Mitochondrial spastic paraplegia (SPGM) is a complex hereditary spastic paraplegia transmitted down the maternal line, reported in one Chinese family in which all affected members across four generations carry a homoplasmic m.1661A>G variant in MT-TV, the mitochondrially encoded transfer RNA for valine. The name reads like a category and is not one. "Mitochondrial spastic paraplegia" could reasonably mean "any HSP with a mitochondrial cause", which would be a grouping - SPG7 and SPG13 are both mitochondrial, and both are curated elsewhere in this knowledge base as separate nuclear-gene diseases. It is not what the term denotes. MONDO:0975951 is equivalent to OMIM:500018, an entry in OMIM's mitochondrial-DNA series created for this one family and this one variant, and the defining feature is not "a mitochondrial cause" but mitochondrial *inheritance*: the lesion is in the mitochondrial genome, so it passes only from mothers, and no nuclear locus is involved. The mechanism proposed is a chain from an mtDNA tRNA variant to a shortage of mitochondrial genomes. Transcriptome sequencing in the affected family showed upregulated mitochondrial autophagy genes, and the authors read that as the route by which the MT-TV variant lowers mtDNA copy number. The fourth generation, with the lowest copy number, had the earliest onset and the most severe disease, which is the entity's internal dose-response argument. Peroneal nerve biopsy showed ultrastructural abnormalities in myelin and mitochondria, so there is peripheral as well as central involvement. Two things should be read with the evidence base in mind. First, this is one family and one paper, and no independent replication exists; the entry curates what that paper reports and marks the inferred steps as inferred. Second, homoplasmy is unusual for a pathogenic mitochondrial tRNA variant and is not obviously good news for pathogenicity: other MT-TV variants act through a steep heteroplasmy threshold, with carriers asymptomatic below about 70 percent mutant load. A homoplasmic variant has no such reservoir of wild-type genomes to explain variable expression, so the within-family variation has to come from somewhere else - which is exactly the copy-number argument the paper makes. It is recorded here as an open question rather than as a settled mechanism.
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name: Mitochondrial Spastic Paraplegia
category: Mendelian
creation_date: "2026-09-17T00:00:00Z"
synonyms:
- SPGM
- spastic paraplegia, mitochondrial
- MT-TV-related hereditary spastic paraplegia
description: >-
Mitochondrial spastic paraplegia (SPGM) is a complex hereditary spastic paraplegia
transmitted down the maternal line, reported in one Chinese family in which all affected
members across four generations carry a homoplasmic m.1661A>G variant in MT-TV, the
mitochondrially encoded transfer RNA for valine.
The name reads like a category and is not one. "Mitochondrial spastic paraplegia" could
reasonably mean "any HSP with a mitochondrial cause", which would be a grouping - SPG7 and
SPG13 are both mitochondrial, and both are curated elsewhere in this knowledge base as
separate nuclear-gene diseases. It is not what the term denotes. MONDO:0975951 is
equivalent to OMIM:500018, an entry in OMIM's mitochondrial-DNA series created for this one
family and this one variant, and the defining feature is not "a mitochondrial cause" but
mitochondrial *inheritance*: the lesion is in the mitochondrial genome, so it passes only
from mothers, and no nuclear locus is involved.
The mechanism proposed is a chain from an mtDNA tRNA variant to a shortage of mitochondrial
genomes. Transcriptome sequencing in the affected family showed upregulated mitochondrial
autophagy genes, and the authors read that as the route by which the MT-TV variant lowers
mtDNA copy number. The fourth generation, with the lowest copy number, had the earliest
onset and the most severe disease, which is the entity's internal dose-response argument.
Peroneal nerve biopsy showed ultrastructural abnormalities in myelin and mitochondria, so
there is peripheral as well as central involvement.
