Mitochondrial DNA Depletion Syndrome 7

Mendelian MONDO:0010060 Pathograph 3 Show in embeddings browser mitochondrial DNA depletion syndrome mitochondrial disease

Mitochondrial DNA depletion syndrome 7 (MTDPS7), also known as infantile-onset spinocerebellar ataxia (IOSCA), is a severe autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in TWNK (Twinkle mtDNA helicase, formerly C10orf2/PEO1). Twinkle is the replicative helicase required for mitochondrial DNA replication; loss-of-function variants impair mtDNA maintenance and produce tissue-specific mtDNA depletion (notably brain and liver) with respiratory chain deficiency. The classic Finnish IOSCA phenotype (founder Y508C variant) presents after normal development to age one year with progressive ataxia, hypotonia, areflexia, athetosis, ophthalmoplegia, sensorineural hearing loss, sensory axonal neuropathy, optic atrophy, autonomic dysfunction, hypergonadotropic hypogonadism in females, and epilepsy that can progress to fatal encephalopathy. Compound-heterozygous TWNK variants can produce a more severe early-onset hepatocerebral encephalopathy with liver involvement resembling Alpers syndrome.

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3
Pathophys.
15
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
2
Subtypes
1
References
1
Deep Research
◆

Subtypes

2
Infantile-Onset Spinocerebellar Ataxia (classic Finnish)
Classic infantile-onset spinocerebellar ataxia caused by the homozygous Finnish founder TWNK Y508C variant. Normal development until age one year, followed by progressive ataxia, hypotonia, athetosis, ophthalmoplegia, sensorineural deafness, sensory axonal neuropathy, optic atrophy, autonomic dysfunction, hypergonadotropic hypogonadism in females, and epilepsy.
Early-onset hepatocerebral encephalopathy
More severe early-onset encephalopathy with hepatic involvement caused by compound-heterozygous TWNK variants (e.g., A318T/Y508C), with liver mtDNA depletion and elevated transaminases, resembling Alpers-Huttenlocher syndrome.
⚙

Pathophysiology

3
Impaired Twinkle Helicase Function and mtDNA Replication
TWNK encodes Twinkle, the replicative helicase of the mitochondrial DNA replisome that unwinds double-stranded mtDNA ahead of polymerase gamma. Recessive TWNK variants (the Finnish founder Y508C and others) impair Twinkle function in a highly tissue- and cell-type-specific manner, compromising mtDNA maintenance. Unlike the dominant PEO mutations that cause multiple mtDNA deletions, the recessive IOSCA variant leaves mtDNA intact but reduces mtDNA copy number (depletion).
neuron CL:0000540
mitochondrial DNA replication GO:0006264 ↓ DECREASED mtDNA maintenance GO:0007005 ⚠ ABNORMAL
Downstream
Tissue-Specific mtDNA Depletion (Brain and Liver) Impaired Twinkle helicase function compromises mtDNA replication, reducing mtDNA copy number in a tissue-specific manner.
Show evidence (2 references)
PMID:16135556 SUPPORT Human Clinical
"we identified two point mutations in the gene C10orf2 encoding Twinkle, a mitochondrial deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice variant Twinky, underlying IOSCA"
Positional cloning identified recessive TWNK (C10orf2) variants encoding the mtDNA-specific helicase Twinkle as the cause of IOSCA.
PMID:17921179 SUPPORT Human Clinical
"Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA)."
Establishes Twinkle as the mitochondrial replicative helicase whose recessive mutations cause IOSCA.
Tissue-Specific mtDNA Depletion (Brain and Liver)
Impaired Twinkle function leads to reduced mtDNA copy number in a context-dependent manner, with depletion documented in brain and liver in IOSCA and prominent liver mtDNA depletion in the hepatocerebral form. mtDNA depletion underlies the classification of this disorder among the mitochondrial DNA depletion syndromes.
hepatocyte CL:0000182 neuron CL:0000540
mitochondrial DNA replication GO:0006264 ↓ DECREASED
Downstream
Respiratory Chain Deficiency Reduced mtDNA copy number lowers the supply of mtDNA-encoded respiratory chain subunits, producing complex I (and complex IV) deficiency.
Show evidence (3 references)
PMID:18775955 SUPPORT Human Clinical
"IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver."
Demonstrates mtDNA depletion in brain and liver in IOSCA patient tissue.
PMID:18775955 SUPPORT Human Clinical
"Our results indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes."
Classifies IOSCA as a mitochondrial DNA depletion syndrome.
PMID:17921179 SUPPORT Human Clinical
"The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected."
Documents prominent liver mtDNA depletion in the hepatocerebral form with relative sparing of muscle, supporting tissue specificity.
Respiratory Chain Deficiency
mtDNA depletion reduces the supply of mtDNA-encoded subunits of the respiratory chain, producing complex I (and complex IV) deficiency, particularly in large neurons. This impairs oxidative phosphorylation and drives the neurodegenerative phenotype.
neuron CL:0000540
oxidative phosphorylation GO:0006119 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED
Show evidence (1 reference)
PMID:18775955 SUPPORT Human Clinical
"In both diseases, especially large neurons show respiratory chain complex I (CI) deficiency, but also CIV is decreased in IOSCA."
Shows respiratory chain complex I deficiency (and reduced complex IV) in large neurons, the downstream consequence of mtDNA depletion.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Mitochondrial DNA Depletion Syndrome 7 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Ear 1
Sensorineural Hearing Loss Sensorineural hearing impairment HP:0000407
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"By adolescence, affected individuals are profoundly deaf and no longer ambulatory"
GeneReviews documents progressive sensorineural deafness culminating in profound deafness by adolescence.
Endocrine 1
Hypergonadotropic Hypogonadism Hypergonadotropic hypogonadism HP:0000815
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
GeneReviews documents hypergonadotropic hypogonadism in females with IOSCA.
Eye 1
Optic Atrophy Optic atrophy HP:0000648
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
GeneReviews lists optic atrophy among progressive IOSCA features.
Metabolism 1
Liver Involvement Elevated circulating hepatic transaminase concentration HP:0002910
Show evidence (1 reference)
PMID:17921179 SUPPORT Human Clinical
"The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases."
Documents elevation of serum transaminases in the compound-heterozygous hepatocerebral cases.
Musculoskeletal 1
Muscle Hypotonia Hypotonia HP:0001252
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
GeneReviews lists muscle hypotonia among the early manifestations of IOSCA.
Nervous System 5
Infantile-Onset Ataxia VERY_FREQUENT Ataxia HP:0001251
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
GeneReviews documents ataxia as a defining early feature of IOSCA following normal development to age one year. Ataxia is the eponymous, near-obligate manifestation of infantile-onset spinocerebellar ataxia, supporting the VERY_FREQUENT band.
Areflexia Areflexia HP:0001284
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
GeneReviews documents loss of deep-tendon reflexes in IOSCA.
Autonomic Dysfunction Abnormality of the autonomic nervous system HP:0002270
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
GeneReviews documents autonomic nervous system dysfunction in IOSCA.
Epilepsy Seizure HP:0001250
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness."
GeneReviews describes the epilepsy spectrum in IOSCA progressing to fatal encephalopathy.
Cerebellar and Brainstem Atrophy Cerebellar atrophy HP:0001272
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:16135556 SUPPORT Human Clinical
"characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy."
The original IOSCA description documents progressive cerebellar and brainstem atrophy.
Other 5
Athetosis Athetosis HP:0002305
Show evidence (2 references)
PMID:20301746 SUPPORT Human Clinical
"followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
GeneReviews lists athetosis among early IOSCA features.
PMID:17921179 SUPPORT Human Clinical
"The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases."
Athetosis was a manifestation in the compound-heterozygous hepatocerebral cases.
Ophthalmoplegia Ophthalmoplegia HP:0000602
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"Ophthalmoplegia and sensorineural deafness develop by age seven years."
GeneReviews documents ophthalmoplegia developing by age seven in IOSCA.
Sensory Axonal Neuropathy Sensory axonal neuropathy HP:0003390
Show evidence (2 references)
PMID:20301746 SUPPORT Human Clinical
"sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
GeneReviews documents sensory axonal neuropathy as a feature of IOSCA.
PMID:16135556 SUPPORT Human Clinical
"characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy."
The original IOSCA description includes sensory axonal neuropathy.
Epilepsia Partialis Continua Epilepsia partialis continua HP:0012847
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness."
GeneReviews documents epilepsia partialis continua in the IOSCA epilepsy progression.
Early-Onset Encephalopathy Progressive encephalopathy HP:0002448
Show evidence (1 reference)
PMID:17921179 SUPPORT Human Clinical
"We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement."
Defines the early-onset hepatocerebral encephalopathy phenotype caused by compound-heterozygous TWNK variants.
🧬

