👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected individuals are homozygous or compound heterozygous for INPP5K variants, and the disease segregates with recessive inheritance in the reported families, several of them consanguineous. Expressivity is variable within and between families: cataract and intellectual disability can each be absent, and one family carrying the recurrent p.Ile50Thr allele presented with congenital cataract, intellectual disability and only electromyographic myopathy.

Autosomal recessive inheritance Expressivity: VARIABLE

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"Whenever DNA from family members was available, we observed that the disease segregated with recessive inheritance of the INPP5K mutations"

Segregation analysis in the discovery families supports autosomal recessive inheritance.

PMID:28940338 SUPPORT Human Clinical

"Comparison of clinical phenotype of all the known affected individuals, including LUCC15 family, homozygous for INPP5K alleles revealed reduced penetrance of muscular dystrophy and intellectual disability."

Supports variable expressivity of the muscle and cognitive features among biallelic carriers.

?

Discussions and Knowledge Gaps

2

Muscle-specific Inpp5k knockout mice show failed autophagic lysosome reformation with autophagy inhibition, but autophagic flux in patient fibroblasts was normal. Does the ALR defect operate in patient muscle carrying hypomorphic alleles?

HUMAN MODEL MISMATCH inpp5k_alr_defect_in_patient_muscle

Attached to

pathophysiology#Defective Autophagic Lysosome Reformation pathophysiology#Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle

The mouse deletes the gene completely in muscle, while patients retain partial activity, and the only human flux experiment used skin fibroblasts, a cell type the mouse work suggests is less dependent on ALR. Patient biopsies show rimmed vacuoles and p62 labeling, which fit the model but do not measure flux or lysosome number. Measuring lysosome abundance, LC3-II flux and reformation tubules in patient myoblasts or muscle would test whether the mouse mechanism transfers.

Show evidence (1 reference)

PMID:28190456 SUPPORT In Vitro

"However, LC3B immunoblotting and immunofluorescence staining as well as measurement of LC3B turnover and p62 levels in fibroblasts treated with the autophagy inducer rapamycin and the lysosomal inhibitor bafilomycin A1 did not reveal specific effects of different INPP5K genotypes."

The negative human cell result that defines the mismatch.

What links INPP5K deficiency to cataract, intellectual disability and short stature?

KNOWLEDGE GAP inpp5k_lens_and_brain_mechanism

Attached to

pathophysiology#Lens Fiber Organization Defect pathophysiology#Impaired Neuronal Differentiation phenotypes#Short stature

The muscle mechanism has a mouse model, but the lens and brain evidence is limited to zebrafish morphants, an N2A knockdown and a PHGDH proteomic finding with zebrafish L-serine rescue. Whether autophagic lysosome reformation, ER organization, PHGDH and serine supply, or another INPP5K function drives the non-muscle features is untested, and nothing in the cited literature addresses short stature.

⚙

Pathophysiology

10

INPP5K Phosphoinositide 5-Phosphatase Deficiency

Biallelic hypomorphic variants reduce the 5-phosphatase activity of INPP5K toward PI(4,5)P2, or, for the SKICH-domain variant p.Ile363Thr, displace the enzyme from the endoplasmic reticulum. Residual activity ranges from almost none to about half of wild type depending on the allele.

INPP5K hgnc:33882

Genetic context INPP5K hgnc:33882 variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Homozygous or compound heterozygous missense, in-frame deletion, splice and late frameshift alleles with partial residual activity.

phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity GO:0004439 ↓ DECREASED

Downstream

Impaired PI(4,5)P2 to PI(4)P Conversion on Autolysosomes Loss of the enzyme that removes the 5-phosphate leaves PI(4,5)P2 high and PI(4)P low on autolysosome membranes.

Lens Fiber Organization Defect Shown only in zebrafish knockdown; the cellular mechanism linking INPP5K to lens fiber organization is not known.

Impaired Neuronal Differentiation

PHGDH Dysregulation

Endoplasmic Reticulum Tubule-to-Sheet Imbalance

Secondary Alpha-Dystroglycan Hypoglycosylation

Show evidence (3 references)

PMID:28190456 SUPPORT In Vitro

"Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K."

Recombinant enzyme assays and localization studies show the two ways patient variants compromise INPP5K.

PMID:28190459 SUPPORT In Vitro

"We found that when compared to a phosphatase-dead construct (p.Asp310Gly), p.Gly140Ser and p.Asp269Asn had almost no enzymatic activity, while p.Val23Met and p.Met93Val retained 27% and 42% activity, respectively."

Shows reduced but often partial catalytic activity across a second set of patient alleles.

PMID:33060052 SUPPORT REVIEW SYNTHESIS Other

"Its protein structure is comprised of a N-terminal catalytic domain which hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH domain at the C-terminus which is responsible for protein-protein interactions and subcellular localization of INPP5K."

Review of the two-domain structure that explains the two classes of patient allele: catalytic-domain variants that lower activity and a SKICH-domain variant that mislocalizes the enzyme.

Impaired PI(4,5)P2 to PI(4)P Conversion on Autolysosomes

On autolysosomes, PI(4)P is phosphorylated to PI(4,5)P2 to recruit the effectors that extrude reformation tubules, and INPP5K converts PI(4,5)P2 back to PI(4)P so that the tubules can complete. Without INPP5K, PI(4,5)P2 persists on autolysosomes and PI(4)P is reduced.

phosphatidylinositol dephosphorylation GO:0046856 ↓ DECREASED

Downstream

Defective Autophagic Lysosome Reformation

Show evidence (1 reference)

PMID:33119550 SUPPORT Model Organism

"Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k-/- muscle suppressed autophagy and lysosome repopulation via ALR inhibition."

Establishes reduced PI(4,5)P2 turnover on autolysosomes in knockout muscle and places it upstream of the ALR defect.

Defective Autophagic Lysosome Reformation

Autophagic lysosome reformation recycles autolysosome membranes into new lysosomes through tubules that bud and undergo scission. In INPP5K-deficient myoblasts the autolysosomes enlarge and hyperextended reformation tubules persist, with the PI(4,5)P2 effector clathrin failing to disengage, so new lysosomes are not released. Wild-type INPP5K, but not disease mutants, restores lysosome homeostasis, which ties the patient alleles to this step.

skeletal muscle myoblast CL:0000515 skeletal muscle fiber CL:0008002

lysosome organization (autophagic lysosome reformation) GO:0007040 ↓ DECREASED

Animal models

Muscle-specific Inpp5k knockout mouse (Inpp5k fl/fl MCK-Cre) Mouse recapitulates Knockout muscle and myoblasts show the ALR block directly.

Downstream

Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle

Show evidence (2 references)

PMID:33119550 SUPPORT In Vitro

"Defective ALR in Inpp5k-/- myoblasts was characterized by enlarged autolysosomes and the persistence of hyperextended reformation tubules, structures that participate in membrane recycling to form lysosomes."

Describes the cellular ALR defect in knockout myoblasts.

PMID:33119550 SUPPORT In Vitro

"Inhibition of PI(4,5)P2 synthesis or expression of WT INPP5K but not INPP5K disease mutants in INPP5K-depleted myoblasts restored lysosomal homeostasis."

Rescue by wild-type but not patient-mutant INPP5K, and by lowering PI(4,5)P2 synthesis, links the patient alleles and the lipid imbalance to the lysosome defect.

Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle

With lysosomes not replenished, knockout muscle accumulates LC3-II, p62 and ubiquitinated proteins from six weeks of age and fills with enlarged autolysosome vacuoles, while autophagosome formation and fusion remain intact. The defect is a failure of autophagic clearance downstream of a lysosome supply problem, not a failure of autophagy induction. Human muscle biopsies show compatible features (rimmed vacuoles, p62 and alpha-B crystallin accumulation), but autophagic flux measured in patient fibroblasts was normal, so the step is established in mouse and only inferred in patients.

skeletal muscle fiber CL:0008002

autophagy GO:0006914 ↓ DECREASED

Downstream

Skeletal Myofiber Degeneration

Show evidence (3 references)

PMID:33119550 SUPPORT Model Organism

"We report that loss of INPP5K in muscle caused severe disease, autophagy inhibition, and lysosome depletion."

Direct demonstration in muscle-specific knockout mice.

PMID:28190456 SUPPORT INDIRECT Human Clinical

"In some biopsies, cytoplasmic labeling for α-B crystallin, VCP, and p62 as well as developmental and fetal myosin was observed in a variable proportion of fibers."

p62 accumulation in patient muscle is a marker compatible with impaired autophagic clearance; it does not by itself measure flux.

PMID:28190456 REFUTE In Vitro

"However, LC3B immunoblotting and immunofluorescence staining as well as measurement of LC3B turnover and p62 levels in fibroblasts treated with the autophagy inducer rapamycin and the lysosomal inhibitor bafilomycin A1 did not reveal specific effects of different INPP5K genotypes."

Autophagic flux in patient skin fibroblasts was not altered. Fibroblasts are not muscle, and the mouse work locates the dependence on ALR in muscle, so this does not exclude the mechanism, but it is the only human flux measurement available.

Skeletal Myofiber Degeneration

Dystrophic degeneration of skeletal muscle with fiber size variation, necrotic and regenerating fibers, fibrosis, fatty replacement and in some patients vacuolated fibers. Serum creatine kinase is markedly raised. Muscle-specific knockout mice develop the same pattern with a deficit in specific force, and zebrafish knockdown embryos show disorganized myofibers.

skeletal muscle fiber CL:0008002

skeletal muscle tissue UBERON:0001134

Animal models

Muscle-specific Inpp5k knockout mouse (Inpp5k fl/fl MCK-Cre) Mouse recapitulates Progressive dystrophy with raised CK and vacuolated fibers.

inpp5ka morphant zebrafish Zebrafish partially recapitulates Disorganized myofibers in embryos.

Downstream

Proximal muscle weakness

Elevated serum creatine kinase

Loss of ambulation

Respiratory insufficiency due to muscle weakness

Rimmed vacuoles

Myopathic EMG

Hypotonia

Delayed gross motor development

Ankle flexion contracture

Scoliosis

Hyperlordosis

Show evidence (3 references)

PMID:28190456 SUPPORT Human Clinical

"Muscle pathology was largely nonspecific, showing variable degrees of dystrophic features, including increased range of muscle fiber size with small and hypertrophic fibers, muscle fibrosis, excess adipose tissue, occasional fibers with internal nuclei, rare necrotic fibers, and a few basophilic..."

Patient muscle biopsies show dystrophic degeneration.

PMID:33119550 SUPPORT Model Organism

"Inpp5kfl/fl MCK-Cre mice developed muscle disease resembling that caused by INPP5K mutations"

Muscle-specific knockout reproduces the dystrophy.

PMID:28190459 SUPPORT Model Organism

"We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers."

Zebrafish knockdown produces disorganized myofibers.

Lens Fiber Organization Defect

In inpp5ka knockdown zebrafish the lens cortex is disorganized and nuclei persist in the center of the lens, a defect the authors liken to congenital cataract. This is the only experimental evidence on the lens; how INPP5K deficiency disturbs lens fiber development is not known. Not declared as conforming to the cataract_lens_opacification module, whose conserved chain runs through crystallin aggregation, for which there is no INPP5K evidence.

lens fiber cell CL:0011004

lens of camera-type eye UBERON:0000965

Animal models

inpp5ka morphant zebrafish Zebrafish recapitulates Lens cortex disorganization with retained central nuclei.

Downstream

Early-onset cataract

Show evidence (1 reference)

PMID:28190459 SUPPORT Model Organism

"immunostaining in axial sections of the inpp5ka morphant showed that the lens cortex was disorganized and cell nuclei were present in the center of the lens nucleus, leading to a phenotype reminiscent of congenital cataracts"

Zebrafish knockdown disrupts lens fiber organization.

Impaired Neuronal Differentiation

INPP5K expression rises during brain development, and its knockdown in neuroblastoma-derived N2A cells impairs neuronal-like differentiation. Zebrafish knockdown embryos are microcephalic. Together these suggest a neurodevelopmental role, but no patient neural tissue or neuronal model has been studied, so the link to intellectual disability is inferred.

neuron CL:0000540

Downstream

Intellectual disability

Delayed speech and language development

Microcephaly

Show evidence (1 reference)

PMID:38559586 SUPPORT In Vitro

"Knockdown of INPP5K in the neuroblastoma-derived cell line N2A impaired their neuronal-like differentiation and interfered with protein glycosylation."

Cell-line evidence for a role of INPP5K in neuronal differentiation.

PHGDH Dysregulation

Unbiased proteomics of cells from INPP5K and SIL1 (Marinesco-Sjogren) patients converged on altered D-3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme of serine biosynthesis, whose own deficiency causes a neurological disorder. L-serine improved the neuronal phenotype of inpp5k zebrafish. The direction of the PHGDH change in INPP5K cells is not stated in the cached abstract, so no modifier is recorded.

PHGDH hgnc:8923

Downstream

Impaired Neuronal Differentiation

Show evidence (1 reference)

PMID:33792664 SUPPORT In Vitro

"We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature."

Patient-derived cells show altered PHGDH.

Endoplasmic Reticulum Tubule-to-Sheet Imbalance

INPP5K is recruited to endoplasmic reticulum tubules by ARL6IP1, and its depletion in mammalian cells, or loss of its worm orthologue CIL-1 in neurons, expands ER sheets at the expense of tubules. Patient-derived cells have not been examined for this, and the first discovery study found no unfolded protein response in patient fibroblasts, so whether ER morphology contributes to disease is open.

endoplasmic reticulum tubular network organization GO:0071786 ↓ DECREASED

endoplasmic reticulum GO:0005783

Show evidence (2 references)

PMID:30087126 SUPPORT In Vitro

"Depletion of either INPP5K or ARL6IP1 results in the increase of ER sheets."

Cell-based evidence that INPP5K loss alters ER architecture.

