CPEO-plus who do not meet clinical criteria for KSS or KSS spectrum can have the following additional multisystemic features: neuropathy, diabetes mellitus, migraine headaches, hypothyroidism, psychiatric involvement, and optic neuropathy. Brain MRI is typically normal. Note: (1) Those with cardiac conduction defect and/or pigmentary retinopathy are instead diagnosed with KSS or KSS spectrum. (2) Childhood onset of progressive ptosis and ophthalmoplegia is more typical of KSS spectrum.
Leigh Syndrome
Leigh syndrome typically begins in infancy or early childhood and is characterized by psychomotor regression or delay (especially with stressors such as infection) with disease manifestations involving the brain stem, basal ganglia, or both. Leigh syndrome involves regression of developmental milestones and lactic acidosis, which are less common in other SLSMDSs. The brain MRI is typically abnormal in SLSMDSs, showing characteristic T2-weighted hyperintense lesions in the basal ganglia and midbrain / brain stem that are often bilaterally symmetric but may fluctuate over time; the globus pallidus is predominantly affected in SLSMD-related Leigh syndrome, whereas other genetic causes of Leigh syndrome result in lesions of the caudate/putamen.
Genotype-Phenotype Correlations
For all mitochondrial DNA (mtDNA) pathogenic variants, including SLSMDs, clinical expressivity depends on three factors:
Tissue vulnerability thresholds likely do not vary substantially among affected individuals, whereas variable proportions of the mtDNA deletion and their tissue distribution may account for the wide spectrum of clinical findings in individuals with KSS.
The SLSMD is present in all tissues in individuals with KSS, is predominantly present in hematopoietic cells of individuals with PS, and is confined to skeletal muscle in individuals with CPEO, explaining the variability in phenotype. Infants with PS may develop KSS later in life due to the gradual decrease in SLSMDs in rapidly dividing blood cells and the gradual increase in SLSMDs in postmitotic tissues.
In some reported cohorts, disease severity and progression correlate with mtDNA heteroplasmy levels as well as mtDNA deletion size and location [Grady et al 2014]. A meta-analysis of published cohorts [Grady et al 2014] compared the degree of cytochrome-c oxidase (COX)-negative fibers on muscle biopsy (as a marker of biochemical severity), age of onset of clinical manifestations, and disease burden (as measured by the Newcastle Mitochondrial Disease Adult Scale [NMDAS]) with the mtDNA deletion size, deletion location, and heteroplasmy level. Grady et al [2014] found that the age of onset of clinical manifestations directly correlated with deletion size, location (e.g., deletions including complex III and IV subunit genes MT-CYB and MT-COX), and heteroplasmy levels, factors that were significant predictors of disease progression as measured by NMDAS scores. A web tool is available for prognosis and predicted disease progression based on these factors: research.ncl.ac.uk/mitoresearch.
In a study of 228 individuals with SLSMDs, deletion length was greater in those with KSS spectrum compared to those with CPEO, and the percentage of heteroplasmy was inversely related to age of onset of manifestations [Mancuso et al 2015].
Thus, the genotype-phenotype correlations in SLSMDSs remains controversial, with some cohorts reporting a correlation between age of onset and deletion size or inclusion of MT-CYB within the deletion and others finding no correlation [Grady et al 2014, Broomfield et al 2015, Mancuso et al 2015].