Genetic Associations

1
TWNK (Biallelic recessive pathogenic variants in TWNK (Twinkle helicase))
Gene: TWNK hgnc:1160
Autosomal recessive
Show evidence (3 references)
PMID:16135556 SUPPORT Human Clinical
"The founder IOSCA mutation, homozygous in all but one of the patients, leads to a Y508C amino acid change in the polypeptides."
Documents the homozygous Finnish founder Y508C variant in TWNK as the cause of classic IOSCA.
PMID:16135556 SUPPORT Human Clinical
"Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder"
Establishes autosomal recessive inheritance of IOSCA.
PMID:17921179 SUPPORT Human Clinical
"We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C)"
Documents compound-heterozygous TWNK variants underlying the hepatocerebral form.
💊

Medical Actions

3
Supportive Care
Action: Supportive Care NCIT:C15747
Management of IOSCA is supportive: hearing loss, sensory axonal neuropathy, ataxia, psychotic behavior, and severe depression are treated in the usual manner, with multidisciplinary surveillance (neurologic, audiologic, and ophthalmologic evaluations). There is no disease-modifying therapy.
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"Treatment of manifestations: Hearing loss, sensory axonal neuropathy, ataxia, psychotic behavior, and severe depression are treated in the usual manner."
GeneReviews describes supportive, symptom-directed management for IOSCA.
Antiseizure Medication
Action: Pharmacotherapy NCIT:C15986
Agent: anticonvulsant agent NCIT:C264
Seizures are managed with antiseizure medication, although conventional antiepileptic drugs (phenytoin and phenobarbital) are ineffective in most affected individuals. Valproate should be avoided because it can cause significant elevation of serum bilirubin and liver enzymes in these patients.
Show evidence (2 references)
PMID:20301746 PARTIAL Human Clinical
"Conventional antiepileptic drugs (phenytoin and phenobarbital) are ineffective in most affected individuals."
GeneReviews notes that conventional antiepileptic drugs are largely ineffective, qualifying the role of antiseizure pharmacotherapy.
PMID:20301746 SUPPORT Human Clinical
"Agents/circumstances to avoid: Valproate, which can cause significant elevation of serum concentration of bilirubin and liver enzymes."
GeneReviews explicitly warns against valproate due to hepatotoxicity risk in these patients.
Genetic Counseling
Action: Genetic Counseling NCIT:C15240
IOSCA is inherited in an autosomal recessive manner. Genetic counseling informs at-risk families; carrier testing and prenatal testing are possible when the familial pathogenic variants are known.
Show evidence (1 reference)
PMID:20301746 SUPPORT Human Clinical
"IOSCA is inherited in an autosomal recessive manner."
GeneReviews documents autosomal recessive inheritance, the basis for genetic counseling.
{ }