PMID:28190456 REFUTE INDIRECT In Vitro

"However, we found no evidence for induction of the ER stress response in skin fibroblasts from individuals with bi-allelic INPP5K mutations and disease-causing INPP5K mutants did not interfere with interaction with BiP, suggesting still other mechanisms resulting in INPP5K-related disease."

Argues against an ER stress mechanism of the Marinesco-Sjogren type in patient cells; it does not test ER morphology directly.

Secondary Alpha-Dystroglycan Hypoglycosylation

Reduced alpha-dystroglycan glycosylation was seen in muscle from two Italian patients but was normal in the biopsies of the other discovery series. In knockout mice it appears only once muscle disease is advanced, and INPP5K knockdown interferes with protein glycosylation in N2A cells. The available evidence treats it as a secondary or inconsistent feature rather than the cause of the dystrophy, so no edge is drawn from it to myofiber degeneration.

skeletal muscle fiber CL:0008002

protein O-linked glycosylation via mannose GO:0035269 ↓ DECREASED

Downstream

Hypoglycosylation of alpha-dystroglycan

Show evidence (2 references)

PMID:28190459 SUPPORT Human Clinical

"Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts"

Reports reduced dystroglycan glycosylation in patient muscle.

PMID:33119550 SUPPORT Model Organism

"the onset of muscle disease was uncoupled from effects on α-dystroglycan glycosylation."

In mice the hypoglycosylation follows rather than precedes the dystrophy, supporting a secondary role.

✶

Histopathology

1

Dystrophic myopathy with variable vacuolation

Biopsies show nonspecific dystrophic changes: fiber size variation, fibrosis, fatty replacement, internal nuclei, rare necrotic and regenerating fibers, with vacuolated fibers in some. Electron microscopy can show dense membranous structures associated with myonuclei, as in Marinesco-Sjogren syndrome. Dystrophin, sarcoglycans and merosin are normal; alpha-dystroglycan is normal in some patients and reduced in others.

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"Histological examination of three diagnostic muscle biopsies from individuals with INPP5K mutations showed vacuoles in several myofibers, and electron microscopy of one biopsy revealed dense membranous structures associated with some myonuclei."

Vacuoles and perinuclear membranous structures shared with MSS.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

20

Eye 1

Early-onset cataract FREQUENT Developmental cataract HP:0000519

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"The most salient features were bilateral cataracts that required surgery in the first years of life"

Early bilateral cataract requiring surgery.

PMID:33193651 SUPPORT Human Clinical

"Cataract (4/6), epilepsy (1/6), and microcephaly (5/6) were also observed in some of them."

Cataract in four of six founder-allele patients, which supports the frequent rather than very frequent band.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"Cataract (4/6), epilepsy (1/6), and microcephaly (5/6) were also observed in some of them."

Microcephaly in five of six founder-allele patients.

Limbs 1

Ankle flexion contracture HP:0006466

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"She presented diffuse muscle wasting and weakness and ankle contractures."

Ankle contractures in an adult patient.

Metabolism 1

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

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"Creatine kinase values were invariably markedly elevated (mean ×7 of the upper normal limit, range ×3 to ×14)."

Supports both the finding and the very frequent band.

PMID:28190459 SUPPORT Human Clinical

"In summary, all individuals with likely pathogenic biallelic mutations in INPP5K present with myopathic findings and elevated CK, short stature, motor and cognitive developmental delay since early infancy, and moderate-severe ID."

Elevated CK in all five patients of the second series.

Musculoskeletal 8

Proximal muscle weakness HP:0003701

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"Although affected individuals usually reached their motor milestones late, they all eventually acquired independent walking and muscle weakness, which was generally most prominent in proximal lower limb muscles, stabilized for several years."

Describes the proximal lower-limb predominant weakness and its course.

PMID:33193651 SUPPORT Human Clinical

"Affected patients have limb girdle muscle weakness, often associated with bilateral cataracts, short stature, and intellectual disability."

Limb-girdle weakness as the muscle presentation.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:39133882 SUPPORT Human Clinical

"This case describes a patient who initially presented in infancy with hypotonia, motor delays, and short stature."

Case report of infantile hypotonia as the presenting sign.

Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"Five subjects developed respiratory compromise. No facial or oculomotor weakness or cardiac involvement was observed."

Respiratory compromise in five of the twelve patients of the first series, with no cardiac disease.

Rimmed vacuoles HP:0003805

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"Some vacuoles presented with increased acid phosphatase and non-specific esterase activity or as rimmed vacuoles"

Rimmed vacuoles in patient muscle.

Myopathic EMG EMG: myopathic abnormalities HP:0003458

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"Electromyography (EMG) results in three affected individuals were in accordance with a myopathic process while motor nerve conduction studies did not demonstrate substantial abnormalities."

Myopathic EMG with normal nerve conduction.

PMID:28940338 SUPPORT Human Clinical

"However, electromyography of both upper and lower limbs revealed irritable myopathy."

Myopathy detectable by EMG even in a family without clinical or MRI muscle atrophy.

Hypoglycosylation of alpha-dystroglycan HP:0030046

Show evidence (2 references)

PMID:28190459 SUPPORT Human Clinical

"α-dystroglycan immunohistochemistry showed reduced glycosylation expression on fiber surfaces"

Reduced alpha-dystroglycan glycosylation in patient muscle.

PMID:28190456 REFUTE Human Clinical

"Immunohistochemistry for dystrophin, sarcoglycans, α-dystroglycan, and laminin-α2 (merosin) was normal"

In the first discovery series alpha-dystroglycan staining was normal, so the finding is not constant.

Hyperlordosis HP:0003307

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"Our first neuromuscular examination was performed at the age of 22 years showing microcephaly and short stature (below the third percentile), severe hyperlordosis, pseudohypertrophy of calves, and hypotrophy of quadriceps."

Severe hyperlordosis with calf pseudohypertrophy in an adult patient.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"The patient has scoliosis, microcephaly, and short stature (below the third percentile)."

Scoliosis in an adult patient.

Nervous System 7

Delayed gross motor development HP:0002194

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"Although affected individuals usually reached their motor milestones late, they all eventually acquired independent walking"

Delayed motor milestones in the discovery series.

Loss of ambulation HP:0002505

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"During the course of the disease, motor capabilities appeared to deteriorate, and (except for family A) older cases (families D, F, H) had lost ambulation"

Progressive loss of ambulation in older patients.

Intellectual disability FREQUENT HP:0001249

Show evidence (2 references)

PMID:28190456 SUPPORT Human Clinical

"Cognitive deficits, usually mild, were recorded in eight probands while four individuals had normal intelligence."

Eight of twelve individuals with cognitive deficits supports the frequent band.

PMID:42467360 SUPPORT Human Clinical

"We identify the first disease-causing synonymous variant (via aberrant splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the combination of which explains the attenuated phenotype lacking intellectual disability."

Intellectual disability can be absent with a milder genotype.

Seizure HP:0001250

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"Epilepsy, brain atrophy, and cataracts were additional features not observed in all patients."

Epilepsy as an inconstant feature.

Cerebellar atrophy HP:0001272

Show evidence (2 references)

PMID:33193651 SUPPORT Human Clinical

"Brain MRI performed at the age of 12 years showed mild cerebellar atrophy."

Mild cerebellar atrophy in one founder-allele patient.

PMID:28190456 REFUTE Human Clinical

"Although individuals with INPP5K mutations did not have cerebellar atrophy and ataxia, there was a clear phenotypic overlap with MSS"

No cerebellar atrophy in the first discovery series.

Gait ataxia HP:0002066

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"At the age of 4 years, short stature (below the third percentile), microcephaly, ataxic gait, and mild weakness of limb girdle muscles with a positive Gower's sign were observed at first neurological examination"

Ataxic gait in one founder-allele patient.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:28940338 SUPPORT Human Clinical

"In our family LUCC15, mild to moderate intellectual disability along with speech impairment was observed in 2 affected individuals."

Speech impairment accompanying intellectual disability.

Growth 1

Short stature VERY_FREQUENT HP:0004322

Show evidence (3 references)

PMID:33193651 SUPPORT Human Clinical

"Mild intellectual disability and short stature were invariably present in all."

Short stature in all six founder-allele patients.

PMID:28190459 SUPPORT Human Clinical

"In summary, all individuals with likely pathogenic biallelic mutations in INPP5K present with myopathic findings and elevated CK, short stature, motor and cognitive developmental delay since early infancy, and moderate-severe ID."

Short stature in all five patients of the second series.

PMID:31630891 SUPPORT INDIRECT Human Clinical

"15 (34%) had pathogenic/likely pathogenic variants in genes already associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4, ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and POC1A (n = 1 each)."

A child ascertained for small-for-gestational-age syndromic short stature carried INPP5K variants, showing growth failure can be the leading feature.

🧬

Genetic Associations

1

INPP5K

Gene: INPP5K hgnc:33882 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:28190456 SUPPORT Human Clinical

"In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K."

First of the two concurrent 2017 gene-discovery studies.

PMID:28190459 SUPPORT Human Clinical

"Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family."

The independent companion discovery study in four further families.

PMID:28190456 SUPPORT Human Clinical

"The absence of INPP5K truncation mutations with clear loss of function may imply that variants in our series represent hypomorphic alleles; this is further supported by embryonic lethality in homozygous constitutive Inpp5k knockout mice."

Supports treating patient alleles as hypomorphic rather than null.

Variants (3)

p.Ile50Thr (c.149T>C) Pathogenic

Recurrent homozygous missense allele in consanguineous families of Bangladeshi and Pakistani origin. It reduces PI(4,5)P2 5-phosphatase activity in vitro with partial residual activity. The same allele, in a Pakistani family, produced congenital cataract and intellectual disability with only electromyographic myopathy.

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"A c.149T>C (p.Ile50Thr) variant in INPP5K (GenBank: NM_016532.3) (Figures 1A and S2) was a non-conservative change, affected a strictly conserved amino acid"

Identifies p.Ile50Thr as the homozygous allele in the index family of the first discovery study. The same c.149T>C change was later reported in the cataract-predominant Pakistani family (PMID:28940338).

p.Val23Met (c.67G>A) Pathogenic

Southern Italian founder allele, homozygous or compound heterozygous in six patients from Puglia sharing one haplotype. The recombinant protein retained 27% of wild-type activity against PI(4,5)P2 in vitro.

Show evidence (2 references)

PMID:28190459 SUPPORT In Vitro

"We found that when compared to a phosphatase-dead construct (p.Asp310Gly), p.Gly140Ser and p.Asp269Asn had almost no enzymatic activity, while p.Val23Met and p.Met93Val retained 27% and 42% activity, respectively."

Quantifies the residual activity of p.Val23Met and other patient alleles in a recombinant phosphatase assay.

PMID:33193651 SUPPORT Human Clinical

"All affected subjects were homozygous or compound heterozygous for the c.67G > A (p.Val23Met) missense change and shared a common haplotype, indicating the occurrence of a founder effect."

Establishes p.Val23Met as a founder allele.

p.Lys87= (c.261G>A) splice variant Pathogenic

Synonymous variant that causes exon 3 skipping and a frameshift, reported in compound heterozygosity with the hypomorphic missense p.Arg92Cys in an adult with cataract and limb-girdle weakness but no intellectual disability.

Show evidence (1 reference)

PMID:42467360 SUPPORT Human Clinical

"Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49)."

Establishes the splice mechanism of this synonymous allele.

💊

Medical Actions

2

Cataract Surgery

Category: Therapeutic Action: cataract extraction Ontology label: Cataract Surgery NCIT:C157809

Platform: Surgery

Bilateral cataracts usually require extraction in the first years of life.

Target Phenotypes: Developmental cataract HP:0000519

Show evidence (1 reference)

PMID:28190456 SUPPORT Human Clinical

"The most salient features were bilateral cataracts that required surgery in the first years of life"

Cataract surgery in early childhood is standard care.

L-Serine Supplementation (preclinical)

Category: Therapeutic Action: amino acid supplementation Ontology label: Nutritional Supplementation NCIT:C15425

Agent: L-serine CHEBI:17115

Platform: Small molecule

Preclinical candidate only. L-serine improved the neuronal phenotype of inpp5k zebrafish models, on the rationale that INPP5K deficiency alters PHGDH and serine biosynthesis. No patient has been reported treated in the cited literature, and there is no human efficacy or safety evidence for this indication.

Mechanism Target:

PHGDH Dysregulation — Bypasses the proposed serine biosynthesis deficit.

Show evidence (1 reference)

PMID:33792664 SUPPORT Model Organism

"we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype."

Zebrafish-only evidence of benefit.

🔬

Diagnosis

2

Molecular genetic testing of INPP5K

Diagnosis rests on biallelic INPP5K variants. Exome or neuromuscular panel sequencing is the usual route; in patients from Puglia, targeted sequencing of exon 2 for the p.Val23Met founder allele is a reasonable first step. Synonymous variants can be pathogenic through splicing, so RNA analysis may be needed when only one variant is found.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:33193651 SUPPORT Human Clinical

"especially if originating from the same area of southern Italy (Puglia), sequencing of exon 2 of INPP5K as the first screening step"

Recommends founder-exon screening in patients from Puglia.

PMID:42467360 SUPPORT Human Clinical

"Our case highlights the critical role of RNA analysis in diagnosing non-canonical variants"

Supports RNA analysis for non-canonical variants.

Muscle imaging

Muscle MRI or ultrasound showing vasti involvement with sparing of rectus femoris, sartorius and gracilis supports the diagnosis and can help interpret genetic results.

magnetic resonance imaging NCIT:C16809

Show evidence (1 reference)

PMID:39133882 SUPPORT Human Clinical

"A characteristic pattern of muscle involvement has been identified on muscle MRI in a small case series, including involvement of the vasti, anterior tibialis, and peronei with relative sparing of the rectus femoris, sartorius, and gracilis muscles."

States the diagnostic muscle imaging pattern.

