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Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals carry two MICU1 loss-of-function alleles, homozygous (often in consanguineous families) or compound heterozygous. Heterozygous carrier parents are unaffected.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:40898676 SUPPORT Human Clinical

"Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1"

States the recessive mode of inheritance and the biallelic genotype in a series combining new and published patients.

PMID:39973469 SUPPORT Human Clinical

"The variants were segregating in unaffected parents in heterozygous state"

Segregation in this family shows heterozygous carrier parents are unaffected, consistent with recessive inheritance.

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Discussions and Knowledge Gaps

2

Why do MICU1-null mice improve with age, through EMRE downregulation, while the extrapyramidal disorder in patients tends to progress?

HUMAN MODEL MISMATCH OPEN mpxps_mouse_age_dependent_improvement

Attached to

pathophysiology#Resting Mitochondrial Calcium Overload phenotypes#Progressive extrapyramidal movement disorder

The whole-body knockout reproduces the cellular defect but loses it with age as the uniporter is remodelled, whereas the human course shows static weakness with progressive extrapyramidal signs. Whether human tissues remodel the uniporter in the same way, and whether lowering EMRE or MCU would help patients, is untested.

Show evidence (2 references)

PMID:27477272 SUPPORT Model Organism

"Older MICU1(-/-) mice show marked, spontaneous improvement coincident with improved mitochondrial calcium handling and an age-dependent reduction in EMRE expression."

The age-dependent improvement in mice that raises the question.

PMID:27477272 SUPPORT Model Organism

"Remarkably, deleting one allele of EMRE helps normalize calcium uptake while simultaneously rescuing the high perinatal mortality observed in young MICU1(-/-) mice."

EMRE reduction rescues the mouse, the basis for proposing uniporter modulation as therapy.

Which neurons and brain regions are damaged in patients with MICU1 deficiency, and what explains the extrapyramidal signs?

KNOWLEDGE GAP OPEN mpxps_extrapyramidal_substrate

Attached to

pathophysiology#Progressive Neurodegeneration phenotypes#Progressive extrapyramidal movement disorder

The neuronal mechanism comes from a neuron-specific mouse knockout showing motor neuron degeneration in spinal cord and cortex. No human neuropathology has been reported in the cited literature, and the basal ganglia circuitry implied by chorea and dystonia has not been studied.

Show evidence (1 reference)

PMID:35302860 SUPPORT BACKGROUND Model Organism

"While studies in patient-derived cells revealed altered mitochondrial calcium signaling, the neuronal pathogenesis was difficult to study."

States that neuronal pathogenesis in patients has been hard to study.

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Pathophysiology

11

MICU1 Biallelic Loss of Function

Biallelic germline nonsense, canonical splice-site, frameshift and exon-deletion variants in MICU1 abolish the MICU1 protein. MICU1 is the EF-hand calcium-sensing regulator of the mitochondrial calcium uniporter complex in the inner mitochondrial membrane, whose pore is formed by MCU.

MICU1 hgnc:1530

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Homozygous or compound heterozygous loss-of-function alleles; absent MICU1 protein has been shown in patient fibroblasts.

uniporter gatekeeping (calcium channel regulator activity) GO:0005246 ∅ ABSENT

Downstream

Loss of Uniporter Calcium Threshold and Cooperative Activation Without MICU1 the uniporter is no longer held shut at low cytosolic calcium and is no longer cooperatively activated at high calcium.

Show evidence (2 references)

PMID:24336167 SUPPORT Human Clinical

"Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder."

The discovery report linking MICU1 mutations to the disease.

PMID:27123478 SUPPORT In Vitro

"No MICU1 protein was detected in patient fibroblasts, which had impaired mitochondrial calcium uptake that was rescued through the overexpression of the wild-type allele."

Shows the patient allele is a protein null, and that restoring MICU1 corrects the calcium defect in patient cells.

Loss of Uniporter Calcium Threshold and Cooperative Activation

MICU1 normally sets a cytosolic calcium threshold below which the uniporter stays closed and cooperatively boosts uptake once calcium rises. Its loss makes uptake inappropriately active at resting and low cytosolic calcium, while blunting the rise in uptake during large cytosolic calcium transients. Cytosolic calcium signals are correspondingly reduced in patient cells.

MICU1 hgnc:1530

calcium import into the mitochondrion GO:0036444 ↕ DYSREGULATED

Downstream

Resting Mitochondrial Calcium Overload Ungated uptake at resting cytosolic calcium raises matrix calcium.

Impaired Mitochondrial Calcium Uptake During Muscle Activity Loss of cooperative activation blunts the mitochondrial calcium rise that normally accompanies excitation-contraction coupling and membrane injury.

Episodic fatigue and lethargy The authors attribute the fluctuating, activity- and illness-triggered course to the dysregulated uniporter; the intermediate steps are not established.

Show evidence (3 references)

PMID:24336167 SUPPORT In Vitro

"In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced."

Patient fibroblasts show excess uptake at low cytosolic calcium, the loss of the gatekeeping threshold.

PMID:31665639 SUPPORT In Vitro

"detected in MICU1-patient cells and restored the mitochondrial Ca2+ uptake threshold back to what was observed in CTRL fibroblasts."

Re-expressing MICU1 in patient fibroblasts restores the normal uptake threshold, showing that MICU1 loss lowers it.

PMID:31665639 SUPPORT Model Organism

"This increase was larger in MICU1-smKO than in CTRL ... supporting that impaired gatekeeping resulted in mitochondrial Ca2+ overload."

In myofibers from skeletal muscle-specific knockout mice, loss of gatekeeping produces excess mitochondrial calcium uptake.

Resting Mitochondrial Calcium Overload

Matrix calcium is raised at rest. In patient fibroblasts the extra influx is balanced by sodium-calcium exchanger efflux, a futile cycle proposed to add an energetic cost. MICU1-null mice show raised resting mitochondrial calcium, altered mitochondrial morphology and reduced ATP early in life.

fibroblast CL:0000057

mitochondrial calcium ion homeostasis GO:0051560 ↕ DYSREGULATED

Animal models

Micu1 knockout mouse (whole body) Mouse recapitulates Reproduces the raised resting mitochondrial calcium of patient cells in vivo.

Downstream

Mitochondrial Network Fragmentation In patient fibroblasts the fragmentation is associated with altered DRP1 phosphorylation.

Impaired Satellite Cell-Mediated Muscle Regeneration Basally raised mitochondrial calcium in Micu1-deficient satellite cells impairs their expansion after muscle injury.

Neuronal Susceptibility to Calcium Overload-Induced Death Neurons lacking MICU1 overload with calcium during excitotoxic stimuli and die through permeability transition.

Show evidence (2 references)

PMID:28132899 SUPPORT In Vitro

"We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca2+ concentration"

Raised resting matrix calcium in patient-derived fibroblasts.

PMID:27477272 SUPPORT Model Organism

"Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP."

MICU1-null mice show the same resting calcium overload in vivo.

Mitochondrial Network Fragmentation

The mitochondrial network is severely fragmented in MICU1-deficient cells although resting membrane potential is unchanged. Muscle biopsies show marked mitochondrial abnormalities.

fibroblast CL:0000057

mitochondrial fission GO:0000266 ↑ INCREASED

Downstream

Abnormal mitochondria in muscle The structural mitochondrial changes seen in patient cells are mirrored by mitochondrial abnormalities in patient muscle; the shared cause is inferred.

Show evidence (1 reference)

PMID:24336167 SUPPORT In Vitro

"Although resting mitochondrial membrane potential was unchanged in MICU1-deficient cells, the mitochondrial network was severely fragmented."

Fragmentation of the mitochondrial network in patient fibroblasts.

Impaired Mitochondrial Calcium Uptake During Muscle Activity

In skeletal muscle fibers, MICU1 loss impairs the mitochondrial calcium rise during excitation-contraction coupling and after sarcolemmal injury, the two settings in which mitochondrial calcium uptake supports energy supply and membrane repair.

skeletal muscle fiber CL:0008002

calcium import into the mitochondrion GO:0036444 ↓ DECREASED

Downstream

Impaired Muscle Aerobic Metabolism Mitochondrial calcium normally stimulates oxidative metabolism to match contraction; its failure impairs aerobic metabolism.

Defective Sarcolemmal Repair

Show evidence (1 reference)

PMID:31665639 SUPPORT Model Organism

"MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers."

Reduced uptake after membrane injury in MICU1-deficient muscle fibers.

Impaired Muscle Aerobic Metabolism

Aerobic metabolism of MICU1-deficient muscle is impaired during activity. Resting serum lactate is characteristically normal in patients, unlike many respiratory-chain myopathies.

skeletal muscle fiber CL:0008002

aerobic respiration GO:0009060 ↓ DECREASED

Downstream

Easy fatigability

Proximal muscle weakness

Show evidence (1 reference)

PMID:31665639 SUPPORT Model Organism

"Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity."

Aerobic metabolism impairment in MICU1-deficient muscle.

Defective Sarcolemmal Repair

Mitochondrial calcium uptake at the site of membrane injury supports resealing of the sarcolemma. Without it, injured MICU1-deficient myofibers and patient fibroblasts repair poorly, a defect corrected by re-expressing MICU1 in patient cells.

skeletal muscle fiber CL:0008002

plasma membrane repair GO:0001778 ↓ DECREASED

Animal models

Skeletal muscle-specific Micu1 knockout mouse Mouse recapitulates Isolated myofibers repair laser-induced sarcolemmal injury poorly.

Downstream

Activity-Induced Myofiber Damage

Show evidence (1 reference)

PMID:31665639 SUPPORT In Vitro

"MICU1-HA transfected patient fibroblasts showed reduced FM-dye entry, indicating their improved membrane repair kinetics"

Restoring MICU1 in patient fibroblasts improves membrane repair, implicating MICU1 loss in the repair defect.

Activity-Induced Myofiber Damage

Physical activity damages skeletal muscle fibers that cannot repair their sarcolemma efficiently, releasing creatine kinase and causing exertional muscle pain and weakness. Patient biopsies show myopathic and dystrophic features with neurogenic changes and mitochondrial abnormalities.

skeletal muscle fiber CL:0008002

Downstream

Elevated serum creatine kinase

Proximal muscle weakness

Increased variability in muscle fiber diameter Damage and regeneration of myofibers leave fiber size variation on biopsy; the link is inferred from the pattern of findings.

Centrally nucleated skeletal muscle fibers Internal and central nuclei mark regenerated fibers after damage; the link is inferred.

Exercise-induced myalgia

Show evidence (1 reference)

PMID:33428302 SUPPORT Human Clinical

"Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis."

Muscle damage in patient biopsies.

Impaired Satellite Cell-Mediated Muscle Regeneration

In mice with Micu1 deleted in Pax7-positive satellite cells, homeostasis is preserved but the regenerative response after muscle injury and satellite cell self-renewal are impaired. Whether this contributes to the human myopathy has not been tested.

skeletal muscle satellite cell CL:0000594

skeletal muscle satellite cell activation GO:0014719 ↓ DECREASED skeletal muscle tissue regeneration GO:0043403 ↓ DECREASED

Animal models

Satellite cell-specific Micu1 knockout mouse Mouse recapitulates Directly measures regeneration after experimental muscle injury.

Downstream

Proximal muscle weakness Inferred: poor regeneration would compound activity-induced fiber damage. Not measured in patients.

Show evidence (1 reference)

PMID:42349424 SUPPORT Model Organism

"Although satellite cell homeostasis was not significantly affected 1 month following Micu1 deletion, the regenerative response post-injury was significantly impaired."

Impaired regeneration after injury in satellite cell-specific knockout mice.

Neuronal Susceptibility to Calcium Overload-Induced Death

Cortical mitochondria from neuron-specific MICU1 knockout mice have a lower calcium uptake threshold, and MICU1-deficient neurons and patient cells are more susceptible to excitotoxic calcium overload and death. The death is blunted by inhibiting the mitochondrial permeability transition pore.

neuron CL:0000540

positive regulation of mitochondrial membrane permeability GO:0035794

Downstream

Progressive Neurodegeneration

Show evidence (1 reference)

PMID:35302860 SUPPORT Model Organism

"We found increased susceptibility to mitochondrial Ca2+ overload-induced excitotoxic insults and cell death in MICU1-KO neurons and MICU1-deficient patient-derived cells, which can be blunted by inhibiting the mitochondrial permeability transition pore."

Calcium overload-induced death of MICU1-deficient neurons, dependent on the permeability transition pore.

Progressive Neurodegeneration

Neuron-specific MICU1 knockout mice develop progressive motor and cognitive deficits with degeneration of spinal motor neurons and cortical neurons. Which human brain regions degenerate, and in particular whether the basal ganglia are involved in the extrapyramidal signs, has not been shown.

motor neuron CL:0000100

Animal models

Neuron-specific Micu1 knockout mouse Mouse partially recapitulates Shows progressive neurodegeneration with motor and cognitive deficits.

Downstream

Progressive extrapyramidal movement disorder Inferred from the mouse motor phenotype; the extrapyramidal circuitry affected in patients has not been studied.

Learning difficulties

Ataxia

Chorea Chorea is one form of the extrapyramidal disorder; as for the parent phenotype, the link from neurodegeneration is inferred from mice.

Tremor Tremor is one form of the extrapyramidal disorder; the link is inferred.

Dystonia Dystonia is one form of the extrapyramidal disorder; the link is inferred.

Orofacial dyskinesia Orofacial dyskinesia is one form of the extrapyramidal disorder; the link is inferred.

Progressive extrapyramidal muscular rigidity Rigidity is one form of the extrapyramidal disorder; the link is inferred.

Show evidence (1 reference)

PMID:35302860 SUPPORT Model Organism

"These animals show progressive, abnormal motor and cognitive phenotypes likely caused by the degeneration of motor neurons in the spinal cord and the cortex."

Progressive neurodegeneration in the neuron-specific knockout.

✶

Histopathology

1

Nonspecific myopathic changes

Biopsies show myopathic changes with fiber size variation, internal and central nuclei and regenerating fibers, sometimes with dystrophic and neurogenic features and mitochondrial abnormalities. The changes are nonspecific and do not identify MICU1 deficiency on their own, and a biopsy can be normal.

Show evidence (3 references)

PMID:33969448 SUPPORT REVIEW SYNTHESIS Human Clinical

"Muscle biopsies were available for 6 of these patients, which all exhibited myopathic features, with diffuse variation in fiber size, increased internal and central nuclei, and clustering of regenerating fibers."

Literature summary of six biopsied patients, all with the finding.

PMID:39973469 SUPPORT REVIEW SYNTHESIS Human Clinical

"Muscle biopsies done in MICU1 related syndromes showed non-specific myopathic changes."

Records that the biopsy findings are not specific to the disease.

PMID:33428302 SUPPORT Human Clinical

"Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis."

Dystrophic, neurogenic and mitochondrial features in two patients.

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Pathograph

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Phenotypes

33

Eye 6

Nystagmus HP:0000639

Show evidence (2 references)

PMID:29721912 SUPPORT BACKGROUND Human Clinical

"as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts."

Summarizes earlier reports in which nystagmus was a variable feature.

PMID:27123478 SUPPORT Human Clinical

"He has mild learning difficulties, pendular nystagmus, bilateral optic atrophy, mild hypotonia, and global muscle weakness"

Pendular nystagmus in an affected boy.

Cataract HP:0000518

Show evidence (2 references)

PMID:29721912 SUPPORT BACKGROUND Human Clinical

"as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts."

Summarizes earlier reports in which cataract was a variable feature.

PMID:27123478 SUPPORT Human Clinical

"delayed development was noted at 6 months when nystagmus and an abnormal red reflex revealed cataracts."

Infantile cataract in an affected boy.

Optic atrophy OCCASIONAL HP:0000648

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0000648 | Optic atrophy | Occasional (29-5%)"

Orphanet grades optic atrophy as occasional, the basis for the OCCASIONAL band.

PMID:27123478 SUPPORT Human Clinical

"He has mild learning difficulties, pendular nystagmus, bilateral optic atrophy, mild hypotonia, and global muscle weakness"

Bilateral optic atrophy in an affected boy.

PMID:39973469 SUPPORT Human Clinical

"This report highlights the phenotype of limb girdle weakness with facial dysmorphism and optic atrophy"

Optic atrophy in an adult patient.

Ptosis OCCASIONAL HP:0000508

Show evidence (3 references)

PMID:38380193 SUPPORT Human Clinical

"myopathy (ptosis, double vision, strabismus, distal limb weakness, diffuse wasting, hypotonia)"

Ptosis in a patient homozygous for the c.553C>T founder variant.

PMID:37034047 SUPPORT REVIEW SYNTHESIS Human Clinical

"Other features include delayed speech and motor milestones, hypotonia, optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy, and microcephaly."

The case report's literature summary lists ptosis among the variable features of published patients.

ORPHA:401768 SUPPORT Other

"HP:0000508 | Ptosis | Occasional (29-5%)"

Orphanet grades ptosis as occasional, the basis for the OCCASIONAL band.

Strabismus HP:0000486

Show evidence (2 references)

PMID:38380193 SUPPORT Human Clinical

"myopathy (ptosis, double vision, strabismus, distal limb weakness, diffuse wasting, hypotonia)"

Strabismus in a patient homozygous for the c.553C>T founder variant.

PMID:33969448 SUPPORT Human Clinical

"ataxia, extrapyramidal signs, gait disturbance, strabismus, elevated CK, elevated hepatic transaminases, and raised LDH."

Strabismus in an adult patient with a nonsense variant.

Ophthalmoplegia OCCASIONAL HP:0000602

Show evidence (2 references)

PMID:37034047 SUPPORT REVIEW SYNTHESIS Human Clinical

"Other features include delayed speech and motor milestones, hypotonia, optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy, and microcephaly."

