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multiple mitochondrial dysfunctions syndrome 5 (MMDS5) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

multiple mitochondrial dysfunctions syndrome 5

MONDO:0033282

Also known as:MMDS5

Overview

GeneticsAutosomal recessive · ISCA1 (chr 9)

ResearchLimited published research (1 article)

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.

Features include always present findings: Feeding difficulties, Seizure, Global developmental delay, and Enlarged brain ventricles (ventriculomegaly) and others; and common findings: Elevated creatine kinase (muscle enzyme) (elevated circulating creatine kinase concentration) and Strabismus. 16 total HPO annotations.

Organ System	Phenotype Count	Example Features
Brain and nerves	6	Loss of previously acquired skills (developmental regression), Seizure, Global developmental delay

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

ISCA1 encodes iron-sulfur cluster assembly 1 (129 aa). Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway. Probably involved in the binding of an intermediate of Fe/S cluster assembly Highest expression in Brain Cerebellar Hemisphere (49.7 TPM) and Brain Frontal Cortex BA9 (42.2 TPM).

Multiple mitochondrial dysfunctions syndrome 5 is associated with mutations in the ISCA1 gene on chromosome 9.

The ISCA1 protein participates in Formation of 4Fe-4S cluster on ISCA1:ISCA2 and Mitochondrial iron-sulfur cluster biogenesis pathways.

ISCA1 is classified as a druggable target with score 0.0.

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 multiple mitochondrial dysfunctions syndrome 5. 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 multiple mitochondrial dysfunctions syndrome 5.

1 publication has been identified in PubMed for multiple mitochondrial dysfunctions syndrome 5. Research spans Basic Science / Preclinical (100%).

Recent Publications

Zhang T (2026). [PMID: 41540060](https://pubmed.ncbi.nlm.nih.gov/41540060/). *NPJ Parkinson's disease*. [Basic Science / Preclinical]

Data assembled from 7 of 12 sources · Last updated Sep 19, 2026, 10:42 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:617613

Orphanet

European rare disease database

Orphanet:569274

GARD

Genetic and Rare Diseases Info Center

GARD:22305

Questions for Your Care Team

→Should my partner and I meet with a genetic counselor to discuss carrier status and family planning?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

← Back to All Diseases

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

multiple mitochondrial dysfunctions syndrome 5

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

multiple mitochondrial dysfunctions syndrome 5

Overview

Clinical Presentation

Genetic Landscape

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

Clinical Guidance

Explore clinical features

Differential Diagnosis

Therapies Under Investigation

Clinical Trials