Source YAML

click to show 
name: Mitochondrial DNA Depletion Syndrome 7
creation_date: "2026-06-03T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
  term:
    id: MONDO:0010060
    label: mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
description: >
  Mitochondrial DNA depletion syndrome 7 (MTDPS7), also known as infantile-onset
  spinocerebellar ataxia (IOSCA), is a severe autosomal recessive
  neurodegenerative disorder caused by biallelic pathogenic variants in TWNK
  (Twinkle mtDNA helicase, formerly C10orf2/PEO1). Twinkle is the replicative
  helicase required for mitochondrial DNA replication; loss-of-function variants
  impair mtDNA maintenance and produce tissue-specific mtDNA depletion (notably
  brain and liver) with respiratory chain deficiency. The classic Finnish IOSCA
  phenotype (founder Y508C variant) presents after normal development to age one
  year with progressive ataxia, hypotonia, areflexia, athetosis, ophthalmoplegia,
  sensorineural hearing loss, sensory axonal neuropathy, optic atrophy, autonomic
  dysfunction, hypergonadotropic hypogonadism in females, and epilepsy that can
  progress to fatal encephalopathy. Compound-heterozygous TWNK variants can
  produce a more severe early-onset hepatocerebral encephalopathy with liver
  involvement resembling Alpers syndrome.
references:
- reference: PMID:20301746
  title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
parents:
- mitochondrial DNA depletion syndrome
- mitochondrial disease
has_subtypes:
- name: IOSCA
  display_name: Infantile-Onset Spinocerebellar Ataxia (classic Finnish)
  description: >
    Classic infantile-onset spinocerebellar ataxia caused by the homozygous
    Finnish founder TWNK Y508C variant. Normal development until age one year,
    followed by progressive ataxia, hypotonia, athetosis, ophthalmoplegia,
    sensorineural deafness, sensory axonal neuropathy, optic atrophy, autonomic
    dysfunction, hypergonadotropic hypogonadism in females, and epilepsy.
- name: Hepatocerebral
  display_name: Early-onset hepatocerebral encephalopathy
  description: >
    More severe early-onset encephalopathy with hepatic involvement caused by
    compound-heterozygous TWNK variants (e.g., A318T/Y508C), with liver mtDNA
    depletion and elevated transaminases, resembling Alpers-Huttenlocher
    syndrome.
pathophysiology:
- name: Impaired Twinkle Helicase Function and mtDNA Replication
  description: >
    TWNK encodes Twinkle, the replicative helicase of the mitochondrial DNA
    replisome that unwinds double-stranded mtDNA ahead of polymerase gamma.
    Recessive TWNK variants (the Finnish founder Y508C and others) impair Twinkle
    function in a highly tissue- and cell-type-specific manner, compromising
    mtDNA maintenance. Unlike the dominant PEO mutations that cause multiple mtDNA
    deletions, the recessive IOSCA variant leaves mtDNA intact but reduces mtDNA
    copy number (depletion).
  downstream:
  - target: Tissue-Specific mtDNA Depletion (Brain and Liver)
    description: >
      Impaired Twinkle helicase function compromises mtDNA replication, reducing
      mtDNA copy number in a tissue-specific manner.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrial DNA replication
    term:
      id: GO:0006264
      label: mitochondrial DNA replication
    modifier: DECREASED
  - preferred_term: mtDNA maintenance
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:16135556
    reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two point mutations in the gene C10orf2 encoding Twinkle, a mitochondrial deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice variant Twinky, underlying IOSCA"
    explanation: >
      Positional cloning identified recessive TWNK (C10orf2) variants encoding the
      mtDNA-specific helicase Twinkle as the cause of IOSCA.
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA)."
    explanation: >
      Establishes Twinkle as the mitochondrial replicative helicase whose
      recessive mutations cause IOSCA.
- name: Tissue-Specific mtDNA Depletion (Brain and Liver)
  description: >
    Impaired Twinkle function leads to reduced mtDNA copy number in a
    context-dependent manner, with depletion documented in brain and liver in
    IOSCA and prominent liver mtDNA depletion in the hepatocerebral form. mtDNA
    depletion underlies the classification of this disorder among the
    mitochondrial DNA depletion syndromes.
  downstream:
  - target: Respiratory Chain Deficiency
    description: >
      Reduced mtDNA copy number lowers the supply of mtDNA-encoded respiratory
      chain subunits, producing complex I (and complex IV) deficiency.
    causal_link_type: DIRECT
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrial DNA replication
    term:
      id: GO:0006264
      label: mitochondrial DNA replication
    modifier: DECREASED
  evidence:
  - reference: PMID:18775955
    reference_title: "Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IOSCA, and to a lesser extent also MIRAS, show mtDNA depletion in the brain and the liver."
    explanation: >
      Demonstrates mtDNA depletion in brain and liver in IOSCA patient tissue.
  - reference: PMID:18775955
    reference_title: "Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that IOSCA is a new member of the mitochondrial DNA depletion syndromes."
    explanation: >
      Classifies IOSCA as a mitochondrial DNA depletion syndrome.
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected."
    explanation: >
      Documents prominent liver mtDNA depletion in the hepatocerebral form with
      relative sparing of muscle, supporting tissue specificity.
- name: Respiratory Chain Deficiency
  description: >
    mtDNA depletion reduces the supply of mtDNA-encoded subunits of the
    respiratory chain, producing complex I (and complex IV) deficiency,
    particularly in large neurons. This impairs oxidative phosphorylation and
    drives the neurodegenerative phenotype.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:18775955
    reference_title: "Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both diseases, especially large neurons show respiratory chain complex I (CI) deficiency, but also CIV is decreased in IOSCA."
    explanation: >
      Shows respiratory chain complex I deficiency (and reduced complex IV) in
      large neurons, the downstream consequence of mtDNA depletion.
phenotypes:
- category: Neurologic
  name: Infantile-Onset Ataxia
  subtype: IOSCA
  description: >
    Progressive ataxia begins in infancy after a period of normal development to
    about age one year, reflecting cerebellar and sensory involvement.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
    explanation: >
      GeneReviews documents ataxia as a defining early feature of IOSCA following
      normal development to age one year. Ataxia is the eponymous, near-obligate
      manifestation of infantile-onset spinocerebellar ataxia, supporting the
      VERY_FREQUENT band.
- category: Neurologic
  name: Muscle Hypotonia
  subtype: IOSCA
  description: >
    Muscle hypotonia is an early feature accompanying the onset of ataxia.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
    explanation: >
      GeneReviews lists muscle hypotonia among the early manifestations of IOSCA.
- category: Neurologic
  name: Areflexia
  subtype: IOSCA
  description: >
    Loss of deep-tendon reflexes accompanies the sensory axonal neuropathy.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
    explanation: >
      GeneReviews documents loss of deep-tendon reflexes in IOSCA.
- category: Neurologic
  name: Athetosis
  description: >
    Athetoid movements are part of the early movement-disorder spectrum, documented
    in both the classic IOSCA and the compound-heterozygous hepatocerebral forms.
  phenotype_term:
    preferred_term: Athetosis
    term:
      id: HP:0002305
      label: Athetosis
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis."
    explanation: >
      GeneReviews lists athetosis among early IOSCA features.
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases."
    explanation: >
      Athetosis was a manifestation in the compound-heterozygous hepatocerebral
      cases.
- category: Neurologic
  name: Ophthalmoplegia
  description: >
    Ophthalmoplegia develops in childhood, typically by age seven years.
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ophthalmoplegia and sensorineural deafness develop by age seven years."
    explanation: >
      GeneReviews documents ophthalmoplegia developing by age seven in IOSCA.
- category: Neurologic
  name: Sensorineural Hearing Loss
  description: >
    Sensorineural deafness develops in childhood; by adolescence affected
    individuals are profoundly deaf.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By adolescence, affected individuals are profoundly deaf and no longer ambulatory"
    explanation: >
      GeneReviews documents progressive sensorineural deafness culminating in
      profound deafness by adolescence.
- category: Neurologic
  name: Sensory Axonal Neuropathy
  description: >
    A sensory axonal neuropathy contributes to the ataxia and areflexia and
    becomes evident over the disease course.
  phenotype_term:
    preferred_term: Sensory axonal neuropathy
    term:
      id: HP:0003390
      label: Sensory axonal neuropathy
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
    explanation: >
      GeneReviews documents sensory axonal neuropathy as a feature of IOSCA.
  - reference: PMID:16135556
    reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy."
    explanation: >
      The original IOSCA description includes sensory axonal neuropathy.
- category: Neurologic
  name: Optic Atrophy
  description: >
    Optic atrophy becomes evident as the disease progresses.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
    explanation: >
      GeneReviews lists optic atrophy among progressive IOSCA features.
- category: Neurologic
  name: Autonomic Dysfunction
  description: >
    Autonomic nervous system dysfunction develops over the disease course.
  phenotype_term:
    preferred_term: Abnormality of the autonomic nervous system
    term:
      id: HP:0002270
      label: Abnormality of the autonomic nervous system
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
    explanation: >
      GeneReviews documents autonomic nervous system dysfunction in IOSCA.
- category: Neurologic
  name: Epilepsy
  description: >
    Epilepsy can develop into a serious and often fatal encephalopathy, with
    myoclonic jerks or focal clonic seizures progressing to epilepsia partialis
    continua and status epilepticus.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness."
    explanation: >
      GeneReviews describes the epilepsy spectrum in IOSCA progressing to fatal
      encephalopathy.
- category: Neurologic
  name: Epilepsia Partialis Continua
  description: >
    Seizures can progress to epilepsia partialis continua and status epilepticus.
  phenotype_term:
    preferred_term: Epilepsia partialis continua
    term:
      id: HP:0012847
      label: Epilepsia partialis continua
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness."
    explanation: >
      GeneReviews documents epilepsia partialis continua in the IOSCA epilepsy
      progression.
- category: Endocrine
  name: Hypergonadotropic Hypogonadism
  description: >
    Hypergonadotropic hypogonadism becomes evident in affected females.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident."
    explanation: >
      GeneReviews documents hypergonadotropic hypogonadism in females with IOSCA.
- category: Neurologic
  name: Cerebellar and Brainstem Atrophy
  description: >
    IOSCA is characterized by progressive atrophy of the cerebellum, brain stem,
    and spinal cord.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16135556
    reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy."
    explanation: >
      The original IOSCA description documents progressive cerebellar and
      brainstem atrophy.
- category: Hepatic
  name: Liver Involvement
  subtype: Hepatocerebral
  description: >
    The hepatocerebral form shows liver involvement with elevation of serum
    transaminases and liver mtDNA depletion, resembling Alpers syndrome.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases."
    explanation: >
      Documents elevation of serum transaminases in the compound-heterozygous
      hepatocerebral cases.
- category: Neurologic
  name: Early-Onset Encephalopathy
  subtype: Hepatocerebral
  description: >
    Compound-heterozygous TWNK variants can manifest as severe early-onset
    encephalopathy with liver involvement, a phenotype reminiscent of Alpers
    syndrome.
  phenotype_term:
    preferred_term: Progressive encephalopathy
    term:
      id: HP:0002448
      label: Progressive encephalopathy
  evidence:
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement."
    explanation: >
      Defines the early-onset hepatocerebral encephalopathy phenotype caused by
      compound-heterozygous TWNK variants.
genetic:
- name: TWNK
  gene_term:
    preferred_term: TWNK
    term:
      id: hgnc:1160
      label: TWNK
  association: Biallelic recessive pathogenic variants in TWNK (Twinkle helicase)
  notes: >
    MTDPS7/IOSCA is caused by biallelic (recessive) pathogenic variants in TWNK
    (formerly C10orf2/PEO1), encoding the Twinkle mitochondrial replicative
    helicase. The classic Finnish IOSCA is caused by the homozygous founder
    Y508C variant; the hepatocerebral form has been reported with
    compound-heterozygous variants (e.g., A318T/Y508C). Dominant TWNK variants
    cause a distinct disorder (autosomal dominant progressive external
    ophthalmoplegia with multiple mtDNA deletions).
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:16135556
      reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder"
      explanation: >
        Establishes autosomal recessive inheritance of IOSCA at the inheritance
        descriptor level.
  evidence:
  - reference: PMID:16135556
    reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The founder IOSCA mutation, homozygous in all but one of the patients, leads to a Y508C amino acid change in the polypeptides."
    explanation: >
      Documents the homozygous Finnish founder Y508C variant in TWNK as the cause
      of classic IOSCA.
  - reference: PMID:16135556
    reference_title: "Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder"
    explanation: >
      Establishes autosomal recessive inheritance of IOSCA.
  - reference: PMID:17921179
    reference_title: "Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C)"
    explanation: >
      Documents compound-heterozygous TWNK variants underlying the hepatocerebral
      form.
treatments:
- name: Supportive Care
  description: >
    Management of IOSCA is supportive: hearing loss, sensory axonal neuropathy,
    ataxia, psychotic behavior, and severe depression are treated in the usual
    manner, with multidisciplinary surveillance (neurologic, audiologic, and
    ophthalmologic evaluations). There is no disease-modifying therapy.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of manifestations: Hearing loss, sensory axonal neuropathy, ataxia, psychotic behavior, and severe depression are treated in the usual manner."
    explanation: >
      GeneReviews describes supportive, symptom-directed management for IOSCA.
- name: Antiseizure Medication
  description: >
    Seizures are managed with antiseizure medication, although conventional
    antiepileptic drugs (phenytoin and phenobarbital) are ineffective in most
    affected individuals. Valproate should be avoided because it can cause
    significant elevation of serum bilirubin and liver enzymes in these patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional antiepileptic drugs (phenytoin and phenobarbital) are ineffective in most affected individuals."
    explanation: >
      GeneReviews notes that conventional antiepileptic drugs are largely
      ineffective, qualifying the role of antiseizure pharmacotherapy.
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Agents/circumstances to avoid: Valproate, which can cause significant elevation of serum concentration of bilirubin and liver enzymes."
    explanation: >
      GeneReviews explicitly warns against valproate due to hepatotoxicity risk in
      these patients.
- name: Genetic Counseling
  description: >
    IOSCA is inherited in an autosomal recessive manner. Genetic counseling
    informs at-risk families; carrier testing and prenatal testing are possible
    when the familial pathogenic variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301746
    reference_title: "Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IOSCA is inherited in an autosomal recessive manner."
    explanation: >
      GeneReviews documents autosomal recessive inheritance, the basis for genetic
      counseling.
📚