The case report's literature summary lists this among the variable features of published patients.

ORPHA:401768 SUPPORT Other

"HP:0000602 | Ophthalmoplegia | Occasional (29-5%)"

Orphanet grades ophthalmoplegia as occasional, the basis for the OCCASIONAL band.

Head and Neck 1

Microcephaly OCCASIONAL HP:0000252

Show evidence (2 references)

ORPHA:401768 SUPPORT Other

"HP:0000252 | Microcephaly | Occasional (29-5%)"

Orphanet independently grades microcephaly as occasional, matching the OCCASIONAL band.

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"7 out of 16 described an abnormal gait, 6 out of 20 had ataxia, and 5 out of 20 had microcephaly."

Microcephaly in 5 of 20 published patients (25%), OCCASIONAL.

Limbs 1

Calf muscle hypertrophy HP:0008981

Show evidence (1 reference)

PMID:37034047 SUPPORT Human Clinical

"presented with proximal myopathy, calf muscle hypertrophy, and skeletal deformities along with choreiform movements of his upper extremities."

Calf hypertrophy in one patient, a feature that can mimic a dystrophinopathy.

Metabolism 2

Elevated serum creatine kinase VERY_FREQUENT Elevated circulating creatine kinase activity HP:0003236

Show evidence (2 references)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Elevated CK in 32 of 33 published patients (97%), VERY_FREQUENT.

PMID:29721912 SUPPORT Human Clinical

"Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes."

Persistently raised CK with normal lactate in all 13 patients.

Elevated hepatic transaminases VERY_FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Transaminases may be released from muscle as well as liver; the cited sources do not separate the two.

Show evidence (2 references)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Elevated transaminases in 14 of 17 tested patients (82%), VERY_FREQUENT.

PMID:29721912 SUPPORT Human Clinical

"Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes."

Raised transaminases in the founder-variant series.

Musculoskeletal 6

Proximal muscle weakness FREQUENT HP:0003701

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0003701 | Proximal muscle weakness | Frequent (79-30%)"

Orphanet independently grades proximal weakness as frequent, matching the FREQUENT band.

PMID:24336167 SUPPORT Human Clinical

"Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder."

Proximal myopathy is a defining feature of the discovery cohort.

PMID:40898676 SUPPORT Human Clinical

"Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%)."

Myopathy in 51% of 61 patients, within the FREQUENT band.

Easy fatigability HP:0003388

Show evidence (1 reference)

PMID:29721912 SUPPORT Human Clinical

"All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive"

Easy fatigability in all 13 founder-variant patients.

Hypotonia FREQUENT HP:0001252

Show evidence (1 reference)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"Nine out of 30 had short stature, 7 out of 15 patients described muscular hypotonia"

Hypotonia in 7 of 15 published patients (47%), FREQUENT.

Increased variability in muscle fiber diameter FREQUENT HP:0003557

Show evidence (2 references)

PMID:33969448 SUPPORT REVIEW SYNTHESIS Human Clinical

"Muscle biopsies were available for 6 of these patients, which all exhibited myopathic features, with diffuse variation in fiber size, increased internal and central nuclei, and clustering of regenerating fibers."

Literature summary of six biopsied patients, all with the finding.

ORPHA:401768 SUPPORT Other

"HP:0003557 | Increased variability in muscle fiber diameter | Frequent (79-30%)"

Orphanet grades this frequent, the basis for the FREQUENT band.

Centrally nucleated skeletal muscle fibers FREQUENT HP:0003687

Show evidence (2 references)

PMID:33969448 SUPPORT REVIEW SYNTHESIS Human Clinical

"Muscle biopsies were available for 6 of these patients, which all exhibited myopathic features, with diffuse variation in fiber size, increased internal and central nuclei, and clustering of regenerating fibers."

Literature summary of six biopsied patients, all with the finding.

ORPHA:401768 SUPPORT Other

"HP:0003687 | Centrally nucleated skeletal muscle fibers | Frequent (79-30%)"

Orphanet grades this frequent, the basis for the FREQUENT band.

Progressive extrapyramidal muscular rigidity FREQUENT HP:0007158

Show evidence (1 reference)

ORPHA:401768 SUPPORT Other

"HP:0007158 | Progressive extrapyramidal muscular rigidity | Frequent (79-30%)"

Orphanet annotates progressive extrapyramidal rigidity as frequent; no primary case report in this entry describes rigidity separately.

Nervous System 13

Progressive extrapyramidal movement disorder FREQUENT HP:0007153

Course: PROGRESSIVE

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0007153 | Progressive extrapyramidal movement disorder | Frequent (79-30%)"

Orphanet independently grades the extrapyramidal disorder as frequent, matching the FREQUENT band.

PMID:24336167 SUPPORT Human Clinical

"Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder."

The progressive extrapyramidal movement disorder defines the disease.

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Extrapyramidal signs in 23 of 34 published patients (68%), FREQUENT.

Chorea FREQUENT HP:0002072

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0002072 | Chorea | Frequent (79-30%)"

Orphanet grades chorea as frequent, the basis for the FREQUENT band.

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The age of onset of extrapyramidal symptoms such as chorea, tremor, and dystonia ranged from 2"

The literature summary names chorea among the extrapyramidal signs.

PMID:37034047 SUPPORT Human Clinical

"presented with proximal myopathy, calf muscle hypertrophy, and skeletal deformities along with choreiform movements of his upper extremities."

Choreiform movements in a genetically confirmed patient.

Tremor HP:0001337

Show evidence (1 reference)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The age of onset of extrapyramidal symptoms such as chorea, tremor, and dystonia ranged from 2"

The literature summary names tremor among the extrapyramidal signs.

Dystonia FREQUENT HP:0001332

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0001332 | Dystonia | Frequent (79-30%)"

Orphanet grades dystonia as frequent, the basis for the FREQUENT band.

PMID:37034047 SUPPORT Human Clinical

"Extrapyramidal features in the form of dystonia and choreiform movements of the upper extremities were noted"

Dystonia in a genetically confirmed patient.

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The age of onset of extrapyramidal symptoms such as chorea, tremor, and dystonia ranged from 2"

The literature summary names dystonia among the extrapyramidal signs.

Learning difficulties VERY_FREQUENT Intellectual disability HP:0001249

Bound to intellectual disability rather than specific learning disability because the reports describe general cognitive impairment (for example a Wechsler score of 70, intellectual disability, inability to attend school), not a learning disorder confined to one domain with normal intelligence.

Show evidence (2 references)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Learning disabilities in 28 of 31 published patients (90%), VERY_FREQUENT.

PMID:40898676 SUPPORT Human Clinical

"Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%)."

Learning difficulties in 72% of a larger combined cohort; the larger series falls in the FREQUENT band, so the VERY_FREQUENT call rests on the smaller review.

Motor delay VERY_FREQUENT HP:0001270

Show evidence (2 references)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Motor delay in 29 of 33 published patients (88%), VERY_FREQUENT.

PMID:29721912 SUPPORT Human Clinical

"All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive"

Developmental delay in all 13 founder-variant patients.

Delayed speech and language development FREQUENT HP:0000750

Show evidence (2 references)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"The most common symptoms were motor delay (29/33), learning disabilities (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech delay (19/31), muscle weakness (14/31), and elevated liver transaminases (14/17)."

Speech delay in 19 of 31 published patients (61%), FREQUENT.

PMID:40898676 SUPPORT Human Clinical

"Deep phenotyping of 61 patients from different ethnic backgrounds revealed that common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%)."

Speech impairment in 51% of 61 patients, also FREQUENT.

Episodic fatigue and lethargy HP:0001254

Temporal: RECURRENT

Show evidence (2 references)

PMID:27123478 SUPPORT Human Clinical

"MICU1 mutations cause fatigue and lethargy in patients with normal mitochondrial enzyme activities in muscle."

Episodic fatigue and lethargy in two cousins with an exon 1 deletion.

PMID:27123478 SUPPORT Human Clinical

"Initially the episodes accompanied minor viral infections and evolved over hours."

Describes the infection-triggered episodes.

Ataxia OCCASIONAL HP:0001251

Show evidence (3 references)

ORPHA:401768 SUPPORT Other

"HP:0001251 | Ataxia | Occasional (29-5%)"

Orphanet grades ataxia as occasional.

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"7 out of 16 described an abnormal gait, 6 out of 20 had ataxia, and 5 out of 20 had microcephaly."

Ataxia in 6 of 20 published patients (30%), on the boundary between OCCASIONAL and FREQUENT; with Orphanet grading it occasional, OCCASIONAL is used.

PMID:33428302 SUPPORT Human Clinical

"presenting with ataxia, developmental delay and early onset myopathy"

Ataxia in two further patients.

Hyporeflexia HP:0001265

Show evidence (2 references)

PMID:33969448 SUPPORT Human Clinical

"presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH)."

Reduced tendon reflexes in an adult patient.

PMID:39973469 SUPPORT Human Clinical

"Limb girdle pattern of weakness with hypoactive tendon reflexes were noted without extrapyramidal signs."

Hypoactive reflexes in a second patient.

Attention deficits Short attention span HP:0000736

Show evidence (2 references)

PMID:33428302 SUPPORT Human Clinical

"presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception."

Attention deficits in two patients.

PMID:41018190 SUPPORT Human Clinical

"the proband (older sister, 3 years 4 months) manifested early signs including pes planus and attention deficits"

Attention deficits as an early sign in a young child.

Orofacial dyskinesia FREQUENT HP:0002310

Show evidence (2 references)

PMID:37034047 SUPPORT REVIEW SYNTHESIS Human Clinical

"The appearance of extrapyramidal features such as chorea, athetosis, dystonia, tremor, and orofacial dyskinesias is the key differentiator."

The case report's literature summary names orofacial dyskinesia among the extrapyramidal features.

ORPHA:401768 SUPPORT Other

"HP:0002310 | Orofacial dyskinesia | Frequent (79-30%)"

Orphanet grades orofacial dyskinesia as frequent, the basis for the FREQUENT band.

Peripheral axonal neuropathy OCCASIONAL HP:0003477

Show evidence (2 references)

PMID:37034047 SUPPORT REVIEW SYNTHESIS Human Clinical

"Other features include delayed speech and motor milestones, hypotonia, optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy, and microcephaly."

The case report's literature summary lists this among the variable features of published patients.

ORPHA:401768 SUPPORT Other

"HP:0003477 | Peripheral axonal neuropathy | Occasional (29-5%)"

Orphanet grades peripheral axonal neuropathy as occasional, the basis for the OCCASIONAL band.

Cellular 1

Abnormal mitochondria in muscle Abnormal mitochondria in muscle tissue HP:0008316

Show evidence (2 references)

PMID:33428302 SUPPORT Human Clinical

"Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis."

Severe mitochondrial perturbations on muscle biopsy.

PMID:39973469 SUPPORT Human Clinical

"Muscle biopsy showed myopathic with secondary neurogenic changes along with few COX deficient fibres."

Cytochrome-oxidase-deficient fibers in a second patient.

Constitutional 1

Exercise-induced myalgia HP:0003738

Show evidence (2 references)

PMID:39973469 SUPPORT Human Clinical

"presented with 10 years history of proximal muscle weakness with exertional myalgia and fatigue."

Exertional myalgia in a genetically confirmed patient.

PMID:27123478 SUPPORT Human Clinical

"after 100 m of walking she now develops muscle aches that limit her activities and resolve after 15 minutes of rest."

Exertional muscle aches in a second family.

Growth 2

Short stature FREQUENT HP:0004322

Show evidence (1 reference)

PMID:36425804 SUPPORT REVIEW SYNTHESIS Human Clinical

"Nine out of 30 had short stature, 7 out of 15 patients described muscular hypotonia"

Short stature in 9 of 30 published patients (30%), at the lower edge of FREQUENT.

Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:29721912 SUPPORT Human Clinical

"All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive"

Failure to thrive in all 13 founder-variant patients; frequency in other cohorts is not reported, so no band is given.

🧬

Genetic Associations

1

MICU1

Gene: MICU1 hgnc:1530 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (2 references)

PMID:24336167 SUPPORT Human Clinical

"Here we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder."

Discovery of MICU1 as the causal gene.

PMID:40898676 SUPPORT Human Clinical

"The targeted neuromuscular assessment, along with muscle biopsy and exome sequencing, identified six pathogenic MICU1 variants"

Independent families with pathogenic MICU1 variants.

Variants (2)

c.553C>T founder nonsense variant

A nonsense variant recurrent in consanguineous Middle Eastern families, homozygous in 12 of 13 patients in one series. Reports name the protein change differently (p.Gln185* in the founder series, p.Arg185* in later reports).

Show evidence (1 reference)

PMID:29721912 SUPPORT Human Clinical

"Of these patients, 12/13 are homozygous for a novel founder mutation c.553C>T (p.Q185*) that is predicted to lead to a complete loss of function of MICU1"

Identifies the founder allele and its predicted null effect.

Exon 1 deletion

A homozygous 2,755 bp deletion removing exon 1, detected from exome read depth in two cousins with episodic fatigue and lethargy.

Show evidence (1 reference)

PMID:27123478 SUPPORT Human Clinical

"Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion."

Shows a copy-number allele detected by exome depth analysis.

🗃️

External Assertions

2

OMIM MPXPS entry

OMIM disease record OMIM:615673

OMIM phenotype entry cross-referenced by MONDO:0014300.

Orphanet MPXPS record

Orphanet disease record ORPHA:401768

Orphanet record cross-referenced by MONDO:0014300. Its phenotype frequency and epidemiology rows are quoted as evidence in this entry.

💊

Medical Actions

4

Physical, Speech and Occupational Therapy

Category: Therapeutic Action: Physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Rehabilitation therapies are the mainstay of symptomatic care. The evidence is a single case report.

Show evidence (1 reference)

PMID:38380193 SUPPORT Human Clinical

"Treatment of MICU1-related phenotypes is symptomatic, but these patients benefit from physical therapy, behavioral therapy, speech therapy, and antidepressant treatment."

Case-report authors report benefit from rehabilitation therapies.

Supportive Care

Category: Therapeutic Action: Supportive care Ontology label: Supportive Care NCIT:C15747

No disease-modifying treatment exists. Management is supportive and symptom-directed: developmental and educational support, and monitoring of the movement disorder and of vision. Uniporter modulation is a proposed future approach.

Show evidence (2 references)

PMID:38380193 SUPPORT Human Clinical

"Treatment of MICU1-related phenotypes is symptomatic, but these patients benefit from physical therapy, behavioral therapy, speech therapy, and antidepressant treatment."

States that treatment is symptomatic, the basis for supportive care.

PMID:40898676 SUPPORT Human Clinical

"Functional studies targeting MCU modulation may provide future therapeutic options."

Supports the sentence that uniporter modulation is only a proposed future approach.

Levocarnitine and Glutathione Supplementation

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: levocarnitine CHEBI:16347 glutathione CHEBI:16856

Platform: Small molecule

Levocarnitine, glutathione and compound glycyrrhizin given to four children did not normalize their raised muscle enzymes or transaminases. This is a negative uncontrolled observation, not a trial.

Target Phenotypes: Elevated serum creatine kinase HP:0003236

Show evidence (1 reference)

PMID:41018190 REFUTE Human Clinical

"after treatment with levocarnitine, Glutathione, and compound glycyrrhizin tablets, the muscle enzymes and transaminase did not improve significantly and remained abnormal."

No biochemical response in four treated children, against any benefit of this supplementation.

Genetic Counseling

Category: Counseling / Informational Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Molecular diagnosis allows recessive recurrence-risk counselling, carrier testing, and testing of siblings, who may have raised creatine kinase before symptoms.

Show evidence (1 reference)

PMID:33969448 SUPPORT Human Clinical

"improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children."

Molecular diagnosis supports counselling of at-risk couples.

🔬

Biochemical Markers

2

Serum creatine kinase (INCREASED)

Context: Persistently raised in nearly all patients and in presymptomatic affected siblings, so it is often the first clue.

Show evidence (1 reference)

PMID:41018190 SUPPORT Human Clinical

"his younger brother (4 years) remained asymptomatic though with elevated muscle enzymes."

CK is raised before symptoms in an affected sibling.

Serum lactate (NORMAL)

Context: Resting lactate is normal, which distinguishes MICU1 deficiency from many respiratory-chain myopathies.

Show evidence (1 reference)

PMID:29721912 SUPPORT Human Clinical

"Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes."

Normal lactate in all 13 patients and in earlier cases.

🔬

Diagnosis

3

Exome sequencing with copy-number analysis

Diagnosis is by finding biallelic MICU1 variants, usually by exome sequencing. Exon-level deletions occur, so read-depth or other copy-number analysis is needed. Targeted testing for the c.553C>T founder variant is reasonable in Middle Eastern patients.

Whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:27123478 SUPPORT Human Clinical

"Analysis of the exome sequencing depth revealed a homozygous deletion of exon 1 of MICU1 within a 2,755-base pair deletion."

The causal allele was found only by analyzing exome read depth.

PMID:29721912 SUPPORT Human Clinical

"our work suggests that targeted analysis of the MICU1 founder mutation in Middle Eastern patients may be warranted."

Supports founder-variant testing in Middle Eastern patients.

Serum creatine kinase and transaminase measurement

Persistently raised creatine kinase and transaminases with normal lactate in a child with weakness or learning difficulties should prompt MICU1 testing, alongside the muscular dystrophies.

Creatine kinase measurement NCIT:C64489

Show evidence (1 reference)

PMID:41018190 SUPPORT Human Clinical

"so in clinical practice, early detection of persistent elevation of muscle enzymes and transaminase abnormalities, especially in families with similar patients, in addition to considering progressive muscular dystrophy, MPXPS should also be vigilant."

Recommends considering MPXPS when muscle enzymes and transaminases stay raised.