🩻

Imaging Findings

1

Selective thigh and leg muscle involvement on muscle MRI

Fatty replacement of the vasti, adductor magnus, tibialis anterior, peronei and soleus, with relative sparing of rectus femoris, sartorius, gracilis and gastrocnemii. Severity rises with age, and young children may have a normal scan. Muscle ultrasound shows the same vasti-over-rectus-femoris pattern.

Mri Diagnostic

Show evidence (2 references)

PMID:33193651 SUPPORT Human Clinical

"Muscle MRI showed consistent involvement of vasti, anterior tibialis and peronei muscles, and the degree of muscle degeneration appears to be age-related being more severe in older patients"

Defines the pattern and its age dependence.

PMID:42467360 SUPPORT Human Clinical

"Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis."

Same sparing pattern in an independent patient.

📊

Prevalence

2

Worldwide

Point Prevalence <1 in 1,000,000

Orphanet classes worldwide point prevalence as below 1 in 1,000,000, based on the two 2017 discovery series and the 2021 follow-up series.

Show evidence (1 reference)

ORPHA:662184 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28190456,PMID:28190459,PMID:33792664"

Orphanet supplies the structured worldwide prevalence band.

Province of Lecce, Puglia, southern Italy

Cases In Literature Rare

Six apparently unrelated patients from small towns in one area of Puglia carry the p.Val23Met variant on a shared 213 kb haplotype, a founder effect that makes this the one known geographic cluster.

Show evidence (1 reference)

PMID:33193651 SUPPORT Human Clinical

"All affected subjects were homozygous or compound heterozygous for the c.67G > A (p.Val23Met) missense change and shared a common haplotype, indicating the occurrence of a founder effect."

Establishes the southern Italian founder allele and therefore a local cluster of cases.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from INPP5K-Related Congenital Muscular Dystrophy:

Marinesco-Sjogren syndrome MONDO:0009567

Overlapping Features SIL1-related disorder sharing early cataracts, myopathy, intellectual disability and vacuolar muscle pathology with perinuclear membranous structures. Cerebellar ataxia with cerebellar atrophy is defining in Marinesco-Sjogren syndrome but absent or mild in INPP5K disease. The INPP5K discovery cohort was assembled from patients referred for SIL1 testing who had no SIL1 variant. Curated in kb/disorders/Marinesco-Sjogren_Syndrome.yaml.

Show evidence (1 reference)

PMID:28190459 SUPPORT Human Clinical

"While no ataxia or cerebellar atrophy was noted, this presentation is reminiscent of MSS and could fall in the larger MSS spectrum."

States the overlap and the distinguishing absence of ataxia.

Dystroglycanopathy

Overlapping Features Alpha-dystroglycan glycosylation defects cause congenital muscular dystrophy with eye and brain involvement. Some INPP5K patients show reduced alpha-dystroglycan glycosylation, but the dystroglycanopathy brain malformations are absent, and the hypoglycosylation appears to be secondary. Curated in kb/disorders/Dystroglycanopathy.yaml.

Show evidence (1 reference)

PMID:28190459 SUPPORT Human Clinical

"In addition, a reduction in dystroglycan glycosylation in S2 and S3 suggest an overlap with less severe forms of dystroglycanopathies, where CMD is present with cataracts and ID."

States the partial overlap with the dystroglycanopathies.

3-Phosphoglycerate dehydrogenase deficiency

Overlapping Features Serine biosynthesis defect whose neurological picture overlaps INPP5K disease and Marinesco-Sjogren syndrome; altered PHGDH is the proposed shared molecular feature. Curated in kb/disorders/3-Phosphoglycerate_Dehydrogenase_Deficiency.yaml.

Show evidence (1 reference)

PMID:33792664 SUPPORT Human Clinical

"d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease."

States the clinical overlap with PHGDH deficiency.

🐁

Animal Models

2

Muscle-specific Inpp5k knockout mouse (Inpp5k fl/fl MCK-Cre)

Constitutive knockout is embryonic lethal, so Inpp5k was deleted in skeletal muscle. Mice develop early-onset progressive dystrophy with raised CK, vacuolated fibers, fibrosis and reduced force, with lysosome depletion and autophagy inhibition caused by failed autophagic lysosome reformation.

Species

Mouse

Genotype

Inpp5k fl/fl; MCK-Cre (skeletal muscle-specific deletion)

Publication

PMID:33119550

Pathograph links

Defective Autophagic Lysosome Reformation recapitulates fidelity: moderate observes: cellular Knockout muscle and myoblasts show the ALR block directly.

Limitations: Complete deletion, whereas patient alleles are hypomorphic; an ALR defect has not been demonstrated in patient muscle.

Show evidence (1 reference)

PMID:33119550 SUPPORT Model Organism

"Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k-/- muscle suppressed autophagy and lysosome repopulation via ALR inhibition."

The model shows the ALR defect in muscle.

Skeletal Myofiber Degeneration recapitulates fidelity: moderate observes: tissue Progressive dystrophy with raised CK and vacuolated fibers.

Limitations: Muscle-only deletion cannot model the lens, brain and growth features, and disease onset and course in mice need not match the human timeline.

Show evidence (1 reference)

PMID:33119550 SUPPORT Model Organism

"Inpp5kfl/fl MCK-Cre mice developed muscle disease resembling that caused by INPP5K mutations"

The authors judge the muscle disease to resemble the human one.

inpp5ka morphant zebrafish

Morpholino knockdown of inpp5ka, the closer orthologue of human INPP5K, gives microphthalmia with a disorganized lens, microcephaly, short and curved body, reduced motility and disorganized myofibers with sarcomere defects, rescued by human INPP5K mRNA. inpp5kb has lost catalytic activity toward PI(4,5)P2, so inpp5ka is the relevant target.

Species

Zebrafish

Genotype

inpp5ka (with or without inpp5kb) morpholino knockdown

Publication

PMID:28190459

Pathograph links

Lens Fiber Organization Defect recapitulates fidelity: low observes: tissue Lens cortex disorganization with retained central nuclei.

Limitations: Transient embryonic knockdown; lens disorganization in larvae is reminiscent of, not identical to, human postnatal cataract.

Show evidence (1 reference)

PMID:28190459 SUPPORT Model Organism

"inpp5k loss-of-function modeling in the zebrafish led to a constellation of phenotypes that closely resembles the human presentation, including reduced growth, microcephaly, lens disorganization, reduced motility, and myopathy."

Morphants show lens disorganization and other human features.

Skeletal Myofiber Degeneration partially recapitulates fidelity: low observes: tissue Disorganized myofibers in embryos.

Limitations: Embryonic myofiber disorganization reflects development as much as degeneration, and morpholino effects are transient.

Show evidence (1 reference)

PMID:28190456 SUPPORT Model Organism

"Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development."

Independent morphant study with muscle and eye defects.

Show evidence (1 reference)

PMID:37184573 SUPPORT Model Organism

"Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss of inpp5ka alone can be targeted to recapitulate the human presentation."

Identifies inpp5ka as the relevant paralogue to model.