Two things should be read with the evidence base in mind. First, this is one family and one
paper, and no independent replication exists; the entry curates what that paper reports and
marks the inferred steps as inferred. Second, homoplasmy is unusual for a pathogenic
mitochondrial tRNA variant and is not obviously good news for pathogenicity: other MT-TV
variants act through a steep heteroplasmy threshold, with carriers asymptomatic below about
70 percent mutant load. A homoplasmic variant has no such reservoir of wild-type genomes to
explain variable expression, so the within-family variation has to come from somewhere
else - which is exactly the copy-number argument the paper makes. It is recorded here as an
open question rather than as a settled mechanism.
disease_term:
preferred_term: mitochondrial spastic paraplegia
term:
id: MONDO:0975951
label: spastic paraplegia, mitochondrial
parents:
- Hereditary Spastic Paraplegia
references:
- reference: PMID:39468830
title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
- reference: PMID:21986556
title: "Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies."
- reference: PMID:24691472
title: "Phenotypic diversity associated with the MT-TV gene m.1644G>A mutation, a matter of quantity."
inheritance:
- name: Mitochondrial inheritance
description: >-
The variant is in the mitochondrial genome, so transmission is matrilineal: every child of
an affected woman inherits it and no child of an affected man does. In the reported family
the variant is present in all affected individuals across four generations. Because it is
homoplasmic there is no heteroplasmy bottleneck to make transmission probabilistic, which
is a recurrence-risk statement quite unlike that of the nuclear-gene spastic paraplegias.
inheritance_term:
preferred_term: Mitochondrial inheritance
term:
id: HP:0001427
label: Mitochondrial inheritance
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP."
explanation: >-
The variant, its homoplasmic state, and the four-generation segregation that establishes
the mode of inheritance.
pathophysiology:
- name: Homoplasmic MT-TV m.1661A>G Variant
biological_scale: MOLECULAR
conforms_to: "mitochondrial_dysfunction#Mitochondrial Damage and mtDNA Mutation"
description: >-
MT-TV encodes the mitochondrial transfer RNA for valine, one of the 22 tRNAs the
mitochondrial genome supplies for translating its own thirteen protein-coding genes. The
reported variant, m.1661A>G, is homoplasmic - present in every copy of the mitochondrial
genome that was sampled - rather than heteroplasmic, which is the usual state for a
pathogenic mt-tRNA variant.
What the variant does to tRNA-Val was not measured. No aminoacylation assay, steady-state
tRNA measurement or mitochondrial translation assay is reported, so the step from variant
to translational defect is a gap rather than a link in this entry: no causal edge below
this node runs through a translational defect. The reduced-copy-number node further down
does bind mitochondrial translation with a DECREASED modifier, but as an expected
consequence of having fewer genomes to translate from rather than as a claim about what
the variant does to the tRNA. That node's notes say so.
genes:
- preferred_term: MT-TV
term:
id: hgnc:7500
label: MT-TV
genetic_context:
genes:
- preferred_term: MT-TV
term:
id: hgnc:7500
label: MT-TV
allele_type: homoplasmic mitochondrial tRNA point variant m.1661A>G
variant_origin: GERMLINE
description: >-
The zygosity slot is deliberately left empty. ZygosityEnum offers heterozygous,
compound heterozygous, homozygous and hemizygous, none of which describes a
mitochondrial genome present in hundreds of copies per cell. The relevant quantity is
homoplasmy versus heteroplasmy, and it is recorded in allele_type and in the node
description instead of being forced into a nuclear-genetics vocabulary.
notes: >-
functional_impact_category is also left empty. The published support is segregation and
rarity, not a measured consequence for tRNA-Val function, and choosing
LOSS_OF_FUNCTION would assert a mechanism nobody has demonstrated for this allele.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP."
explanation: The variant and the segregation evidence that it is the cause.
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The rare MT-TV m.1661A > G mutation is associated with HSP."
explanation: >-
The conclusion as the authors state it. Worth noting that they write "is associated
with" rather than "causes", which is the level of claim this entry follows.