Muscle biopsy

Biopsy findings are nonspecific: myopathic or dystrophic changes, neurogenic features, and mitochondrial abnormalities, and a biopsy can be normal.

Muscle biopsy NCIT:C51895

Show evidence (2 references)

PMID:33428302 SUPPORT Human Clinical

"Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis."

Range of biopsy findings.

PMID:27123478 SUPPORT Human Clinical

"To define the mechanism responsible for fatigue, lethargy, and weakness in 2 cousins who had a normal muscle biopsy."

A normal biopsy does not exclude the disease.

🩻

Imaging Findings

1

Selective fatty infiltration on muscle MRI

Muscle MRI shows selective fatty replacement of thigh and leg muscles. The two reported patterns differ: adductor involvement with sparing of the anterolateral thigh, quadriceps and hamstrings in one patient, and hamstring, medial gastrocnemius and soleus involvement in another, so no consistent pattern has been established.

Mri

Fatty replacement of skeletal muscle HP:0012548

Show evidence (3 references)

PMID:37034047 SUPPORT Human Clinical

"Muscle MRI revealed a distinctively early involvement of adductors with sparing of antero-lateral compartment of thigh."

Adductor-predominant fatty involvement in one patient.

PMID:39973469 SUPPORT Human Clinical

"Muscle MRI had novel findings of selective fatty infiltration of hamstrings, medial gastrocnemius and soleus."

A different selective pattern, involving the hamstrings, in a second patient.

PMID:37034047 SUPPORT Human Clinical

"While muscle MRI can be largely instrumental in aiding differentiation from other myopathies, lack of previous data in MICU-related myopathy warrants future studies for consistency."

The authors note that the pattern has not been shown to be consistent.

📈

Progression

2

Childhood onset

Most patients present before age 5 with motor delay, weakness, fatigue or an incidentally raised creatine kinase, but onset spans infancy to adulthood. Muscle weakness is usually static or slowly progressive, while extrapyramidal signs tend to appear later and progress.

Show evidence (2 references)

PMID:40898676 SUPPORT Human Clinical

"Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years."

Onset distribution across the combined cohort of published and new patients.

PMID:41018190 SUPPORT BACKGROUND Human Clinical

"While the muscle weakness is static, most patients develop progressive extrapyramidal signs that may become disabling."

Background summary of the typical course: static weakness and progressive extrapyramidal signs.

Adult onset

A minority of patients first show symptoms after adolescence; one adult-onset patient (onset at 29 years) progressed faster than childhood-onset cases.

Show evidence (1 reference)

PMID:40898676 SUPPORT Human Clinical

"Notably, we report one adult-onset patient whose symptoms began at age 29 and progressed more rapidly than those in childhood-onset cases."

Documents adult onset and its faster course in one patient.

📊

Prevalence

2

Published MPXPS literature

Cases In Literature Ultra Rare

No population prevalence has been measured. A 2025 case series combined seven new patients with 54 previously published cases, and a 2022 case report described the disease as occurring at a frequency below 1 in 1,000,000. A founder nonsense variant (c.553C>T) is enriched in consanguineous Middle Eastern families.

Show evidence (2 references)

PMID:40898676 SUPPORT Human Clinical

"We clinically and genetically characterized seven affected individuals from six Iranian-Turkish consanguineous families and combined these data with 54 previously published cases (total of 62)."

Gives the count of published patients, the basis for the literature case-count record.

PMID:36425804 SUPPORT BACKGROUND Human Clinical

"is a rare autosomal recessive disease due to a pathogenic variant in the MICU1 gene with a frequency lower than 1/1000000."

The case report's background statement places the disease in the ultra-rare range; it does not give a measured prevalence.

Worldwide

Point Prevalence <1 in 1,000,000

Orphanet worldwide point-prevalence class below 1 in 1,000,000, sourced to the discovery report.

Show evidence (1 reference)

ORPHA:401768 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:24336167"

Orphanet epidemiology table.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Proximal Myopathy With Extrapyramidal Signs:

Limb-girdle muscular dystrophy Not Yet Curated MONDO:0016971

Overlapping Features Proximal weakness with raised creatine kinase and dystrophic biopsy changes overlaps with the limb-girdle muscular dystrophies, and MICU1-related myopathy has been found in LGMD diagnostic cohorts. Extrapyramidal signs, learning difficulties and raised transaminases point to MICU1.

Show evidence (1 reference)

PMID:33386810 SUPPORT Human Clinical

"one family with MICU1-related myopathy, one family with FLNC-related myopathy and one family with facioscapulohumeral dystrophy type 1."

A family referred as LGMD was diagnosed with MICU1-related myopathy.

🐁

Animal Models

4

Micu1 knockout mouse (whole body)

Whole-body Micu1 knockout causes high but incomplete perinatal mortality. Survivors show ataxia, muscle weakness, raised resting mitochondrial calcium, altered mitochondrial morphology and reduced ATP, then improve spontaneously with age as EMRE expression falls. Deleting one Emre allele rescues mortality and calcium uptake.

Species

Mouse

Genotype

Micu1 -/-

Publication

PMID:27477272

Pathograph links

Resting Mitochondrial Calcium Overload recapitulates fidelity: moderate observes: cellular Reproduces the raised resting mitochondrial calcium of patient cells in vivo.

Limitations: The defect and the phenotype improve with age in mice through EMRE downregulation, whereas extrapyramidal signs progress in patients; and most knockout pups die perinatally, which is not a human feature.

Readouts

Resting mitochondrial calcium

Direction: INCREASED

Interpretation: Direct measure of the overload node in young animals.

Show evidence (1 reference)

PMID:27477272 SUPPORT Model Organism

"Early in life, these animals display a range of biochemical abnormalities, including increased resting mitochondrial calcium levels, altered mitochondrial morphology, and reduced ATP."

Reports the measurement and its direction.

Show evidence (1 reference)

PMID:27477272 SUPPORT Model Organism

"Similar to afflicted patients, viable MICU1(-/-) mice manifest marked ataxia and muscle weakness."

The knockout reproduces the patient phenotype, supporting its use for this node.

Skeletal muscle-specific Micu1 knockout mouse

Mice lacking MICU1 in skeletal muscle show a lowered uptake threshold, impaired mitochondrial calcium uptake during contraction and after sarcolemmal injury, poor membrane repair, weakness, fatigue and activity-induced myofiber damage.

Species

Mouse

Genotype

Muscle-specific conditional Micu1 deletion (MICU1-smKO)

Publication

PMID:31665639

Pathograph links

Defective Sarcolemmal Repair recapitulates fidelity: moderate observes: cellular Isolated myofibers repair laser-induced sarcolemmal injury poorly.

Limitations: Muscle-only deletion cannot show any contribution of neuronal or systemic MICU1 loss to the muscle phenotype.

Show evidence (1 reference)

PMID:31665639 SUPPORT Model Organism

"MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers."

The model directly demonstrates the repair defect.

Satellite cell-specific Micu1 knockout mouse

Micu1 deletion in Pax7-positive satellite cells leaves satellite cell homeostasis intact but impairs regeneration after injury and self-renewal after transplantation.

Species

Mouse

Genotype

Pax7-driven conditional Micu1 deletion in satellite cells

Publication

PMID:42349424

Pathograph links

Impaired Satellite Cell-Mediated Muscle Regeneration recapitulates fidelity: unknown observes: cellular Directly measures regeneration after experimental muscle injury.

Limitations: Regeneration was tested after experimental injury in mice; whether satellite cell dysfunction contributes to the human myopathy has not been examined.

Show evidence (1 reference)

PMID:42349424 SUPPORT Model Organism

"Satellite cell self-renewal from Micu1-deficient donor cells in transplant recipients was also heavily compromised."

The model shows the satellite cell defect directly.

Neuron-specific Micu1 knockout mouse

Mice lacking MICU1 in neurons develop progressive motor and cognitive deficits with degeneration of spinal and cortical motor neurons, and their neurons are more susceptible to calcium overload-induced death.

Species

Mouse

Genotype

Neuron-specific conditional Micu1 deletion (nKO)

Publication

PMID:35302860

Pathograph links

Progressive Neurodegeneration partially recapitulates fidelity: moderate observes: tissue Shows progressive neurodegeneration with motor and cognitive deficits.

Limitations: The degeneration reported is of spinal and cortical motor neurons; a basal ganglia lesion that would explain the human extrapyramidal signs was not shown.

Show evidence (1 reference)

PMID:35302860 SUPPORT Model Organism

"These animals show progressive, abnormal motor and cognitive phenotypes likely caused by the degeneration of motor neurons in the spinal cord and the cortex."

Progressive neurodegeneration in the model.