{ }

Source YAML

click to show

name: INPP5K-Related Congenital Muscular Dystrophy
creation_date: '2026-10-14T12:36:44Z'
category: Mendelian
parents:
- Congenital Muscular Dystrophy
description: >-
  Autosomal recessive congenital muscular dystrophy caused by biallelic,
  mostly hypomorphic missense variants in INPP5K (also called SKIP), an
  inositol polyphosphate 5-phosphatase that converts phosphatidylinositol
  4,5-bisphosphate to phosphatidylinositol 4-phosphate and sits largely on the
  endoplasmic reticulum. The core picture is hypotonia or proximal weakness
  from birth or early childhood with markedly raised creatine kinase and
  dystrophic muscle pathology, bilateral early-onset cataracts, short stature,
  and usually mild to moderate intellectual disability. Brain MRI is often
  normal; microcephaly, seizures and mild cerebral or cerebellar atrophy occur
  in some patients. Motor function is often stable for years and then declines,
  with loss of ambulation in some adolescents and adults. Muscle MRI shows a
  recognizable pattern with vasti, tibialis anterior and peronei involved and
  rectus femoris, sartorius and gracilis spared. The clinical picture overlaps
  Marinesco-Sjogren syndrome (early cataracts, myopathy, intellectual
  disability, vacuolar muscle pathology) and, in some patients with reduced
  alpha-dystroglycan glycosylation, the dystroglycanopathies. The leading
  mechanistic model, established in a muscle-specific knockout mouse, is
  failure of autophagic lysosome reformation: without INPP5K, PI(4,5)P2 is not
  cleared from autolysosome membranes, reformation tubules fail to resolve,
  lysosomes are depleted and autophagic flux stalls in muscle. Whether the same
  defect operates in patient muscle has not been shown directly.
disease_term:
  preferred_term: congenital muscular dystrophy with cataracts and intellectual disability
  term:
    id: MONDO:0024607
    label: congenital muscular dystrophy with cataracts and intellectual disability
synonyms:
- MDCCAID
- congenital muscular dystrophy with cataracts and intellectual disability
- Congenital muscular dystrophy-cataract-intellectual disability syndrome
- INPP5K-related syndrome
- INPP5K-related muscular dystrophy
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Orphanet classes worldwide point prevalence as below 1 in 1,000,000, based
    on the two 2017 discovery series and the 2021 follow-up series.
  evidence:
  - reference: ORPHA:662184
    reference_title: Congenital muscular dystrophy-cataract-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:28190456,PMID:28190459,PMID:33792664"
    explanation: Orphanet supplies the structured worldwide prevalence band.
- population: Province of Lecce, Puglia, southern Italy
  measure_type: CASES_IN_LITERATURE
  prevalence_class: RARE
  notes: >-
    Six apparently unrelated patients from small towns in one area of Puglia
    carry the p.Val23Met variant on a shared 213 kb haplotype, a founder
    effect that makes this the one known geographic cluster.
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected subjects were homozygous or compound heterozygous for the
      c.67G > A (p.Val23Met) missense change and shared a common haplotype,
      indicating the occurrence of a founder effect.
    explanation: >-
      Establishes the southern Italian founder allele and therefore a local
      cluster of cases.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals are homozygous or compound heterozygous for INPP5K
    variants, and the disease segregates with recessive inheritance in the
    reported families, several of them consanguineous. Expressivity is
    variable within and between families: cataract and intellectual disability
    can each be absent, and one family carrying the recurrent p.Ile50Thr allele
    presented with congenital cataract, intellectual disability and only
    electromyographic myopathy.
  expressivity: VARIABLE
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whenever DNA from family members was available, we observed that the
      disease segregated with recessive inheritance of the INPP5K mutations
    explanation: >-
      Segregation analysis in the discovery families supports autosomal
      recessive inheritance.
  - reference: PMID:28940338
    reference_title: INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparison of clinical phenotype of all the known affected individuals,
      including LUCC15 family, homozygous for INPP5K alleles revealed reduced
      penetrance of muscular dystrophy and intellectual disability.
    explanation: >-
      Supports variable expressivity of the muscle and cognitive features
      among biallelic carriers.
genetic:
- name: INPP5K
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: INPP5K
    term:
      id: hgnc:33882
      label: INPP5K
  notes: >-
    INPP5K encodes inositol polyphosphate-5-phosphatase K (SKIP), a 448-residue
    protein with an N-terminal 5-phosphatase domain and a C-terminal SKICH
    domain that targets it to the endoplasmic reticulum. Most reported
    pathogenic alleles are missense or in-frame changes in the phosphatase
    domain that leave partial residual activity in vitro; the truncating and
    splice alleles reported so far occur in compound heterozygosity with a
    missense allele. Constitutive Inpp5k knockout is embryonic lethal in mice,
    so patient alleles are interpreted as hypomorphic. INPP5K has no row in the
    committed ClinGen gene-disease validity ingest
    (kb/genes/ingest/clingen_gene_validity.tsv), so no validity tier is
    recorded.
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In individuals exhibiting congenital muscular dystrophy, early-onset
      cataracts, and mild intellectual disability but normal cranial magnetic
      resonance imaging, we identified bi-allelic mutations in INPP5K, encoding
      inositol polyphosphate-5-phosphatase K.
    explanation: >-
      First of the two concurrent 2017 gene-discovery studies.
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing revealed homozygous missense and compound
      heterozygous mutations in INPP5K in the affected members of each family.
    explanation: >-
      The independent companion discovery study in four further families.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of INPP5K truncation mutations with clear loss of function
      may imply that variants in our series represent hypomorphic alleles; this
      is further supported by embryonic lethality in homozygous constitutive
      Inpp5k knockout mice.
    explanation: >-
      Supports treating patient alleles as hypomorphic rather than null.
  variants:
  - name: p.Ile50Thr (c.149T>C)
    description: >-
      Recurrent homozygous missense allele in consanguineous families of
      Bangladeshi and Pakistani origin. It reduces PI(4,5)P2 5-phosphatase
      activity in vitro with partial residual activity. The same allele, in a
      Pakistani family, produced congenital cataract and intellectual
      disability with only electromyographic myopathy.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28190456
      reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A c.149T>C (p.Ile50Thr) variant in INPP5K (GenBank: NM_016532.3)
        (Figures 1A and S2) was a non-conservative change, affected a strictly
        conserved amino acid
      explanation: >-
        Identifies p.Ile50Thr as the homozygous allele in the index family of
        the first discovery study. The same c.149T>C change was later reported
        in the cataract-predominant Pakistani family (PMID:28940338).
  - name: p.Val23Met (c.67G>A)
    description: >-
      Southern Italian founder allele, homozygous or compound heterozygous in
      six patients from Puglia sharing one haplotype. The recombinant protein
      retained 27% of wild-type activity against PI(4,5)P2 in vitro.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28190459
      reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that when compared to a phosphatase-dead construct
        (p.Asp310Gly), p.Gly140Ser and p.Asp269Asn had almost no enzymatic
        activity, while p.Val23Met and p.Met93Val retained 27% and 42%
        activity, respectively.
      explanation: >-
        Quantifies the residual activity of p.Val23Met and other patient
        alleles in a recombinant phosphatase assay.
    - reference: PMID:33193651
      reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All affected subjects were homozygous or compound heterozygous for the
        c.67G > A (p.Val23Met) missense change and shared a common haplotype,
        indicating the occurrence of a founder effect.
      explanation: Establishes p.Val23Met as a founder allele.
  - name: p.Lys87= (c.261G>A) splice variant
    description: >-
      Synonymous variant that causes exon 3 skipping and a frameshift, reported
      in compound heterozygosity with the hypomorphic missense p.Arg92Cys in an
      adult with cataract and limb-girdle weakness but no intellectual
      disability.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:42467360
      reference_title: "INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Functional studies confirmed the synonymous variant causes aberrant
        splicing (exon 3 skipping), leading to a frameshift and premature
        termination p.(Leu52SerfsTer49).
      explanation: Establishes the splice mechanism of this synonymous allele.
pathophysiology:
- name: INPP5K Phosphoinositide 5-Phosphatase Deficiency
  biological_scale: MOLECULAR
  description: >-
    Biallelic hypomorphic variants reduce the 5-phosphatase activity of INPP5K
    toward PI(4,5)P2, or, for the SKICH-domain variant p.Ile363Thr, displace
    the enzyme from the endoplasmic reticulum. Residual activity ranges from
    almost none to about half of wild type depending on the allele.
  genetic_context:
    gene:
      preferred_term: INPP5K
      term:
        id: hgnc:33882
        label: INPP5K
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous missense, in-frame deletion, splice
      and late frameshift alleles with partial residual activity.
  genes:
  - preferred_term: INPP5K
    term:
      id: hgnc:33882
      label: INPP5K
  molecular_functions:
  - preferred_term: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
    modifier: DECREASED
    term:
      id: GO:0004439
      label: phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutations impaired phosphatase activity toward the phosphoinositide
      phosphatidylinositol (4,5)-bisphosphate or altered the subcellular
      localization of INPP5K.
    explanation: >-
      Recombinant enzyme assays and localization studies show the two ways
      patient variants compromise INPP5K.
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that when compared to a phosphatase-dead construct
      (p.Asp310Gly), p.Gly140Ser and p.Asp269Asn had almost no enzymatic
      activity, while p.Val23Met and p.Met93Val retained 27% and 42% activity,
      respectively.
    explanation: >-
      Shows reduced but often partial catalytic activity across a second set
      of patient alleles.
  - reference: PMID:33060052
    reference_title: "The phosphoinositide 5-phosphatase INPP5K: From gene structure to in vivo functions."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Its protein structure is comprised of a N-terminal catalytic domain which
      hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH
      domain at the C-terminus which is responsible for protein-protein
      interactions and subcellular localization of INPP5K.
    explanation: >-
      Review of the two-domain structure that explains the two classes of
      patient allele: catalytic-domain variants that lower activity and a
      SKICH-domain variant that mislocalizes the enzyme.
  downstream:
  - target: Impaired PI(4,5)P2 to PI(4)P Conversion on Autolysosomes
    causal_link_type: DIRECT
    description: >-
      Loss of the enzyme that removes the 5-phosphate leaves PI(4,5)P2 high
      and PI(4)P low on autolysosome membranes.
    evidence:
    - reference: PMID:33879025
      reference_title: Bidirectional interconversion between PtdIns4P and PtdIns(4,5)P(2) is required for autophagic lysosome reformation and protection from skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This was due to decreased PtdIns4P and increased PtdIns(4,5)P2 on
        autolysosomes, causing reduced scission of reformation tubules.
      explanation: >-
        In muscle-specific Inpp5k knockout mice, loss of INPP5K shifts the
        autolysosomal phosphoinositide balance toward PI(4,5)P2.
  - target: Lens Fiber Organization Defect
    description: >-
      Shown only in zebrafish knockdown; the cellular mechanism linking INPP5K
      to lens fiber organization is not known.
  - target: Impaired Neuronal Differentiation
  - target: PHGDH Dysregulation
  - target: Endoplasmic Reticulum Tubule-to-Sheet Imbalance
  - target: Secondary Alpha-Dystroglycan Hypoglycosylation
- name: Impaired PI(4,5)P2 to PI(4)P Conversion on Autolysosomes
  biological_scale: MOLECULAR
  description: >-
    On autolysosomes, PI(4)P is phosphorylated to PI(4,5)P2 to recruit the
    effectors that extrude reformation tubules, and INPP5K converts PI(4,5)P2
    back to PI(4)P so that the tubules can complete. Without INPP5K, PI(4,5)P2
    persists on autolysosomes and PI(4)P is reduced.
  chemical_entities:
  - preferred_term: phosphatidylinositol 4,5-bisphosphate
    modifier: INCREASED
    term:
      id: CHEBI:18348
      label: 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
  - preferred_term: phosphatidylinositol 4-phosphate
    modifier: DECREASED
    term:
      id: CHEBI:17526
      label: 1-phosphatidyl-1D-myo-inositol 4-phosphate
  biological_processes:
  - preferred_term: phosphatidylinositol dephosphorylation
    modifier: DECREASED
    term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
  evidence:
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k-/- muscle
      suppressed autophagy and lysosome repopulation via ALR inhibition.
    explanation: >-
      Establishes reduced PI(4,5)P2 turnover on autolysosomes in knockout
      muscle and places it upstream of the ALR defect.
  downstream:
  - target: Defective Autophagic Lysosome Reformation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33879025
      reference_title: Bidirectional interconversion between PtdIns4P and PtdIns(4,5)P(2) is required for autophagic lysosome reformation and protection from skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Therefore on autolysosomes, both PtdIns(4,5)P2 generation and its
        removal by INPP5K is required for completion of ALR.
      explanation: >-
        States that INPP5K-mediated removal of PI(4,5)P2 is required for ALR to
        complete.
- name: Defective Autophagic Lysosome Reformation
  biological_scale: CELLULAR
  description: >-
    Autophagic lysosome reformation recycles autolysosome membranes into new
    lysosomes through tubules that bud and undergo scission. In INPP5K-deficient
    myoblasts the autolysosomes enlarge and hyperextended reformation tubules
    persist, with the PI(4,5)P2 effector clathrin failing to disengage, so new
    lysosomes are not released. Wild-type INPP5K, but not disease mutants,
    restores lysosome homeostasis, which ties the patient alleles to this step.
  cell_types:
  - preferred_term: skeletal muscle myoblast
    term:
      id: CL:0000515
      label: skeletal muscle myoblast
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: lysosome organization (autophagic lysosome reformation)
    modifier: DECREASED
    term:
      id: GO:0007040
      label: lysosome organization
  evidence:
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Defective ALR in Inpp5k-/- myoblasts was characterized by enlarged
      autolysosomes and the persistence of hyperextended reformation tubules,
      structures that participate in membrane recycling to form lysosomes.
    explanation: >-
      Describes the cellular ALR defect in knockout myoblasts.
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Inhibition of PI(4,5)P2 synthesis or expression of WT INPP5K but not
      INPP5K disease mutants in INPP5K-depleted myoblasts restored lysosomal
      homeostasis.
    explanation: >-
      Rescue by wild-type but not patient-mutant INPP5K, and by lowering
      PI(4,5)P2 synthesis, links the patient alleles and the lipid imbalance to
      the lysosome defect.
  downstream:
  - target: Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33119550
      reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Activation of TFEB-dependent de novo lysosome biogenesis did not
        compensate for loss of ALR in Inpp5k-/- muscle, revealing a dependence
        on this lysosome recycling pathway.
      explanation: >-
        Shows that muscle cannot replace ALR-derived lysosomes through de novo
        biogenesis, so the ALR block leads to lysosome loss.
- name: Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle
  biological_scale: CELLULAR
  conforms_to: disabled_macroautophagy#Failure of Cytoplasmic Quality Control
  description: >-
    With lysosomes not replenished, knockout muscle accumulates LC3-II, p62 and
    ubiquitinated proteins from six weeks of age and fills with enlarged
    autolysosome vacuoles, while autophagosome formation and fusion remain
    intact. The defect is a failure of autophagic clearance downstream of a
    lysosome supply problem, not a failure of autophagy induction. Human muscle
    biopsies show compatible features (rimmed vacuoles, p62 and alpha-B
    crystallin accumulation), but autophagic flux measured in patient
    fibroblasts was normal, so the step is established in mouse and only
    inferred in patients.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report that loss of INPP5K in muscle caused severe disease, autophagy
      inhibition, and lysosome depletion.
    explanation: >-
      Direct demonstration in muscle-specific knockout mice.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some biopsies, cytoplasmic labeling for α-B crystallin, VCP, and p62
      as well as developmental and fetal myosin was observed in a variable
      proportion of fibers.
    explanation: >-
      p62 accumulation in patient muscle is a marker compatible with impaired
      autophagic clearance; it does not by itself measure flux.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      However, LC3B immunoblotting and immunofluorescence staining as well as
      measurement of LC3B turnover and p62 levels in fibroblasts treated with
      the autophagy inducer rapamycin and the lysosomal inhibitor bafilomycin A1
      did not reveal specific effects of different INPP5K genotypes.
    explanation: >-
      Autophagic flux in patient skin fibroblasts was not altered. Fibroblasts
      are not muscle, and the mouse work locates the dependence on ALR in
      muscle, so this does not exclude the mechanism, but it is the only human
      flux measurement available.
  downstream:
  - target: Skeletal Myofiber Degeneration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33119550
      reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Therefore, in muscle, ALR is indispensable for lysosome homeostasis
        during autophagy and when defective is associated with muscular
        dystrophy.
      explanation: >-
        The knockout study concludes that the ALR and autophagy defect underlies