- reference: PMID:21986556
reference_title: "Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The complete mtDNA sequencing of both patients revealed two transitions in the mitochondrial tRNA(Val) gene (MT-TV) (m.1628C>T in Patient 1, and m.1644G>A in Patient 2)."
explanation: >-
Prior-probability evidence that MT-TV is a real disease locus rather than a chance
finding. INDIRECT because these are different variants causing a different phenotype -
mitochondrial cardiomyopathy - and they say nothing about m.1661A>G specifically.
downstream:
- target: Upregulation of Mitochondrial Autophagy Gene Expression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The authors infer this direction from the transcriptome data. What lies between an
mt-tRNA variant and a mitophagy transcriptional programme is not established, which is
why the link is recorded with unknown intermediates rather than as a direct effect.
- name: Upregulation of Mitochondrial Autophagy Gene Expression
biological_scale: MOLECULAR
description: >-
Transcriptome sequencing of the affected family showed mitochondrial autophagy genes
expressed above normal. The authors offer this as the mechanism by which the MT-TV variant
depletes mitochondrial genomes: more mitophagy, fewer mitochondria, fewer copies of mtDNA.
Two caveats belong on this node. The measurement is transcript abundance, not mitophagic
flux, and upregulated transcription of autophagy genes is as consistent with a compensatory
response to damaged mitochondria as with a primary driver of their removal. The direction
of causation between this node and the next is therefore the paper's interpretation, and
the paper itself words it as a suggestion.
biological_processes:
- preferred_term: mitophagy
modifier: INCREASED
term:
id: GO:0000423
label: mitophagy
cellular_components:
- preferred_term: mitochondrion
term:
id: GO:0005739
label: mitochondrion
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number."
explanation: >-
The measurement and the causal reading the authors put on it, in their own hedged
wording.
downstream:
- target: Reduced Mitochondrial DNA Copy Number
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Reduced Mitochondrial DNA Copy Number
biological_scale: CELLULAR
conforms_to: "mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress"
description: >-
Fewer copies of the mitochondrial genome per cell. This is the node that carries the
entity's explanatory weight, because it is what the authors use to account for variation
within the family: the fourth generation has the lowest copy number, the earliest onset
and the most severe disease.
The conformance to the mitochondrial dysfunction module's bioenergetic node follows the
precedent of the mtDNA depletion entries in this knowledge base. It should be read as
placing this entity in that family of mechanisms, not as a claim that oxidative
phosphorylation was measured here - it was not. No respiratory chain assay, ATP
measurement or oxidative stress marker is reported for this family.
biological_processes:
- preferred_term: mitochondrial DNA metabolic process
modifier: DECREASED
term:
id: GO:0032042
label: mitochondrial DNA metabolic process
- preferred_term: mitochondrial translation
modifier: DECREASED
term:
id: GO:0032543
label: mitochondrial translation
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number."
explanation: >-
The within-family dose-response that ties copy number to severity and onset, with the
authors' own hedges intact.
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes."
explanation: The causal claim the paper draws from that observation, stated as a possibility.
notes: >-
Both process modifiers on this node are inferences from the measured copy number, not
measurements, and neither should be read as a second lesion.
Mitochondrial translation is bound DECREASED as the expected consequence of having fewer
mitochondrial genomes to transcribe and translate from. No translation assay is reported
for this family.
The mtDNA process is bound to GO:0032042 mitochondrial DNA metabolic process rather than
to GO:0006264 mitochondrial DNA replication, and the distinction is load-bearing here. The
entry's causal model is increased removal of mitochondrial genomes through mitophagy, so
binding decreased replication would assert an independent lesion in mtDNA synthesis that
the pathograph never places and the paper never observed. It would also cut across a
principled split already present in the corpus: GO:0006264 is used where the lesion is in
the replication machinery itself (POLG, TWNK, TYMP entries), and GO:0032042 where a
depletion has no replication lesion behind it (Pearson syndrome, Kearns-Sayre syndrome,
Behr syndrome). MT-TV is a tRNA gene; there is no replication machinery in this causal
story.