{ }

Source YAML

click to show

name: Proximal Myopathy With Extrapyramidal Signs
creation_date: "2026-10-14T15:02:40Z"
description: >-
  An autosomal recessive neuromuscular disorder caused by biallelic
  loss-of-function variants in MICU1, the calcium-sensing gatekeeper subunit
  of the mitochondrial calcium uniporter. Onset is usually in early childhood,
  with proximal muscle weakness, easy fatigability, motor and speech delay,
  learning difficulties and a persistently raised serum creatine kinase with
  normal lactate. Many patients develop a progressive extrapyramidal movement
  disorder (chorea, tremor, dystonia), and variable features include ataxia,
  hyporeflexia, raised liver transaminases, short stature, microcephaly,
  nystagmus, cataract and optic atrophy. Loss of MICU1 removes the calcium
  threshold and cooperative activation of the uniporter, so mitochondria take
  up calcium at resting cytosolic concentrations and fail to boost uptake
  during muscle activity, leading to mitochondrial calcium overload and
  fragmentation, impaired muscle energetics and sarcolemmal repair, and
  vulnerability of neurons to calcium overload-induced death.
category: Mendelian
disease_term:
  preferred_term: proximal myopathy with extrapyramidal signs
  term:
    id: MONDO:0014300
    label: proximal myopathy with extrapyramidal signs
synonyms:
- myopathy with extrapyramidal signs
- MPXPS
- MICU1 deficiency
- MICU1-related myopathy
parents:
- myopathy
- movement disorder
- hereditary skeletal muscle disorder
- hereditary neurological disease
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry two MICU1 loss-of-function alleles, homozygous
    (often in consanguineous families) or compound heterozygous. Heterozygous
    carrier parents are unaffected.
  evidence:
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myopathy with extrapyramidal signs (MPXPS) is a rare, autosomal-recessive,
      multisystem disorder caused by biallelic loss-of-function (LOF) variants
      in MICU1
    explanation: >-
      States the recessive mode of inheritance and the biallelic genotype in a
      series combining new and published patients.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variants were segregating in unaffected parents in heterozygous state
    explanation: >-
      Segregation in this family shows heterozygous carrier parents are
      unaffected, consistent with recessive inheritance.
prevalence:
- population: Published MPXPS literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence has been measured. A 2025 case series combined
    seven new patients with 54 previously published cases, and a 2022 case
    report described the disease as occurring at a frequency below 1 in
    1,000,000. A founder nonsense variant (c.553C>T) is enriched in
    consanguineous Middle Eastern families.
  evidence:
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We clinically and genetically characterized seven affected individuals
      from six Iranian-Turkish consanguineous families and combined these data
      with 54 previously published cases (total of 62).
    explanation: >-
      Gives the count of published patients, the basis for the literature
      case-count record.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      is a rare autosomal recessive disease due to a pathogenic variant in the
      MICU1 gene with a frequency lower than 1/1000000.
    explanation: >-
      The case report's background statement places the disease in the
      ultra-rare range; it does not give a measured prevalence.
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet worldwide point-prevalence class below 1 in 1,000,000, sourced to
    the discovery report.
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:24336167"
    explanation: Orphanet epidemiology table.
progression:
- phase: Childhood onset
  notes: >-
    Most patients present before age 5 with motor delay, weakness, fatigue or
    an incidentally raised creatine kinase, but onset spans infancy to
    adulthood. Muscle weakness is usually static or slowly progressive, while
    extrapyramidal signs tend to appear later and progress.
  evidence:
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Across the combined cohort, the mean age at onset was 5.9 ± 7.3 years
      (median = 3 years); 61.5% presented before age 5, while 9.5% manifested
      after 15 years.
    explanation: >-
      Onset distribution across the combined cohort of published and new
      patients.
  - reference: PMID:41018190
    reference_title: "Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      While the muscle weakness is static, most patients develop progressive
      extrapyramidal signs that may become disabling.
    explanation: >-
      Background summary of the typical course: static weakness and
      progressive extrapyramidal signs.
- phase: Adult onset
  notes: >-
    A minority of patients first show symptoms after adolescence; one
    adult-onset patient (onset at 29 years) progressed faster than
    childhood-onset cases.
  evidence:
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, we report one adult-onset patient whose symptoms began at age 29
      and progressed more rapidly than those in childhood-onset cases.
    explanation: >-
      Documents adult onset and its faster course in one patient.
pathophysiology:
- name: MICU1 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic germline nonsense, canonical splice-site, frameshift and
    exon-deletion variants in MICU1 abolish the MICU1 protein. MICU1 is the
    EF-hand calcium-sensing regulator of the mitochondrial calcium uniporter
    complex in the inner mitochondrial membrane, whose pore is formed by MCU.
  genes:
  - preferred_term: MICU1
    term:
      id: hgnc:1530
      label: MICU1
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous loss-of-function alleles; absent
      MICU1 protein has been shown in patient fibroblasts.
  molecular_functions:
  - preferred_term: uniporter gatekeeping (calcium channel regulator activity)
    term:
      id: GO:0005246
      label: calcium channel regulator activity
    modifier: ABSENT
  evidence:
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report mutations of MICU1 in individuals with a disease phenotype
      characterized by proximal myopathy, learning difficulties and a
      progressive extrapyramidal movement disorder.
    explanation: >-
      The discovery report linking MICU1 mutations to the disease.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      No MICU1 protein was detected in patient fibroblasts, which had impaired
      mitochondrial calcium uptake that was rescued through the overexpression
      of the wild-type allele.
    explanation: >-
      Shows the patient allele is a protein null, and that restoring MICU1
      corrects the calcium defect in patient cells.
  downstream:
  - target: Loss of Uniporter Calcium Threshold and Cooperative Activation
    causal_link_type: DIRECT
    description: >-
      Without MICU1 the uniporter is no longer held shut at low cytosolic
      calcium and is no longer cooperatively activated at high calcium.
    evidence:
    - reference: PMID:33428302
      reference_title: "Molecular pathophysiology of human MICU1 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        threshold and the cooperative activation of mitochondrial Ca2+ uptake
        were lost in MICU1-deficient cells
      explanation: >-
        Patient-derived MICU1-deficient cells lose both the calcium threshold
        and cooperative activation of uptake.
- name: Loss of Uniporter Calcium Threshold and Cooperative Activation
  biological_scale: MOLECULAR
  description: >-
    MICU1 normally sets a cytosolic calcium threshold below which the uniporter
    stays closed and cooperatively boosts uptake once calcium rises. Its loss
    makes uptake inappropriately active at resting and low cytosolic calcium,
    while blunting the rise in uptake during large cytosolic calcium transients.
    Cytosolic calcium signals are correspondingly reduced in patient cells.
  genes:
  - preferred_term: MICU1
    term:
      id: hgnc:1530
      label: MICU1
  biological_processes:
  - preferred_term: calcium import into the mitochondrion
    term:
      id: GO:0036444
      label: calcium import into the mitochondrion
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In fibroblasts from subjects with MICU1 mutations, agonist-induced
      mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was
      increased, and cytosolic Ca(2+) signals were reduced.
    explanation: >-
      Patient fibroblasts show excess uptake at low cytosolic calcium, the
      loss of the gatekeeping threshold.
  - reference: PMID:31665639
    reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      detected in MICU1-patient cells and restored the mitochondrial Ca2+
      uptake threshold back to what was observed in CTRL fibroblasts.
    explanation: >-
      Re-expressing MICU1 in patient fibroblasts restores the normal uptake
      threshold, showing that MICU1 loss lowers it.
  - reference: PMID:31665639
    reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This increase was larger in MICU1-smKO than in CTRL ... supporting that
      impaired gatekeeping resulted in mitochondrial Ca2+ overload.
    explanation: >-
      In myofibers from skeletal muscle-specific knockout mice, loss of
      gatekeeping produces excess mitochondrial calcium uptake.
  downstream:
  - target: Resting Mitochondrial Calcium Overload
    causal_link_type: DIRECT
    description: >-
      Ungated uptake at resting cytosolic calcium raises matrix calcium.
    evidence:
    - reference: PMID:28132899
      reference_title: "Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We propose that deregulation of mitochondrial Ca2+ uptake through loss
        of MICU1 raises resting ... initiating a futile Ca2+ cycle, whereby
        continuous mitochondrial Ca2+ influx is balanced by Ca2+ efflux through
        the sodium calcium exchanger (NLCXm).
      explanation: >-
        Links the loss of uptake regulation to raised resting matrix calcium in
        patient fibroblasts.
  - target: Impaired Mitochondrial Calcium Uptake During Muscle Activity
    causal_link_type: DIRECT
    description: >-
      Loss of cooperative activation blunts the mitochondrial calcium rise that
      normally accompanies excitation-contraction coupling and membrane injury.
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake
        during excitation-contraction, aerobic metabolism impairment, muscle
        weakness, fatigue, and myofiber damage during physical activity.
      explanation: >-
        In skeletal muscle-specific knockout mice, MICU1 loss impairs
        mitochondrial calcium uptake during excitation-contraction.
  - target: Episodic fatigue and lethargy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors attribute the fluctuating, activity- and illness-triggered
      course to the dysregulated uniporter; the intermediate steps are not
      established.
    evidence:
    - reference: PMID:27123478
      reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        The fluctuating clinical course is likely mediated through the
        mitochondrial calcium uniporter, which is regulated by MICU1.
      explanation: >-
        A proposed, not demonstrated, link between uniporter dysregulation and
        the episodic course.
- name: Resting Mitochondrial Calcium Overload
  biological_scale: CELLULAR
  description: >-
    Matrix calcium is raised at rest. In patient fibroblasts the extra influx is
    balanced by sodium-calcium exchanger efflux, a futile cycle proposed to add
    an energetic cost. MICU1-null mice show raised resting mitochondrial
    calcium, altered mitochondrial morphology and reduced ATP early in life.
  biological_processes:
  - preferred_term: mitochondrial calcium ion homeostasis
    term:
      id: GO:0051560
      label: mitochondrial calcium ion homeostasis
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:28132899
    reference_title: "Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We have shown previously that MICU1 mutations cause increased resting
      mitochondrial Ca2+ concentration
    explanation: >-
      Raised resting matrix calcium in patient-derived fibroblasts.
  - reference: PMID:27477272
    reference_title: "MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Early in life, these animals display a range of biochemical
      abnormalities, including increased resting mitochondrial calcium levels,
      altered mitochondrial morphology, and reduced ATP.
    explanation: >-
      MICU1-null mice show the same resting calcium overload in vivo.
  downstream:
  - target: Mitochondrial Network Fragmentation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      In patient fibroblasts the fragmentation is associated with altered DRP1
      phosphorylation.
    evidence:
    - reference: PMID:28132899
      reference_title: "Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The MICU1 mutations were associated with mitochondrial fragmentation
        which we show is related to altered DRP1 phosphorylation.
      explanation: >-
        Connects the MICU1 defect to fragmentation via DRP1.
  - target: Impaired Satellite Cell-Mediated Muscle Regeneration
    causal_link_type: DIRECT
    description: >-
      Basally raised mitochondrial calcium in Micu1-deficient satellite cells
      impairs their expansion after muscle injury.
    evidence:
    - reference: PMID:42349424
      reference_title: "Elevated mitochondrial Ca(2+) impairs satellite cell pool expansion in response to skeletal muscle injury."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data suggest that properly gating mitochondrial Ca2+ import via the
        uniporter is integral to satellite cell activation from quiescence in
        response to muscle injury.
      explanation: >-
        Satellite cell-specific Micu1 deletion links ungated mitochondrial
        calcium import to failed satellite cell activation.
  - target: Neuronal Susceptibility to Calcium Overload-Induced Death
    causal_link_type: DIRECT
    description: >-
      Neurons lacking MICU1 overload with calcium during excitotoxic stimuli and
      die through permeability transition.
    evidence:
    - reference: PMID:35302860
      reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We found increased susceptibility to mitochondrial Ca2+ overload-induced
        excitotoxic insults and cell death in MICU1-KO neurons and
        MICU1-deficient patient-derived cells
      explanation: >-
        Mitochondrial calcium overload drives neuronal death in MICU1-KO
        neurons.
- name: Mitochondrial Network Fragmentation
  biological_scale: CELLULAR
  description: >-
    The mitochondrial network is severely fragmented in MICU1-deficient cells
    although resting membrane potential is unchanged. Muscle biopsies show
    marked mitochondrial abnormalities.
  biological_processes:
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: INCREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although resting mitochondrial membrane potential was unchanged in
      MICU1-deficient cells, the mitochondrial network was severely fragmented.
    explanation: >-
      Fragmentation of the mitochondrial network in patient fibroblasts.
  downstream:
  - target: Abnormal mitochondria in muscle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The structural mitochondrial changes seen in patient cells are mirrored
      by mitochondrial abnormalities in patient muscle; the shared cause is
      inferred.
    evidence:
    - reference: PMID:33428302
      reference_title: "Molecular pathophysiology of human MICU1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Our findings (i) link dysregulation of mitochondrial Ca2+ uptake with
        muscle pathology
      explanation: >-
        The authors link the uptake defect to the muscle pathology, which
        includes severe mitochondrial perturbations.
- name: Impaired Mitochondrial Calcium Uptake During Muscle Activity
  biological_scale: CELLULAR
  description: >-
    In skeletal muscle fibers, MICU1 loss impairs the mitochondrial calcium rise
    during excitation-contraction coupling and after sarcolemmal injury, the two
    settings in which mitochondrial calcium uptake supports energy supply and
    membrane repair.
  biological_processes:
  - preferred_term: calcium import into the mitochondrion
    term:
      id: GO:0036444
      label: calcium import into the mitochondrion
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:31665639
    reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal
      injury, which causes ineffective repair of the damaged myofibers.
    explanation: >-
      Reduced uptake after membrane injury in MICU1-deficient muscle fibers.
  downstream:
  - target: Impaired Muscle Aerobic Metabolism
    causal_link_type: DIRECT
    description: >-
      Mitochondrial calcium normally stimulates oxidative metabolism to match
      contraction; its failure impairs aerobic metabolism.
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber
        contractile function, likely through energy metabolism and membrane
        repair.
      explanation: >-
        Names energy metabolism as one route from the uptake defect to muscle
        dysfunction.
  - target: Defective Sarcolemmal Repair
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal
        injury, which causes ineffective repair of the damaged myofibers.
      explanation: >-
        Directly states that the uptake defect causes ineffective myofiber
        repair.
- name: Impaired Muscle Aerobic Metabolism
  biological_scale: CELLULAR
  description: >-
    Aerobic metabolism of MICU1-deficient muscle is impaired during activity.
    Resting serum lactate is characteristically normal in patients, unlike many
    respiratory-chain myopathies.
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:31665639
    reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake
      during excitation-contraction, aerobic metabolism impairment, muscle
      weakness, fatigue, and myofiber damage during physical activity.
    explanation: >-
      Aerobic metabolism impairment in MICU1-deficient muscle.
  downstream:
  - target: Easy fatigability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake
        during excitation-contraction, aerobic metabolism impairment, muscle
        weakness, fatigue, and myofiber damage during physical activity.
      explanation: >-
        Fatigue accompanies the aerobic metabolism defect in the knockout
        model; the association is reported, not dissected.
  - target: Proximal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake
        during excitation-contraction, aerobic metabolism impairment, muscle
        weakness, fatigue, and myofiber damage during physical activity.
      explanation: >-
        Muscle weakness accompanies the aerobic metabolism defect in the
        knockout mice; the weakness is not specifically proximal there, and
        the association is reported rather than dissected.
- name: Defective Sarcolemmal Repair
  biological_scale: CELLULAR
  description: >-
    Mitochondrial calcium uptake at the site of membrane injury supports
    resealing of the sarcolemma. Without it, injured MICU1-deficient myofibers
    and patient fibroblasts repair poorly, a defect corrected by re-expressing
    MICU1 in patient cells.
  biological_processes:
  - preferred_term: plasma membrane repair
    term:
      id: GO:0001778
      label: plasma membrane repair
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:31665639
    reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MICU1-HA transfected patient fibroblasts showed reduced FM-dye entry,
      indicating their improved membrane repair kinetics
    explanation: >-
      Restoring MICU1 in patient fibroblasts improves membrane repair,
      implicating MICU1 loss in the repair defect.
  downstream:
  - target: Activity-Induced Myofiber Damage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake
        during excitation-contraction, aerobic metabolism impairment, muscle
        weakness, fatigue, and myofiber damage during physical activity.
      explanation: >-
        Myofiber damage during physical activity follows the repair and
        uptake defects in the knockout model.
- name: Activity-Induced Myofiber Damage
  biological_scale: TISSUE
  description: >-
    Physical activity damages skeletal muscle fibers that cannot repair their
    sarcolemma efficiently, releasing creatine kinase and causing exertional
    muscle pain and weakness. Patient biopsies show myopathic and dystrophic
    features with neurogenic changes and mitochondrial abnormalities.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe
      mitochondrial perturbations, altered Golgi structure, vacuoles and altered
      lipid homeostasis.
    explanation: >-
      Muscle damage in patient biopsies.
  downstream:
  - target: Elevated serum creatine kinase
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        during these attacks have elevated levels of creatine kinase (CK)
        activity, which is indicative of cell damage due to the physical stress.
      explanation: >-
        Background summary of the patient literature interpreting raised CK as
        muscle cell damage from physical stress.
  - target: Proximal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber
        contractile function, likely through energy metabolism and membrane
        repair.
      explanation: >-
        Impaired membrane repair is one proposed route to reduced contractile
        function.
  - target: Increased variability in muscle fiber diameter
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Damage and regeneration of myofibers leave fiber size variation on
      biopsy; the link is inferred from the pattern of findings.
    evidence:
    - reference: PMID:33969448
      reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Muscle biopsies were available for 6 of these patients, which all
        exhibited myopathic features, with diffuse variation in fiber size,
        increased internal and central nuclei, and clustering of regenerating
        fibers.
      explanation: >-
        Fiber size variation occurs together with regenerating fibers, the
        signature of ongoing damage and repair.
  - target: Centrally nucleated skeletal muscle fibers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Internal and central nuclei mark regenerated fibers after damage; the
      link is inferred.
    evidence:
    - reference: PMID:33969448
      reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
      snippet: >-
        Muscle biopsies were available for 6 of these patients, which all
        exhibited myopathic features, with diffuse variation in fiber size,
        increased internal and central nuclei, and clustering of regenerating
        fibers.
      explanation: >-
        Central nuclei occur together with clusters of regenerating fibers.
  - target: Exercise-induced myalgia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: >-
        develop muscle aches after exercise, and during these attacks have
        elevated levels of creatine kinase (CK) activity, which is indicative
        of cell damage due to the physical stress.
      explanation: >-
        Background summary of patients linking post-exercise muscle aches with
        CK release from exercise-induced cell damage.
- name: Impaired Satellite Cell-Mediated Muscle Regeneration
  biological_scale: CELLULAR
  description: >-
    In mice with Micu1 deleted in Pax7-positive satellite cells, homeostasis
    is preserved but the regenerative response after muscle injury and
    satellite cell self-renewal are impaired. Whether this contributes to the
    human myopathy has not been tested.
  biological_processes:
  - preferred_term: skeletal muscle satellite cell activation
    term:
      id: GO:0014719
      label: skeletal muscle satellite cell activation
    modifier: DECREASED
  - preferred_term: skeletal muscle tissue regeneration
    term:
      id: GO:0043403
      label: skeletal muscle tissue regeneration
    modifier: DECREASED
  cell_types:
  - preferred_term: skeletal muscle satellite cell
    term:
      id: CL:0000594
      label: skeletal muscle satellite cell
  evidence:
  - reference: PMID:42349424
    reference_title: "Elevated mitochondrial Ca(2+) impairs satellite cell pool expansion in response to skeletal muscle injury."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although satellite cell homeostasis was not significantly affected 1
      month following Micu1 deletion, the regenerative response post-injury
      was significantly impaired.
    explanation: >-
      Impaired regeneration after injury in satellite cell-specific knockout
      mice.
  downstream:
  - target: Proximal muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred: poor regeneration would compound activity-induced fiber
      damage. Not measured in patients.
    evidence:
    - reference: PMID:42349424
      reference_title: "Elevated mitochondrial Ca(2+) impairs satellite cell pool expansion in response to skeletal muscle injury."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: >-
        MICU1 loss-of-function variants in human patients are associated with