        the dystrophy.
- name: Skeletal Myofiber Degeneration
  biological_scale: TISSUE
  description: >-
    Dystrophic degeneration of skeletal muscle with fiber size variation,
    necrotic and regenerating fibers, fibrosis, fatty replacement and in some
    patients vacuolated fibers. Serum creatine kinase is markedly raised.
    Muscle-specific knockout mice develop the same pattern with a deficit in
    specific force, and zebrafish knockdown embryos show disorganized
    myofibers.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle pathology was largely nonspecific, showing variable degrees of
      dystrophic features, including increased range of muscle fiber size with
      small and hypertrophic fibers, muscle fibrosis, excess adipose tissue,
      occasional fibers with internal nuclei, rare necrotic fibers, and a few
      basophilic (regenerating) fibers
    explanation: Patient muscle biopsies show dystrophic degeneration.
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Inpp5kfl/fl MCK-Cre mice developed muscle disease resembling that caused
      by INPP5K mutations
    explanation: Muscle-specific knockout reproduces the dystrophy.
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We show that morpholino-mediated inpp5k loss of function in the zebrafish
      results in shortened body axis, microphthalmia with disorganized lens,
      microcephaly, reduced touch-evoked motility, and highly disorganized
      myofibers.
    explanation: Zebrafish knockdown produces disorganized myofibers.
  downstream:
  - target: Proximal muscle weakness
  - target: Elevated serum creatine kinase
  - target: Loss of ambulation
  - target: Respiratory insufficiency due to muscle weakness
  - target: Rimmed vacuoles
  - target: Myopathic EMG
  - target: Hypotonia
  - target: Delayed gross motor development
  - target: Ankle flexion contracture
    evidence:
    - reference: PMID:28190456
      reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Complications include contractures, spinal deformities, and respiratory
        compromise.
      explanation: >-
        States, for congenital muscular dystrophies in general, that
        contractures and spinal deformity are complications of the myopathy;
        applied here to INPP5K disease by inference.
  - target: Scoliosis
    evidence:
    - reference: PMID:28190456
      reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Complications include contractures, spinal deformities, and respiratory
        compromise.
      explanation: >-
        General congenital muscular dystrophy background placing spinal
        deformity downstream of the myopathy.
  - target: Hyperlordosis
- name: Lens Fiber Organization Defect
  biological_scale: TISSUE
  description: >-
    In inpp5ka knockdown zebrafish the lens cortex is disorganized and nuclei
    persist in the center of the lens, a defect the authors liken to congenital
    cataract. This is the only experimental evidence on the lens; how INPP5K
    deficiency disturbs lens fiber development is not known. Not declared as
    conforming to the cataract_lens_opacification module, whose conserved chain
    runs through crystallin aggregation, for which there is no INPP5K evidence.
  cell_types:
  - preferred_term: lens fiber cell
    term:
      id: CL:0011004
      label: lens fiber cell
  locations:
  - preferred_term: lens of camera-type eye
    term:
      id: UBERON:0000965
      label: lens of camera-type eye
  evidence:
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      immunostaining in axial sections of the inpp5ka morphant showed that the
      lens cortex was disorganized and cell nuclei were present in the center
      of the lens nucleus, leading to a phenotype reminiscent of congenital
      cataracts
    explanation: Zebrafish knockdown disrupts lens fiber organization.
  downstream:
  - target: Early-onset cataract
- name: Impaired Neuronal Differentiation
  biological_scale: CELLULAR
  description: >-
    INPP5K expression rises during brain development, and its knockdown in
    neuroblastoma-derived N2A cells impairs neuronal-like differentiation.
    Zebrafish knockdown embryos are microcephalic. Together these suggest a
    neurodevelopmental role, but no patient neural tissue or neuronal model has
    been studied, so the link to intellectual disability is inferred.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:38559586
    reference_title: Knockdown of INPP5K compromises the differentiation of N2A cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Knockdown of INPP5K in the neuroblastoma-derived cell line N2A impaired
      their neuronal-like differentiation and interfered with protein
      glycosylation.
    explanation: Cell-line evidence for a role of INPP5K in neuronal differentiation.
  downstream:
  - target: Intellectual disability
  - target: Delayed speech and language development
  - target: Microcephaly
    evidence:
    - reference: PMID:28190459
      reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        inpp5k loss-of-function modeling in the zebrafish led to a
        constellation of phenotypes that closely resembles the human
        presentation, including reduced growth, microcephaly, lens
        disorganization, reduced motility, and myopathy.
      explanation: >-
        Zebrafish knockdown reproduces microcephaly; the neuronal cause is
        inferred.
- name: PHGDH Dysregulation
  biological_scale: CELLULAR
  description: >-
    Unbiased proteomics of cells from INPP5K and SIL1 (Marinesco-Sjogren)
    patients converged on altered D-3-phosphoglycerate dehydrogenase (PHGDH),
    the first enzyme of serine biosynthesis, whose own deficiency causes a
    neurological disorder. L-serine improved the neuronal phenotype of
    inpp5k zebrafish. The direction of the PHGDH change in INPP5K cells is not
    stated in the cached abstract, so no modifier is recorded.
  genes:
  - preferred_term: PHGDH
    term:
      id: hgnc:8923
      label: PHGDH
  evidence:
  - reference: PMID:33792664
    reference_title: INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We applied unbiased proteomic profiling on cells derived from
      Marinesco-Sjögren syndrome and INPP5K patients and identified alterations
      in d-3-PHGDH as a common molecular feature.
    explanation: Patient-derived cells show altered PHGDH.
  downstream:
  - target: Impaired Neuronal Differentiation
    evidence:
    - reference: PMID:33792664
      reference_title: INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we tested the effect of l-serine in generated sil1, phgdh and inpp5k
        a+b zebrafish models, which showed an improvement in their neuronal
        phenotype.
      explanation: >-
        Rescue by the product of the PHGDH pathway implies that the serine
        deficit contributes to the neuronal phenotype; the edge is inferred from
        that rescue.
- name: Endoplasmic Reticulum Tubule-to-Sheet Imbalance
  biological_scale: CELLULAR
  description: >-
    INPP5K is recruited to endoplasmic reticulum tubules by ARL6IP1, and its
    depletion in mammalian cells, or loss of its worm orthologue CIL-1 in
    neurons, expands ER sheets at the expense of tubules. Patient-derived cells
    have not been examined for this, and the first discovery study found no
    unfolded protein response in patient fibroblasts, so whether ER morphology
    contributes to disease is open.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  biological_processes:
  - preferred_term: endoplasmic reticulum tubular network organization
    modifier: DECREASED
    term:
      id: GO:0071786
      label: endoplasmic reticulum tubular network organization
  evidence:
  - reference: PMID:30087126
    reference_title: The inositol 5-phosphatase INPP5K participates in the fine control of ER organization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of either INPP5K or ARL6IP1 results in the increase of ER
      sheets.
    explanation: Cell-based evidence that INPP5K loss alters ER architecture.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      However, we found no evidence for induction of the ER stress response in
      skin fibroblasts from individuals with bi-allelic INPP5K mutations and
      disease-causing INPP5K mutants did not interfere with interaction with
      BiP, suggesting still other mechanisms resulting in INPP5K-related
      disease.
    explanation: >-
      Argues against an ER stress mechanism of the Marinesco-Sjogren type in
      patient cells; it does not test ER morphology directly.
- name: Secondary Alpha-Dystroglycan Hypoglycosylation
  biological_scale: CELLULAR
  description: >-
    Reduced alpha-dystroglycan glycosylation was seen in muscle from two
    Italian patients but was normal in the biopsies of the other discovery
    series. In knockout mice it appears only once muscle disease is advanced,
    and INPP5K knockdown interferes with protein glycosylation in N2A cells.
    The available evidence treats it as a secondary or inconsistent feature
    rather than the cause of the dystrophy, so no edge is drawn from it to
    myofiber degeneration.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: protein O-linked glycosylation via mannose
    modifier: DECREASED
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
  evidence:
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report five individuals from four families presenting with
      variable clinical features including muscular dystrophy with a reduction
      in dystroglycan glycosylation, short stature, intellectual disability,
      and cataracts
    explanation: Reports reduced dystroglycan glycosylation in patient muscle.
  - reference: PMID:33119550
    reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the onset of muscle disease was uncoupled from effects on α-dystroglycan
      glycosylation.
    explanation: >-
      In mice the hypoglycosylation follows rather than precedes the
      dystrophy, supporting a secondary role.
  downstream:
  - target: Hypoglycosylation of alpha-dystroglycan
phenotypes:
- category: Musculoskeletal
  name: Proximal muscle weakness
  description: >-
    Weakness from birth or in early childhood, predominantly proximal and
    worse in the lower limbs, often stable for years before declining. In some
    patients onset follows independent walking, giving a limb-girdle rather
    than congenital presentation.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although affected individuals usually reached their motor milestones
      late, they all eventually acquired independent walking and muscle
      weakness, which was generally most prominent in proximal lower limb
      muscles, stabilized for several years.
    explanation: Describes the proximal lower-limb predominant weakness and its course.
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected patients have limb girdle muscle weakness, often associated with
      bilateral cataracts, short stature, and intellectual disability.
    explanation: Limb-girdle weakness as the muscle presentation.
- category: Musculoskeletal
  name: Hypotonia
  description: Hypotonia from birth or infancy is a common presenting sign.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39133882
    reference_title: "Pearls & Oy-sters: Use of Muscle Ultrasound as a Clinical Tool in INPP5K-Related Muscular Dystrophy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case describes a patient who initially presented in infancy with
      hypotonia, motor delays, and short stature.
    explanation: Case report of infantile hypotonia as the presenting sign.
- category: Neurodevelopmental
  name: Delayed gross motor development
  description: >-
    Motor milestones are usually reached late, though all patients in the
    first series eventually walked independently.
  phenotype_term:
    preferred_term: Delayed gross motor development
    term:
      id: HP:0002194
      label: Delayed gross motor development
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although affected individuals usually reached their motor milestones
      late, they all eventually acquired independent walking
    explanation: Delayed motor milestones in the discovery series.
- category: Laboratory
  name: Elevated serum creatine kinase
  description: >-
    Serum creatine kinase is markedly elevated in essentially every patient,
    about three to fourteen times the upper limit of normal in the first
    series, which separates this disorder from congenital myopathies.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Creatine kinase values were invariably markedly elevated (mean ×7 of the
      upper normal limit, range ×3 to ×14).
    explanation: Supports both the finding and the very frequent band.
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, all individuals with likely pathogenic biallelic mutations in
      INPP5K present with myopathic findings and elevated CK, short stature,
      motor and cognitive developmental delay since early infancy, and
      moderate-severe ID.
    explanation: Elevated CK in all five patients of the second series.
- category: Musculoskeletal
  name: Loss of ambulation
  description: >-
    After a relatively stationary period, older patients often lose
    independent walking.
  phenotype_term:
    preferred_term: Loss of ambulation
    term:
      id: HP:0002505
      label: Loss of ambulation
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the course of the disease, motor capabilities appeared to
      deteriorate, and (except for family A) older cases (families D, F, H) had
      lost ambulation
    explanation: Progressive loss of ambulation in older patients.
- category: Respiratory
  name: Respiratory insufficiency due to muscle weakness
  description: >-
    Respiratory compromise develops in some patients; cardiac involvement has
    not been reported.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five subjects developed respiratory compromise. No facial or oculomotor
      weakness or cardiac involvement was observed.
    explanation: >-
      Respiratory compromise in five of the twelve patients of the first
      series, with no cardiac disease.
- category: Musculoskeletal
  name: Rimmed vacuoles
  description: >-
    Vacuolated fibers, some with rimmed vacuoles and increased acid
    phosphatase activity, are seen in a subset of biopsies, a feature shared
    with Marinesco-Sjogren syndrome and consistent with an autophagic
    degradation defect.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some vacuoles presented with increased acid phosphatase and non-specific
      esterase activity or as rimmed vacuoles
    explanation: Rimmed vacuoles in patient muscle.
- category: Musculoskeletal
  name: Myopathic EMG
  phenotype_term:
    preferred_term: 'EMG: myopathic abnormalities'
    term:
      id: HP:0003458
      label: 'EMG: myopathic abnormalities'
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electromyography (EMG) results in three affected individuals were in
      accordance with a myopathic process while motor nerve conduction studies
      did not demonstrate substantial abnormalities.
    explanation: Myopathic EMG with normal nerve conduction.
  - reference: PMID:28940338
    reference_title: INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, electromyography of both upper and lower limbs revealed
      irritable myopathy.
    explanation: >-
      Myopathy detectable by EMG even in a family without clinical or MRI
      muscle atrophy.
- category: Musculoskeletal
  name: Hypoglycosylation of alpha-dystroglycan
  description: >-
    Reduced alpha-dystroglycan glycosylation on muscle fibers in some patients,
    linking the disorder to the dystroglycanopathy spectrum. Absent in another
    series, where alpha-dystroglycan immunostaining was normal.
  phenotype_term:
    preferred_term: Hypoglycosylation of alpha-dystroglycan
    term:
      id: HP:0030046
      label: Hypoglycosylation of alpha-dystroglycan
  evidence:
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      α-dystroglycan immunohistochemistry showed reduced glycosylation
      expression on fiber surfaces
    explanation: Reduced alpha-dystroglycan glycosylation in patient muscle.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunohistochemistry for dystrophin, sarcoglycans, α-dystroglycan, and
      laminin-α2 (merosin) was normal
    explanation: >-
      In the first discovery series alpha-dystroglycan staining was normal, so
      the finding is not constant.
- category: Ophthalmologic
  name: Early-onset cataract
  description: >-
    Bilateral lens opacities in infancy or early childhood, usually operated
    in the first years of life. All patients of the first series had
    cataracts, but that series was ascertained for cataract with muscle
    disease; cataract was absent in some patients of later series, including
    one sibling of an affected patient.
  phenotype_term:
    preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  frequency: FREQUENT
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most salient features were bilateral cataracts that required surgery
      in the first years of life
    explanation: Early bilateral cataract requiring surgery.
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cataract (4/6), epilepsy (1/6), and microcephaly (5/6) were also
      observed in some of them.
    explanation: >-
      Cataract in four of six founder-allele patients, which supports the
      frequent rather than very frequent band.
- category: Neurodevelopmental
  name: Intellectual disability
  description: >-
    Usually mild in the first series and moderate to severe in the second;
    some patients have normal intelligence, and a hypomorphic genotype has
    been reported without intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cognitive deficits, usually mild, were recorded in eight probands while
      four individuals had normal intelligence.
    explanation: >-
      Eight of twelve individuals with cognitive deficits supports the
      frequent band.
  - reference: PMID:42467360
    reference_title: "INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identify the first disease-causing synonymous variant (via aberrant
      splicing) and a novel hypomorphic missense variant p.(Arg92Cys), the
      combination of which explains the attenuated phenotype lacking
      intellectual disability.
    explanation: Intellectual disability can be absent with a milder genotype.
- category: Growth
  name: Short stature
  description: >-
    Short stature, often below the third centile, is constant in the second
    and founder-allele series and can be the presenting problem.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild intellectual disability and short stature were invariably present in
      all.
    explanation: Short stature in all six founder-allele patients.
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, all individuals with likely pathogenic biallelic mutations in
      INPP5K present with myopathic findings and elevated CK, short stature,
      motor and cognitive developmental delay since early infancy, and
      moderate-severe ID.
    explanation: Short stature in all five patients of the second series.
  - reference: PMID:31630891
    reference_title: Genetic Disorders in Prenatal Onset Syndromic Short Stature Identified by Exome Sequencing.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      15 (34%) had pathogenic/likely pathogenic variants in genes already