downstream:
- target: Myelin and Mitochondrial Ultrastructural Abnormality in Peripheral Nerve
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Length-Dependent Degeneration of Corticospinal Axons
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Myelin and Mitochondrial Ultrastructural Abnormality in Peripheral Nerve
biological_scale: TISSUE
description: >-
Peroneal nerve biopsy in the affected family showed ultrastructural abnormalities of both
myelin and mitochondria. This is the only tissue-level observation in the entity and the
only direct evidence that the mitochondrial lesion reaches a nerve.
It is also the evidence that SPGM is a complex rather than a pure spastic paraplegia: a
peripheral nerve abnormality is outside the corticospinal tract. What the abstract does
not give is any clinical neurophysiology, so whether the affected individuals have a
clinically manifest neuropathy, and of what kind, is not recorded here.
cell_types:
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
cellular_components:
- preferred_term: myelin sheath
term:
id: GO:0043209
label: myelin sheath
locations:
- preferred_term: peroneal (fibular) nerve
term:
id: UBERON:0035652
label: fibular nerve
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria."
explanation: The tissue finding, in the only sentence the source gives about it.
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family."
explanation: >-
The tissue the biopsy came from, which is what makes this a peripheral rather than a
central observation.
- name: Length-Dependent Degeneration of Corticospinal Axons
biological_scale: CELLULAR
conforms_to: "corticospinal_tract_axonopathy#Distal Length-Dependent Degeneration of Long CNS Axons"
description: >-
The convergence point shared with every other hereditary spastic paraplegia: the
corticospinal axons running from motor cortex to lumbosacral cord degenerate from their
distal ends, because a supply failure bites hardest where the supply line is longest.
Mitochondria are among the things those axons must transport furthest, which is why
mitochondrial lesions - SPG7 and SPG13 among the nuclear ones - recur as causes of this
syndrome.
This node is inferred for SPGM, not observed. No central nervous system tissue, imaging or
electrophysiology is reported for this family; what is reported is the clinical syndrome
of complex HSP, and the node is here because it is the mechanism that syndrome names. It
conforms to the corticospinal tract axonopathy module for the same reason, and the
conformance should be read as a claim about which final common pathway this entity joins,
not as a claim that the degeneration was demonstrated.
cell_types:
- preferred_term: upper motor neuron
term:
id: CL:0008048
label: upper motor neuron
locations:
- preferred_term: corticospinal tract
term:
id: UBERON:0002707
label: corticospinal tract
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases."
explanation: >-
The syndrome definition, quoted from the paper's own background. INDIRECT and BACKGROUND
because it establishes what HSP is rather than showing corticospinal degeneration in
this family, which nobody has looked for.
downstream:
- target: Progressive Spastic Paraplegia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- target: Lower Limb Spasticity
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Progressive Spastic Paraplegia
category: Nervous System
description: >-
The defining clinical picture, present in all affected members of the family across four
generations. The source names the syndrome as complex HSP without listing the additional
features that make it complex, beyond the peripheral nerve abnormality found on biopsy.
frequency: OBLIGATE
phenotype_term:
preferred_term: Progressive spastic paraplegia
term:
id: HP:0007020
label: Progressive spastic paraplegia
notes: >-
OBLIGATE because the variant is described as present in all affected individuals, and
because a family is ascertained through its neurological syndrome so no unaffected carrier
could have been counted. The number of affected individuals is not given in the abstract,
so there is no denominator to state; four generations are reported.
The phenotype is curated from the paper's own definition of HSP together with its
statement that this family has complex HSP. That is a diagnosis-level claim rather than a
per-patient examination finding, and it is the strongest claim the available source
supports.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP."
explanation: >-
The diagnosis in this family, stated as complex HSP, and the fact that it is shared
across four generations.