References & Deep Research

References

1
PMID:20301746
Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 24 citations 2026-06-03T23:57:31.742379

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Mitochondrial DNA Depletion Syndrome 7
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Mitochondrial DNA Depletion Syndrome 7 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Disease Characteristics Research Report: Mitochondrial DNA Depletion Syndrome 7 (MTDPS7; MPV17-related)

Executive summary

Mitochondrial DNA depletion syndrome 7 (MTDPS7) is a nuclear-gene, autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder caused by biallelic pathogenic variants in MPV17, encoding a mitochondrial inner membrane protein. The most common clinical presentation is an infantile hepatocerebral phenotype with cholestasis/acute liver failure, recurrent hypoglycemia, lactic acidosis, and later neurological involvement; mortality is frequently in infancy, though selected patients can survive long-term after liver transplantation. Recent (2023) real-world data from a tertiary liver center provide subgroup-specific mortality and transplant outcomes, and 2023 mechanistic model-organism work further supports an MPV17 ion-channel/nucleotide-homeostasis role in mtDNA stability. (vara2023hepaticpresentationsof pages 1-2, corra2023drosophilampv17forms pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 1-2)

1. Disease information

1.1 Definition (current understanding)

MTDPS7 belongs to the broader mtDNA depletion syndromes, which are “severe autosomal recessive disorders associated with decreased mtDNA copy number in clinically affected tissues.” (Uusimaa 2014, Eur J Hum Genet, published online 2013; print 2014-02 issue; DOI https://doi.org/10.1038/ejhg.2013.112) (uusimaa2014clinicalbiochemicalcellular pages 1-2)

In MPV17-related disease, the characteristic phenotype is hepatocerebral: early liver disease/failure is typically the presenting system, with neurological features often evolving later. In one large MPV17 cohort, “All patients manifested liver disease. Poor feeding, hypoglycaemia, raised serum lactate, hypotonia and faltering growth were common presenting features.” (Uusimaa 2014) (uusimaa2014clinicalbiochemicalcellular pages 1-2)

1.2 Key identifiers

A complete identifier panel (OMIM/Orphanet/MeSH/ICD-10/ICD-11) was not retrievable from the provided tool evidence in this run; the report therefore supplies only identifiers available in the retrieved sources and flags others as unavailable.

