Mitochondrial disorders: Understanding mitochondrial DNA point mutations and deletion syndromes.

ABSTRACT: Mitochondrial disorders arise from DNA mutations in either the mitochondrial DNA (mtDNA) or nuclear DNA genomes. This article focuses on a mtDNA base-pair mutation associated with neuropathy, ataxia, and retinitis pigmentosa and Leigh syndrome and the large-scale mtDNA deletion associated with Kearns-Sayre syndrome. Disease sequelae and management strategies are reviewed, along with implications for the nurse practitioner in primary or specialty care.

Pearson syndrome: a multisystem mitochondrial disease with bone marrow failure.

Pearson syndrome (PS) is a rare fatal mitochondrial disorder caused by single large-scale mitochondrial DNA deletions (SLSMDs). Most patients present with anemia in infancy. Bone marrow cytology with vacuolization in erythroid and myeloid precursors and ring-sideroblasts guides to the correct diagnosis, which is established by detection of SLSMDs. Non hematological symptoms suggesting a mitochondrial disease are often lacking at initial presentation, thus PS is an important differential diagnosis in isolated hypogenerative anemia in infancy. Spontaneous resolution of anemia occurs in two-third of patients at the age of 1-3 years, while multisystem non-hematological complications such as failure to thrive, muscle hypotonia, exocrine pancreas insufficiency, renal tubulopathy and cardiac dysfunction develop during the clinical course. Some patients with PS experience a phenotypical change to Kearns-Sayre syndrome. In the absence of curative therapy, the prognosis of patients with PS is dismal. Most patients die of acute lactic acidosis and multi-organ failure in early childhood. There is a great need for the development of novel therapies to alter the natural history of patients with PS.

Potpourri of retinopathies in rare eye disease - A case series.

This case series describes the ocular and retinal manifestations of rare eye diseases in systemic syndromes. This observational case series consists of five patients with varied ophthalmic manifestations and documentation of imaging in rare pediatric and adult retinopathies. Two patients had Kearns Sayre syndrome (KSS) based on the classical triad of external ophthalmoplegia, pigmentary retinopathy, and onset before 20 years of age. In one patient of KSS, the mitochondrial retinopathy was seen in an asymmetric pattern, and the second patient presented with KSS after being mis-diagnosed as myasthenia gravis elsewhere. A case of Senior Loken syndrome in pediatric age is described in this series with varied ophthalmic manifestations ranging from retinitis pigmentosa to orbital abscess. This series also enlightens features of Hallervorden Spatz syndrome presenting with bull's eye maculopathy and a case of spino-cerebellar ataxia type 7 presenting with pigmentary retinopathy.

Kearns-Sayre syndrome: expanding spectrum of a "novel" mitochondrial leukomyeloencephalopathy.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease associated to a widespread cerebral leukodystrophy. MRI shows a typical centripetal pattern where U-fibers are mainly affected with a relative spare of periventricular white matter. Recently, different patterns of spinal cord involvement have been described in KSS. Here we report 4 new cases with typical cerebral leukodystrophy associated with spinal cord lesions. A pattern characterized by abnormal signal intensity in the H gray matter and posterior columns was found in 2 patients, while the remaining 2 presented a peculiar involvement of the spinal trigeminal nuclei at the junction of low medulla and cervical cord. MRI spinal cord involvement in KSS is probably an underestimated finding and should be evaluated in the diagnostic work up of these patients.

Pediatric single large-scale mtDNA deletion syndromes: The power of patient reported outcomes.

There is a limited understanding of system-level clinical outcomes and interventions associated with single large-scale mitochondrial DNA deletion syndromes (SLSMDS). Additionally, no research exists that describes patient reported outcomes (PROs) of children with SLSMDS. A global and observational registry was established to understand the multi-systemic course of SLSMDS and track clinical outcomes. The development and design of the registry is described. Demographic characteristics, history and diagnoses, and system level prevalence of problems and interventions are reported for 42 children. System level problems and interventions include information on the following body systems: audiology, cardiac, endocrine, gastrointestinal (including pancreatic and hepatobiliary system), hematological, metabolic, neurological (including autonomic, mobility, & learning), ophthalmic, psychiatric, renal, and respiratory. Results emphasize the need of patient registries and suggest that the diagnostic odyssey and burden of disease for children with SLSMDS is significant. System-level findings may help families and clinical providers with diagnosis, prognostication, and treatment. A multidisciplinary team of clinical experts with a central coordinating specialist for children with SLSMDS is recommended.