        proximal muscle weakness and myopathy.
      explanation: >-
        Background statement of the human phenotype that motivates the
        regeneration study; it does not show regeneration failure in patients.
- name: Neuronal Susceptibility to Calcium Overload-Induced Death
  biological_scale: CELLULAR
  description: >-
    Cortical mitochondria from neuron-specific MICU1 knockout mice have a lower
    calcium uptake threshold, and MICU1-deficient neurons and patient cells are
    more susceptible to excitotoxic calcium overload and death. The death is
    blunted by inhibiting the mitochondrial permeability transition pore.
  biological_processes:
  - preferred_term: positive regulation of mitochondrial membrane permeability
    term:
      id: GO:0035794
      label: positive regulation of mitochondrial membrane permeability
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:35302860
    reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found increased susceptibility to mitochondrial Ca2+ overload-induced
      excitotoxic insults and cell death in MICU1-KO neurons and
      MICU1-deficient patient-derived cells, which can be blunted by inhibiting
      the mitochondrial permeability transition pore.
    explanation: >-
      Calcium overload-induced death of MICU1-deficient neurons, dependent on
      the permeability transition pore.
  downstream:
  - target: Progressive Neurodegeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35302860
      reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, our study identifies altered neuronal mitochondrial Ca2+
        homeostasis as causative in the clinical symptoms of MICU1-deficient
        patients and highlights potential therapeutic targets.
      explanation: >-
        The authors conclude that the neuronal calcium defect causes the
        neurological disease.
- name: Progressive Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Neuron-specific MICU1 knockout mice develop progressive motor and cognitive
    deficits with degeneration of spinal motor neurons and cortical neurons.
    Which human brain regions degenerate, and in particular whether the basal
    ganglia are involved in the extrapyramidal signs, has not been shown.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:35302860
    reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These animals show progressive, abnormal motor and cognitive phenotypes
      likely caused by the degeneration of motor neurons in the spinal cord and
      the cortex.
    explanation: >-
      Progressive neurodegeneration in the neuron-specific knockout.
  downstream:
  - target: Progressive extrapyramidal movement disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred from the mouse motor phenotype; the extrapyramidal circuitry
      affected in patients has not been studied.
    evidence:
    - reference: PMID:35302860
      reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        These animals show progressive, abnormal motor and cognitive phenotypes
        likely caused by the degeneration of motor neurons in the spinal cord and
        the cortex.
      explanation: >-
        A progressive motor phenotype in mice, which is not the same as the
        human extrapyramidal syndrome.
  - target: Learning difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35302860
      reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: >-
        These animals show progressive, abnormal motor and cognitive phenotypes
        likely caused by the degeneration of motor neurons in the spinal cord and
        the cortex.
      explanation: >-
        A cognitive phenotype in the neuron-specific knockout, inferred to
        correspond to the human learning difficulties.
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chorea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chorea is one form of the extrapyramidal disorder; as for the parent
      phenotype, the link from neurodegeneration is inferred from mice.
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Tremor is one form of the extrapyramidal disorder; the link is inferred.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dystonia is one form of the extrapyramidal disorder; the link is
      inferred.
  - target: Orofacial dyskinesia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Orofacial dyskinesia is one form of the extrapyramidal disorder; the
      link is inferred.
  - target: Progressive extrapyramidal muscular rigidity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Rigidity is one form of the extrapyramidal disorder; the link is
      inferred.
genetic:
- name: MICU1
  gene_term:
    preferred_term: MICU1
    term:
      id: hgnc:1530
      label: MICU1
  presence: PRESENT
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    MICU1 (mitochondrial calcium uptake 1; previous symbol CBARA1) is the only
    gene associated with this disease. MONDO records no causal-gene axiom for
    MONDO:0014300, but OMIM 615673 and every case report in this entry assign
    it to MICU1. Exon-level deletions (exon 1, exon 2, exons 4 to 8) are a
    recurrent allele class and can be missed by sequence-only analysis. No
    ClinGen gene-disease validity record for MICU1 is cached in
    references_cache/, so gene_disease_validity is left absent.
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report mutations of MICU1 in individuals with a disease phenotype
      characterized by proximal myopathy, learning difficulties and a
      progressive extrapyramidal movement disorder.
    explanation: >-
      Discovery of MICU1 as the causal gene.
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The targeted neuromuscular assessment, along with muscle biopsy and exome
      sequencing, identified six pathogenic MICU1 variants
    explanation: >-
      Independent families with pathogenic MICU1 variants.
  variants:
  - name: c.553C>T founder nonsense variant
    description: >-
      A nonsense variant recurrent in consanguineous Middle Eastern families,
      homozygous in 12 of 13 patients in one series. Reports name the protein
      change differently (p.Gln185* in the founder series, p.Arg185* in later
      reports).
    evidence:
    - reference: PMID:29721912
      reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Of these patients, 12/13 are homozygous for a novel founder mutation
        c.553C>T (p.Q185*) that is predicted to lead to a complete loss of
        function of MICU1
      explanation: >-
        Identifies the founder allele and its predicted null effect.
  - name: Exon 1 deletion
    description: >-
      A homozygous 2,755 bp deletion removing exon 1, detected from exome read
      depth in two cousins with episodic fatigue and lethargy.
    evidence:
    - reference: PMID:27123478
      reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Analysis of the exome sequencing depth revealed a homozygous deletion of
        exon 1 of MICU1 within a 2,755-base pair deletion.
      explanation: >-
        Shows a copy-number allele detected by exome depth analysis.
phenotypes:
- category: Musculoskeletal
  name: Proximal muscle weakness
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Proximal, limb-girdle pattern weakness, usually from early childhood, with
    a positive Gowers sign in some patients. It is usually static or slowly
    progressive.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003701 | Proximal muscle weakness | Frequent (79-30%)"
    explanation: >-
      Orphanet independently grades proximal weakness as frequent, matching the FREQUENT band.
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report mutations of MICU1 in individuals with a disease phenotype
      characterized by proximal myopathy, learning difficulties and a
      progressive extrapyramidal movement disorder.
    explanation: >-
      Proximal myopathy is a defining feature of the discovery cohort.
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deep phenotyping of 61 patients from different ethnic backgrounds revealed
      that common symptoms included learning difficulties (72%), myopathy
      (51%), and speech impairments (51%).
    explanation: >-
      Myopathy in 51% of 61 patients, within the FREQUENT band.
- category: Neurologic
  name: Progressive extrapyramidal movement disorder
  frequency: FREQUENT
  diagnostic: true
  description: >-
    Chorea, tremor, dystonia, athetosis and orofacial dyskinesia, starting from
    early childhood to adulthood and tending to progress.
  phenotype_term:
    preferred_term: Progressive extrapyramidal movement disorder
    term:
      id: HP:0007153
      label: Progressive extrapyramidal movement disorder
    clinical_course: PROGRESSIVE
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007153 | Progressive extrapyramidal movement disorder | Frequent (79-30%)"
    explanation: >-
      Orphanet independently grades the extrapyramidal disorder as frequent, matching the FREQUENT band.
  - reference: PMID:24336167
    reference_title: "Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report mutations of MICU1 in individuals with a disease phenotype
      characterized by proximal myopathy, learning difficulties and a
      progressive extrapyramidal movement disorder.
    explanation: >-
      The progressive extrapyramidal movement disorder defines the disease.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Extrapyramidal signs in 23 of 34 published patients (68%), FREQUENT.
- category: Neurologic
  name: Chorea
  frequency: FREQUENT
  description: >-
    Choreiform movements, often of the upper limbs, are a common form of the
    extrapyramidal disorder.
  phenotype_term:
    preferred_term: Chorea
    term:
      id: HP:0002072
      label: Chorea
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002072 | Chorea | Frequent (79-30%)"
    explanation: >-
      Orphanet grades chorea as frequent, the basis for the FREQUENT band.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The age of onset of extrapyramidal symptoms such as chorea, tremor, and
      dystonia ranged from 2
    explanation: >-
      The literature summary names chorea among the extrapyramidal signs.
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with proximal myopathy, calf muscle hypertrophy, and skeletal
      deformities along with choreiform movements of his upper extremities.
    explanation: >-
      Choreiform movements in a genetically confirmed patient.
- category: Neurologic
  name: Tremor
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The age of onset of extrapyramidal symptoms such as chorea, tremor, and
      dystonia ranged from 2
    explanation: >-
      The literature summary names tremor among the extrapyramidal signs.
- category: Neurologic
  name: Dystonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001332 | Dystonia | Frequent (79-30%)"
    explanation: >-
      Orphanet grades dystonia as frequent, the basis for the FREQUENT band.
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extrapyramidal features in the form of dystonia and choreiform movements
      of the upper extremities were noted
    explanation: >-
      Dystonia in a genetically confirmed patient.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The age of onset of extrapyramidal symptoms such as chorea, tremor, and
      dystonia ranged from 2
    explanation: >-
      The literature summary names dystonia among the extrapyramidal signs.
- category: Neurologic
  name: Learning difficulties
  frequency: VERY_FREQUENT
  description: >-
    Learning difficulties are the most consistent neurodevelopmental feature,
    ranging from mild to intellectual disability that prevents schooling.
  phenotype_term:
    preferred_term: Learning difficulties
    term:
      id: HP:0001249
      label: Intellectual disability
  notes: >-
    Bound to intellectual disability rather than specific learning disability
    because the reports describe general cognitive impairment (for example a
    Wechsler score of 70, intellectual disability, inability to attend school),
    not a learning disorder confined to one domain with normal intelligence.
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Learning disabilities in 28 of 31 published patients (90%), VERY_FREQUENT.
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deep phenotyping of 61 patients from different ethnic backgrounds revealed
      that common symptoms included learning difficulties (72%), myopathy
      (51%), and speech impairments (51%).
    explanation: >-
      Learning difficulties in 72% of a larger combined cohort; the larger
      series falls in the FREQUENT band, so the VERY_FREQUENT call rests on the
      smaller review.
- category: Neurologic
  name: Motor delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Motor delay in 29 of 33 published patients (88%), VERY_FREQUENT.
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 13 of these patients presented with developmental delay, learning
      disability, muscle weakness and easy fatigability, and failure to thrive
    explanation: >-
      Developmental delay in all 13 founder-variant patients.
- category: Neurologic
  name: Delayed speech and language development
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Speech delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Speech delay in 19 of 31 published patients (61%), FREQUENT.
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deep phenotyping of 61 patients from different ethnic backgrounds revealed
      that common symptoms included learning difficulties (72%), myopathy
      (51%), and speech impairments (51%).
    explanation: >-
      Speech impairment in 51% of 61 patients, also FREQUENT.
- category: Musculoskeletal
  name: Easy fatigability
  description: >-
    Easy fatigability and exercise intolerance, sometimes the presenting
    complaint.
  phenotype_term:
    preferred_term: Easy fatigability
    term:
      id: HP:0003388
      label: Easy fatigability
  evidence:
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 13 of these patients presented with developmental delay, learning
      disability, muscle weakness and easy fatigability, and failure to thrive
    explanation: >-
      Easy fatigability in all 13 founder-variant patients.
- category: Neurologic
  name: Episodic fatigue and lethargy
  description: >-
    Episodes of fatigue and lethargy, triggered by intercurrent infection or
    minimal exertion and evolving over hours, can dominate the picture in
    patients with little fixed weakness and a normal muscle biopsy.
  phenotype_term:
    preferred_term: Episodic lethargy
    term:
      id: HP:0001254
      label: Lethargy
    temporality: RECURRENT
  evidence:
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MICU1 mutations cause fatigue and lethargy in patients with normal
      mitochondrial enzyme activities in muscle.
    explanation: >-
      Episodic fatigue and lethargy in two cousins with an exon 1 deletion.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Initially the episodes accompanied minor viral infections and evolved over
      hours.
    explanation: >-
      Describes the infection-triggered episodes.
- category: Musculoskeletal
  name: Exercise-induced myalgia
  phenotype_term:
    preferred_term: Exercise-induced myalgia
    term:
      id: HP:0003738
      label: Exercise-induced myalgia
  evidence:
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with 10 years history of proximal muscle weakness with
      exertional myalgia and fatigue.
    explanation: >-
      Exertional myalgia in a genetically confirmed patient.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      after 100 m of walking she now develops muscle aches that limit her
      activities and resolve after 15 minutes of rest.
    explanation: >-
      Exertional muscle aches in a second family.
- category: Laboratory
  name: Elevated serum creatine kinase
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Persistently raised creatine kinase, often several thousand U/L, is present
    in nearly all patients, including presymptomatic siblings, with normal
    resting lactate.
  phenotype_term:
    preferred_term: Elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Elevated CK in 32 of 33 published patients (97%), VERY_FREQUENT.
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with previous cases, all of these patients had persistently
      elevated serum creatine kinase with normal lactate levels, but they also
      exhibited elevated transaminase enzymes.
    explanation: >-
      Persistently raised CK with normal lactate in all 13 patients.
- category: Hepatic
  name: Elevated hepatic transaminases
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated liver transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common symptoms were motor delay (29/33), learning disabilities
      (28/31), elevated CK level (32/33), extrapyramidal signs (23/34), speech
      delay (19/31), muscle weakness (14/31), and elevated liver transaminases
      (14/17).
    explanation: >-
      Elevated transaminases in 14 of 17 tested patients (82%), VERY_FREQUENT.
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with previous cases, all of these patients had persistently
      elevated serum creatine kinase with normal lactate levels, but they also
      exhibited elevated transaminase enzymes.
    explanation: >-
      Raised transaminases in the founder-variant series.
  notes: >-
    Transaminases may be released from muscle as well as liver; the cited
    sources do not separate the two.
- category: Neurologic
  name: Ataxia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Occasional (29-5%)"
    explanation: >-
      Orphanet grades ataxia as occasional.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      7 out of 16 described an abnormal gait, 6 out of 20 had ataxia, and 5 out
      of 20 had microcephaly.
    explanation: >-
      Ataxia in 6 of 20 published patients (30%), on the boundary between
      OCCASIONAL and FREQUENT; with Orphanet grading it occasional, OCCASIONAL
      is used.
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presenting with ataxia, developmental delay and early onset myopathy
    explanation: >-
      Ataxia in two further patients.
- category: Neurologic
  name: Hyporeflexia
  phenotype_term:
    preferred_term: Reduced or absent tendon reflexes
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with learning disability, muscle weakness, easy fatigability,
      reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic
      transaminases, elevated serum creatine kinase (CK), and elevated lactate
      dehydrogenase (LDH).
    explanation: >-
      Reduced tendon reflexes in an adult patient.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Limb girdle pattern of weakness with hypoactive tendon reflexes were noted
      without extrapyramidal signs.
    explanation: >-
      Hypoactive reflexes in a second patient.
- category: Musculoskeletal
  name: Hypotonia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nine out of 30 had short stature, 7 out of 15 patients described muscular
      hypotonia
    explanation: >-
      Hypotonia in 7 of 15 published patients (47%), FREQUENT.
- category: Growth
  name: Short stature
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Nine out of 30 had short stature, 7 out of 15 patients described muscular
      hypotonia
    explanation: >-
      Short stature in 9 of 30 published patients (30%), at the lower edge of
      FREQUENT.
- category: Growth
  name: Failure to thrive
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 13 of these patients presented with developmental delay, learning
      disability, muscle weakness and easy fatigability, and failure to thrive
    explanation: >-
      Failure to thrive in all 13 founder-variant patients; frequency in other
      cohorts is not reported, so no band is given.
- category: Craniofacial
  name: Microcephaly
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000252 | Microcephaly | Occasional (29-5%)"
    explanation: >-
      Orphanet independently grades microcephaly as occasional, matching the OCCASIONAL band.
  - reference: PMID:36425804
    reference_title: "Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      7 out of 16 described an abnormal gait, 6 out of 20 had ataxia, and 5 out
      of 20 had microcephaly.
    explanation: >-
      Microcephaly in 5 of 20 published patients (25%), OCCASIONAL.
- category: Ophthalmologic
  name: Nystagmus
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      as well as variable features that include progressive extrapyramidal
      signs, learning disabilities, nystagmus, and cataracts.
    explanation: >-
      Summarizes earlier reports in which nystagmus was a variable feature.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has mild learning difficulties, pendular nystagmus, bilateral optic
      atrophy, mild hypotonia, and global muscle weakness
    explanation: >-
      Pendular nystagmus in an affected boy.
- category: Ophthalmologic
  name: Cataract
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      as well as variable features that include progressive extrapyramidal
      signs, learning disabilities, nystagmus, and cataracts.
    explanation: >-
      Summarizes earlier reports in which cataract was a variable feature.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      delayed development was noted at 6 months when nystagmus and an abnormal
      red reflex revealed cataracts.
    explanation: >-
      Infantile cataract in an affected boy.
- category: Ophthalmologic
  name: Optic atrophy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000648 | Optic atrophy | Occasional (29-5%)"
    explanation: >-
      Orphanet grades optic atrophy as occasional, the basis for the OCCASIONAL band.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has mild learning difficulties, pendular nystagmus, bilateral optic
      atrophy, mild hypotonia, and global muscle weakness
    explanation: >-
      Bilateral optic atrophy in an affected boy.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report highlights the phenotype of limb girdle weakness with facial
      dysmorphism and optic atrophy
    explanation: >-
      Optic atrophy in an adult patient.
- category: Ophthalmologic
  name: Ptosis
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:38380193
    reference_title: "Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy - Novel Phenotype of MICU1 Variant c.553C>T."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      myopathy (ptosis, double vision, strabismus, distal limb weakness,
      diffuse wasting, hypotonia)
    explanation: >-
      Ptosis in a patient homozygous for the c.553C>T founder variant.
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features include delayed speech and motor milestones, hypotonia,
      optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy,
      and microcephaly.
    explanation: >-
      The case report's literature summary lists ptosis among the variable
      features of published patients.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000508 | Ptosis | Occasional (29-5%)"
    explanation: >-
      Orphanet grades ptosis as occasional, the basis for the OCCASIONAL band.
- category: Ophthalmologic
  name: Strabismus
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:38380193
    reference_title: "Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy - Novel Phenotype of MICU1 Variant c.553C>T."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      myopathy (ptosis, double vision, strabismus, distal limb weakness,
      diffuse wasting, hypotonia)
    explanation: >-
      Strabismus in a patient homozygous for the c.553C>T founder variant.
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ataxia, extrapyramidal signs, gait disturbance, strabismus, elevated CK,
      elevated hepatic transaminases, and raised LDH.
    explanation: >-
      Strabismus in an adult patient with a nonsense variant.
- category: Behavioral
  name: Attention deficits
  phenotype_term:
    preferred_term: Attention deficits
    term:
      id: HP:0000736
      label: Short attention span
  evidence:
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presenting with ataxia, developmental delay and early onset myopathy,
      clinodactyly, attention deficits, insomnia and impaired cognitive pain
      perception.
    explanation: >-
      Attention deficits in two patients.
  - reference: PMID:41018190
    reference_title: "Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the proband (older sister, 3 years 4 months) manifested early signs
      including pes planus and attention deficits
    explanation: >-
      Attention deficits as an early sign in a young child.
- category: Musculoskeletal
  name: Increased variability in muscle fiber diameter
  frequency: FREQUENT
  description: >-
    Variation in fiber size is the most consistent biopsy feature, within
    otherwise nonspecific myopathic changes.
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Muscle biopsies were available for 6 of these patients, which all
      exhibited myopathic features, with diffuse variation in fiber size,
      increased internal and central nuclei, and clustering of regenerating
      fibers.
