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fatal multiple mitochondrial dysfunctions syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

fatal multiple mitochondrial dysfunctions syndrome

MONDO:0017338

Also known as:multiple mitochondrial dysfunctions syndromeMMDSfatal multiple mitochondrial dysfunction syndrome

Overview

Multiple mitochondrial dysfunctions syndrome describes a group of rare inborn errors of energy metabolism due to defects in mitochondrial [4Fe-4S] protein assembly. Patients present with a neonatal/infancy onset of metabolic lactic acidosis (that may be associated with hyperglycinemia and other abnormal metabolic testing results), muscular hypotonia, absence of psychomotor development or developmental regression, as well as abnormal neuroimaging findings (including leukodystrophy, brain developmental defects, white matter abnormalities, cerebral atrophy), and other variable clinical features (e.g., optic atrophy, cardiomyopathy, pulmonary hypertension, seizures, and dysmorphic features). Early fatal outcome is usual.

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

No HPO annotations are available for this condition.

GeneReviews

Clinical Guidance

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 . All individuals with ISCA1-MMDS presented with early onset and progressive neurodegeneration.

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS) is a severe neurodegenerative condition; consensus clinical diagnostic criteria have not been published.

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

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for fatal multiple mitochondrial dysfunctions syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ISCA1-MMDS, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis in Individuals with ISCA1-MMDS

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 7. Recommended Surveillance for Individuals with ISCA1-MMDS

System/Concern

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for fatal multiple mitochondrial dysfunctions syndrome.

10 publications have been identified in PubMed for fatal multiple mitochondrial dysfunctions syndrome. Research spans Case Report / Case Series (30%), Basic Science / Preclinical (30%), and Epidemiology / Natural History (20%).

Research Type	Count	% of Total
Patient case studies	3	30%

Data assembled from 4 of 12 sources · Last updated Sep 19, 2026, 11:54 AM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

Orphanet

European rare disease database

Orphanet:289573

GARD

Genetic and Rare Diseases Info Center

GARD:12632

Questions for Your Care Team

→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

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GeneReviews

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 ISCA1-related multiple mitochondrial dysfunctions syndrome (ISCA1-MMDS), the constellation of extensive leukodystrophy, pigmentary retinopathy, and biochemical evidence of mitochondrial involvement is suggestive of the disorder, but these features can also be seen in other conditions. Table 4. Disorders to Consider in the Differential Diagnosis of ISCA1-MMDS

Disorder	Gene	MOI	Clinical Features of Differential Diagnosis Disorder
NFU1	AR	Feeding difficulties, muscle weakness, decreasing responsiveness, neurologic regression; WM lesions on brain MRI	Pulmonary hypertension, obstructive vasculopathy; Spongiform degeneration, WM necrosis Multiple mitochondrial dysfunctions syndrome 2 (OMIM 614299)
BOLA3	AR	Visual impairment, spasticity; Leukodystrophy; Onset in infancy	Cardiomyopathy, hepatomegaly; Extrapyramidal signs, ataxia, myoclonus Multiple mitochondrial dysfunctions syndrome 3 (OMIM 615330)
IBA57	AR	WM abnormalities	Onset in utero, IUGR; Microcephaly, dysmorphic features (retrognathia, high-arched palate, widely spaced nipples), arthrogryposis, severe hypotonia; Hypoplasia of corpus callosum medulla oblongata ISCA2-related mitochondrial disorder (multiple mitochondrial dysfunctions syndrome 4)
ISCA2	AR	Loss of developmental milestones, spasticity, nystagmus; WM abnormalities; Lactic acidosis	plasma CSF glycine levels Metachromatic leukodystrophy (See Arylsulfatase A Deficiency OMIM 249900.)
PSAP	AR	Neurologic regression; Leukodystrophy; Spasticity	urinary sulfatide excretion Krabbe disease
GALC	AR	Neurologic regression, spasticity; Leukodystrophy	galactocerebrosidase activity (See Krabbe disease.) Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation
DARS2	AR	Neurologic regression	Spotty or confluent cerebral WM changes w/relative sparing of subcortical WM; Involvement of dorsal columns, lateral corticospinal tracts, medial lemniscus in medulla oblongata Childhood ataxia with central nervous system hypomyelination/vanishing white matter
EIF2B5	AR	Neurologic regression, spasticity; Leukodystrophy; MRI findings:bilateral symmetric diffuse changes in cerebral hemispheres isointense w/CSF;cystic breakdown of WM on proton density or FLAIR images;mild-to-severe cerebellar atrophy; Ovarian dysgenesis in females Canavan disease	—
ASPA	AR	Neurologic regression; Leukodystrophy	Macrocephaly; MRI findings:symmet...

Source: GeneReviews — "ISCA1-Related Multiple Mitochondrial Dysfunctions Syndrome"

Kisho

fatal multiple mitochondrial dysfunctions syndrome

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

Recent Publications

fatal multiple mitochondrial dysfunctions syndrome

Overview

Clinical Presentation

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Medical References

External Resources

Orphanet

GARD

Subtypes

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

Recent Publications