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases."
explanation: >-
What the diagnosis means clinically. BACKGROUND because it is the paper's framing of the
disease category, not an examination finding in this family.
- name: Lower Limb Spasticity
category: Nervous System
description: >-
The component of the syndrome that gives it its name: increased tone in the legs from loss
of descending corticospinal inhibition of the stretch reflex. Curated separately from the
paraplegia term so that the sign is queryable on its own.
frequency: OBLIGATE
phenotype_term:
preferred_term: Lower limb spasticity
term:
id: HP:0002061
label: Lower limb spasticity
notes: >-
Same denominator and same caveat as the paraplegia phenotype: taken from the syndrome
definition the paper gives together with its statement that this family has complex HSP,
not from a reported examination of individual family members.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases."
explanation: >-
Names lower limb spasticity as a defining feature of the syndrome this family is
reported to have.
histopathology:
- name: Ultrastructural abnormality of myelin and mitochondria in peroneal nerve
finding_term:
preferred_term: ultrastructural abnormality of myelin and mitochondria on peroneal nerve biopsy
term:
id: NCIT:C43265
label: Ultrastructural Finding
description: >-
Electron microscopy of peroneal nerve from the affected family showed abnormalities of both
myelin and mitochondria. Recorded as histopathology rather than as a phenotype because it
is a tissue-level microscopic observation and there is no reported clinical
neurophysiology to support a clinical neuropathy phenotype.
diagnostic: false
notes: >-
The bound term is the generic NCIT Ultrastructural Finding, because NCIT has no term for
this specific combination of findings and the preferred_term carries the specificity. The
abstract does not say how many family members were biopsied or what the abnormalities
were, so no frequency is recorded and the description does not go beyond the source.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria."
explanation: The finding itself, in the source's own words.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No prevalence estimate exists. One family has been reported, in one paper, and no second
family carrying m.1661A>G has been published. No rate is recorded because none has been
measured, and the abstract does not give the number of affected individuals in the family.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family."
explanation: The whole published case series, which is a single pedigree.
progression:
- phase: Earlier onset and greater severity in successive generations
notes: >-
The one longitudinal observation in the entity, and it is across generations rather than
within a patient. Fourth-generation affected individuals had earlier onset and more severe
symptoms than their forebears. The authors label this presumptive anticipation and offer
decreasing mtDNA copy number as the mechanism.
Two reasons to hold this loosely. Apparent anticipation in a pedigree is a classic
ascertainment artefact - later generations are examined earlier in life and with more
awareness of the family diagnosis - and the abstract reports no correction for it. And the
copy-number explanation is offered as a possibility by the authors themselves, in the same
sentence.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number."
explanation: >-
The generational pattern and both of the authors' proposed explanations for it, with
their hedges.
- phase: Course within an individual
notes: >-
Not reported. The source gives no age of onset, no rate of progression, no functional
scale and no follow-up for any individual, so nothing is recorded here beyond the fact
that HSP is by definition progressive. This phase exists to mark the absence.
genetic:
- name: MT-TV
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: MT-TV
term:
id: hgnc:7500
label: MT-TV
features: >-
MT-TV is the mitochondrially encoded transfer RNA for valine. The SPGM variant is
m.1661A>G, homoplasmic in all affected members of the one reported family. MT-TV is an
established disease locus in its own right: other variants in it cause mitochondrial
cardiomyopathy with neurological features (m.1628C>T, m.1644G>A) and Leigh-like disease at
high mutant load.
notes: >-
No causal gene is recorded in MONDO for MONDO:0975951, and NCBI mim2gene_medgen maps
OMIM:500018 to GeneID `-` with no GeneMap source. That blank is not the same signal it was
for the gene-less DFNB loci: OMIM's 5-series is its mitochondrial-DNA phenotype series, and
those entries are not gene-mapped through the nuclear GeneMap that mim2gene_medgen reads.