Kearns Sayre syndrome: a rare etiology of complete atrioventricular block in children (case report).

Kearns Sayre syndrome is a rare mitochondrial abnormality first described in 1958, characterized by a triad associating progressive external ophthalmoplegia, ptosis, and pigmentary retinopathy with progressive alteration of cardiac conduction, which determines the vital prognosis of this entity. Here we report the case of a 13-year-old child of consanguineous parents who consults for recurrent syncope. The clinical exam found bilateral ptosis with complete atrioventricular block on electrocardiogram. The ophthalmological exam found pigmentary retinopathy. The patient underwent successful implantation of a double chamber pacemaker within 24 hours of admission, with an uneventful postoperative course. This case report highlights the interest of systematically assessing cardiac complications in children with mitochondrial disease such as Kearns Sayre syndrome, especially since cardiac involvement is the major prognostic factor in this disease.

Retinoschisis associated with Kearns-Sayre syndrome.

BACKGROUND: Kearns-Sayre Syndrome (KSS) is characterized by pigmentary retinopathy, external ophthalmoplegia and heart block. We report on a now 24-year-old male with clinical retinoschisis and molecularly confirmed KSS. MATERIALS AND METHODS: Physical and complete ophthalmic examination, molecular diagnosis. RESULTS: Over nine years of follow-up, the subject manifested progressive signs and symptoms of KSS, including external ophthalmoplegia/strabismus, ptosis, pigmentary retinopathy, corneal edema, Type I diabetes mellitus, gut dysmotility, sensorineural deafness and heart block. At age 21 he was incidentally found to have retinoschisis on optical coherence tomography that remained stable over three years follow-up. Sequencing of the RS1 gene revealed no pathogenic variants, effectively ruling out co-existing X-linked retinoschisis. CONCLUSIONS: These findings suggest retinoschisis may be a rare manifestation of KSS. A trial of a carbonic anhydrase inhibitor was frustrated by coexisting corneal edema associated with the condition.

Mitochondrial single-stranded DNA binding protein novel de novo SSBP1 mutation in a child with single large-scale mtDNA deletion (SLSMD) clinically manifesting as Pearson, Kearns-Sayre, and Leigh syndromes.

Mitochondrial DNA (mtDNA) genome integrity is essential for proper mitochondrial respiratory chain function to generate cellular energy. Nuclear genes encode several proteins that function at the mtDNA replication fork, including mitochondrial single-stranded DNA-binding protein (SSBP1), which is a tetrameric protein that binds and protects single-stranded mtDNA (ssDNA). Recently, two studies have reported pathogenic variants in SSBP1 associated with hearing loss, optic atrophy, and retinal degeneration. Here, we report a 14-year-old Chinese boy with severe and progressive mitochondrial disease manifestations across the full Pearson, Kearns-Sayre, and Leigh syndromes spectrum, including infantile anemia and bone marrow failure, growth failure, ptosis, ophthalmoplegia, ataxia, severe retinal dystrophy of the rod-cone type, sensorineural hearing loss, chronic kidney disease, multiple endocrine deficiencies, and metabolic strokes. mtDNA genome sequencing identified a single large-scale 5 kilobase mtDNA deletion (m.8629_14068del5440), present at 68% and 16% heteroplasmy in the proband's fibroblast cell line and blood, respectively, suggestive of a mtDNA maintenance defect. On trio whole exome blood sequencing, the proband was found to harbor a novel de novo heterozygous mutation c.79G>A (p.E27K) in SSBP1. Size exclusion chromatography of p.E27K SSBP1 revealed it remains a stable tetramer. However, differential scanning fluorimetry demonstrated p.E27K SSBP1 relative to wild type had modestly decreased thermostability. Functional assays also revealed p.E27K SSBP1 had altered DNA binding. Molecular modeling of SSBP1 tetramers with varying combinations of mutant subunits predicted general changes in surface accessible charges, strength of inter-subunit interactions, and protein dynamics. Overall, the observed changes in protein dynamics and DNA binding behavior suggest that p.E27K SSBP1 can interfere with DNA replication and precipitate the introduction of large-scale mtDNA deletions. Thus, a single large-scale mtDNA deletion (SLSMD) with manifestations across the clinical spectrum of Pearson, Kearns-Sayre, and Leigh syndromes may result from a nuclear gene disorder disrupting mitochondrial DNA replication.

