Diagnostic Criteria

ISCA2-related mitochondrial disorder (IRMD) is a severe neurodegenerative condition; consensus clinical diagnostic criteria have not been published.

Suggestive Findings

IRMD should be suspected in infants with the following neurologic, ophthalmologic, head imaging, and supportive laboratory findings.

Neurologic findings

• Progressive loss of developmental milestones, typically beginning between ages three and seven months

• Spasticity

• Impaired speech

Ophthalmologic features

• Optic atrophy

• Nystagmus

Head MRI findings

• Diffuse bilateral symmetric signal abnormality in cerebral white matter

• In some cases, signal abnormalities in the corpus callosum, internal capsule, midbrain, middle cerebellar peduncles, and cervical spinal cord

Supportive laboratory findings

• Biochemical screening

Source: GeneReviews — "ISCA2-Related Mitochondrial Disorder"

Differential Diagnosis

The differential diagnosis of neurologic regression with white matter disease in infancy is extensive. Diagnostic algorithms for genetic leukodystrophy disorders have been published. In ISCA2-related mitochondrial disorder (IRMD), the constellation of extensive periventricular leukodystrophy, optic atrophy, and biochemical and/or histopathologic evidence of mitochondrial involvement is suggestive of the disorder but can also be seen in other conditions.

Table 2.

Disorders to Consider in the Differential Diagnosis of ISCA2-Related Mitochondrial Disorder (IRMD)

Differential Disorder | Gene(s) | MOI | Clinical Features of Differential Disorder

Overlapping w/IRMD | Distinguishing from IRMD

Multiple mitochondrial dysfunctions syndrome 1 | NFU1 | AR |

Source: GeneReviews — "ISCA2-Related Mitochondrial Disorder"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ISCA2-related mitochondrial disorder (IRMD), the following evaluations are recommended if they have not already been completed:

• Neurologic evaluation to assess for tone and spasticity

• Ophthalmologic examination to assess for optic atrophy

• Brain MRI and MRS

• Assessment of feeding problems, with consideration of a swallowing study

• Assessment of nutritional status by monitoring growth parameters and serum chemistries, such as albumin and total protein

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, neurologist, and dietician. Feeding via nasogastric tube or gastrostomy will be required in most cases. Standard treatment for epilepsy is indicated for those who have seizures. Recurrent chest infections may require ventilator support in addition to antimicrobial therapy.

Developmental Delay/ Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay/ intellectual disability in the United States; standard recommendations may vary from country to country. Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy.

Source: GeneReviews — "ISCA2-Related Mitochondrial Disorder"

Surveillance Guidelines

Periodic evaluation of swallowing function is suggested. Abnormal swallowing may prompt consideration of placement of a feeding tube.

Source: GeneReviews — "ISCA2-Related Mitochondrial Disorder"