      associated with growth disturbance: COL2A1 (n = 2), SRCAP (n = 2), AFF4,
      ACTG1, ANKRD11, BCL11B, BRCA1, CDKN1C, GINS1, INPP5K, KIF11, KMT2A, and
      POC1A (n = 1 each).
    explanation: >-
      A child ascertained for small-for-gestational-age syndromic short
      stature carried INPP5K variants, showing growth failure can be the
      leading feature.
- category: Neurologic
  name: Microcephaly
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cataract (4/6), epilepsy (1/6), and microcephaly (5/6) were also
      observed in some of them.
    explanation: Microcephaly in five of six founder-allele patients.
- category: Neurologic
  name: Seizure
  description: Febrile or focal seizures and epilepsy occur in a minority of patients.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epilepsy, brain atrophy, and cataracts were additional features not
      observed in all patients.
    explanation: Epilepsy as an inconstant feature.
- category: Neurologic
  name: Cerebellar atrophy
  description: >-
    Brain MRI is normal in most patients. Mild cerebellar atrophy has been
    documented in a few, unlike the defining cerebellar atrophy of
    Marinesco-Sjogren syndrome.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI performed at the age of 12 years showed mild cerebellar
      atrophy.
    explanation: Mild cerebellar atrophy in one founder-allele patient.
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although individuals with INPP5K mutations did not have cerebellar
      atrophy and ataxia, there was a clear phenotypic overlap with MSS
    explanation: No cerebellar atrophy in the first discovery series.
- category: Neurologic
  name: Gait ataxia
  description: >-
    An ataxic gait has been described in occasional patients, one of them with
    mild cerebellar atrophy. Ataxia is not a core feature, which separates the
    disorder from Marinesco-Sjogren syndrome.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the age of 4 years, short stature (below the third percentile),
      microcephaly, ataxic gait, and mild weakness of limb girdle muscles with a
      positive Gower's sign were observed at first neurological examination
    explanation: Ataxic gait in one founder-allele patient.
- category: Neurodevelopmental
  name: Delayed speech and language development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:28940338
    reference_title: INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our family LUCC15, mild to moderate intellectual disability along with
      speech impairment was observed in 2 affected individuals.
    explanation: Speech impairment accompanying intellectual disability.
- category: Musculoskeletal
  name: Hyperlordosis
  phenotype_term:
    preferred_term: Hyperlordosis
    term:
      id: HP:0003307
      label: Hyperlordosis
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our first neuromuscular examination was performed at the age of 22 years
      showing microcephaly and short stature (below the third percentile),
      severe hyperlordosis, pseudohypertrophy of calves, and hypotrophy of
      quadriceps.
    explanation: Severe hyperlordosis with calf pseudohypertrophy in an adult patient.
- category: Musculoskeletal
  name: Ankle flexion contracture
  phenotype_term:
    preferred_term: Ankle flexion contracture
    term:
      id: HP:0006466
      label: Ankle flexion contracture
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She presented diffuse muscle wasting and weakness and ankle contractures.
    explanation: Ankle contractures in an adult patient.
- category: Musculoskeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient has scoliosis, microcephaly, and short stature (below the
      third percentile).
    explanation: Scoliosis in an adult patient.
histopathology:
- name: Dystrophic myopathy with variable vacuolation
  description: >-
    Biopsies show nonspecific dystrophic changes: fiber size variation,
    fibrosis, fatty replacement, internal nuclei, rare necrotic and
    regenerating fibers, with vacuolated fibers in some. Electron microscopy
    can show dense membranous structures associated with myonuclei, as in
    Marinesco-Sjogren syndrome. Dystrophin, sarcoglycans and merosin are
    normal; alpha-dystroglycan is normal in some patients and reduced in
    others.
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological examination of three diagnostic muscle biopsies from
      individuals with INPP5K mutations showed vacuoles in several myofibers,
      and electron microscopy of one biopsy revealed dense membranous
      structures associated with some myonuclei.
    explanation: Vacuoles and perinuclear membranous structures shared with MSS.
imaging_findings:
- name: Selective thigh and leg muscle involvement on muscle MRI
  modality: MRI
  description: >-
    Fatty replacement of the vasti, adductor magnus, tibialis anterior, peronei
    and soleus, with relative sparing of rectus femoris, sartorius, gracilis
    and gastrocnemii. Severity rises with age, and young children may have a
    normal scan. Muscle ultrasound shows the same vasti-over-rectus-femoris
    pattern.
  diagnostic: true
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle MRI showed consistent involvement of vasti, anterior tibialis and
      peronei muscles, and the degree of muscle degeneration appears to be
      age-related being more severe in older patients
    explanation: Defines the pattern and its age dependence.
  - reference: PMID:42467360
    reference_title: "INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern
      of selective fatty infiltration, with severe involvement of gluteal and
      thigh muscles and striking sparing of the rectus femoris, sartorius, and
      gracilis.
    explanation: Same sparing pattern in an independent patient.
diagnosis:
- name: Molecular genetic testing of INPP5K
  description: >-
    Diagnosis rests on biallelic INPP5K variants. Exome or neuromuscular panel
    sequencing is the usual route; in patients from Puglia, targeted
    sequencing of exon 2 for the p.Val23Met founder allele is a reasonable
    first step. Synonymous variants can be pathogenic through splicing, so RNA
    analysis may be needed when only one variant is found.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33193651
    reference_title: "A Recurrent Pathogenic Variant of INPP5K Underlies Autosomal Recessive Congenital Muscular Dystrophy With Cataracts and Intellectual Disability: Evidence for a Founder Effect in Southern Italy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      especially if originating from the same area of southern Italy (Puglia),
      sequencing of exon 2 of INPP5K as the first screening step
    explanation: Recommends founder-exon screening in patients from Puglia.
  - reference: PMID:42467360
    reference_title: "INPP5K-related muscular dystrophy caused by a novel synonymous splicing variant in a Chinese patient: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case highlights the critical role of RNA analysis in diagnosing
      non-canonical variants
    explanation: Supports RNA analysis for non-canonical variants.
- name: Muscle imaging
  description: >-
    Muscle MRI or ultrasound showing vasti involvement with sparing of rectus
    femoris, sartorius and gracilis supports the diagnosis and can help
    interpret genetic results.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39133882
    reference_title: "Pearls & Oy-sters: Use of Muscle Ultrasound as a Clinical Tool in INPP5K-Related Muscular Dystrophy: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A characteristic pattern of muscle involvement has been identified on
      muscle MRI in a small case series, including involvement of the vasti,
      anterior tibialis, and peronei with relative sparing of the rectus
      femoris, sartorius, and gracilis muscles.
    explanation: States the diagnostic muscle imaging pattern.
differential_diagnoses:
- name: Marinesco-Sjogren syndrome
  description: >-
    SIL1-related disorder sharing early cataracts, myopathy, intellectual
    disability and vacuolar muscle pathology with perinuclear membranous
    structures. Cerebellar ataxia with cerebellar atrophy is defining in
    Marinesco-Sjogren syndrome but absent or mild in INPP5K disease. The INPP5K
    discovery cohort was assembled from patients referred for SIL1 testing who
    had no SIL1 variant. Curated in kb/disorders/Marinesco-Sjogren_Syndrome.yaml.
  disease_term:
    preferred_term: Marinesco-Sjogren syndrome
    term:
      id: MONDO:0009567
      label: Marinesco-Sjogren syndrome
  evidence:
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While no ataxia or cerebellar atrophy was noted, this presentation is
      reminiscent of MSS and could fall in the larger MSS spectrum.
    explanation: States the overlap and the distinguishing absence of ataxia.
- name: Dystroglycanopathy
  description: >-
    Alpha-dystroglycan glycosylation defects cause congenital muscular
    dystrophy with eye and brain involvement. Some INPP5K patients show reduced
    alpha-dystroglycan glycosylation, but the dystroglycanopathy brain
    malformations are absent, and the hypoglycosylation appears to be
    secondary. Curated in kb/disorders/Dystroglycanopathy.yaml.
  evidence:
  - reference: PMID:28190459
    reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, a reduction in dystroglycan glycosylation in S2 and S3
      suggest an overlap with less severe forms of dystroglycanopathies, where
      CMD is present with cataracts and ID.
    explanation: States the partial overlap with the dystroglycanopathies.
- name: 3-Phosphoglycerate dehydrogenase deficiency
  description: >-
    Serine biosynthesis defect whose neurological picture overlaps INPP5K
    disease and Marinesco-Sjogren syndrome; altered PHGDH is the proposed
    shared molecular feature. Curated in
    kb/disorders/3-Phosphoglycerate_Dehydrogenase_Deficiency.yaml.
  evidence:
  - reference: PMID:33792664
    reference_title: INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      d-3-PHGDH modulates the production of l-serine and mutations in this
      enzyme were previously associated with a neurological phenotype, which
      clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease.
    explanation: States the clinical overlap with PHGDH deficiency.
treatments:
- name: Cataract Surgery
  description: Bilateral cataracts usually require extraction in the first years of life.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cataract extraction
    term:
      id: NCIT:C157809
      label: Cataract Surgery
  target_phenotypes:
  - preferred_term: Developmental cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most salient features were bilateral cataracts that required surgery
      in the first years of life
    explanation: Cataract surgery in early childhood is standard care.
- name: L-Serine Supplementation (preclinical)
  description: >-
    Preclinical candidate only. L-serine improved the neuronal phenotype of
    inpp5k zebrafish models, on the rationale that INPP5K deficiency alters
    PHGDH and serine biosynthesis. No patient has been reported treated in the
    cited literature, and there is no human efficacy or safety evidence for
    this indication.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: amino acid supplementation
    term:
      id: NCIT:C15425
      label: Nutritional Supplementation
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_mechanisms:
  - target: PHGDH Dysregulation
    description: Bypasses the proposed serine biosynthesis deficit.
  evidence:
  - reference: PMID:33792664
    reference_title: INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b
      zebrafish models, which showed an improvement in their neuronal
      phenotype.
    explanation: Zebrafish-only evidence of benefit.
animal_models:
- name: Muscle-specific Inpp5k knockout mouse (Inpp5k fl/fl MCK-Cre)
  species: Mouse
  genotype: Inpp5k fl/fl; MCK-Cre (skeletal muscle-specific deletion)
  publication: PMID:33119550
  description: >-
    Constitutive knockout is embryonic lethal, so Inpp5k was deleted in
    skeletal muscle. Mice develop early-onset progressive dystrophy with raised
    CK, vacuolated fibers, fibrosis and reduced force, with lysosome depletion
    and autophagy inhibition caused by failed autophagic lysosome reformation.
  modeled_mechanisms:
  - target: Defective Autophagic Lysosome Reformation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Knockout muscle and myoblasts show the ALR block directly.
    limitations: >-
      Complete deletion, whereas patient alleles are hypomorphic; an ALR
      defect has not been demonstrated in patient muscle.
    evidence:
    - reference: PMID:33119550
      reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k-/- muscle
        suppressed autophagy and lysosome repopulation via ALR inhibition.
      explanation: The model shows the ALR defect in muscle.
  - target: Skeletal Myofiber Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Progressive dystrophy with raised CK and vacuolated fibers.
    limitations: >-
      Muscle-only deletion cannot model the lens, brain and growth features,
      and disease onset and course in mice need not match the human timeline.
    evidence:
    - reference: PMID:33119550
      reference_title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Inpp5kfl/fl MCK-Cre mice developed muscle disease resembling that caused
        by INPP5K mutations
      explanation: The authors judge the muscle disease to resemble the human one.
- name: inpp5ka morphant zebrafish
  species: Zebrafish
  genotype: inpp5ka (with or without inpp5kb) morpholino knockdown
  publication: PMID:28190459
  description: >-
    Morpholino knockdown of inpp5ka, the closer orthologue of human INPP5K,
    gives microphthalmia with a disorganized lens, microcephaly, short and
    curved body, reduced motility and disorganized myofibers with sarcomere
    defects, rescued by human INPP5K mRNA. inpp5kb has lost catalytic activity
    toward PI(4,5)P2, so inpp5ka is the relevant target.
  modeled_mechanisms:
  - target: Lens Fiber Organization Defect
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Lens cortex disorganization with retained central nuclei.
    limitations: >-
      Transient embryonic knockdown; lens disorganization in larvae is
      reminiscent of, not identical to, human postnatal cataract.
    evidence:
    - reference: PMID:28190459
      reference_title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        inpp5k loss-of-function modeling in the zebrafish led to a
        constellation of phenotypes that closely resembles the human
        presentation, including reduced growth, microcephaly, lens
        disorganization, reduced motility, and myopathy.
      explanation: Morphants show lens disorganization and other human features.
  - target: Skeletal Myofiber Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: Disorganized myofibers in embryos.
    limitations: >-
      Embryonic myofiber disorganization reflects development as much as
      degeneration, and morpholino effects are transient.
    evidence:
    - reference: PMID:28190456
      reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Downregulation of INPP5K orthologs in zebrafish embryos disrupted
        muscle fiber morphology and resulted in abnormal eye development.
      explanation: Independent morphant study with muscle and eye defects.
  evidence:
  - reference: PMID:37184573
    reference_title: Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Since most human mutations are missense changes disrupting phosphatase
      activity, we propose that loss of inpp5ka alone can be targeted to
      recapitulate the human presentation.
    explanation: Identifies inpp5ka as the relevant paralogue to model.
discussions:
- discussion_id: inpp5k_alr_defect_in_patient_muscle
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Muscle-specific Inpp5k knockout mice show failed autophagic lysosome
    reformation with autophagy inhibition, but autophagic flux in patient
    fibroblasts was normal. Does the ALR defect operate in patient muscle
    carrying hypomorphic alleles?
  attaches_to:
  - pathophysiology#Defective Autophagic Lysosome Reformation
  - pathophysiology#Lysosome Depletion and Autophagic Flux Inhibition in Skeletal Muscle
  rationale: >-
    The mouse deletes the gene completely in muscle, while patients retain
    partial activity, and the only human flux experiment used skin
    fibroblasts, a cell type the mouse work suggests is less dependent on ALR.
    Patient biopsies show rimmed vacuoles and p62 labeling, which fit the model
    but do not measure flux or lysosome number. Measuring lysosome abundance,
    LC3-II flux and reformation tubules in patient myoblasts or muscle would
    test whether the mouse mechanism transfers.
  evidence:
  - reference: PMID:28190456
    reference_title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, LC3B immunoblotting and immunofluorescence staining as well as
      measurement of LC3B turnover and p62 levels in fibroblasts treated with
      the autophagy inducer rapamycin and the lysosomal inhibitor bafilomycin A1
      did not reveal specific effects of different INPP5K genotypes.
    explanation: The negative human cell result that defines the mismatch.
- discussion_id: inpp5k_lens_and_brain_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    What links INPP5K deficiency to cataract, intellectual disability and short
    stature?
  attaches_to:
  - pathophysiology#Lens Fiber Organization Defect
  - pathophysiology#Impaired Neuronal Differentiation
  - phenotypes#Short stature
  rationale: >-
    The muscle mechanism has a mouse model, but the lens and brain evidence is
    limited to zebrafish morphants, an N2A knockdown and a PHGDH proteomic
    finding with zebrafish L-serine rescue. Whether autophagic lysosome
    reformation, ER organization, PHGDH and serine supply, or another INPP5K
    function drives the non-muscle features is untested, and nothing in the
    cited literature addresses short stature.
references:
- reference: PMID:28190456
  title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
- reference: PMID:28190459
  title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
- reference: PMID:33119550
  title: Defective lysosome reformation during autophagy causes skeletal muscle disease.
notes: >-
  Lump/split. The cataract-predominant Pakistani family (PMID:28940338),
  reported as INPP5K congenital cataract, carries p.Ile50Thr, the same
  homozygous allele as most families of the first discovery series, and its
  affected members also have intellectual disability and EMG myopathy. It is
  treated as variable expressivity of this disease, not a separate allelic
  disorder. Cases presenting after walking was achieved, more like a
  limb-girdle dystrophy, are likewise included. INPP5K disease is kept
  separate from Marinesco-Sjogren syndrome (SIL1): different gene, cerebellar
  ataxia absent or mild, and no unfolded protein response in patient cells,
  with the overlap recorded as a differential diagnosis. No grouping currently
  fits: the glycosylation-disorder groupings cover primary glycosylation
  defects, whereas alpha-dystroglycan hypoglycosylation here is inconstant and
  appears secondary.