The gene is named unambiguously in the defining paper and in the OMIM entry title, so the
identity is not in doubt; what the blank reflects is the file's scope, not a missing
answer. A curator repeating the mapped-locus test on this concept should read it that way.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The rare MT-TV m.1661A > G mutation is associated with HSP."
explanation: The gene-disease statement, at the strength the authors give it.
- reference: PMID:24691472
reference_title: "Phenotypic diversity associated with the MT-TV gene m.1644G>A mutation, a matter of quantity."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The mutation appeared to have a very steep threshold effect with asymptomatic life up to 70% mutation proportion, progressive encephalopathy above 80% and severe Leigh-like syndrome above 95% mutation."
explanation: >-
How a different MT-TV variant behaves, and the reason homoplasmy in SPGM is worth
remarking on: for m.1644G>A, disease requires a very high mutant load and carriers below
it are well. INDIRECT because it concerns a different variant and a different phenotype.
diagnosis:
- name: Mitochondrial genome sequencing in spastic paraplegia with a maternal pedigree pattern
description: >-
The practical lesson of this entity is a testing-strategy one. Nuclear exome and
spastic-paraplegia gene panels do not reliably cover the mitochondrial genome, so a family
whose transmission is matrilineal can remain undiagnosed through a complete nuclear
workup. The reported family was solved by adding mitochondrial genome analysis, with
transcriptome sequencing and nerve biopsy in support.
A homoplasmic variant adds a second trap: pipelines and interpretation guidelines for
mitochondrial variants are tuned to heteroplasmy, and a variant present at 100 percent can
be filtered as a private polymorphism.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family."
explanation: The investigations that made the diagnosis in the one reported family.
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases."
explanation: >-
The clause about many cases having no known genetic cause, which is the argument for
extending testing beyond the nuclear panel. BACKGROUND because it is the paper's framing
of the field.
- reference: PMID:21986556
reference_title: "Mitochondrial tRNA valine as a recurrent target for mutations involved in mitochondrial cardiomyopathies."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "The functional and molecular analyses reported here suggest that the MT-TV gene should be routinely considered in the diagnosis of mitochondrial cardiomyopathies."
explanation: >-
An independent argument that MT-TV deserves routine attention in diagnosis. INDIRECT
because it is made about cardiomyopathy rather than about spastic paraplegia.
treatments:
- name: Genetic Counselling for Mitochondrial Inheritance
description: >-
The counselling here is not the counselling for a nuclear recessive or dominant spastic
paraplegia, which is why it is curated rather than assumed. Transmission is matrilineal:
an affected or carrier woman passes the variant to all of her children, an affected man to
none of his. Because the variant is homoplasmic there is no heteroplasmy bottleneck, so
the usual mitochondrial hedge about unpredictable transmitted load does not apply, and by
the same token the reproductive options that work by selecting for low mutant load -
preimplantation genetic testing in particular - have nothing to select on.
Counselling does not act on the mechanism. It is curated because it is the only
intervention the genotype itself indicates, and because getting the inheritance pattern
wrong in a spastic paraplegia family has direct consequences for who is offered testing.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP."
explanation: >-
The homoplasmic mitochondrial variant and the four-generation matrilineal pattern, which
are the two facts counselling turns on.
notes: >-
No treatment is reported for any member of the family. Symptomatic management of spasticity
- baclofen, tizanidine, botulinum toxin, physiotherapy - is standard for hereditary spastic
paraplegia and is curated on the parent Hereditary Spastic Paraplegia entry, where it
belongs; it is not repeated here, because nothing in the source records what these patients
received and duplicating the parent's treatment list would assert otherwise.
discussions:
- discussion_id: spgm_homoplasmy_versus_heteroplasmy_threshold
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- "pathophysiology#Homoplasmic MT-TV m.1661A>G Variant"
- "pathophysiology#Reduced Mitochondrial DNA Copy Number"
prompt: >-
If m.1661A>G is homoplasmic in every affected member, what explains the variation in onset
and severity between generations, and why are some maternal-line relatives unaffected?
rationale: >-
Pathogenic mitochondrial tRNA variants are usually heteroplasmic, and heteroplasmy is what
does the explanatory work: for MT-TV m.1644G>A the threshold is steep enough that carriers
below about 70 percent mutant load live asymptomatic lives, encephalopathy appears above 80
percent, and Leigh-like disease above 95 percent. A homoplasmic variant removes that
variable entirely. Every cell in every affected member carries the variant in every genome,
so nothing about mutant load can account for one generation being affected earlier and more
severely than another, or for any unaffected matrilineal relative.
