Summary
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.
Diagnosis
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
Ophthalmologic features
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
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.
Recommended Genomic Testing
A multigene panel that includes ISCA2 and other genes of interest (see Differential Diagnosis) may be considered first. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Further Testing to Consider
Single-gene testing may (rarely) be considered if the clinical features are highly suggestive of IRMD. Only one pathogenic variant has been identified, and it is likely a founder variant [Al-Hassnan et al 2015]. Targeted analysis for this variant may be considered in consanguineous families from Saudi Arabia.
Table 1.
Molecular Genetic Testing Used in ISCA2-Related Mitochondrial Disorder
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| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|
|
ISCA2
| Targeted testing for c.229G>A pathogenic variant 3 | 18/19 4 |
| Sequence analysis 5 | ~100% 3 |
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 |
- 1.
- 2.
- 3.
One pathogenic founder variant has been reported [Al-Hassnan et al 2015]. Compound heterozygosity for two variants (c.295delT and c.334A>G) has been reported in a single affected individual [Toldo et al 2018], whose features differed slightly from the originally described cohort of individuals, who were all homozygous for the founder variant.
- 4.
- 5.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Clinical Characteristics
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.
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)
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| Differential Disorder | Gene(s) | MOI | Clinical Features of Differential Disorder |
|---|
| Overlapping w/IRMD | Distinguishing from IRMD |
|---|
| Multiple mitochondrial dysfunctions syndrome 1 |
NFU1
| AR |
Feeding difficulties Muscle weakness Decreasing responsiveness Neurologic regression White matter lesions on brain MRI Lactic acidosis ↓ activity of mt respiratory complexes
|
|
| Multiple mitochondrial dysfunctions syndrome 2 |
BOLA3
| AR |
|
Cardiomyopathy Hepatomegaly Extrapyramidal signs Ataxia Myoclonus
|
| Multiple mitochondrial dysfunctions syndrome 3 |
IBA57
| AR |
|
Onset in utero Intrauterine growth restriction Microcephaly Dysmorphic features (retrognathia, high-arched palate, widely spaced nipples) Arthrogryposis Severe hypotonia Polymicrogyria Hypoplasia of the corpus callosum Hypoplasia of the medulla oblongata
|
|
ISCA1-related multiple mitochondrial dysfunctions syndrome
|
ISCA1
| AR |
| Abnormalities of cortical migration |
|
Metachromatic leukodystrophy
| ARSA or PSAP | AR | Neurologic regression Leukodystrophy Spasticity
| ↑ urinary sulfatide excretion |
|
Krabbe disease
|
GALC
| AR | Neurologic regression Leukodystrophy Spasticity
| Pattern of MRI findings incl involvement of thalami & caudate |
|
Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
|
DARS2
| AR |
| Pattern of MRI findings |
|
Childhood ataxia with central nervous system hypomyelination/vanishing white matter
|
EIF2B1
EIF2B2
EIF2B3
EIF2B4
EIF2B5
| AR |
Neurologic regression Leukodystrophy Spasticity Optic atrophy
|
|
|
Canavan disease
|
ASPA
| AR |
Neurologic regression Leukodystrophy Optic atrophy
|
|
|
Alexander disease
|
GFAP
| AD |
Neurologic regression Leukodystrophy Spasticity Optic atrophy
|
Macrocephaly Pattern of MRI findings
|
|
Leigh syndrome
| Hetero-geneous | AR
XL
mt |
|
Hypertrophic cardiomyopathy Hypertrichosis Renal tubulopathy Liver involvement Bilateral symmetric T2-weighted hyperintensities in the basal ganglia &/or brain stem on MRI Basal ganglia involvement
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
Other leukodystrophies and lysosomal storage diseases. Other progressive degenerative disorders that manifest in infancy can mimic IRMD. In the presence of leukodystrophy, other conditions to consider include Pelizaeus-Merzbacher disease and GM2 gangliosidoses (Tay-Sachs disease [hexosaminidase A deficiency] and Sandhoff disease).
See OMIM Multiple Mitochondrial Dysfunctions Syndrome Phenotypic Series to view genes associated with this phenotype in OMIM.
Management
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. In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:
Gross Motor Dysfunction
Physical therapy is recommended to maximize mobility.
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
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
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
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.