Exophthalmos in Kearns-Sayre syndrome.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA (mtDNA) deletion syndrome that typically presents before 20 years of age and is characterized by chronic progressive external ophthalmoplegia, pigmentary retinopathy, and a combination of cardiac conduction defects, cerebellar ataxia, and elevated cerebrospinal fluid protein levels. The mtDNA defects interfere with oxidative phosphorylation and can affect a number of cellular energy processes in various organs. We report the case of a 15-year-old girl with KSS that was uniquely associated with bilateral, symmetrical exophthalmos.

Prophylactic pacemaker placement at first signs of conduction disease in Kearns-Sayre syndrome.

Cardiac conduction disease affects patients with Kearns-Sayre syndrome. We report a young asymptomatic patient with Kearns-Sayre syndrome with abnormal conduction on electrocardiogram and Holter monitor, although not advanced atrioventricular block. She underwent prophylactic pacemaker placement, and rapidly developed complete atrioventricular block, which resulted in 100% ventricular pacing. It may be reasonable to consider prophylactic pacemaker implantation in patients with Kearns-Sayre syndrome with evidence of cardiac conduction disease even without overt atrioventricular block given its unpredictable progression to complete atrioventricular block.

Scleral contact lenses for the management of complicated ptosis.

PURPOSE: To present the management of three patients suffering from ptosis of various etiologies, with scleral contact lenses. MATERIAL AND METHODS: Three patients (five eyes) with ptosis resulting from levator dehiscence due to long-term rigid gas permeable contact lens wear for keratoconus, phthisis bulbi, and myopathy due to Kearns-Sayre syndrome were identified during a 2-year period. They were fitted with scleral contact lenses in order to provide cosmesis by lifting the upper eyelid with the bulk of the lens, and simultaneously provide vision correction where applicable. RESULTS: The scleral contact lenses provided comfortable wear, significantly improved cosmesis as both palpebral aperture and marginal reflex distance were increased, and visual acuity was also subjectively and objectively improved. Two of the patients opted for the scleral contact lenses, whereas the parents of the third patient, a 10-year-old girl with Kearns-Sayre syndrome, chose to undergo ptosis surgery due to handling issues of the scleral contact lenses. CONCLUSION: Scleral contact lenses can be a useful addition to the treatment option for patients with complicated ptosis.

A case of hypopituitarism accompanying Kearns-Sayre syndrome treated with human chorionic gonadotropin: A case report and literature review.

Kearns-Sayre syndrome (KSS) is a disorder caused by mutations in mitochondrial DNA. Here, we report an unusual case of Kearns-Sayre syndrome accompanied by hypopituitarism (deficiencies in reproductive and growth hormones). A 20-year-old male presented with growth retardation for the last 8 years, as well as the following findings: short stature, delayed puberty, myasthenia, an extraocular movement deficit, drooping eyelids, pectus carinatum and scoliosis. Cerebral enhanced magnetic resonance imaging revealed dysplasias of the pituitary, white matter and cerebellum. Laboratory work-up showed subnormal testosterone and growth hormone levels, a subnormal testicular volume, sensorineural deafness, pigmentary retinopathy, complete right bundle branch block and left anterior bundle branch block. Pathological examination revealed ragged red muscle fibres. Thus, this rare case involved the coexistence of Kearns-Sayre syndrome and hypopituitarism in a patient. Administration of coenzyme Q10 for the KSS and hormone replacement therapy for the endocrinopathies were performed for treatment of this patient.