The authors supply mtDNA copy number as the substitute variable, and the internal evidence
is consistent with it: the fourth generation has the lowest copy number, the earliest onset
and the worst disease. But copy number is itself a phenotype, measured in blood or another
accessible tissue at one point in time, and it can fall as a consequence of disease or of
age as easily as it can drive it. Nuclear modifiers and mitochondrial haplogroup background
are untested alternatives.
This matters beyond the one family. A homoplasmic variant carries a weaker pathogenicity
argument than a heteroplasmic one, because it cannot be shown to segregate with disease
within a pedigree - everyone in the maternal line has it. The entity therefore rests on
rarity, the tissue findings, and the copy-number correlation rather than on a
dose-response in mutant load.
proposed_experiments:
- experiment_id: spgm_copy_number_and_modifier_study
name: Tissue-resolved mtDNA copy number and modifier screen in the reported pedigree
description: >-
Measure mtDNA copy number in more than one tissue and at more than one time point across
affected and unaffected matrilineal relatives, alongside full mitochondrial haplogroup
assignment and nuclear sequencing for candidate modifiers of mtDNA maintenance. Include
unaffected maternal-line relatives, who are the informative group and whom the original
report does not describe.
readouts:
- name: mtDNA copy number in affected versus unaffected matrilineal relatives
target: "pathophysiology#Reduced Mitochondrial DNA Copy Number"
direction: DECREASED
interpretation: >-
A copy-number difference that tracks affected status independently of age would support
the authors' model. Equal copy number in unaffected carriers would refute it and point
at a nuclear modifier or at the variant being a bystander.
- discussion_id: spgm_single_family_replication
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- "genetic#MT-TV"
prompt: >-
Has any second family with a mitochondrial spastic paraplegia phenotype been found to
carry m.1661A>G, or any other MT-TV variant?
rationale: >-
The whole entity is one pedigree and one publication. A PubMed search for `MT-TV` on
2026-09-17 returned sixteen records, all of which were read by title: three GeneReviews
overviews, the defining paper itself, and twelve reports of other phenotypes -
mitochondrial cardiomyopathy (PMID:21986556, PMID:30642647), Leigh and Leigh-like disease
(PMID:24691472, PMID:38039350), childhood epilepsy (PMID:40115461, PMID:39243325), an
adult phenotype expansion (PMID:38973423), camptocormia with a shuffling gait
(PMID:28396884), and mtDNA findings in kidney disease. None is a second spastic paraplegia
family. A broader search for `mitochondrial tRNA valine mutation` returns 47 records and
was not read exhaustively, so the claim here is that no second SPGM family appears in the
gene-symbol literature rather than that none exists anywhere. SPGM is at present a
singleton, and OMIM's own designation carries no more weight than the one report behind
it.
