Clinical Guidance

No clinically relevant genotype-phenotype correlations have been identified.

Source: GeneReviews — "POLG-Related Disorders"

Diagnostic Criteria

Suggestive Findings

POLG-related disorders comprise a continuum of overlapping phenotypes. A POLG-related disorder should be suspected in individuals with combinations of the following clinical features and laboratory and neuroimaging findings. Clinical features. Clinical features form a continuum but vary in their age of onset. Apart from progressive external ophthalmoplegia (PEO)/ ptosis, other features could present at any time from infancy to adulthood. The most common clinical features by age of onset are:

• Prior to age 12 years (early-onset disease):

• Liver involvement (See .)

• Feeding difficulties

• Seizures

• Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia)

• Between age 12 and 40 years (juvenile/adult-onset disease):

Source: GeneReviews — "POLG-Related Disorders"

Differential Diagnosis

Table 4. Genes of Interest in the Differential Diagnosis of POLG-Related Disorders

Management Guidelines

No clinical practice guidelines for POLG-related disorders have been published, although consensus statement guidelines for primary mitochondrial diseases are available .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with POLG-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended. Evaluation should always include measures of functional neurologic status.

Table 5.

POLG-Related Disorders: Recommended Evaluations Following Initial Diagnosis

System | Evaluation | Comment

Neurologic

| Neurologic eval | • To incl brain MRI1

• Consider EEG video EEG if seizures are a concern.

Ataxia

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

Development

| Developmental assessment | • To incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education, need for speech therapy

Neurobehavioral/

Psychiatric

| Neuropsychiatric eval | For persons age 12 mos: screening for concerns incl sleep disturbances, ADHD, anxiety, /or findings suggestive of ASD. Formal neuropsychological eval can be considered for those w/any concerns identified on screening.

Depression screen | Assess for mood disturbances.

Musculoskeletal

| Orthopedics/ physical medicine rehab/ PT OT eval | To inc...

Source: GeneReviews — "POLG-Related Disorders"

Clinical Guidance

Valproic acid (Depakene®) and sodium divalproate (divalproex) (Depakote®) should be avoided because of the risk of precipitating and/or accelerating liver disease . As with some other mitochondrial diseases, physical stressors such as infection, fever, dehydration, and anorexia can result in a sudden deterioration and should be avoided if possible.

Source: GeneReviews — "POLG-Related Disorders"

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 — "POLG-Related Disorders"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, evaluations by a multidisciplinary team including neurologist, biochemical geneticist, hepatologist or gastroenterologist, physiatrist, psychiatrist, neuropsychologist and/or psychologist, ophthalmologist, and pulmonologist are recommended. No standard-of-care guidelines regarding the recommended frequency of evaluations exist; surveillance should be guided by clinical features, and the schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the recommendations in can be considered.

Table 7.

POLG-related disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

• EEG video EEG monitoring (e.g., for suspicion of subclinical status epilepticus or EPC, to determine if events are seizures or non-epileptic movements)

| At each visit

Development

| Monitor developmental progress educational needs.

Neurobehavioral/

Psychiatric

| Assessment for anxiety, ADHD, ASD, aggression, depression

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

Liver function metabolic status

| • Complete blood count

Source: GeneReviews — "POLG-Related Disorders"