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.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Mito Foundation
Australia
Phone: 61-1-300-977-180
Email: info@mito.org.au
The Charlie Gard Foundation
United Kingdom
Email: hello@thecharliegardfoundation.org
United Mitochondrial Disease Foundation
Phone: 888-317-UMDF (8633)
Email: info@umdf.org
RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A.
ISCA2-Related Mitochondrial Disorder: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Gene structure. The longest transcript of ISCA2, NM_194279.3, has four exons. For a detailed summary of gene, transcript, and protein information, see Table A, Gene.
Pathogenic variants. One pathogenic founder variant has been reported to date [Alazami et al 2015, Al-Hassnan et al 2015, Alaimo et al 2018, Alfadhel et al 2018]. Toldo et al [2018] reported a single affected individual who was a compound heterozygote for novel ISCA2 variants (Table 3).
Table 3.
ISCA2 Pathogenic Variants Discussed in This GeneReview
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| DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
|---|
| c.229G>A | p.Gly77Ser |
NM_194279.3
NP_919255.2
|
| c.295delT 1 | p.Phe99LeufsTer18 |
| c.334A>G 1 | p.Ser112Gly |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Normal gene product. The ISCA2
NM_194279.3 transcript encodes the 154-amino-acid protein iron-sulfur cluster assembly 2 homolog, mitochondrial (NP_919255.2). It is an A-type iron-sulfur cluster (ISC) protein that has a critical functional domain for iron-sulfur (Fe-S) biogenesis. The protein helps in maturation of mitochondrial iron-sulfur cluster assembly.
Abnormal gene product. Experimental studies indicate that p.Gly77Ser leads to reduced complex II and VI activity in the tested patients' muscle tissues [Alaimo et al 2018, Toldo et al 2018]. Loss of ISCA2 has been shown to diminish mitochondrial membrane potential, the mitochondrial network, basal and maximal respiration, and ATP production and to disrupt the 4Fe-4S cluster machinery [Alaimo et al 2018].
References
Literature Cited
Alaimo JT, Besse A, Alston CL, Pang K, Appadurai V, Samanta M, Smpokou P, McFarland R, Taylor RW, Bonnen PE. Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.
Hum Mutat. 2018;39:537–49. [
PMC free article: PMC5839994] [
PubMed: 29297947]
Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA, Faqeih E, Alhashem A, Bashiri FA, Al-Owain M, Kentab AY, Sogaty S, Al Tala S, Temsah MH, Tulbah M, Aljelaify RF, Alshahwan SA, Seidahmed MZ, Alhadid AA, Aldhalaan H, AlQallaf F, Kurdi W, Alfadhel M, Babay Z, Alsogheer M, Kaya N, Al-Hassnan ZN, Abdel-Salam GM, Al-Sannaa N, Al Mutairi F, El Khashab HY, Bohlega S, Jia X, Nguyen HC, Hammami R, Adly N, Mohamed JY, Abdulwahab F, Ibrahim N, Naim EA, Al-Younes B, Meyer BF, Hashem M, Shaheen R, Xiong Y, Abouelhoda M, Aldeeri AA, Monies DM, Alkuraya FS. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.
Cell Rep. 2015;10:148–61. [
PubMed: 25558065]
Alfadhel M, Nashabat M, Alrifai MT, Alshaalan H, Al Mutairi F, Al-Shahrani SA, Plecko B, Almass R, Alsagob M, Almutairi FB, Al-Rumayyan A, Al-Twaijri W, Al-Owain M, Taylor RW, Kaya N. Further delineation of the phenotypic spectrum of ISCA2 defect: a report of ten new cases.
Eur J Paediatr Neurol. 2018;22:46–55. [
PubMed: 29122497]
Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, Almass R, Al-Harazi OS, Al-Hindi H, Malibari OI, Almutari FB, Tulbah S, Alhadeq F, Al-Sheddi T, Alamro R, AlAsmari A, Almuntashri M, Alshaalan H, Al-Mohanna FA, Colak D, Kaya N. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.
J Med Genet. 2015;52:186–94. [
PubMed: 25539947]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Genet Med. 2015;17:405–24. [
PMC free article: PMC4544753] [
PubMed: 25741868]
Toldo I, Nosadini M, Boscardin C, Talenti G, Manara R, Lamantea E, Legati A, Ghezzi D, Perilongo G, Sartori S. Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.
Metab Brain Dis. 2018;33:805–12. [
PubMed: 29359243]