  • MONDO: Open Targets links mitochondrial DNA depletion syndrome to MONDO_0018158 and associates this disease entity to MPV17 (ENSG00000115204) with multiple literature items. (Open Targets platform: https://platform.opentargets.org) (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17)

1.3 Synonyms / alternative names

Commonly used synonyms in the retrieved literature include: - MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (uusimaa2014clinicalbiochemicalcellular pages 1-2) - MPV17-related mitochondrial DNA depletion syndrome (abduljalil2023fulminantneonatalliver pages 1-2) - Navajo neurohepatopathy (an MPV17 allelic presentation, classically associated with p.Arg50Gln). (uusimaa2014clinicalbiochemicalcellular pages 5-7)

1.4 Evidence source type

This entry integrates: - Aggregated disease-level resources: MONDO/Open Targets mapping of disease–gene association. (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17) - Primary human clinical evidence: cohort studies and case reports (e.g., Uusimaa 2014; Vara 2023; Abduljalil 2023). (uusimaa2014clinicalbiochemicalcellular pages 1-2, vara2023hepaticpresentationsof pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2) - Mechanistic/model systems evidence: mouse/in vitro channel studies and Drosophila mechanistic work. (antonenkov2015thehumanmitochondrial pages 1-2, corra2023drosophilampv17forms pages 1-2)

Identifier system ID Label Notes Supporting citation IDs
Disease name — Mitochondrial DNA Depletion Syndrome 7 Mendelian mtDNA maintenance disorder caused by MPV17 deficiency; hepatocerebral presentation with liver-predominant disease. (uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)
Gene-disease association / MONDO MONDO_0018158 mitochondrial DNA depletion syndrome Open Targets links MONDO_0018158 to MPV17 (ENSG00000115204) with literature support; URL: https://platform.opentargets.org (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17)
Gene ENSG00000115204 MPV17 Approved symbol: MPV17; mitochondrial inner membrane protein MPV17; nuclear gene underlying the MPV17-related hepatocerebral MDDS phenotype. (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17, uusimaa2014clinicalbiochemicalcellular pages 1-2, antonenkov2015thehumanmitochondrial pages 1-2)
Clinical subtype / descriptor — MPV17-related hepatocerebral mitochondrial DNA depletion syndrome Uusimaa 2014 describes MPV17 mutations as an important cause of the hepatocerebral form of mtDNA depletion syndrome; URL: https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 1-2)
Synonym — MPV17-related mitochondrial DNA depletion syndrome Common literature synonym for the same MPV17-associated disease spectrum. (uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)
Synonym — MPV17-related hepatocerebral mitochondrial DNA maintenance disorder Abduljalil 2023 places the condition within hepatocerebral mitochondrial DNA maintenance disorders; URL: https://doi.org/10.1155/2023/4514552 (abduljalil2023fulminantneonatalliver pages 1-2)
Synonym — Navajo neurohepatopathy Recognized MPV17-related presentation/allelic disorder name in the literature, especially associated with p.Arg50Gln in prior reports. (uusimaa2014clinicalbiochemicalcellular pages 5-7, antonenkov2015thehumanmitochondrial pages 1-2)
Inheritance — Autosomal recessive Both Uusimaa 2014 and Abduljalil 2023 describe mtDNA depletion/maintenance disorders due to MPV17 as autosomal recessive nuclear-gene disorders. (uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)
Resource note — Aggregated disease-level resources + individual patient reports Identifier mapping comes from aggregated knowledge resources (Open Targets/MONDO), while phenotype and synonym usage are supported by cohort studies and case reports. (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17, uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)

Table: This table summarizes key identifiers, naming conventions, and inheritance information for MPV17-related mitochondrial DNA depletion syndrome 7. It combines ontology/resource mapping with primary clinical literature so the disease entry can be normalized across knowledge bases.

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic (homozygous or compound heterozygous) pathogenic variants in MPV17 (nuclear gene), leading to reduced mtDNA copy number in affected tissues and downstream respiratory chain dysfunction. MPV17-related disease is described as “an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17.” (Antonenkov 2015, J Biol Chem, 2015-05; DOI https://doi.org/10.1074/jbc.m114.608083) (antonenkov2015thehumanmitochondrial pages 1-2)

2.2 Risk factors

  • Genetic: autosomal recessive inheritance; consanguinity and family history are frequently present in reported severe infantile cases. (abduljalil2023fulminantneonatalliver pages 1-2)
  • Environmental/other: no specific environmental exposures were supported in the retrieved evidence as causal risk factors for MPV17-related MTDPS7.

2.3 Protective factors / gene–environment interactions

No protective variants or gene–environment interactions specific to MTDPS7 were identified in the retrieved evidence.

3. Phenotypes

3.1 Core phenotype spectrum (human)

Hepatic (dominant early phenotype): - Infantile-onset cholestasis or acute liver failure with coagulopathy. - In a tertiary liver-center cohort (2002–2019), MPV17 liver involvement developed at median 2.5 months. (Vara 2023, J Inherit Metab Dis, 2023-05; DOI https://doi.org/10.1002/jimd.12633) (vara2023hepaticpresentationsof pages 1-2)

Metabolic/biochemical: - Hypoglycemia: common presenting feature. (uusimaa2014clinicalbiochemicalcellular pages 1-2) - Lactic acidosis / elevated lactate: common but variable. - In Uusimaa 2014, initial/plasma lactate ranged 3–21.4 mmol/L; importantly, normal lactate was observed in some patients at least once, emphasizing imperfect sensitivity of lactate as a screening biomarker. (uusimaa2014clinicalbiochemicalcellular pages 4-5, uusimaa2014clinicalbiochemicalcellular pages 3-4)

Neurologic: - Hypotonia is commonly present early. (uusimaa2014clinicalbiochemicalcellular pages 1-2) - Neurologic involvement can develop and may influence transplant candidacy/outcomes (see prognosis/treatment). In a 24-patient hepatic MDDS cohort, 18/24 had neurological involvement (not all MPV17). (vara2023hepaticpresentationsof pages 1-2) - A neonatal case report described hypotonia and nystagmus, with later clinical deterioration and death at 2 weeks. (Abduljalil 2023, Case Rep Hepatol, 2023-06; https://doi.org/10.1155/2023/4514552) (abduljalil2023fulminantneonatalliver pages 1-2)

3.2 Suggested HPO terms (non-exhaustive; for knowledge-base annotation)

(ontology suggestions; not claims) - Liver failure: HP:0001399 - Cholestasis: HP:0001396 - Hypoglycemia: HP:0001943 - Lactic acidosis: HP:0003128 - Elevated blood lactate: HP:0002151 - Failure to thrive: HP:0001508 - Hypotonia: HP:0001252 - Developmental delay: HP:0001263 - Nystagmus: HP:0000639 - Seizures: HP:0001250

3.3 Quality of life impact

Formal QoL instruments were not reported in the retrieved MTDPS7-specific primary evidence; however, the severe infantile course with liver failure, hypoglycemic crises, and neurodevelopmental impairment implies profound functional impact. (uusimaa2014clinicalbiochemicalcellular pages 1-2, vara2023hepaticpresentationsof pages 1-2)