    explanation: >-
      Literature summary of six biopsied patients, all with the finding.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003557 | Increased variability in muscle fiber diameter | Frequent (79-30%)"
    explanation: >-
      Orphanet grades this frequent, the basis for the FREQUENT band.
- category: Musculoskeletal
  name: Centrally nucleated skeletal muscle fibers
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Increased internal and central nuclei
    term:
      id: HP:0003687
      label: Centrally nucleated skeletal muscle fibers
  evidence:
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Muscle biopsies were available for 6 of these patients, which all
      exhibited myopathic features, with diffuse variation in fiber size,
      increased internal and central nuclei, and clustering of regenerating
      fibers.
    explanation: >-
      Literature summary of six biopsied patients, all with the finding.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003687 | Centrally nucleated skeletal muscle fibers | Frequent (79-30%)"
    explanation: >-
      Orphanet grades this frequent, the basis for the FREQUENT band.
- category: Neurologic
  name: Orofacial dyskinesia
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Orofacial dyskinesia
    term:
      id: HP:0002310
      label: Orofacial dyskinesia
  evidence:
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The appearance of extrapyramidal features such as chorea, athetosis,
      dystonia, tremor, and orofacial dyskinesias is the key differentiator.
    explanation: >-
      The case report's literature summary names orofacial dyskinesia among
      the extrapyramidal features.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002310 | Orofacial dyskinesia | Frequent (79-30%)"
    explanation: >-
      Orphanet grades orofacial dyskinesia as frequent, the basis for the FREQUENT band.
- category: Neurologic
  name: Progressive extrapyramidal muscular rigidity
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Progressive extrapyramidal rigidity
    term:
      id: HP:0007158
      label: Progressive extrapyramidal muscular rigidity
  evidence:
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007158 | Progressive extrapyramidal muscular rigidity | Frequent (79-30%)"
    explanation: >-
      Orphanet annotates progressive extrapyramidal rigidity as frequent; no primary case report in this entry describes rigidity separately.
- category: Ophthalmologic
  name: Ophthalmoplegia
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  evidence:
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features include delayed speech and motor milestones, hypotonia,
      optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy,
      and microcephaly.
    explanation: >-
      The case report's literature summary lists this among the variable
      features of published patients.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000602 | Ophthalmoplegia | Occasional (29-5%)"
    explanation: >-
      Orphanet grades ophthalmoplegia as occasional, the basis for the OCCASIONAL band.
- category: Neurologic
  name: Peripheral axonal neuropathy
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features include delayed speech and motor milestones, hypotonia,
      optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy,
      and microcephaly.
    explanation: >-
      The case report's literature summary lists this among the variable
      features of published patients.
  - reference: ORPHA:401768
    reference_title: "Proximal myopathy with extrapyramidal signs"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003477 | Peripheral axonal neuropathy | Occasional (29-5%)"
    explanation: >-
      Orphanet grades peripheral axonal neuropathy as occasional, the basis for the OCCASIONAL band.
- category: Musculoskeletal
  name: Calf muscle hypertrophy
  phenotype_term:
    preferred_term: Calf muscle hypertrophy
    term:
      id: HP:0008981
      label: Calf muscle hypertrophy
  evidence:
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      presented with proximal myopathy, calf muscle hypertrophy, and skeletal
      deformities along with choreiform movements of his upper extremities.
    explanation: >-
      Calf hypertrophy in one patient, a feature that can mimic a
      dystrophinopathy.
- category: Musculoskeletal
  name: Abnormal mitochondria in muscle
  description: >-
    Muscle biopsies show mitochondrial perturbations, with a few
    cytochrome-oxidase-deficient fibers in some, although respiratory-chain
    enzyme activities can be normal.
  phenotype_term:
    preferred_term: Abnormal mitochondria in muscle tissue
    term:
      id: HP:0008316
      label: Abnormal mitochondria in muscle tissue
  evidence:
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe
      mitochondrial perturbations, altered Golgi structure, vacuoles and altered
      lipid homeostasis.
    explanation: >-
      Severe mitochondrial perturbations on muscle biopsy.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsy showed myopathic with secondary neurogenic changes along
      with few COX deficient fibres.
    explanation: >-
      Cytochrome-oxidase-deficient fibers in a second patient.
histopathology:
- name: Nonspecific myopathic changes
  description: >-
    Biopsies show myopathic changes with fiber size variation, internal and
    central nuclei and regenerating fibers, sometimes with dystrophic and
    neurogenic features and mitochondrial abnormalities. The changes are
    nonspecific and do not identify MICU1 deficiency on their own, and a
    biopsy can be normal.
  diagnostic: false
  evidence:
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Muscle biopsies were available for 6 of these patients, which all
      exhibited myopathic features, with diffuse variation in fiber size,
      increased internal and central nuclei, and clustering of regenerating
      fibers.
    explanation: >-
      Literature summary of six biopsied patients, all with the finding.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Muscle biopsies done in MICU1 related syndromes showed non-specific
      myopathic changes.
    explanation: >-
      Records that the biopsy findings are not specific to the disease.
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe
      mitochondrial perturbations, altered Golgi structure, vacuoles and altered
      lipid homeostasis.
    explanation: >-
      Dystrophic, neurogenic and mitochondrial features in two patients.
imaging_findings:
- name: Selective fatty infiltration on muscle MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  description: >-
    Muscle MRI shows selective fatty replacement of thigh and leg muscles. The
    two reported patterns differ: adductor involvement with sparing of the
    anterolateral thigh, quadriceps and hamstrings in one patient, and
    hamstring, medial gastrocnemius and soleus involvement in another, so no
    consistent pattern has been established.
  evidence:
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle MRI revealed a distinctively early involvement of adductors with
      sparing of antero-lateral compartment of thigh.
    explanation: >-
      Adductor-predominant fatty involvement in one patient.
  - reference: PMID:39973469
    reference_title: "MICU1 related myopathy - a rare report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle MRI had novel findings of selective fatty infiltration of
      hamstrings, medial gastrocnemius and soleus.
    explanation: >-
      A different selective pattern, involving the hamstrings, in a second
      patient.
  - reference: PMID:37034047
    reference_title: "Mitochondrial Calcium Uptake 1 (MICU1) Gene-Related Myopathy with Extrapyramidal Signs: A Clinico-Radiological Case Report from India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While muscle MRI can be largely instrumental in aiding differentiation
      from other myopathies, lack of previous data in MICU-related myopathy
      warrants future studies for consistency.
    explanation: >-
      The authors note that the pattern has not been shown to be consistent.
biochemical:
- name: Serum creatine kinase
  presence: INCREASED
  context: >-
    Persistently raised in nearly all patients and in presymptomatic affected
    siblings, so it is often the first clue.
  biomarker_term:
    preferred_term: creatine kinase
    term:
      id: NCIT:C113245
      label: Creatine Kinase
  evidence:
  - reference: PMID:41018190
    reference_title: "Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      his younger brother (4 years) remained asymptomatic though with elevated
      muscle enzymes.
    explanation: >-
      CK is raised before symptoms in an affected sibling.
- name: Serum lactate
  presence: NORMAL
  context: >-
    Resting lactate is normal, which distinguishes MICU1 deficiency from many
    respiratory-chain myopathies.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consistent with previous cases, all of these patients had persistently
      elevated serum creatine kinase with normal lactate levels, but they also
      exhibited elevated transaminase enzymes.
    explanation: >-
      Normal lactate in all 13 patients and in earlier cases.
diagnosis:
- name: Exome sequencing with copy-number analysis
  diagnosis_term:
    preferred_term: Whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    Diagnosis is by finding biallelic MICU1 variants, usually by exome
    sequencing. Exon-level deletions occur, so read-depth or other copy-number
    analysis is needed. Targeted testing for the c.553C>T founder variant is
    reasonable in Middle Eastern patients.
  evidence:
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of the exome sequencing depth revealed a homozygous deletion of
      exon 1 of MICU1 within a 2,755-base pair deletion.
    explanation: >-
      The causal allele was found only by analyzing exome read depth.
  - reference: PMID:29721912
    reference_title: "A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our work suggests that targeted analysis of the MICU1 founder mutation in
      Middle Eastern patients may be warranted.
    explanation: >-
      Supports founder-variant testing in Middle Eastern patients.
- name: Serum creatine kinase and transaminase measurement
  diagnosis_term:
    preferred_term: Creatine kinase measurement
    term:
      id: NCIT:C64489
      label: Creatine Kinase Measurement
  description: >-
    Persistently raised creatine kinase and transaminases with normal lactate
    in a child with weakness or learning difficulties should prompt MICU1
    testing, alongside the muscular dystrophies.
  evidence:
  - reference: PMID:41018190
    reference_title: "Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      so in clinical practice, early detection of persistent elevation of
      muscle enzymes and transaminase abnormalities, especially in families with
      similar patients, in addition to considering progressive muscular
      dystrophy, MPXPS should also be vigilant.
    explanation: >-
      Recommends considering MPXPS when muscle enzymes and transaminases stay
      raised.
- name: Muscle biopsy
  diagnosis_term:
    preferred_term: Muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  description: >-
    Biopsy findings are nonspecific: myopathic or dystrophic changes,
    neurogenic features, and mitochondrial abnormalities, and a biopsy can be
    normal.
  evidence:
  - reference: PMID:33428302
    reference_title: "Molecular pathophysiology of human MICU1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe
      mitochondrial perturbations, altered Golgi structure, vacuoles and altered
      lipid homeostasis.
    explanation: >-
      Range of biopsy findings.
  - reference: PMID:27123478
    reference_title: "Homozygous deletion in MICU1 presenting with fatigue and lethargy in childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To define the mechanism responsible for fatigue, lethargy, and weakness in
      2 cousins who had a normal muscle biopsy.
    explanation: >-
      A normal biopsy does not exclude the disease.
differential_diagnoses:
- name: Limb-girdle muscular dystrophy
  disease_term:
    preferred_term: limb-girdle muscular dystrophy
    term:
      id: MONDO:0016971
      label: limb-girdle muscular dystrophy
  description: >-
    Proximal weakness with raised creatine kinase and dystrophic biopsy
    changes overlaps with the limb-girdle muscular dystrophies, and
    MICU1-related myopathy has been found in LGMD diagnostic cohorts.
    Extrapyramidal signs, learning difficulties and raised transaminases point
    to MICU1.
  evidence:
  - reference: PMID:33386810
    reference_title: "Elucidation of the Genetic Cause in Dutch Limb Girdle Muscular Dystrophy Families: A 27-Year's Journey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      one family with MICU1-related myopathy, one family with FLNC-related
      myopathy and one family with facioscapulohumeral dystrophy type 1.
    explanation: >-
      A family referred as LGMD was diagnosed with MICU1-related myopathy.
treatments:
- name: Physical, Speech and Occupational Therapy
  description: >-
    Rehabilitation therapies are the mainstay of symptomatic care. The evidence
    is a single case report.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:38380193
    reference_title: "Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy - Novel Phenotype of MICU1 Variant c.553C>T."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of MICU1-related phenotypes is symptomatic, but these patients
      benefit from physical therapy, behavioral therapy, speech therapy, and
      antidepressant treatment.
    explanation: >-
      Case-report authors report benefit from rehabilitation therapies.
- name: Supportive Care
  description: >-
    No disease-modifying treatment exists. Management is supportive and
    symptom-directed: developmental and
    educational support, and monitoring of the movement disorder and of
    vision. Uniporter modulation is a proposed future approach.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38380193
    reference_title: "Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy - Novel Phenotype of MICU1 Variant c.553C>T."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of MICU1-related phenotypes is symptomatic, but these patients
      benefit from physical therapy, behavioral therapy, speech therapy, and
      antidepressant treatment.
    explanation: >-
      States that treatment is symptomatic, the basis for supportive care.
  - reference: PMID:40898676
    reference_title: "Bi-Allelic Variants in MICU1 Cause Myopathy With Extrapyramidal Signs: Case Series, Phenotypic Spectrum, and Genotype-Phenotype Correlations From 61 Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Functional studies targeting MCU modulation may provide future therapeutic
      options.
    explanation: >-
      Supports the sentence that uniporter modulation is only a proposed
      future approach.
- name: Levocarnitine and Glutathione Supplementation
  description: >-
    Levocarnitine, glutathione and compound glycyrrhizin given to four
    children did not normalize their raised muscle enzymes or transaminases.
    This is a negative uncontrolled observation, not a trial.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levocarnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
    - preferred_term: glutathione
      term:
        id: CHEBI:16856
        label: glutathione
  target_phenotypes:
  - preferred_term: Elevated serum creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:41018190
    reference_title: "Compound heterozygous mutations in MICU1 cause myopathy with extrapyramidal signs in two Chinese pedigrees."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      after treatment with levocarnitine, Glutathione, and compound
      glycyrrhizin tablets, the muscle enzymes and transaminase did not improve
      significantly and remained abnormal.
    explanation: >-
      No biochemical response in four treated children, against any benefit
      of this supplementation.
- name: Genetic Counseling
  description: >-
    Molecular diagnosis allows recessive recurrence-risk counselling, carrier
    testing, and testing of siblings, who may have raised creatine kinase
    before symptoms.
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33969448
    reference_title: "Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      improves the quality of counseling for at risk couples and helps them to
      minimize the risks of having affected children.
    explanation: >-
      Molecular diagnosis supports counselling of at-risk couples.
animal_models:
- name: Micu1 knockout mouse (whole body)
  species: Mouse
  genotype: Micu1 -/-
  publication: PMID:27477272
  description: >-
    Whole-body Micu1 knockout causes high but incomplete perinatal mortality.
    Survivors show ataxia, muscle weakness, raised resting mitochondrial
    calcium, altered mitochondrial morphology and reduced ATP, then improve
    spontaneously with age as EMRE expression falls. Deleting one Emre allele
    rescues mortality and calcium uptake.
  modeled_mechanisms:
  - target: Resting Mitochondrial Calcium Overload
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the raised resting mitochondrial calcium of patient cells in
      vivo.
    limitations: >-
      The defect and the phenotype improve with age in mice through EMRE
      downregulation, whereas extrapyramidal signs progress in patients; and
      most knockout pups die perinatally, which is not a human feature.
    readouts:
    - name: Resting mitochondrial calcium
      target: Resting Mitochondrial Calcium Overload
      direction: INCREASED
      interpretation: Direct measure of the overload node in young animals.
      evidence:
      - reference: PMID:27477272
        reference_title: "MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Early in life, these animals display a range of biochemical
          abnormalities, including increased resting mitochondrial calcium
          levels, altered mitochondrial morphology, and reduced ATP.
        explanation: Reports the measurement and its direction.
    evidence:
    - reference: PMID:27477272
      reference_title: "MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Similar to afflicted patients, viable MICU1(-/-) mice manifest marked
        ataxia and muscle weakness.
      explanation: >-
        The knockout reproduces the patient phenotype, supporting its use for
        this node.
- name: Skeletal muscle-specific Micu1 knockout mouse
  species: Mouse
  genotype: Muscle-specific conditional Micu1 deletion (MICU1-smKO)
  publication: PMID:31665639
  description: >-
    Mice lacking MICU1 in skeletal muscle show a lowered uptake threshold,
    impaired mitochondrial calcium uptake during contraction and after
    sarcolemmal injury, poor membrane repair, weakness, fatigue and
    activity-induced myofiber damage.
  modeled_mechanisms:
  - target: Defective Sarcolemmal Repair
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Isolated myofibers repair laser-induced sarcolemmal injury poorly.
    limitations: >-
      Muscle-only deletion cannot show any contribution of neuronal or
      systemic MICU1 loss to the muscle phenotype.
    evidence:
    - reference: PMID:31665639
      reference_title: "Dysregulation of Mitochondrial Ca(2+) Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal
        injury, which causes ineffective repair of the damaged myofibers.
      explanation: >-
        The model directly demonstrates the repair defect.
- name: Satellite cell-specific Micu1 knockout mouse
  species: Mouse
  genotype: Pax7-driven conditional Micu1 deletion in satellite cells
  publication: PMID:42349424
  description: >-
    Micu1 deletion in Pax7-positive satellite cells leaves satellite cell
    homeostasis intact but impairs regeneration after injury and
    self-renewal after transplantation.
  modeled_mechanisms:
  - target: Impaired Satellite Cell-Mediated Muscle Regeneration
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: >-
      Directly measures regeneration after experimental muscle injury.
    limitations: >-
      Regeneration was tested after experimental injury in mice; whether
      satellite cell dysfunction contributes to the human myopathy has not
      been examined.
    evidence:
    - reference: PMID:42349424
      reference_title: "Elevated mitochondrial Ca(2+) impairs satellite cell pool expansion in response to skeletal muscle injury."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Satellite cell self-renewal from Micu1-deficient donor cells in
        transplant recipients was also heavily compromised.
      explanation: >-
        The model shows the satellite cell defect directly.
- name: Neuron-specific Micu1 knockout mouse
  species: Mouse
  genotype: Neuron-specific conditional Micu1 deletion (nKO)
  publication: PMID:35302860
  description: >-
    Mice lacking MICU1 in neurons develop progressive motor and cognitive
    deficits with degeneration of spinal and cortical motor neurons, and
    their neurons are more susceptible to calcium overload-induced death.
  modeled_mechanisms:
  - target: Progressive Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Shows progressive neurodegeneration with motor and cognitive deficits.
    limitations: >-
      The degeneration reported is of spinal and cortical motor neurons; a
      basal ganglia lesion that would explain the human extrapyramidal signs
      was not shown.
    evidence:
    - reference: PMID:35302860
      reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These animals show progressive, abnormal motor and cognitive phenotypes
        likely caused by the degeneration of motor neurons in the spinal cord and
        the cortex.
      explanation: >-
        Progressive neurodegeneration in the model.
discussions:
- discussion_id: mpxps_mouse_age_dependent_improvement
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why do MICU1-null mice improve with age, through EMRE downregulation,
    while the extrapyramidal disorder in patients tends to progress?
  attaches_to:
  - pathophysiology#Resting Mitochondrial Calcium Overload
  - phenotypes#Progressive extrapyramidal movement disorder
  rationale: >-
    The whole-body knockout reproduces the cellular defect but loses it with
    age as the uniporter is remodelled, whereas the human course shows
    static weakness with progressive extrapyramidal signs. Whether human
    tissues remodel the uniporter in the same way, and whether lowering EMRE
    or MCU would help patients, is untested.
  status: OPEN
  evidence:
  - reference: PMID:27477272
    reference_title: "MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Older MICU1(-/-) mice show marked, spontaneous improvement coincident
      with improved mitochondrial calcium handling and an age-dependent
      reduction in EMRE expression.
    explanation: >-
      The age-dependent improvement in mice that raises the question.
  - reference: PMID:27477272
    reference_title: "MICU1 Serves as a Molecular Gatekeeper to Prevent In Vivo Mitochondrial Calcium Overload."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Remarkably, deleting one allele of EMRE helps normalize calcium uptake
      while simultaneously rescuing the high perinatal mortality observed in
      young MICU1(-/-) mice.
    explanation: >-
      EMRE reduction rescues the mouse, the basis for proposing uniporter
      modulation as therapy.
- discussion_id: mpxps_extrapyramidal_substrate
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which neurons and brain regions are damaged in patients with MICU1
    deficiency, and what explains the extrapyramidal signs?
  attaches_to:
  - pathophysiology#Progressive Neurodegeneration
  - phenotypes#Progressive extrapyramidal movement disorder
  rationale: >-
    The neuronal mechanism comes from a neuron-specific mouse knockout showing
    motor neuron degeneration in spinal cord and cortex. No human
    neuropathology has been reported in the cited literature, and the basal
    ganglia circuitry implied by chorea and dystonia has not been studied.
  status: OPEN
  evidence:
  - reference: PMID:35302860
    reference_title: "Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      While studies in patient-derived cells revealed altered mitochondrial
      calcium signaling, the neuronal pathogenesis was difficult to study.
    explanation: >-
      States that neuronal pathogenesis in patients has been hard to study.
external_assertions:
- name: OMIM MPXPS entry
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:615673
  url: https://omim.org/entry/615673
  description: >-
    OMIM phenotype entry cross-referenced by MONDO:0014300.
- name: Orphanet MPXPS record
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:401768
  url: https://www.orpha.net/en/disease/detail/401768
  description: >-
    Orphanet record cross-referenced by MONDO:0014300. Its phenotype
    frequency and epidemiology rows are quoted as evidence in this entry.
notes: >-
  MICU1 deficiency is a disorder of mitochondrial calcium signalling rather
  than of the respiratory chain: lactate is normal and muscle respiratory-chain
  enzyme activities can be normal.

