Clinical characteristics.

Infants with ISCA2-related mitochondrial disorder (IRMD) typically attain normal development in the first months of life. At age three to seven months, affected individuals usually present with a triad of neurodevelopmental regression, nystagmus with optic atrophy, and diffuse white matter disease. As the disease progresses, global psychomotor regression continues at a variable pace and seizures may develop. Affected children become vegetative within one to two years. During their vegetative state, which may persist for years, affected individuals are prone to recurrent chest infections that may require ventilator support. Most affected individuals die during early childhood.

Diagnosis/testing.

The diagnosis of ISCA2-related mitochondrial disorder is established in a proband by the identification of biallelic pathogenic variants in ISCA2 on molecular genetic testing.

Management.

Treatment of manifestations: Treatment is primarily supportive and may require input from a geneticist, neurologist, dietician, and developmental specialist. A feeding tube (nasogastric or gastrostomy) is typically required. Standard treatment for epilepsy. Recurrent chest infections may require ventilator support in addition to antimicrobial therapy. Referral to early intervention services is recommended. For muscle tone abnormalities including hypertonia, baclofen and/or Botox^® may be considered.

Prevention of secondary complications: Constipation may become problematic and may require ensuring adequate hydration and/or treatment with stool softeners or laxatives.

Surveillance: Periodic evaluation of swallowing function is suggested.

Genetic counseling.

ISCA2-related mitochondrial disorder is inherited in an autosomal recessive manner. At conception, each sib of an affected individual with IRMD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the ISCA2 pathogenic variants in the family are known.

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
  • Serum and CSF lactate may be elevated, but this is not a consistent finding.
  • Plasma and CSF glycine levels are usually elevated [Alaimo et al 2018, Alfadhel et al 2018].
  • Plasma acylcarnitine and urine organic acids analyses are usually unremarkable [Al-Hassnan et al 2015].
• Respiratory chain enzyme analysis on muscle tissue reveals deficient activity of complex II and IV [Alaimo et al 2018, Toldo et al 2018].

Note: (1) Respiratory chain enzyme analysis is not required to make the diagnosis. (2) More invasive testing that requires a skin or muscle biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample (see Establishing the Diagnosis).

Establishing the Diagnosis

The diagnosis of ISCA2-related mitochondrial disorder is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in ISCA2 on molecular genetic testing (see Table 1)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ISCA2 variants of uncertain significance (or of one known ISCA2 pathogenic variant and one ISCA2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include use of a multigene panel, more comprehensive genomic testing, and (rarely) single-gene testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of IRMD is similar to a wide range of neurodegenerative conditions, genomic testing is typically pursued first.

Clinical Description

Only 20 individuals with this condition have been reported [Alazami et al 2015, Al-Hassnan et al 2015, Alaimo et al 2018, Alfadhel et al 2018, Toldo et al 2018]. Infants with IRMD attain normal development in the first months of life. At age three to seven months 18 out of 18 individuals reported have experienced progressive loss of milestones with irritability, inattention, and inability to perform previously acquired motor skills. Nystagmus on presentation has been reported in eight of 12 individuals assessed. Clinical evaluation reveals central hypotonia that progresses to limb spasticity and hyperreflexia (18/18). Optic atrophy with progressive loss of vision has been observed in 18 of 18 affected individuals evaluated. As the disease progresses, global psychomotor regression continues at a variable pace and seizures (3/10) may develop. Seizures are generalized tonic-clonic and are responsive to anticonvulsant treatment [Alfadhel et al 2018]. Affected children become vegetative within one to two years. During their vegetative state, which may persist for years, affected individuals are prone to recurrent chest infections that may require ventilator support. Most affected individuals die during early childhood. As the disease is severe with no known cure, continuing to provide supportive care, including invasive ventilation, must be seriously reviewed. Progressive multiorgan (liver, kidney, heart) failure has not been observed in this condition.

Dysmorphic features (low-set ears, broad nasal bridge, short fourth metacarpals, cutaneous toe syndactyly) have been rarely observed (2/18) [Alaimo et al 2018].

A rapidly progressive severe course with neonatal leukoencephalopathy and death at age three months was reported in a single affected individual who had biallelic novel (non-founder) pathogenic ISCA2 variants [Toldo et al 2018].

Since so few cases have been identified, understanding of the clinical phenotypic spectrum and natural history continues to evolve.

Neuroimaging with brain MRI typically demonstrates extensive diffuse bilateral symmetric signal abnormality in cerebral periventricular white matter, most often sparing the U-fibers. These changes are hyperintense on T₂-weighted images. Signal abnormalities can also be seen in other areas of the brain (see Suggestive Findings), although the basal ganglia are usually spared [Al-Hassnan et al 2015]. High lactate, glycine, and glutamine/glutamate peaks may also be seen in brain MR spectroscopy [Alaimo et al 2018, Alfadhel et al 2018, Toldo et al 2018].

Muscle biopsy from one affected individual has been analyzed; it demonstrated minimal histologic changes [Al-Hassnan et al 2015]. The hematoxylin- and eosin-stained frozen sections of the skeletal muscle showed mild to moderate variation in myofiber size with moderately to severely atrophic fibers in a random distribution. There were no significant myopathic features, such as fiber degeneration, regeneration, or hypertrophy. Ragged red fibers were not observed. Ultrastructural examination of a representative preserved area showed normal myofibrillar organization and cellular organelles with only a few small accumulations of structurally normal mitochondria.

Genotype-Phenotype Correlations

One affected infant who had diffuse hypotonia, a rapidly progressive course, and no optic atrophy was found to have biallelic novel (non-founder) pathogenic ISCA2 variants (see Table 1, footnote 3) [Toldo et al 2018]. It is unclear whether the atypical presentation was a result of the novel variants or an instance of the clinical variability often seen among individuals with the same condition.

Prevalence

The prevalence of IRMD is unknown. Twenty affected individuals from 18 families have been reported in the literature [Alazami et al 2015, Al-Hassnan et al 2015, Alaimo et al 2018, Alfadhel et al 2018]. Most (19/20) of the affected individuals reported are from Saudi Arabia, which may suggest a higher prevalence of the disorder in Arabs. A single affected individual from Italy has been reported [Toldo et al 2018].

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.

Prevention of Secondary Complications

With the progression of the disease, constipation can be a problem. Adequate hydration, stool softeners, and laxatives may help in avoiding severe constipation.

Surveillance

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

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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

Mode of Inheritance

ISCA2-related mitochondrial disorder is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one ISCA2 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with ISCA2-related mitochondrial disorder are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an ISCA2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the ISCA2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the ISCA2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 22 February 2018 (ma) Review posted live
• 31 July 2017 (znah) Original submission

Literature Cited

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