4. Genetic / molecular information

4.1 Causal gene

  • MPV17 (mitochondrial inner membrane protein MPV17; nuclear gene; Ensembl ENSG00000115204). (OpenTargets Search: Mitochondrial DNA depletion syndrome,Mitochondrial DNA depletion syndrome 7,Navajo neurohepatopathy-MPV17)

4.2 Inheritance

  • Autosomal recessive. Multiple sources explicitly describe MPV17-related mtDNA depletion as autosomal recessive. (uusimaa2014clinicalbiochemicalcellular pages 1-2, antonenkov2015thehumanmitochondrial pages 1-2)

4.3 Pathogenic variants (representative; not exhaustive)

In a 17-patient cohort, Uusimaa et al. identified 12 different MPV17 pathogenic mutations (11 novel), spanning missense and truncating alleles and including recurrent/known alleles. (uusimaa2014clinicalbiochemicalcellular pages 5-7)

Representative variants reported in the retrieved evidence: - p.Arg50Gln (p.R50Q) (classically reported in Navajo neurohepatopathy). (uusimaa2014clinicalbiochemicalcellular pages 5-7) - p.Arg41Trp, p.Pro64Arg, p.Gly94Arg, p.Pro98Leu. (uusimaa2014clinicalbiochemicalcellular pages 5-7)

Genotype–phenotype: Uusimaa 2014 describes a “loose relationship” between genotype and clinical phenotype, but suggests severe hepatic mtDNA depletion and earlier presentation/death correlate more strongly than variant class alone; some missense genotypes may retain residual function. (uusimaa2014clinicalbiochemicalcellular pages 5-7, uusimaa2014clinicalbiochemicalcellular pages 4-5)

4.4 Functional consequences

Mechanistic data support MPV17 as an inner mitochondrial membrane factor involved in maintaining mtDNA integrity and mitochondrial homeostasis: - Channel activity & membrane potential: recombinant MPV17 forms a regulated “non-selective channel” and modulates mitochondrial membrane potential and ROS. (Antonenkov 2015) (antonenkov2015thehumanmitochondrial pages 1-2) - Nucleotide homeostasis & mtDNA replication: a 2023 Drosophila study summarizes and extends evidence that MPV17 deficiency can perturb mitochondrial nucleotide pools and contribute to mtDNA replication stress/arrest, consistent with mtDNA instability as the common downstream feature. (corra2023drosophilampv17forms pages 1-2)

4.5 Suggested GO / pathway annotations (for curation)

(ontology suggestions; not claims) - GO Biological Process: mtDNA maintenance, mitochondrial genome replication, oxidative phosphorylation, response to oxidative stress - GO Cellular Component: mitochondrial inner membrane

5. Environmental information

No disease-specific environmental toxins, lifestyle triggers, or infectious precipitants were supported by the retrieved evidence for MTDPS7. Clinical decompensation is typically driven by intrinsic metabolic vulnerability (e.g., fasting intolerance/hypoglycemia) and progressive organ failure. (bottani2014aavmediatedliverspecificmpv17 pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 1-2)

6. Mechanism / pathophysiology

6.1 Causal chain (integrated model)

  1. Biallelic MPV17 loss of function (nuclear gene) → impaired MPV17 function in mitochondrial inner membrane. (antonenkov2015thehumanmitochondrial pages 1-2)
  2. Disruption of mitochondrial homeostasis, including altered membrane potential/ROS and (supported by model-organism literature) impaired mitochondrial nucleotide balance → compromised mtDNA replication/maintenance. (antonenkov2015thehumanmitochondrial pages 1-2, corra2023drosophilampv17forms pages 1-2)
  3. Tissue-specific mtDNA depletion, particularly in liver (and variable in muscle/brain), leading to reduced respiratory-chain capacity and energy failure. Uusimaa reports liver mtDNA depletion in all available liver samples and correlation of profound depletion with severe early-onset disease. (uusimaa2014clinicalbiochemicalcellular pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 5-7)
  4. Clinical manifestations: liver failure/cholestasis, recurrent hypoglycemia, lactic acidosis, growth failure, then neurological disease (hypotonia, developmental delay, neuropathy, seizures). (uusimaa2014clinicalbiochemicalcellular pages 1-2, bottani2014aavmediatedliverspecificmpv17 pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)

6.2 Cell types and tissues implicated (suggested CL/UBERON terms)

(ontology suggestions; not claims) - Primary anatomical sites: liver (UBERON:0002107), brain (UBERON:0000955), skeletal muscle (UBERON:0001134) - Cell types: hepatocyte (CL:0000182), neurons (CL:0000540), skeletal muscle fiber (CL:0000187)

7. Anatomical structures affected

Primary: liver. In the Uusimaa cohort, all patients manifested liver disease, and liver mtDNA depletion was a consistent tissue finding where measured. (uusimaa2014clinicalbiochemicalcellular pages 1-2)

Secondary / extrahepatic: nervous system involvement is common and may progress over time (e.g., hypotonia early; neuropathy later), though detailed frequencies by feature were not fully extractable from the retrieved corpus. (bottani2014aavmediatedliverspecificmpv17 pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)

8. Temporal development

  • Typical onset: neonatal/infancy, with median hepatic presentation in early months in a tertiary cohort. (vara2023hepaticpresentationsof pages 1-2)
  • Progression: often rapidly progressive hepatic failure in infancy with high mortality, though survival into childhood/adulthood occurs in subsets, particularly when hepatic disease is stabilized (including in selected post-transplant cases). (vara2023hepaticpresentationsof pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 5-7)

9. Inheritance and population

9.1 Epidemiology

No general-population prevalence/incidence estimates were retrieved in the provided evidence.

9.2 Navajo neurohepatopathy

The Navajo neurohepatopathy designation reflects a population-associated MPV17 presentation/allele (p.R50Q), but population-level frequency statistics were not available in the retrieved evidence set. (uusimaa2014clinicalbiochemicalcellular pages 5-7)

10. Diagnostics

10.1 Clinical suspicion and biochemical workup

Typical findings include liver dysfunction, hypoglycemia, and hyperlactatemia/lactic acidosis, but lactate can be variable and sometimes normal, especially in acute liver failure contexts. (uusimaa2014clinicalbiochemicalcellular pages 4-5, vara2023hepaticpresentationsof pages 10-10)

10.2 Tissue testing

  • mtDNA depletion testing: Uusimaa 2014 demonstrated liver mtDNA depletion in all 7/7 tested livers and described mosaic depletion detection in fibroblasts using PicoGreen staining/nucleoid visualization. (uusimaa2014clinicalbiochemicalcellular pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 5-7)

10.3 Genetic testing (recommended)

Case reports and cohort experiences emphasize the necessity of rapid genetic testing in infantile liver failure/mitochondrial hepatopathy. - Abduljalil 2023: “Genetic testing of mitochondrial DNA depletion syndromes should be a part of liver failure workup …” (as summarized in their abstract context). (abduljalil2023fulminantneonatalliver pages 1-2) - Vara 2023 recommends “rapid genetic testing” in infantile acute liver failure when considering liver transplantation. (vara2023hepaticpresentationsof pages 1-2)