  Rejected mechanism. INPP5K also hydrolyzes PI(3,4,5)P3 and restrains AKT
  signaling in muscle, and knockout muscle shows AKT and mTOR hyperactivation,
  but an AKT inhibitor rescued neither the autophagy defect nor the dystrophy
  (PMID:33119550, full text), and patient fibroblasts showed no change in AKT
  phosphorylation after IGF-II stimulation (PMID:28190456, full text). AKT
  signaling is therefore not modelled as a disease node.

  Identifier caveats for the deep-research report in research/
  (INPP5K-Related_Congenital_Muscular_Dystrophy-deep-research-openscientist.md).
  It gives OMIM 616827 as the phenotype number; MONDO maps OMIM 616827 to
  autosomal recessive limb-girdle muscular dystrophy type 2W (MONDO:0014788),
  and the correct number for this disease is OMIM 617404. It gives HGNC:21940
  for INPP5K, which returns nothing from the HGNC REST service; the gene is
  hgnc:33882. It also states that no mouse disease model has been published,
  which the muscle-specific knockout (PMID:33119550) contradicts. Its
  prevalence and carrier-frequency figures are its own gnomAD calculations,
  not published estimates, and are not used here.

  No GeneReviews chapter names this disorder.

📚

References & Deep Research

References

3

PMID:28190456

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

No top-level findings curated for this source.

PMID:28190459

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.

No top-level findings curated for this source.

PMID:33119550

Defective lysosome reformation during autophagy causes skeletal muscle disease.

No top-level findings curated for this source.

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 (2)

Record notes

Lump/split. The cataract-predominant Pakistani family (PMID:28940338), reported as INPP5K congenital cataract, carries p.Ile50Thr, the same homozygous allele as most families of the first discovery series, and its affected members also have intellectual disability and EMG myopathy. It is treated as variable expressivity of this disease, not a separate allelic disorder. Cases presenting after walking was achieved, more like a limb-girdle dystrophy, are likewise included. INPP5K disease is kept separate from Marinesco-Sjogren syndrome (SIL1): different gene, cerebellar ataxia absent or mild, and no unfolded protein response in patient cells, with the overlap recorded as a differential diagnosis. No grouping currently fits: the glycosylation-disorder groupings cover primary glycosylation defects, whereas alpha-dystroglycan hypoglycosylation here is inconstant and appears secondary. Rejected mechanism. INPP5K also hydrolyzes PI(3,4,5)P3 and restrains AKT signaling in muscle, and knockout muscle shows AKT and mTOR hyperactivation, but an AKT inhibitor rescued neither the autophagy defect nor the dystrophy (PMID:33119550, full text), and patient fibroblasts showed no change in AKT phosphorylation after IGF-II stimulation (PMID:28190456, full text). AKT signaling is therefore not modelled as a disease node. Identifier caveats for the deep-research report in research/ (INPP5K-Related_Congenital_Muscular_Dystrophy-deep-research-openscientist.md). It gives OMIM 616827 as the phenotype number; MONDO maps OMIM 616827 to autosomal recessive limb-girdle muscular dystrophy type 2W (MONDO:0014788), and the correct number for this disease is OMIM 617404. It gives HGNC:21940 for INPP5K, which returns nothing from the HGNC REST service; the gene is hgnc:33882. It also states that no mouse disease model has been published, which the muscle-specific knockout (PMID:33119550) contradicts. Its prevalence and carrier-frequency figures are its own gnomAD calculations, not published estimates, and are not used here. No GeneReviews chapter names this disorder.

Create: INPP5K-Related Congenital Muscular Dystrophy · 2026-10-14T13:45:03Z · View source

New entry for MONDO:0024607 (INPP5K, autosomal recessive), replacing stub Congenital_Muscular_Dystrophy_With_Cataracts_And_Intellectual_Disability. Lump/split: one DISEASE entry; the cataract-predominant Pakistani family (PMID:28940338) carries the same p.Ile50Thr allele as the first discovery families and is treated as variable expressivity, not a separate allelic disorder; kept separate from Marinesco-Sjogren syndrome (SIL1) and recorded as a differential, with Dystroglycanopathy and 3-phosphoglycerate dehydrogenase deficiency. No grouping fits. Pathograph: INPP5K 5-phosphatase deficiency -> impaired PI(4,5)P2 to PI(4)P conversion on autolysosomes -> defective autophagic lysosome reformation -> lysosome depletion and autophagic flux inhibition (conforms_to disabled_macroautophagy#Failure of Cytoplasmic Quality Control) -> skeletal myofiber degeneration -> muscle phenotypes, mainly from the muscle-specific knockout mouse (PMID:33119550, PMID:33879025), with the negative human fibroblast flux result (PMID:28190456) recorded as REFUTE and as a HUMAN_MODEL_MISMATCH discussion. Lens, neuronal differentiation, PHGDH, ER tubule/sheet and secondary alpha-dystroglycan hypoglycosylation nodes are branch nodes with zebrafish, cell-line or proteomic support. AKT hyperactivation is recorded in notes as a rejected mechanism (AKT inhibition did not rescue). Two animal models (Inpp5k fl/fl MCK-Cre mouse; inpp5ka morphant zebrafish) with modeled_mechanisms. Treatments: cataract surgery; L-serine marked preclinical (zebrafish only). Prevalence from ORPHA:662184 (below 1 in 1,000,000), fetched via just fetch-reference, which downloaded the drifted Orphadata release without changing the manifest pin. Deep research: one OpenScientist report (research/INPP5K-Related_Congenital_Muscular_Dystrophy-deep-research-openscientist.md). Reference validation 15/15 resolved, 0 unresolved, 0 off topic; term validation needs_review (HP:0001251 label, obsolete GO:0006486). just preflight-dr returned WARN: the report cites OMIM 616827, which MONDO maps to LGMD R 2W (MONDO:0014788); INPP5K is mentioned 63 times and no rival gene is discussed, so the WARN is an identifier error, not a wrong-disease report. The report also gives HGNC:21940 for INPP5K (not resolvable at HGNC REST; correct id hgnc:33882) and states no mouse model exists (contradicted by PMID:33119550); no identifiers were taken from the report. Report citations used: 28190456, 28190459, 33193651, 28940338, 33792664, 33060052, 38559586, 39133882, 42467360. Report citations not used: 19250614, 19272022, 20336382, 22403078, 22682687, 26170120 (insulin/AKT signalling, porcine SKIP expression, generic 5-phosphatase reviews and a tumour-suppressor locus study; not about the disease mechanism). Additional references found by PubMed search: 33119550, 33879025, 30087126, 37184573, 31630891. No GeneReviews chapter (just check-genereviews --online: NO_CHAPTER); no ClinGen validity row for INPP5K. Validation: just validate, validate-terms, count-verified-snippets (84/84), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-block-scalar-comments, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-reference-titles, check-snippet-grading, check-retired-support-prose, check-folded-hyphens and validate-disorders all passed.

OpenScientist ▸

INPP5K-Related Congenital Muscular Dystrophy: A Comprehensive Disease Characteristics Report

openscientist-autonomous 15 citations 2026-10-14T13:21:03.225427

INPP5K-Related Congenital Muscular Dystrophy: A Comprehensive Disease Characteristics Report

Disease: INPP5K-Related Congenital Muscular Dystrophy MONDO ID: MONDO:0024607 · OMIM phenotype: #616827 (MDCCAID/MDCCAIS) · Gene: INPP5K (607875; HGNC:21940; NCBI Gene 51763; UniProt Q9BT40) Category: Mendelian, autosomal recessive

Summary

INPP5K-Related Congenital Muscular Dystrophy (also termed Muscular Dystrophy, Congenital, with Cataracts and Intellectual Disability, OMIM #616827) is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function or hypomorphic variants in INPP5K, the gene encoding inositol polyphosphate-5-phosphatase K — also known as SKIP (Skeletal muscle and Kidney enriched Inositol Phosphatase). The disorder was first defined in 2017 by two independent landmark papers in the American Journal of Human Genetics (PMID: 28190459; PMID: 28190456). The clinical core is a recognizable tetrad: congenital/early-onset muscular dystrophy with hypotonia and weakness, early-onset (often congenital) cataracts, short stature, and mild intellectual disability, typically with a normal cranial MRI — a feature that distinguishes it from classic dystroglycanopathies. The phenotype straddles two overlapping disease spectra: dystroglycanopathy (through α-dystroglycan hypoglycosylation) and Marinesco-Sjögren syndrome (sharing infantile cataracts, myopathy, and in a subset ataxia).

Mechanistically, INPP5K/SKIP is a phosphoinositide 5-phosphatase that hydrolyzes PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃, is enriched at the endoplasmic reticulum (and present at the plasma membrane, cytosol and nucleus), and normally dampens insulin-driven PI3K-AKT-GSK3β signaling while promoting myoblast differentiation. Pathogenic variants cause disease by two non-exclusive routes: loss of catalytic phosphatase activity and mislocalization via disruption of the C-terminal SKICH domain. Downstream consequences demonstrated across patient cells and animal models include α-dystroglycan hypoglycosylation, BiP/HSPA5-associated ER stress, and a striking convergence with Marinesco-Sjögren syndrome on dysregulation of d-3-phosphoglycerate dehydrogenase (PHGDH) and reduced L-serine biosynthesis. The latter is therapeutically important: L-serine supplementation rescued neuronal phenotypes in inpp5k, sil1, and phgdh zebrafish models, providing a rational — though not yet clinically tested — experimental therapy.

The disease is ultra-rare, with only ~30–40 patients reported worldwide since 2017 and no formal prevalence estimate. Computational population genetics generated in this investigation reinforce the biology: gnomAD constraint metrics (pLI ≈ 0, LOEUF ≈ 0.87) confirm INPP5K is loss-of-function tolerant in the heterozygous state, consistent with a recessive mechanism; GTEx shows INPP5K is ubiquitously expressed (≈10–62 TPM across 54 tissues), indicating the tissue specificity of disease reflects differential cellular vulnerability rather than restricted expression; and a gnomAD-derived estimate places the predicted biallelic pLoF birth prevalence at a lower bound of ~1 per million (carrier frequency ~1 in 500). There is no approved disease-modifying therapy; management is supportive (cataract surgery, physiotherapy, developmental and visual support).

Key Findings

Finding 1 — Biallelic INPP5K mutations are causal (autosomal recessive)

INPP5K-CMD is an autosomal recessive congenital muscular dystrophy caused by biallelic INPP5K mutations, established definitively by two independent 2017 AJHG papers. Osborn et al. (PMID: 28190459) reported 5 individuals from 4 families with homozygous missense and compound heterozygous mutations identified by whole-exome sequencing. Wiessner et al. (PMID: 28190456) independently identified bi-allelic mutations in additional families. INPP5K encodes inositol polyphosphate-5-phosphatase K (SKIP), a phosphoinositide 5-phosphatase that hydrolyzes PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃.

"Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle." — Osborn et al. PMID: 28190459

"we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K." — Wiessner et al. PMID: 28190456

Key identifiers: OMIM phenotype #616827 (MDCCAID/MDCCAIS); gene INPP5K OMIM 607875; MONDO:0024607; Ensembl ENSG00000132376; locus 17p13.3 (GRCh38 chr17:1,494,577–1,516,742). HGNC: INPP5K (HGNC:21940). UniProt: Q9BT40 (INP5K_HUMAN). Evidence source: [human clinical]* (WES cohorts) plus functional validation.

Finding 2 — Clinical tetrad with marked variable expressivity

The core clinical presentation is a tetrad of muscular dystrophy, early-onset cataracts, short stature, and mild intellectual disability, typically with normal cranial MRI — the latter distinguishing it from classic dystroglycanopathies. Muscle involvement presents as congenital/early hypotonia and weakness. The phenotype overlaps both dystroglycanopathy and Marinesco-Sjögren syndrome.

"In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K" — Wiessner et al. PMID: 28190456

Expressivity is markedly variable with reduced penetrance of individual features. A consanguineous Pakistani family (LUCC15) presented with congenital cataract and mild–moderate intellectual disability but no overt muscular dystrophy or cerebellar atrophy on MRI, with only an irritable myopathy on EMG (PMID: 28940338):

"Comparison of clinical phenotype of all the known affected individuals, including LUCC15 family, homozygous for INPP5K alleles revealed reduced penetrance of muscular dystrophy and intellectual disability." — PMID: 28940338

At the milder end, a Chinese patient (PMID: 42467360) had adolescent-onset limb-girdle weakness and bilateral cataracts from age 5, lacking intellectual disability, and showed a characteristic selective muscle MRI pattern:

"Muscle magnetic resonance imaging (MRI) revealed a characteristic pattern of selective fatty infiltration, with severe involvement of gluteal and thigh muscles and striking sparing of the rectus femoris, sartorius, and gracilis." — PMID: 42467360

Suggested HPO terms:

Phenotype	HPO term	Onset	Frequency (qualitative)
Congenital muscular dystrophy / weakness	HP:0003560 (Muscular dystrophy), HP:0003701 (Proximal muscle weakness)	Congenital–childhood	Frequent (variable)
Neonatal hypotonia	HP:0001319	Neonatal	Frequent
Cataract (early-onset/congenital)	HP:0000518 (Cataract), HP:0000519 (Congenital cataract)	Congenital–childhood	Very frequent
Short stature	HP:0004322	Childhood	Frequent
Intellectual disability, mild	HP:0001256	Childhood	Variable (reduced penetrance)
Elevated serum creatine kinase	HP:0003236	—	Frequent
Ataxia (subset, MSS-overlap)	HP:0001251	Variable	Subset

Finding 3 — Mechanism: phosphoinositide dysregulation → dystroglycan hypoglycosylation, ER stress, and PHGDH/L-serine deficiency

Loss of INPP5K function dysregulates phosphoinositide signaling with branching downstream consequences. INPP5K hydrolyzes PtdIns(4,5)P₂ and PtdIns(3,4,5)P₃, is enriched at the ER (also plasma membrane, cytosol, nucleus), and its C-terminal SKICH domain mediates protein interactions and localization; it regulates insulin signaling, the ER stress response, myoblast differentiation, cytoskeleton/actin organization, cell adhesion and migration (PMID: 33060052).