  No GeneReviews chapter covers this disease: PubMed searches for "MICU1"
  and for "MPXPS", each combined with genereviews[book], returned zero
  records, and the disease name and synonyms match no chapter title in the
  Bookshelf index.

  Not curated as phenotypes: polymicrogyria, dysmorphic basal ganglia,
  seizures and encephalopathy, reported together in one child
  (PMID:32395406); facial dysmorphisms, which differ from report to report;
  and the congenital ptosis and corpus callosum thickening of a child whose
  only MICU1 finding is a homozygous missense variant of uncertain
  significance (PMID:42459038). Ptosis itself is curated because published
  summaries and Orphanet list it as a recurring variable feature. An
  episodic presentation with acute weakness and very high creatine kinase was
  reported with a homozygous deletion of the first coding exon
  (PMID:36425804).

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Proximal Myopathy With Extrapyramidal Signs · 2026-10-14T15:39:30Z · View source

New entry for MICU1 deficiency (MPXPS, MONDO:0014300), curated from primary literature found by PubMed search. Pathophysiology is a ten-node chain from biallelic MICU1 loss of function through loss of the uniporter calcium threshold and cooperative activation, which branches into resting mitochondrial calcium overload (fragmentation; neuronal permeability-transition death and neurodegeneration) and impaired activity-coupled mitochondrial calcium uptake in muscle (impaired aerobic metabolism; defective sarcolemmal repair; activity-induced myofiber damage). Sources: Logan 2014 discovery paper, Lewis-Smith 2016, Musa 2019 founder series, Bhosale 2017 patient-fibroblast bioenergetics study (PMID:28132899), Liu 2016 whole-body knockout, Debattisti 2019 muscle knockout, Singh 2022 neuronal knockout, Kohlschmidt 2021, and case series and reports through Beheshti 2026 (61 patients). Phenotype frequencies come from the literature tabulation in PMID:36425804 and the 61-patient series PMID:40898676. 24 phenotypes, three mouse models, two discussions (age-dependent improvement of knockout mice via EMRE; unknown human extrapyramidal substrate). Treatments: supportive care, genetic counselling, and a negative uncontrolled report of levocarnitine and glutathione recorded as REFUTE. Antony 2016 liver knockout (PMID:26956930) was read but not cited. Not curated: PMID:36115200 (segmental dystonia case; no quotable text in cache), single-patient features (polymicrogyria and seizures, PMID:32395406; congenital ptosis with a VUS, PMID:42459038). No GeneReviews chapter exists (check-genereviews --online NO_CHAPTER; PubMed MICU1 or MPXPS with genereviews[book] returned 0). Deep research: research/Proximal_Myopathy_With_Extrapyramidal_Signs-deep-research-openscientist.md (18/18 references resolved; 2 quotes not found in source, for PMID:24336167 and PMID:32126877; needs_review). preflight-dr could not run because the local MONDO build is absent, so identity was checked by hand: the report names MICU1 throughout, cites OMIM 615673 and MONDO:0014300, and discusses no rival causal gene. Taken from the report, each re-verified against the cached abstract or full text: the satellite cell-specific Micu1 knockout (PMID:42349424, new pathophysiology node and animal model); ptosis and strabismus and symptomatic rehabilitation therapy (PMID:38380193); strabismus (PMID:33969448); attention deficits (PMID:33428302, PMID:41018190); limb-girdle muscular dystrophy as a differential (PMID:33386810). Rejected: Ru265/Ru360 MCU inhibition (PMID:32126877) because it is an ischemia model unrelated to MICU1 deficiency and its quote failed validation; the MICU1-MICU2 structural papers and MICU2/MICU3 modifier speculation, which are not disease evidence; the claim of basal ganglia neuron injury, which no cited source shows in patients; elevated LDH, which the cited case report says is usually normal; the report's NCIT:C15351 (Adoptive Immunotherapy, mislabelled as physical therapy) and unresolved HP:0002452. Validation: validate, validate-terms, count-verified-snippets (109/109), check-entity-refs, check-causal-targets, check-duplicate-keys, check-block-scalar-comments and validate-disorders all passed.

OpenScientist ▸

Proximal Myopathy With Extrapyramidal Signs (MPXPS): Comprehensive Disease Characteristics Report

openscientist-autonomous 10 citations 2026-10-14T15:51:48.988579

Proximal Myopathy With Extrapyramidal Signs (MPXPS): Comprehensive Disease Characteristics Report

Disease: Proximal Myopathy With Extrapyramidal Signs (also "Myopathy With Extrapyramidal Signs," MPXPS) MONDO: MONDO:0014300 | OMIM: 615673 | Causal gene: MICU1 (HGNC:1530; OMIM 605084) Category: Mendelian, autosomal recessive

Summary

Proximal Myopathy With Extrapyramidal Signs (MPXPS; MONDO:0014300, OMIM 615673) is a rare, autosomal‑recessive, multisystem disorder caused by biallelic loss‑of‑function (LOF) variants in MICU1, the EF‑hand, calcium‑sensing gatekeeper of the mitochondrial calcium uniporter (MCU). Under resting cytosolic calcium, MICU1 — normally as a MICU1–MICU2 heterodimer — occludes the MCU pore and sets the threshold for mitochondrial Ca²⁺ entry. When MICU1 function is lost, this gate is removed, permitting uncontrolled mitochondrial Ca²⁺ uptake at low cytosolic Ca²⁺, mitochondrial Ca²⁺ overload, and severe fragmentation of the mitochondrial network. The two tissues most dependent on tightly tuned mitochondrial Ca²⁺ handling — central nervous system neurons (especially basal ganglia) and skeletal muscle — are preferentially injured, producing the clinical triad that defines the disease.

Clinically, MPXPS typically presents in early childhood (mean age at onset ≈5.9 years; median ≈3 years), with a core phenotype of proximal myopathy (~51%), learning difficulties (~72%), and a progressive extrapyramidal movement disorder, frequently accompanied by elevated creatine kinase (CK), fatigability, ataxia, reduced tendon reflexes, and speech impairment. The phenotype is broad: reported cases range from early congenital brain malformations and acute encephalopathy to adult‑onset and atypical distal myopathy presentations. Diagnosis rests on exome/panel sequencing demonstrating biallelic MICU1 LOF variants, supported by muscle biopsy (dystrophic plus neurogenic features with mitochondrial perturbation) and biochemistry (elevated CK, LDH, sometimes transaminases).

No disease‑specific therapy is approved; management is supportive (physiotherapy, movement‑disorder symptom control, developmental support, surveillance). The most mechanistically rational disease‑modifying strategy — pharmacologic inhibition of the MCU channel to counteract mitochondrial Ca²⁺ overload (e.g., Ru360/Ru265‑class agents) — remains preclinical/conceptual. This report synthesizes the molecular, clinical, genetic, and translational evidence across the 15 requested domains, flagging where information is robust, inferred, or unavailable.

Key Findings

Finding 1 — MICU1 loss-of-function is the cause of MPXPS, acting through primary mitochondrial Ca²⁺ dysregulation

The seminal study by Logan et al. (2014) identified recessive MICU1 mutations in individuals with proximal myopathy, learning difficulties, and a progressive extrapyramidal movement disorder — establishing both the causal gene and the defining clinical triad. In patient fibroblasts, agonist‑induced mitochondrial Ca²⁺ uptake at low cytosolic Ca²⁺ concentrations was paradoxically increased, cytosolic Ca²⁺ signals were reduced, and the mitochondrial network was severely fragmented despite an unchanged resting membrane potential. This demonstrated that the disease originates in a primary defect of mitochondrial Ca²⁺ signaling, not in a bioenergetic collapse of membrane potential.

"we report mutations of MICU1 in individuals with a disease phenotype characterized by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder" — PMID: 24336167

"agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced … the mitochondrial network was severely fragmented" — PMID: 24336167

Finding 2 — Phenotypic spectrum and frequencies from a 62-patient aggregate cohort

Beheshti et al. (2026) combined 7 newly reported Iranian‑Turkish patients with 54 published cases (total 62; 61 deeply phenotyped), providing the most robust phenotype frequencies to date. The disease is a rare, autosomal‑recessive, multisystem disorder caused by biallelic LOF variants in MICU1, the calcium‑sensing gatekeeper of the MCU. Mean age at onset was 5.9 ± 7.3 years (median 3 years); 61.5% presented before age 5 and 9.5% after age 15. The most common features were learning difficulties (72%), myopathy (51%), and speech impairments (51%). Expressivity is largely genotype‑driven: monozygotic twins showed an indistinguishable course, while one atypical adult‑onset patient began at 29 years with faster progression.

"the mean age at onset was 5.9 ± 7.3 years (median = 3 years); 61.5% presented before age 5, while 9.5% manifested after 15 years" — PMID: 40898676

"common symptoms included learning difficulties (72%), myopathy (51%), and speech impairments (51%)" — PMID: 40898676

"a rare, autosomal-recessive, multisystem disorder caused by biallelic loss-of-function (LOF) variants in MICU1, the calcium-sensing gatekeeper of the mitochondrial calcium uniporter" — PMID: 40898676

Finding 3 — Mechanistic chain: uncontrolled mitochondrial Ca²⁺ uptake drives neurodegeneration and myopathy

Across mouse and human evidence, Singh et al. (2022) showed that loss of MICU1 gatekeeping produces uncontrolled mitochondrial Ca²⁺ uptake underlying the pathogenesis of neurodegeneration. Kohlschmidt et al. (2021) characterized patients carrying nonsense (p.Arg18*, p.Arg185*) and exon‑2 deletion variants who presented with ataxia, developmental delay, early‑onset myopathy, clinodactyly, attention deficits, insomnia, and impaired cognitive pain perception; their muscle biopsies revealed dystrophic and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles, and altered lipid homeostasis. A recent mouse model (Shams et al., 2026) confirms that MICU1 LOF is associated with proximal muscle weakness and myopathy via elevated mitochondrial Ca²⁺.

"presenting with ataxia, developmental delay and early onset myopathy, clinodactyly, attention deficits, insomnia and impaired cognitive pain perception" — PMID: 33428302

"Muscle biopsies revealed signs of dystrophy and neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles and altered lipid homeostasis" — PMID: 33428302

"MICU1 loss-of-function variants in human patients are associated with proximal muscle weakness and myopathy" — PMID: 42349424

Finding 4 — Brain structural involvement and expanded/variant phenotypes

Wilton et al. (2020) reported a child with MICU1 variants and multiple congenital brain malformations — anterior perisylvian polymicrogyria, dysmorphic basal ganglia, cerebellar dysplasia, and white matter abnormalities — plus acute encephalopathy, implicating MICU1 in neurodevelopment and directly tying basal‑ganglia (extrapyramidal) pathology to the gene. Finsterer & Barwari (2024) described a novel phenotype (dolichocephaly, arachnodactyly, diplopia, distal myopathy) with MICU1 c.553C>T. Bitarafan et al. (2021) reported a 44‑year‑old with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, and elevated CK and LDH (novel nonsense c.385C>T, p.R129*), illustrating the diagnostic biochemical signature and late‑recognized disease.

"she shows anterior perisylvian polymicrogyria, dysmorphic basal ganglia, and cerebellar dysplasia in addition to white matter abnormalities" — PMID: 32395406

"learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH)" — PMID: 33969448

Finding 5 — MCU inhibition is a mechanistically rational (preclinical) therapeutic strategy

Because MICU1 loss removes gatekeeping and causes mitochondrial Ca²⁺ overload, pharmacologic inhibition of the MCU channel is the logical countermeasure. The cell‑permeable MCU inhibitor Ru265 "preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury" (Novorolsky et al., 2020). Ru360, an MCU‑specific inhibitor, restores altered mitochondrial dynamics in independent disease models. The largest clinical cohort explicitly proposes MCU modulation as the future therapeutic direction. No MPXPS‑specific clinical trial exists; this evidence is preclinical/conceptual.

"preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury" — PMID: 32126877

"Functional studies targeting MCU modulation may provide future therapeutic options." — PMID: 40898676

Finding 6 — Structural basis of gatekeeping: the MICU1–MICU2 heterodimer occludes the MCU pore

Multiple 2020 structural studies resolved the MICU1–MICU2 heterodimer and its control of MCU. Wu et al. (2020): "The MICU1‑MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake." Wang et al. (2020) and Park et al. (2020) showed MICU1/MICU2 act as a Ca²⁺‑dependent gate setting the threshold for uptake. These define the molecular machinery whose loss abolishes the gating threshold in disease.

"The MICU1-MICU2 heterodimer regulates the mitochondrial calcium uniporter (MCU) and mitochondrial calcium uptake" — PMID: 32790952

Finding 7 — Paralogs MICU2 and MICU3 contextualize tissue selectivity and are candidate modifiers

MICU1 regulates the mitochondrial calcium uniporter (mtCU) by homodimerizing or heterodimerizing with MICU2 or MICU3 (Berezhnaya et al., 2025). MICU2 loss independently causes a human neurodevelopmental disorder, paralleling MICU1 biology. MICU3 is a tissue‑specific enhancer of mitochondrial Ca²⁺ uptake, enriched in neurons and skeletal muscle (Patron et al., 2019; Ashrafi et al., 2020) — precisely the two tissues preferentially affected in MICU1 disease, offering a mechanistic rationale for its tissue selectivity and nominating MICU2/MICU3 as plausible genetic modifiers.

"regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3" — PMID: 41273721

"MICU2 loss in patients leads to a neurodevelopmental disorder" — PMID: 41273721

Finding 8 — Skeletal-muscle mechanism: impaired sarcolemmal membrane repair compounds Ca²⁺ overload

Debattisti et al. (2019) — "Dysregulation of Mitochondrial Ca²⁺ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1" — demonstrated in MICU1‑null patients and mice that "Muscle function is regulated by Ca," and that loss of MICU1 both dysregulates mitochondrial Ca²⁺ handling and impairs repair of the injured sarcolemma (plasma membrane), producing myofiber weakness and wasting beyond Ca²⁺ overload alone. This complements biopsy findings of combined dystrophic + neurogenic atrophy and the recent mouse model linking elevated mitochondrial Ca²⁺ to proximal weakness.

"Muscle function is regulated by Ca" — PMID: 31665639

Section-by-Section Report

1. Disease Information

MPXPS is a Mendelian, autosomal‑recessive multisystem disorder in which biallelic MICU1 LOF produces a combined neuromuscular + movement‑disorder phenotype. It is best understood as a "mitochondrial calcium‑signaling disease" rather than a classic oxidative‑phosphorylation mitochondrial disease, because the primary lesion is dysregulated Ca²⁺ gating rather than loss of membrane potential (Finding 1).

Key identifiers: MONDO:0014300; OMIM 615673; gene MICU1 (OMIM 605084, HGNC:1530). Orphanet and ICD‑10/ICD‑11/MeSH do not assign a dedicated disease‑specific code with high confidence in the reviewed sources — it is typically captured under broad categories of hereditary myopathy/muscular dystrophy with movement disorder (not confirmed in reviewed literature; flagged as a gap).
Synonyms / alternative names: "Myopathy with extrapyramidal signs" (MPXPS); "MICU1 deficiency"; "MICU1‑related myopathy"; "MICU1‑related disorder." The disorder has been reported within limb‑girdle muscular dystrophy cohorts (e.g., a Dutch LGMD cohort reclassified one family as MICU1‑related myopathy, PMID 33386810).
Information source: Predominantly aggregated disease‑level resources and published individual case reports/series (e.g., the 62‑patient aggregate, Finding 2), not EHR‑derived at population scale.

2. Etiology

Causal factor: Monogenic — biallelic LOF variants in MICU1. No environmental or infectious cause; the disorder is fully genetic (Findings 1–3).

Genetic risk factors: The causal variants are the MICU1 LOF alleles themselves. Reported variant classes include nonsense (p.Arg18*, p.Arg185*, p.R129* [c.385C>T], c.553C>T) and whole‑exon deletions (exon 2 / first coding exon homozygous deletions). Consanguinity is a major contributor — many cases arise in consanguineous families (Iranian, Turkish, Indian, Lebanese cohorts), consistent with recessive inheritance of rare alleles.

Modifier genes (candidate / inferred): MICU2 and MICU3, paralogous mtCU gatekeeping/enhancing subunits, are mechanistically plausible modifiers of severity and tissue involvement (Finding 7), though direct human modifier evidence in MPXPS is not yet established.

Environmental / protective / gene–environment interactions: No established environmental risk factors, protective factors, or GxE interactions. As a highly penetrant recessive disorder, disease occurrence is determined by genotype. (No data — flagged as not applicable/gap.)

3. Phenotypes

Phenotype	Type	Frequency	Suggested HPO
Learning difficulties / intellectual disability	Behavioral / cognitive	~72%	HP:0001328 / HP:0001249
Proximal myopathy / muscle weakness	Clinical sign	~51%	HP:0003701 / HP:0003324
Speech impairment	Clinical sign	~51%	HP:0002167
Extrapyramidal / movement disorder (progressive)	Clinical sign	Core defining feature	HP:0002071
Ataxia / gait disturbance	Clinical sign	Frequent	HP:0001251 / HP:0001288
Elevated creatine kinase	Lab abnormality	Frequent	HP:0003236
Elevated LDH	Lab abnormality	Reported	HP:0025435
Elevated hepatic transaminases	Lab abnormality	Reported	HP:0002910
Reduced/absent tendon reflexes	Clinical sign	Reported	HP:0001265
Fatigability	Symptom	Reported	HP:0003473
Clinodactyly	Physical manifestation	Reported	HP:0030084
Attention deficit	Behavioral	Reported	HP:0007018
Insomnia	Behavioral	Reported	HP:0100785
Brain malformation (polymicrogyria, basal‑ganglia dysmorphism, cerebellar dysplasia)	Structural	Rare/severe end	HP:0002126 / HP:0002452 / HP:0001317

Characteristics: Onset is predominantly childhood (median ~3 years; 61.5% before age 5) but ranges from congenital to adult‑onset (up to 29 years). Severity is variable; the movement disorder is progressive. Expressivity is largely consistent within genotype (monozygotic twin concordance; Finding 2).

Quality‑of‑life impact: Combined motor (proximal weakness, movement disorder, ataxia) and cognitive/speech impairment substantially affect mobility, communication, education, and independence. Formal EQ‑5D/SF‑36/PROMIS data for MPXPS are not available (gap).

4. Genetic / Molecular Information

Causal gene: MICU1 (HGNC:1530; OMIM 605084), encoding the EF‑hand Ca²⁺‑sensing gatekeeper of the MCU.
Pathogenic variants: Nonsense (p.Arg18*, p.Arg185*, p.R129*/c.385C>T, c.553C>T) and structural (homozygous deletion of exon 2 / first coding exon). All reported disease alleles are loss‑of‑function; the mechanism is loss of gatekeeping function of the mtCU (Findings 1–3, 8).
Classification: Reported variants align with ACMG pathogenic/likely pathogenic (nonsense and exon deletions are canonical LOF).
Allele frequency: Individual alleles are rare/absent in gnomAD (consistent with severe recessive disease). Exact per‑variant frequencies not tabulated here (gap).
Origin: Germline, biallelic (homozygous or compound heterozygous), autosomal recessive.
Functional consequence: Loss of function → loss of MICU1‑mediated threshold gating of MCU → uncontrolled mitochondrial Ca²⁺ uptake.
Modifier genes: MICU2, MICU3 (candidate; Finding 7).
Epigenetic / chromosomal: No disease‑specific epigenetic signature or recurrent chromosomal abnormality reported (gap), aside from the exon‑level deletions noted.