10.4 Differential diagnosis

In infantile cholestasis/acute liver failure, the differential includes other hepatic mitochondrial DNA depletion syndromes (e.g., DGUOK, POLG) which can have overlapping presentations; in Vara 2023, sodium valproate exposure precipitated liver injury in POLG patients (important differential clue for POLG rather than MPV17). (vara2023hepaticpresentationsof pages 1-2)

11. Outcome / prognosis

11.1 Mortality statistics (recent cohort)

In Vara et al. (single tertiary liver center; 2002–2019): - Overall cohort mortality: 17/24 died at median age 8 months. - MPV17 subgroup: 5/10 died at median age 8 months. (vara2023hepaticpresentationsof pages 1-2)

The mortality/long-term survival distribution for MPV17 patients is illustrated in their Table 1 (image extraction from Table 1 available). (vara2023hepaticpresentationsof media 88fd76c6, vara2023hepaticpresentationsof media 95df983a)

11.2 Prognostic factors

Across the retrieved evidence, severe hepatic mtDNA depletion correlated with earlier presentation and death, whereas neurological evolution can also critically influence outcomes (including post-transplant outcomes). (uusimaa2014clinicalbiochemicalcellular pages 5-7, priyadarshini2025hepatocerebralmitochondrialdna pages 1-2)

12. Treatment

12.1 Current clinical management (real-world)

Supportive care remains central. - Bottani 2014 states: “Liver transplantation and frequent feeding using slow-release carbohydrates are the only available therapies …” for MPV17-related hepatocerebral mtDNA depletion syndrome, noting that survivors may later develop progressive neuropathy. (Bottani 2014, Mol Ther, 2014-01; https://doi.org/10.1038/mt.2013.230) (bottani2014aavmediatedliverspecificmpv17 pages 1-2)

Liver transplantation (LT): - Vara 2023 provides long-term post-LT survival in 3 MPV17 patients (alive at 19, 18, 3 years post-LT). (vara2023hepaticpresentationsof pages 1-2) - However, transplant outcomes are heterogeneous; Bottani 2014 notes that among 10 transplanted MPV17 patients in literature, 5 died early post-LT (multiorgan failure/sepsis). (bottani2014aavmediatedliverspecificmpv17 pages 1-2)

12.2 Experimental / clinical trial landscape

Nucleoside therapy trial explicitly including MPV17: - NCT04802707 (ClinicalTrials.gov; first posted 2021; status Recruiting) is a Phase 2, single-arm, open-label study of oral deoxycytidine + deoxythymidine for mitochondrial DNA depletion syndromes; inclusion explicitly lists pathogenic variants including MPV17, making it directly relevant to MTDPS7. Dose escalates to 400 mg/kg/day through a stepwise schedule (100→200→300→400 mg/kg) with long treatment duration. Primary/secondary outcomes include clinical responder measures (NPMDS/ANMDS), GDF15, and safety endpoints. (NCT04802707 chunk 1)

Broader primary mitochondrial disease trials potentially relevant to MPV17 subsets: - NCT05162768 (SPIMD-301 / NuPower) elamipretide Phase 3 trial (start 2022-04-29; completed 2024-12-04) enrolled adults with nuclear DNA mutation–associated primary mitochondrial myopathy; gene lists include MPV17 among eligible nuclear genes, though this trial targets myopathy phenotypes and excludes severe neurologic impairment and prior solid-organ transplant. (NCT05162768 chunk 1, NCT05162768 chunk 2)

12.3 Suggested MAXO terms (for curation)

(ontology suggestions; not claims) - Liver transplantation: MAXO:0001175 (or closest available MAXO transplant term) - Dietary modification / frequent feeding / cornstarch therapy: dietary intervention MAXO term - Genetic testing: diagnostic genomic sequencing MAXO term

13. Prevention

Primary prevention is not applicable in the traditional sense for an autosomal recessive Mendelian disorder; prevention focuses on genetic counseling and reproductive options. - Given recessive inheritance and recurrent familial cases, counseling and carrier testing/cascade testing are relevant (supported by recessive inheritance and familial recurrence in reported cases). (uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary disease analogs were identified in the retrieved evidence.

15. Model organisms

  • Mouse models: Mpv17 knockout mice show liver mtDNA depletion and have been used for mechanistic and gene-replacement experiments; AAV-mediated liver-specific MPV17 expression restored mtDNA and prevented diet-induced liver failure in mice, providing proof-of-concept for gene replacement strategies (preclinical). (bottani2014aavmediatedliverspecificmpv17 pages 1-2)
  • Drosophila: Corrà 2023 demonstrates Drosophila Mpv17 forms an ion channel and regulates energy metabolism, supporting conserved mechanistic roles relevant to mtDNA stability. (corra2023drosophilampv17forms pages 1-2)

Recent developments & latest research emphasis (2023–2024)

