Clinical Guidance

For all mitochondrial DNA (mtDNA) pathogenic variants, including SLSMDs, clinical expressivity depends on three factors:

• Relative abundance of mtDNA with the deletion (heteroplasmy load)

• Tissue distribution of mtDNA with the deletion

• Tissue vulnerability to impaired oxidative metabolism (threshold effect)

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Penetrance

Penetrance is a function of the proportion of mtDNA with the deletion. However, the authors are not aware of any non-penetrant individuals. To date, individuals with low-level heteroplasmy (e.g., 25%-33% in muscle) are symptomatic .

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Diagnostic Criteria

A diagnostic algorithm has been proposed for single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) by .

Suggestive Findings

SLSMDSs should be suspected in probands with clinical features present in any of the following overlapping phenotypes.

Kearns-Sayre Syndrome (KSS)/ Kearns-Sayre Syndrome Spectrum (KSS Spectrum)

Clinical features. Onset before age 20 years with the classic clinical triad of:

• Pigmentary retinopathy (progressive vision impairment due to rod-cone dystrophy), the pivotal feature that distinguishes KSS from chronic progressive external ophthalmoplegia (CPEO)

• CPEO including ptosis

• Cardiac conduction abnormality including bundle branch block, which may progress to complete heart block

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Differential Diagnosis

Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) must be differentiated from other disorders associated with ophthalmoplegia. The ptosis in individuals with single large-scale mitochondrial DNA deletion syndromes (SLSMDSs) is typically asymmetric, compared to the other causes listed in , in which the ptosis is typically more symmetric as well as fluctuating.

Table 4.

Disorders with Progressive External Ophthalmoplegia to Consider in the Differential Diagnosis of KSS and CPEO

Gene | Disorder | MOI | Features of This Disorder Not Typically Associated with KSS or CPEO

~35 genes incl:CHATCHRNECOLQDOK7RAPSN | Congenital myasthenic syndromes (See also Myasthenia Gravis after this table.) | ARAD1 | • Primary muscle disorders

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with a single large-scale mitochondrial DNA deletion syndrome (SLSMDS), the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 6. Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Clinical Guidance

Volatile anesthetic hypersensitivity may occur. Avoid prolonged treatment with propofol (30-60 minutes) . Guidelines for anesthesia in individuals with mitochondrial disease are available . Note: Previously, avoidance of numerous medications was recommended in individuals with primary mitochondrial disorders including SLSMDSs. However, a recent expert review panel utilizing a Delphi consensus method updated the recommendations on medication safety and advised affected individuals to consult with the physician managing their mitochondrial disease.

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"

Surveillance Guidelines

The Mitochondrial Medicine Society (MMS) published surveillance standards (summarized in ) for individuals with mitochondrial disease to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations . Table 8. Single Large-Scale Mitochondrial DNA Deletion Syndromes: Recommended Surveillance

Source: GeneReviews — "Single Large-Scale Mitochondrial DNA Deletion Syndromes"