Clinical characteristics.

ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Affected individuals may also demonstrate elevated blood lactate levels with an elevated lipid-lactate peak on brain MR spectroscopy. Further brain MRI findings may include extensive cerebral and cerebellar deep white matter hyperintensities, marked dilatation of the cerebral ventricles, and pachygyria. Prognosis is poor and most individuals succumb to an intercurrent illness in early childhood.

Diagnosis/testing.

The diagnosis of ISCA1-MMDS is established in a proband with suggestive findings and/or biallelic pathogenic variants in ISCA1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is primarily supportive. A feeding tube (nasogastric or gastrostomy) may be required. Standard treatment for spasticity, seizures, abnormal vision, and hearing loss.

Prevention of secondary complications: Adequate hydration, stool softeners, and laxatives may help to prevent severe constipation.

Surveillance: Assessment for new neurologic manifestations, safety of oral intake, adequate nutrition, and evidence of respiratory insufficiency and aspiration at each visit. Monitor constipation, developmental progress, growth parameters, and family needs at each visit. Ophthalmologic and audiologic evaluations annually or based on clinical suspicion.

Genetic counseling.

ISCA1-related multiple mitochondrial dysfunctions syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual with ISCA1-MMDS 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 pregnancies at increased risk are possible if the pathogenic ISCA1 variants in the family are known.

Suggestive Findings

ISCA1-MMDS should be suspected in individuals with the following neurologic, ophthalmologic, head imaging, and supportive laboratory findings.

Neurologic findings

• Early-infantile onset and progressive neurologic deterioration
• Early-onset seizures, often developing before age six months
• Incessant cry
• Spasticity
• Exaggerated deep tendon reflexes
• Early death

Ophthalmologic features

• Nystagmus
• Pigmentary retinopathy

Head MRI findings

• Diffuse bilateral symmetric signal abnormality in the deep cerebral and cerebellar white matter; white matter abnormalities may also involve the corpus callosum, pons, and spinal cord.
• Pachygyria
• Ventriculomegaly
• Elevated lipid-lactate peak on MR spectroscopy

Supportive laboratory findings

• Elevated plasma lactate
• Elevated serum creatinine phosphokinase

Establishing the Diagnosis

The diagnosis of ISCA1-MMDS is established in a proband with suggestive findings and/or biallelic pathogenic variants in ISCA1 identified by molecular genetic testing (see Table 1).

Because the phenotype of ISCA1-MMDS is indistinguishable from many other inherited disorders with neurodegeneration and leukodystrophy, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of ISCA1, followed by gene-targeted deletion/duplication analysis) may be considered if the clinical findings are highly suggestive of ISCA1-MMDS.

• A multigene panel that includes ISCA1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing (including mitochondrial sequencing) is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition typically characterized by either no attainment of developmental milestones or very early loss of achieved milestones, seizures in early infancy, development of spasticity with exaggerated deep tendon reflexes, nystagmus, and risk for sensorineural hearing loss. Seven individuals from five unrelated families with this condition have been identified to date [Shukla et al 2017, Shukla et al 2018, Torraco et al 2018]. All individuals with ISCA1-MMDS presented with early onset and progressive neurodegeneration.

Cognitive/motor development

• Six of the seven affected individuals either did not attain any developmental milestone or showed very early loss of achieved milestones.
• One individual reported by Torraco et al [2018] showed a milder phenotype. Early regression was seen, followed by slow attainment of milestones and delayed development.
  • The proband lost head control at age three months.
  • He regained head control and was able to sit with support at 18 months.
  • He achieved the ability to sit without support by age four years.
  • At age six years, he could speak in sentences.

Neurologic

• Occipitofrontal circumference ranged from normal to -6 SD at the time of evaluation [Shukla et al 2018].
  Progressive microcephaly was noted in only one individual for whom head circumference at birth was available. His head circumference was noted to be normal at birth and fell to -2 SD at six months [Shukla et al 2018].
• Six of the seven individuals developed seizures between age two and four months.
• Clinical examination revealed spasticity and exaggerated deep tendon reflexes.
• Two of seven had incessant cry.

Ophthalmologic

• Nystagmus was observed in two individuals [Shukla et al 2017, Torraco et al 2018].
• Pigmentary retinopathy was seen in one individual.

Hearing. Bilateral sensorineural hearing loss was identified by brain stem evoked response audiometry in two individuals [Shukla et al 2018,Torraco et al 2018].

Feeding. One of the seven individuals had severe dysphagia necessitating a Nissen fundoplication with gastrostomy tube placement [Torraco et al 2018].

Biochemical testing results

• Elevated blood lactate was observed in six of the seven individuals.
• In one individual, elevated creatine phosphokinase level was observed [Shukla et al 2017].
• Respiratory chain enzyme analysis on fibroblasts revealed deficient levels of mitochondrial complex I and II enzymes [Torraco et al 2018].

Note: More invasive testing that requires a skin biopsy sample may be bypassed in favor of molecular genetic testing on a peripheral blood sample.

Prognosis. All the affected individuals succumbed during an intercurrent illness. The affected individuals from India did not survive beyond age five years. The affected individual from Italy lived to age 11 years. No definitive treatment other than supportive care is available at present.

Neuroimaging with brain MRI shows a characteristic and recognizable pattern:

• Extensive cerebral and cerebellar deep white matter hyperintensities were noted in all individuals.
• Marked dilatation of the cerebral ventricles and pachygyria were seen in four families (see Genotype-Phenotype Correlations).
• Elevated lipid-lactate peak was seen on brain MR spectroscopy [Shukla et al 2017, Shukla et al 2018].

Genotype-Phenotype Correlations

Though very few individuals are reported with this condition, there appears to be striking similarity in clinical and brain imaging features in individuals with the c.259G>A variant.

• In four families with biallelic c.259G>A variants, all affected individuals had marked dilatation of the cerebral ventricles with pachygyria [Shukla et al 2017, Shukla et al 2018].
• The individual reported by Torraco et al [2018], who was homozygous for the c.29T>G variant, did not show ventriculomegaly or any cortical abnormalities.

One affected individual homozygous for the c.29T>G missense variant showed milder clinical as well as radiologic features and succumbed to this condition at age 11 years [Torraco et al 2018]. It is unclear whether the clinical course in this affected individual was due to the genotype or to baseline phenotypic variability of this condition.

Prevalence

The prevalence of ISCA1-MMDS is unknown. Seven affected individuals from five families have been reported [Shukla et al 2017, Shukla et al 2018, Torraco et al 2018]. Six individuals are reported from the southwestern part of India [Shukla et al 2017, Shukla et al 2018]; one individual of Italian descent is reported from outside this region [Torraco et al 2018].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ISCA1-MMDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The mainstay of treatment is supportive and is best provided by a multidisciplinary team including a geneticist, pediatric neurologist or neurologist, and dietician. The following recommendations are based on the experience from a small number of affected individuals. The spectrum of disease may evolve with reports of additional affected people. Treatment options should be considered based on the observed phenotype.