  1. 2023 clinical outcomes in hepatic MDDS: Vara 2023 provides modern real-world mortality and long-term liver transplant survival for MPV17 patients in a single-center cohort, refining candidate selection considerations. (vara2023hepaticpresentationsof pages 1-2, vara2023hepaticpresentationsof media 88fd76c6)
  2. 2023 neonatal fulminant liver failure case: Abduljalil 2023 underscores that MPV17 disease may present as neonatal shock/sepsis-like illness with severe coagulopathy and rapid death, reinforcing the need for early genomic testing. (abduljalil2023fulminantneonatalliver pages 1-2)
  3. 2023 mechanistic conservation: Corrà 2023 strengthens MPV17’s functional interpretation as an ion channel tied to nucleotide homeostasis/energy metabolism, consistent with mtDNA instability being the shared downstream lesion. (corra2023drosophilampv17forms pages 1-2)
  4. 2024–2025 translational landscape: completion of a Phase 3 elamipretide nuclear-mutation primary mitochondrial disease trial (NCT05162768) provides a benchmark for drug development feasibility in nuclear gene mitochondrial disorders, though it is not disease-specific to MPV17 hepatocerebral MTDPS7. (NCT05162768 chunk 1)
Category Finding (with numbers where available) Evidence type (cohort/case report/model) Publication (year, journal) + URL Supporting citation IDs
Phenotype / cohort overview Single-center pediatric hepatic MDDS cohort: n=24 total, including 10 MPV17 cases; median age at presentation 3 months overall; liver involvement in MPV17 developed at median 2.5 months. Human cohort Vara et al., 2023, Journal of Inherited Metabolic Disease — https://doi.org/10.1002/jimd.12633 (vara2023hepaticpresentationsof pages 1-2, vara2023hepaticpresentationsof pages 10-10)
Natural history / mortality In the same cohort, 17/24 died at median age 8 months; among MPV17 patients, 5/10 died at median 8 months. Authors conclude MPV17 often causes early-onset/neonatal acute liver failure or rapidly progressive cholestasis with death before 12 months in many cases. Human cohort Vara et al., 2023, Journal of Inherited Metabolic Disease — https://doi.org/10.1002/jimd.12633 (vara2023hepaticpresentationsof pages 1-2)
Liver transplantation outcomes 3 MPV17 patients underwent liver transplantation at median age 24 months (range 5–132 months) and were alive at 19, 18, and 3 years post-transplant, supporting that a subset may benefit from LT. Human cohort Vara et al., 2023, Journal of Inherited Metabolic Disease — https://doi.org/10.1002/jimd.12633 (vara2023hepaticpresentationsof pages 1-2, vara2023hepaticpresentationsof pages 10-10, vara2023hepaticpresentationsof media 88fd76c6)
Core presenting features In a 17-patient MPV17 cohort, all patients had liver disease; common features were poor feeding, hypoglycaemia, raised serum lactate, hypotonia, and faltering growth. Human cohort Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 1-2)
Biochemical findings Initial/plasma lactate ranged 3–21.4 mmol/L; CSF lactate up to 5.1 mmol/L; notably five patients had at least one normal blood or CSF lactate, so normal lactate does not exclude disease. Human cohort Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 4-5, uusimaa2014clinicalbiochemicalcellular pages 3-4)
Tissue mtDNA depletion / severity correlation mtDNA depletion in liver was demonstrated in all 7/7 cases with liver tissue available; severe liver mtDNA depletion (<~20% of age-matched controls) correlated with earlier onset and more severe course/death. Mosaic mtDNA depletion was also seen in fibroblasts. Human cohort / cellular Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 1-2, uusimaa2014clinicalbiochemicalcellular pages 5-7, uusimaa2014clinicalbiochemicalcellular pages 4-5)
Histology / organ involvement Liver histology showed variable necrosis, steatosis, cholestasis, fibrosis, with abnormal respiratory-chain enzymology in a subset. Human cohort Vara et al., 2023, Journal of Inherited Metabolic Disease — https://doi.org/10.1002/jimd.12633 (vara2023hepaticpresentationsof pages 1-2)
Neonatal fulminant presentation 2023 neonatal case: presented with hypoglycemia, jaundice, hypotonia, rotatory nystagmus, severe coagulopathy, hyperlactatemia, aminoaciduria; homozygous pathogenic MPV17 missense variant found; infant died at 2 weeks with refractory ascites. Human case report Abduljalil et al., 2023, Case Reports in Hepatology — https://doi.org/10.1155/2023/4514552 (abduljalil2023fulminantneonatalliver pages 1-2)
Supportive management / transplant experience Review of available therapy noted frequent feeding using slow-release carbohydrates/cornstarch to prevent fatal hypoglycemia; among 10 transplanted MPV17 patients reported in literature, 5 died early after LT from multiorgan failure or sepsis. Human literature summary / translational Bottani et al., 2014, Molecular Therapy — https://doi.org/10.1038/mt.2013.230 (bottani2014aavmediatedliverspecificmpv17 pages 1-2)
Inheritance Disease is autosomal recessive; cases arise in homozygous or compound heterozygous states, often in consanguineous families. Human cohort / case report Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112; Abduljalil et al., 2023, Case Reports in Hepatology — https://doi.org/10.1155/2023/4514552 (uusimaa2014clinicalbiochemicalcellular pages 1-2, abduljalil2023fulminantneonatalliver pages 1-2)
Key pathogenic variants Uusimaa 2014 identified 12 MPV17 mutations (11 novel) in 17 patients, including p.Arg50Gln (p.R50Q), p.Arg41Trp, p.Pro64Arg, p.Gly94Arg, and p.Pro98Leu; mutation classes included missense and truncating alleles. Human cohort Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 5-7, uusimaa2014clinicalbiochemicalcellular pages 3-4)
Genotype-phenotype note p.R50Q is the classic Navajo neurohepatopathy-associated allele. Uusimaa 2014 suggested some missense genotypes (e.g., p.Arg41Trp, p.Pro64Arg, p.Pro98Leu, p.R50Q) may retain residual function and show relatively milder survival than severe truncating/other alleles, although genotype-phenotype correlation was described as loose. Human cohort Uusimaa et al., 2014, European Journal of Human Genetics — https://doi.org/10.1038/ejhg.2013.112 (uusimaa2014clinicalbiochemicalcellular pages 5-7, uusimaa2014clinicalbiochemicalcellular pages 4-5)
Mechanistic function of MPV17 MPV17 encodes an inner mitochondrial membrane protein that forms a regulated non-selective channel (~1.8 nm pore) and modulates mitochondrial membrane potential and ROS, linking loss of function to mtDNA instability. In vitro / mouse model Antonenkov et al., 2015, Journal of Biological Chemistry — https://doi.org/10.1074/jbc.m114.608083 (antonenkov2015thehumanmitochondrial pages 1-2)
Mechanistic insight into depletion Drosophila and prior mouse work support that MPV17 loss perturbs mitochondrial nucleotide homeostasis (including reduced dGTP/dTTP), increases aberrant riboGTP incorporation, and contributes to mtDNA replication arrest/depletion; Drosophila Mpv17 also formed a channel and affected energy metabolism. Model organism / mechanistic Corrà et al., 2023, iScience — https://doi.org/10.1016/j.isci.2023.107955 (corra2023drosophilampv17forms pages 1-2)

Table: This table summarizes clinically important phenotype, natural history, outcomes, pathogenic variants, and mechanistic findings for MPV17-related mitochondrial DNA depletion syndrome. It is designed to support disease knowledge base curation with specific numbers and citation-backed genotype-phenotype notes.

Notes on missing elements (tooling limitation transparency)

  • OMIM/Orphanet/MeSH/ICD identifiers, prevalence/incidence estimates, and formal QoL statistics were not present in the retrieved evidence and therefore could not be cited here.
  • Variant allele frequencies (e.g., gnomAD), ClinVar classifications, and GTR testing-lab listings were not retrievable using the current tool set in this run; the variant list reflects only the variants explicitly present in the retrieved full-text evidence.

References

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  2. (corra2023drosophilampv17forms pages 1-2): Samantha Corrà, Vanessa Checchetto, Michele Brischigliaro, Chiara Rampazzo, Emanuela Bottani, Cristina Gagliani, Katia Cortese, Cristiano De Pittà, Marco Roverso, Diego De Stefani, Sara Bogialli, Massimo Zeviani, Carlo Viscomi, Ildiko Szabò, and Rodolfo Costa. Drosophila mpv17 forms an ion channel and regulates energy metabolism. iScience, 26:107955, Oct 2023. URL: https://doi.org/10.1016/j.isci.2023.107955, doi:10.1016/j.isci.2023.107955. This article has 11 citations and is from a peer-reviewed journal.

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  14. (priyadarshini2025hepatocerebralmitochondrialdna pages 1-2): Prerna Priyadarshini, Sanjeev Kumar Verma, Manisha Verma, and S. N. Singh. Hepatocerebral mitochondrial dna depletion syndrome due to mpv17 mutation presenting with cholestasis and progressive liver failure in an infant. Journal of Rare Diseases, Oct 2025. URL: https://doi.org/10.1007/s44162-025-00125-7, doi:10.1007/s44162-025-00125-7. This article has 0 citations.

  15. (NCT04802707 chunk 1): Kenneth Myers, MD. Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome. Kenneth Myers, MD. 2021. ClinicalTrials.gov Identifier: NCT04802707

  16. (NCT05162768 chunk 1): Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD). Stealth BioTherapeutics Inc.. 2022. ClinicalTrials.gov Identifier: NCT05162768

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