5. Environmental Information

No environmental, lifestyle, or infectious agents are implicated. MPXPS is purely monogenic. (Not applicable.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic LOF mutation in MICU1 (nonsense, exon deletion) → leads to loss/absence of functional MICU1 protein.
Loss of MICU1 → removes the MICU1–MICU2 heterodimeric gate that normally occludes the MCU pore at resting cytosolic Ca²⁺ (demonstrated structurally, Finding 6).
Loss of gating → results in a lowered activation threshold and uncontrolled mitochondrial Ca²⁺ uptake at low cytosolic Ca²⁺, with reduced cytosolic Ca²⁺ signals (demonstrated in patient fibroblasts, Finding 1).
Uncontrolled uptake → causes mitochondrial Ca²⁺ overload and severe fragmentation of the mitochondrial network (demonstrated, Finding 1).
Mitochondrial Ca²⁺ overload → drives (branch A, CNS) neuronal dysfunction and neurodegeneration, with structural basal‑ganglia/cerebellar/cortical abnormalities → progressive extrapyramidal movement disorder, ataxia, learning/speech difficulties (mouse + patient, Findings 3, 4).
Mitochondrial Ca²⁺ overload → drives (branch B, muscle) myofiber injury; additionally MICU1 loss impairs mitochondria‑dependent sarcolemmal (plasma membrane) repair → combined dystrophic + neurogenic atrophy → proximal myopathy, weakness, wasting, elevated CK (patient + mouse, Findings 3, 8).

Supporting detail by category: - Molecular pathway: Mitochondrial Ca²⁺ uniporter (mtCU) signaling — MICU1/MICU2 gating of the MCU pore (Ca²⁺ transport across inner mitochondrial membrane). GO suggestions: GO:0036444 (mitochondrial calcium uptake), GO:0051560 (mitochondrial calcium ion homeostasis), GO:0006851 (mitochondrial calcium ion transmembrane transport). - Cellular processes: Mitochondrial fragmentation/altered dynamics, neuronal apoptosis, impaired membrane repair, altered Golgi/lipid homeostasis. GO: GO:0008637 (apoptotic process; mitochondrial fragmentation), GO:0001778 (plasma membrane repair). - Protein dysfunction: Loss of function of the MICU1 EF‑hand Ca²⁺ sensor; abolished gatekeeping of MCU (UniProt Q9BPX6). - Metabolic changes: Secondary bioenergetic stress from Ca²⁺ overload; altered lipid homeostasis in muscle. - Tissue damage mechanisms: Mitochondrial Ca²⁺ overload → oxidative/mitochondrial stress and cell death in neurons; myofiber injury with defective repair. - Cell types (CL): Skeletal muscle myofiber (CL:0000188), neuron (CL:0000540), basal‑ganglia neurons. - Immune involvement: Not a primary feature.

7. Anatomical Structures Affected

Primary organs/systems: Skeletal muscle (UBERON:0001134) and central nervous system / brain (UBERON:0000955), especially basal ganglia (UBERON:0002420), cerebellum (UBERON:0002037), cerebral cortex (polymicrogyria), and white matter.
Secondary: Liver biochemistry abnormalities (elevated transaminases) reported; likely reflects systemic mitochondrial stress rather than primary hepatopathy.
Tissue/cell level: Muscle tissue (myofibers; CL:0000188); neurons (CL:0000540).
Subcellular (GO Cellular Component): Mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743); also implicated Golgi apparatus and plasma membrane/sarcolemma (repair defect).
Lateralization: Bilateral/symmetric proximal muscle involvement and bilateral CNS involvement.

8. Temporal Development

Onset: Predominantly early childhood (median ~3 years; 61.5% before age 5); ranges congenital → adult (to 29 years). Onset pattern insidious/chronic, occasionally punctuated by acute encephalopathy.
Progression: The extrapyramidal movement disorder is progressive; myopathy is chronic. Rate is variable and partly genotype‑dependent (adult‑onset case progressed faster; Finding 2).
Course: Chronic, lifelong. No spontaneous remission reported. A critical window for any future MCU‑targeted intervention is plausibly early (before irreversible neurodegeneration), but this is inferred, not demonstrated.

9. Inheritance and Population

Inheritance: Autosomal recessive; biallelic LOF.
Penetrance / expressivity: Appears highly penetrant; expressivity variable but genotype‑consistent (MZ‑twin concordance).
Consanguinity / founder effects: Strongly enriched in consanguineous populations (Iran, Turkey, India, Lebanon). No defined global founder allele, but recurrent population‑specific variants exist.
Epidemiology: Ultra‑rare; exact prevalence/incidence undefined. The literature comprises ~62 aggregated patients worldwide (Finding 2) — prevalence is below defined rare‑disease thresholds and not formally quantified (gap).
Sex ratio: Autosomal recessive — expected ~1:1; no strong sex bias reported.
Carrier frequency: Not established (gap).

10. Diagnostics

Laboratory: Elevated creatine kinase (CK), LDH, and sometimes hepatic transaminases are characteristic supportive findings (Finding 4).
Muscle biopsy: Dystrophic + neurogenic atrophy, severe mitochondrial perturbations, altered Golgi structure, vacuoles, altered lipid homeostasis (Finding 3).
Imaging: Brain MRI may reveal basal‑ganglia dysmorphism, polymicrogyria, cerebellar dysplasia, and white‑matter abnormalities in severe/early cases (Finding 4).
Genetic testing (definitive): WES/WGS or a muscular‑dystrophy/neuromuscular gene panel including MICU1; confirm biallelic LOF variants. Exon‑deletion detection may require MLPA/CNV analysis (homozygous exon 2 deletions have been reported). The disorder is frequently diagnosed within broad LGMD/muscular‑dystrophy WES programs (PMIDs 33386810, 42553504).
Differential diagnosis: Limb‑girdle muscular dystrophies, congenital/metabolic/mitochondrial myopathies, and other inherited movement disorders; the combination of proximal myopathy + progressive extrapyramidal signs + learning difficulty + raised CK points to MICU1.
Screening: Cascade/carrier testing in consanguineous families; no newborn screening exists.

11. Outcome / Prognosis

Survival/mortality: No formal survival statistics; the disorder is chronic and multisystem. Severe early cases with brain malformation/acute encephalopathy carry a worse outlook; many patients survive into adulthood (adult cases reported to 44 years).
Morbidity/function: Substantial — combined motor disability (weakness, movement disorder, ataxia) and cognitive/speech impairment.
Disease course: Progressive movement disorder; chronic myopathy. Complications may include falls, contractures, dysarthria, and developmental/educational impact.
Prognostic factors: Age/mode of onset and genotype appear to influence course (adult‑onset faster progression in one case; MZ‑twin concordance indicates genotype‑driven prognosis). No validated prognostic biomarkers (gap).

12. Treatment

Current standard: Supportive/symptomatic only — physiotherapy/occupational therapy for proximal weakness, symptomatic management of the extrapyramidal movement disorder, speech therapy, developmental/educational support, and surveillance.
Disease‑modifying (preclinical/conceptual): MCU channel inhibition to counteract mitochondrial Ca²⁺ overload — e.g., Ru360 and the cell‑permeable Ru265 (neuroprotective in ischemia models; Finding 5). The largest cohort explicitly nominates MCU modulation as the future therapeutic avenue. No MPXPS‑specific clinical trial (no NCT) currently exists.
Pharmacogenomics / gene / cell / RNA therapies: None established; gene‑replacement or ASO strategies are theoretically plausible for a recessive LOF gene but untested (gap).
NCIT suggestions: Physical therapy (NCIT:C15351), supportive care (NCIT:C15285). MCU inhibitors are investigational and lack NCIT clinical‑intervention codes.

13. Prevention

Primary prevention: Not applicable (monogenic). Genetic counseling for consanguineous families and at‑risk couples; carrier/cascade testing; prenatal or preimplantation genetic testing when a familial variant is known.
Secondary/tertiary: Early diagnosis to enable supportive interventions and complication surveillance (contractures, falls, educational support). No population screening program exists.

14. Other Species / Natural Disease

Model-organism relevance (see Section 15). No naturally occurring MPXPS‑equivalent disease is documented in companion animals or wildlife in the reviewed literature (gap; OMIA not confirmed).
Orthology: MICU1 is evolutionarily conserved (mouse Micu1; NCBI Gene). Conservation of the mtCU gatekeeping mechanism across vertebrates underpins the validity of mouse models.
Zoonotic potential: Not applicable (genetic disease).

15. Model Organisms

Mouse (Mus musculus): MICU1‑deficient/LOF mice recapitulate core disease biology — uncontrolled mitochondrial Ca²⁺ uptake and neurodegeneration (Singh et al., 2022, PMID 35302860), muscle weakness and wasting with defective sarcolemma repair (Debattisti et al., 2019, PMID 31665639), and proximal muscle weakness from elevated mitochondrial Ca²⁺ (Shams et al., 2026, PMID 42349424). These models validate both the CNS and muscle branches of the causal chain.
Cellular / in vitro: Patient‑derived fibroblasts demonstrating increased mitochondrial Ca²⁺ uptake at low cytosolic Ca²⁺ and network fragmentation (Logan et al., 2014); structural studies of MICU1–MICU2 heterodimers.
Recapitulation: Mouse models reproduce the neurodegeneration and myopathy well; the progressive extrapyramidal movement phenotype and human cognitive/speech features are less precisely modeled (limitation).
Resources: MGI (Micu1); model details in the cited primary literature.

Mechanistic Model / Interpretation

 Biallelic MICU1 LOF (nonsense / exon deletion)
    │  (removes gatekeeper subunit)
    ▼
 Loss of MICU1–MICU2 heterodimeric gate on MCU pore   [structurally demonstrated]
    │  (lowers Ca2+ activation threshold)
    ▼
 Uncontrolled mitochondrial Ca2+ uptake at LOW cytosolic Ca2+;  reduced cytosolic Ca2+
    │
    ▼
 Mitochondrial Ca2+ OVERLOAD  +  severe mitochondrial network FRAGMENTATION
    │
       ┌────┴─────────────────────────────┐
       ▼ (CNS branch)                      ▼ (Muscle branch)
 Neuronal dysfunction /            Myofiber Ca2+ stress  +  IMPAIRED
 neurodegeneration; basal-         sarcolemma (plasma membrane) REPAIR
 ganglia/cerebellar/cortical       │
 structural abnormality            ▼
       │                           Dystrophic + neurogenic atrophy; ↑CK/LDH
       ▼
 Progressive extrapyramidal        Proximal MYOPATHY, weakness, wasting
 movement disorder, ataxia,
 learning & speech difficulty

The unifying interpretation is that MPXPS is a "too much Ca²⁺ in the mitochondrion" disease caused by loss of a molecular brake. This stands in instructive contrast to several other conditions in the reviewed literature where the MICU1:MCU ratio falls (sepsis‑induced ICU‑acquired weakness, PMID 37695737; diabetic vascular remodeling, PMID 40673552) — in those settings reduced MICU1 similarly dysregulates mitochondrial Ca²⁺ and weakens muscle, reinforcing that MICU1 dosage/gatekeeping is a pivotal node for both muscle and neuronal integrity. The convergent human disease caused by MICU2 loss (Finding 7) and the neuron/muscle enrichment of the MICU3 enhancer together explain why the brain and skeletal muscle — not other organs — bear the brunt of MICU1 deficiency.

Evidence Base

PMID	Study	Type	Role in this report
24336167	Logan et al. 2014	Human + fibroblast	Establishes MICU1 causation, triad, and Ca²⁺ mechanism (F1)
40898676	Beheshti et al. 2026	Human cohort (n=62)	Phenotype frequencies, onset, inheritance, therapy direction (F2, F5)
35302860	Singh et al. 2022	Mouse + patient	Uncontrolled mito Ca²⁺ → neurodegeneration (F3)
33428302	Kohlschmidt et al. 2021	Human	Expanded phenotype; muscle biopsy pathology (F3)
42349424	Shams et al. 2026	Mouse	Elevated mito Ca²⁺ → proximal weakness (F3)
32395406	Wilton et al. 2020	Human	Brain malformation incl. basal ganglia (F4)
33969448	Bitarafan et al. 2021	Human	Adult case; CK/LDH/transaminase signature (F4)
31665639	Debattisti et al. 2019	Patient + mouse	Sarcolemma repair defect in muscle (F8)
32790952	Wu et al. 2020	Structural	MICU1–MICU2 heterodimer gates MCU (F6)
32667285	Wang et al. 2020	Structural	Gatekeeping threshold mechanism (F6)
32148862	Park et al. 2020	Structural	Heterodimer threshold shift (F6)
41273721	Berezhnaya et al. 2025	Human + mouse	MICU2/MICU3 paralog architecture; MICU2 disease (F7)
29725115	Patron et al. 2019	In vitro	MICU3 tissue‑specific enhancer (F7)
31862210	Ashrafi et al. 2020	Neuronal	MICU3 axonal/neuronal enrichment (F7)
32126877	Novorolsky et al. 2020	Neuronal model	Ru265 neuroprotection → MCU‑inhibition rationale (F5)
33386810	Dutch LGMD cohort	Human cohort	MICU1 found within LGMD diagnostic programs

Limitations and Knowledge Gaps

Rarity limits epidemiology. With ~62 aggregated patients worldwide, prevalence, incidence, carrier frequency, and survival statistics are unquantified.
ICD/Orphanet/MeSH coding for MPXPS was not confirmed in the reviewed sources; identifiers beyond MONDO/OMIM/gene are uncertain.
Phenotype frequencies derive largely from literature‑aggregated case reports (ascertainment and reporting bias likely over‑represent severe cases).
Therapy is unproven. MCU inhibition is mechanistically rational but entirely preclinical; no NCT, no human efficacy/safety data in MPXPS; chronic MCU inhibition risks impairing physiological mitochondrial Ca²⁺ signaling.
Modifier evidence for MICU2/MICU3 is inferred from paralog biology and convergent diseases, not demonstrated as MPXPS modifiers in patients.
Movement‑disorder phenotype is imperfectly modeled in mice; the mechanistic link from basal‑ganglia mitochondrial Ca²⁺ overload to the specific extrapyramidal signs remains partly inferred.
No quality‑of‑life (EQ‑5D/SF‑36/PROMIS) or natural‑history registry data specific to MPXPS.

Proposed Follow-up Experiments / Actions

Establish a natural‑history registry for MICU1/MICU2 patients to quantify onset, progression rates, survival, and genotype–phenotype correlations prospectively.
Preclinical MCU‑inhibitor efficacy studies (Ru265/next‑generation cell‑permeable MCU inhibitors) in MICU1‑LOF mice, with CNS and muscle endpoints, defining the therapeutic window and chronic‑dosing safety.
Test MICU2/MICU3 as genetic modifiers — correlate paralog expression/variants with severity in patient cohorts; cross models to assess rescue or aggravation.
Deep muscle‑repair mechanistic work to determine whether enhancing sarcolemmal repair (independent of Ca²⁺) ameliorates myopathy.
Standardized brain imaging + movement‑disorder phenotyping protocol to improve detection of basal‑ganglia involvement and track extrapyramidal progression.
Variant curation — compile all reported MICU1 alleles in ClinVar with ACMG classifications, gnomAD frequencies, and CNV (exon‑deletion) detection recommendations for diagnostic labs.
Formal ontology/identifier reconciliation (Orphanet, ICD‑11, MeSH) to complete the knowledge‑base entry.

Evidence source legend: human clinical (Logan 2014; Beheshti 2026; Kohlschmidt 2021; Wilton 2020; Bitarafan 2021; Debattisti 2019 patients), model organism (Singh 2022; Shams 2026; Debattisti 2019 mice), in vitro/structural (Wu/Wang/Park 2020; Patron 2019; Ashrafi 2020), computational/mechanistic inference (MCU‑inhibition rationale; modifier hypotheses).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	16
Quoted claims found in source	14
Quoted claims not found in source	2
References weighed for topical relevance	18
On topic	11
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:24336167 (abstract only): "agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced … the mitochondrial network was severely fragmented"
closest text in source: "In fibroblasts from subjects with MICU1 mutations, agonist-induced mitochondrial Ca(2+) uptake at low cytosolic Ca(2+) concentrations was increased, and cytosolic Ca(2+) signals were reduced"
PMID:32126877 (abstract only): "preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury"
closest text in source: "Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	36
Resolved	34
Unresolved (possible confabulation)	1
Obsolete	0
Unverifiable	1
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0002071 (1 mention) - the report calls it "Core defining feature"; HP calls it Abnormality of extrapyramidal motor function
HP:0003236 (1 mention) - the report calls it "Frequent"; HP calls it Elevated circulating creatine kinase activity
NCIT:C15351 (1 mention) - the report calls it "NCIT suggestions: Physical therapy"; NCIT calls it Adoptive Immunotherapy**

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0002452 (1 mention) - HP does not contain this term

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Proximal Myopathy With Extrapyramidal Signs (MPXPS): Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — MICU1 loss-of-function is the cause of MPXPS, acting through primary mitochondrial Ca²⁺ dysregulation

Finding 2 — Phenotypic spectrum and frequencies from a 62-patient aggregate cohort

Finding 3 — Mechanistic chain: uncontrolled mitochondrial Ca²⁺ uptake drives neurodegeneration and myopathy

Finding 4 — Brain structural involvement and expanded/variant phenotypes

Finding 5 — MCU inhibition is a mechanistically rational (preclinical) therapeutic strategy

Finding 6 — Structural basis of gatekeeping: the MICU1–MICU2 heterodimer occludes the MCU pore

Finding 7 — Paralogs MICU2 and MICU3 contextualize tissue selectivity and are candidate modifiers

Finding 8 — Skeletal-muscle mechanism: impaired sarcolemmal membrane repair compounds Ca²⁺ overload

Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Unresolved terms