Replication is what would move it. The specific test is cheap, because mitochondrial genome
data already exist in most large undiagnosed-HSP cohorts and simply have not been
interrogated for MT-TV in families with a maternal transmission pattern.
proposed_experiments:
- experiment_id: spgm_mtdna_reanalysis_in_undiagnosed_hsp_cohorts
name: Reanalysis of mitochondrial genomes in genetically undiagnosed HSP cohorts
description: >-
Interrogate existing sequencing data from undiagnosed hereditary spastic paraplegia
cohorts for MT-TV and other mt-tRNA variants, stratified by whether the pedigree is
compatible with matrilineal transmission, and report the yield whether positive or
negative.
readouts:
- name: Number of independent HSP families with a pathogenic MT-TV variant
target: "genetic#MT-TV"
interpretation: >-
A second independent family would establish the entity. A well-powered negative result
would argue that m.1661A>G is a private finding in one pedigree and that SPGM should be
reconsidered rather than curated as a disease.
external_assertions:
- name: OMIM spastic paraplegia, mitochondrial record
source: OMIM
assertion_type: disease_record
external_id: OMIM:500018
url: https://omim.org/entry/500018
description: >-
The OMIM phenotype record under which SPGM was designated, created for the family reported
by Shi et al. It sits in OMIM's 5-series, which is the mitochondrial-DNA phenotype series,
and that placement is itself the identity evidence: it says the entity is defined by a
mitochondrial-genome lesion rather than by having a mitochondrial mechanism. Recorded here
rather than under mappings because the DiseaseMappings class carries only ICD-10-CM,
ICD-11, MONDO and NCIT slots. NCBI mim2gene_medgen maps this MIM number to GeneID `-`,
which reflects that the 5-series is outside the nuclear gene map rather than an absent
gene.
evidence:
- reference: PMID:39468830
reference_title: "A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The rare MT-TV m.1661A > G mutation is associated with HSP."
explanation: The gene-disease finding on which the OMIM designation rests.
notes: >-
Scope decision: curated as a DISEASE, against the initial suspicion that it would be a
GROUPING. The name invites the grouping reading - many hereditary spastic paraplegias have a
mitochondrial cause, and SPG7 and SPG13 are both curated or curatable as nuclear-gene
entities - but that is not what the term denotes. MONDO:0975951 is equivalent to OMIM:500018,
an entry in OMIM's mitochondrial-DNA phenotype series created for one family and one variant,
m.1661A>G in MT-TV. The stub records no MONDO descendants, which agrees. The defining feature
is mitochondrial *inheritance*, not a mitochondrial mechanism, and that is a property no
nuclear-gene HSP shares.
Identity resolution, since the stub and MONDO both record no causal gene: MONDO:0975951
cross-references OMIM:500018, whose MedGen record (C5974902) states the entity is
characterised by matrilineal inheritance of progressive lower limb weakness and spasticity
and cites Shi et al. 2025. NCBI mim2gene_medgen maps OMIM:500018 to GeneID `-`, but that
blank means something different here from what it meant for DFNB46 in #11978: OMIM's 5-series
is outside the nuclear gene map that file reads, so the absence is about the file's scope
rather than about the concept. The gene is named unambiguously in the defining paper. A
search of `kb/` for MT-TV, m.1661 and mitochondrial spastic paraplegia found no existing
coverage; the KB has a parent Hereditary Spastic Paraplegia entry and several nuclear SPG
entries, none of which is this.
Evidence balance, stated rather than smoothed. One family, one paper, no replication. The
measured facts are the variant and its segregation, the transcriptome result, the mtDNA copy
number correlation, and the nerve biopsy. Everything else is inference: the step from the
tRNA variant to any translational defect is not measured and no node asserts it; the
corticospinal node is inferred from the clinical diagnosis and says so; the DECREASED
modifier on mitochondrial translation is an expectation from copy number and its node notes
say so. Two slots are deliberately left empty rather than filled with a plausible value -
genetic_context.zygosity, because no ZygosityEnum value describes homoplasmy, and
functional_impact_category, because no functional consequence has been demonstrated for this
allele.
No deep-research run was commissioned. The entity has a sixteen-record literature at the gene
level, all of which was reviewed by title here, and a single paper at the disease level; a
provider run on a 2025 singleton entity carries a real risk of returning a different disease,
and there is no body of literature for it to synthesise. Two knowledge-gap discussions record
what would actually change the picture: replication in a second family, and a test of the
copy-number model in unaffected matrilineal relatives.