"Its protein structure is comprised of a N-terminal catalytic domain which hydrolyses both PtdIns(4,5)P2 and PtdIns(3,4,5)P3, followed by a SKICH domain at the C-terminus which is responsible for protein-protein interactions and subcellular localization of INPP5K." — PMID: 33060052

The mechanism branches into: (1) dystroglycanopathy — muscular dystrophy is characterized by hypoglycosylation of dystroglycan (PMID: 38559586; Osborn et al. reported reduced dystroglycan glycosylation); (2) ER stress — INPP5K interacts with the ER chaperone HSPA5/BiP, implicating protein processing/ER proteostasis (PMID: 28190459); and (3) metabolic convergence — unbiased proteomics showed INPP5K and SIL1 (Marinesco-Sjögren) pathologies converge on dysregulation of d-3-PHGDH, reducing L-serine production, with L-serine administration rescuing neuronal phenotypes in zebrafish models (PMID: 33792664).

"we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature." — Hathazi et al. PMID: 33792664

"muscular dystrophy is characterized by the hypoglycosylation of dystroglycan" — PMID: 38559586

INPP5K knockdown in N2A neuroblastoma cells impaired neuronal-like differentiation and interfered with protein glycosylation (PMID: 38559586). Evidence source: [human clinical / in vitro / model organism].

Finding 4 — INPP5K/SKIP dampens insulin PI3K-AKT signaling and promotes myogenesis; models recapitulate muscle/eye/brain defects

SKIP is a 5-phosphatase that hydrolyzes PtdIns(3,4,5)P₃ → PtdIns(3,4)P₂ and PtdIns(4,5)P₂ → PtdIns(4)P, negatively regulating insulin-induced PI3K-Akt-GSK3β-glycogen synthase signaling in skeletal muscle (PMID: 22403078; PMID: 19272022). In C2C12 myoblasts, SKIP knockdown increased insulin-induced Akt/GSK-3β phosphorylation and glycogen synthesis, while overexpression decreased it (PMID: 19250614). SKIP is transcriptionally upregulated during muscle differentiation and regulated by MyoD (PMID: 20336382).

"Insulin-induced phosphorylation of Akt (protein kinase B) and GSK-3beta (Glycogen synthase kinase), subsequent dephosphorylation of glycogen synthase and glycogen synthesis were increased by inhibiting the expression of SKIP, whereas the insulin-induced glycogen synthesis was decreased by overexpression of WT-SKIP." — PMID: 19250614

"Porcine SKIP was expressed abundantly in skeletal muscle tissue and was transcriptionally upregulated during skeletal muscle differentiation. Analysis of the porcine SKIP promoter sequence demonstrated that MyoD was involved in regulating SKIP mRNA expression in myotubes" — PMID: 20336382

Model organisms recapitulate the human phenotype. Morpholino inpp5k knockdown in zebrafish produces shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers:

"morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers" — Osborn et al. PMID: 28190459

INPP5K is one of the 10 mammalian inositol polyphosphate 5-phosphatases, a family that includes OCRL (Lowe syndrome), INPP5E (Joubert syndrome), and SHIP2 (insulin resistance). Evidence source: [in vitro / model organism / review].

Finding 5 — Ultra-rare recessive inheritance; consanguinity, recurrent alleles, broadening variant spectrum

Inheritance is autosomal recessive (biallelic): homozygous in consanguineous families or compound heterozygous (PMID: 28190459; PMID: 28190456). Only ~30–40 patients have been reported worldwide since 2017; no formal prevalence/incidence estimate exists. The variant spectrum spans missense, frameshift, nonsense, deletions, and splice-altering variants. A Chinese patient carried a synonymous c.261G>A p.(Lys87=) that causes exon 3 skipping → frameshift p.(Leu52SerfsTer49), combined with missense c.274C>T p.(Arg92Cys) (PMID: 42467360). A recurrent pathogenic INPP5K variant was described in a European cohort (PMID: 33193651). Alleles affecting the catalytic domain impair PtdIns(4,5)P₂ phosphatase activity, while SKICH domain alleles alter localization (PMID: 28190456).

"Functional studies confirmed the synonymous variant causes aberrant splicing (exon 3 skipping), leading to a frameshift and premature termination p.(Leu52SerfsTer49). According to American College of Medical Genetics and Genomics guidelines, the c.274C>T and c.261G>A variants were classified as likely pathogenic and pathogenic, respectively." — PMID: 42467360

A consanguineous Pakistani family carried homozygous c.149T>C p.(Ile50Thr) presenting predominantly as congenital cataract with reduced penetrance of muscle/cognitive features (PMID: 28940338), supporting a role for modifiers:

"These phenotypic variabilities may be due to epigenetic factors and/or genetic modifiers." — PMID: 28940338

Finding 6 — Clinical overlap with Marinesco-Sjögren syndrome

Hathazi et al. (PMID: 33792664) describe that Marinesco-Sjögren syndrome (biallelic SIL1 mutations) is characterized by cataracts in infancy, myopathy and ataxia — features also associated with the INPP5K disorder — and that both converge molecularly on d-3-PHGDH/L-serine dysregulation. This defines a Marinesco-Sjögren-overlap end of the INPP5K spectrum, in addition to the dystroglycanopathy overlap. However, overt cerebellar atrophy is typically absent on MRI in core INPP5K-CMD patients (PMID: 28190456; PMID: 28940338), so ataxia/cerebellar involvement occurs only in a subset.

"Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K." — PMID: 33792664

Finding 7 — gnomAD constraint confirms LoF tolerance (recessive mechanism)

Computational constraint analysis (this investigation, gnomAD v2.1.1) for INPP5K (ENSG00000132376; 17p13.3): pLI = 4.5×10⁻⁸ (≈0, NOT loss-of-function intolerant); observed/expected pLoF (oe_lof) = 0.654 (90% CI 0.50–0.87), LOEUF ≈ 0.87; observed pLoF = 35 vs expected 53.5; missense Z = 0.64 (oe_mis = 0.94, not missense-constrained); synonymous Z = −0.79. These metrics indicate heterozygous carriers tolerate loss of function, exactly as expected for a recessive, biallelic disease mechanism. Evidence source: [computational].

Finding 8 — GTEx shows ubiquitous expression → vulnerability, not restriction

GTEx v8 median expression of INPP5K (ENSG00000132376.19) across 54 tissues (this investigation): expressed everywhere, range 9.7–62.3 TPM, median ~30.6 TPM. Highest: thyroid 62.3, testis 54.3, tibial nerve 52.9, subcutaneous adipose 51.7, lung 51.4. Disease-relevant tissues: skeletal muscle 26.6; cerebellum 33.2 / cerebellar hemisphere 31.3 (highest brain regions); cortex 21.3; heart 15.6–16.2; kidney cortex 14.6 / medulla 17.3. Lowest: liver 9.7, pancreas 10.6. Because expression is ubiquitous, the tissue selectivity of INPP5K-CMD (muscle, lens, brain) reflects differential cellular vulnerability rather than restricted expression. Evidence source: [computational].

Finding 9 — gnomAD-derived prevalence estimate: ~1 per million (lower bound)

From gnomAD r2.1.1 variant-level data (926 variants; 27 predicted LoF alleles: frameshift, stop-gained, splice donor/acceptor, start/stop-lost), the summed pLoF allele frequency q ≈ 1.03×10⁻³. Under Hardy-Weinberg: pLoF carrier frequency ≈ 2q ≈ 2.06×10⁻³ (~1 in 486); expected pLoF/pLoF homozygous birth prevalence ≈ q² ≈ 1.06×10⁻⁶ (~1 in ~946,000). This is a lower bound (excludes pathogenic missense/hypomorphic alleles, which account for most reported cases), consistent with the ultra-rare clinical observation of only ~30–40 patients worldwide. Evidence source: [computational].

Mechanistic Model / Interpretation

Causal chain (initiating lesion → clinical manifestation)

Biallelic pathogenic variants in INPP5K (catalytic-domain alleles or SKICH-domain alleles) → loss of INPP5K 5-phosphatase activity toward PtdIns(4,5)P₂/PtdIns(3,4,5)P₃ and/or mislocalization of the protein away from the ER membrane. (Demonstrated — PMID 28190456.)
Loss of phosphoinositide turnover → dysregulated phosphoinositide pools at the ER and plasma membrane, disturbing membrane identity, vesicular trafficking, cytoskeletal/actin organization, cell adhesion and migration. (Demonstrated/inferred — PMID 33060052.)
Branch A — Insulin/PI3K-AKT signaling: loss of SKIP removes a brake on insulin-induced PI3K-Akt-GSK3β-glycogen synthase signaling, perturbing myoblast growth/differentiation homeostasis. (Demonstrated in myoblasts — PMID 19250614, 22403078.)
Branch B — ER proteostasis: INPP5K interacts with the ER chaperone HSPA5/BiP; its loss implicates impaired ER protein processing / ER stress response. (Inferred from interaction + MSS convergence — PMID 28190459, 33060052.)
Branch C — Glycosylation: ER/trafficking dysfunction → hypoglycosylation of α-dystroglycan → weakened dystroglycan–extracellular-matrix link in muscle → sarcolemmal fragility and dystrophic muscle. (Demonstrated — PMID 38559586, 28190459.) This places INPP5K-CMD within the dystroglycanopathy spectrum.
Branch D — Serine metabolism: INPP5K loss → dysregulation of d-3-PHGDH → reduced L-serine biosynthesis → impaired neuronal (and likely lens/muscle) development. Shared with SIL1/Marinesco-Sjögren syndrome. (Demonstrated; rescued by L-serine in zebrafish — PMID 33792664.)
Convergence of branches A–D during development → impaired differentiation and maintenance of myoblasts, lens fiber cells, and neurons → clinical tetrad of muscular dystrophy, early-onset cataracts, short stature, and mild intellectual disability, with Marinesco-Sjögren overlap (ataxia in a subset). (Demonstrated phenotypically — PMID 28190456, 28190459, 28940338.)

  Biallelic INPP5K variants (catalytic / SKICH)
 │
   loss of PtdIns(4,5)P2 / PtdIns(3,4,5)P3 5-phosphatase activity
     + mislocalization from ER
 │
   dysregulated phosphoinositide pools (ER / PM)
┌────────────┬────────────┬─────────────┐
  (A) ↑insulin/   (B) BiP/HSPA5  (C) α-DG       (D) PHGDH ↓
   PI3K-AKT-GSK3β   ER stress     hypoglyco-      → L-serine ↓
   dysregulation                  sylation
└────────────┴─────┬──────┴─────────────┘
  impaired myoblast / lens / neuron differentiation
 │
   Muscular dystrophy + cataracts + short stature + mild ID
   (normal brain MRI; MSS/dystroglycanopathy overlap)

Upstream vs downstream

Upstream (initiating): INPP5K enzymatic/localization loss; phosphoinositide dysregulation.
Midstream (branching effectors): PI3K-AKT dysregulation, ER stress/BiP, glycosylation machinery, PHGDH/serine pathway.
Downstream (clinical): dystrophic muscle, cataractous lens, impaired neurodevelopment, growth restriction.

Cell types and biological processes (ontology suggestions)

Category	Suggested terms
Cell types (CL)	skeletal muscle myoblast (CL:0000515), skeletal muscle fiber (CL:0008002), lens fiber cell (CL:0011004), neuron (CL:0000540)
Biological processes (GO)	phosphatidylinositol dephosphorylation (GO:0046856), skeletal muscle cell differentiation (GO:0035914), protein glycosylation (GO:0006486), response to endoplasmic reticulum stress (GO:0034976), L-serine biosynthetic process (GO:0006564), insulin receptor signaling pathway (GO:0008286)
Cellular components (GO CC)	endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cytosol (GO:0005829), nucleus (GO:0005634)
Anatomy (UBERON)	skeletal muscle tissue (UBERON:0001134), lens of camera-type eye (UBERON:0000965), cerebellum (UBERON:0002037), brain (UBERON:0000955)
Chemical entities (CHEBI)	PtdIns(4,5)P₂ (CHEBI:83416), PtdIns(3,4,5)P₃ (CHEBI:16618), L-serine (CHEBI:17115)

Section-by-Section Content

1. Disease Information

A rare autosomal recessive congenital muscular dystrophy defined by muscle, lens, growth and cognitive involvement. Identifiers: MONDO:0024607; OMIM #616827 (phenotype), 607875 (gene); ICD-10 G71.0 (muscular dystrophy, nearest applicable); MeSH — no dedicated descriptor (covered under Muscular Dystrophies). Synonyms: Muscular dystrophy, congenital, with cataracts and intellectual disability (MDCCAID); INPP5K-related muscular dystrophy; SKIP-related congenital muscular dystrophy; congenital muscular dystrophy with cataracts and mild cognitive impairment. Information is derived from aggregated disease-level resources and small published case series* (individual-patient reports), not large EHR datasets.

2. Etiology

Primary cause: monogenic — biallelic (homozygous or compound heterozygous) pathogenic variants in INPP5K. Genetic risk factors: the causal variants themselves; consanguinity substantially increases risk of homozygosity. Modifiers: epigenetic factors and/or genetic modifiers proposed to explain reduced penetrance/variable expressivity (PMID: 28940338). Environmental/protective/gene-environment factors: none established — this is a Mendelian disorder with no known environmental, infectious, lifestyle, or protective contributions. Not applicable: environmental toxins, infectious agents, lifestyle factors.

3. Phenotypes

See Finding 2 table. Core: muscular dystrophy/weakness (HP:0003560), neonatal hypotonia (HP:0001319), cataract (HP:0000518/HP:0000519), short stature (HP:0004322), mild intellectual disability (HP:0001256), elevated CK (HP:0003236). Onset is congenital to childhood (occasionally adolescent for weakness in milder cases). Severity ranges mild→moderate; course is slowly progressive to relatively stable. Quality-of-life impact: motor disability affecting ambulation; visual impairment from cataracts (surgically correctable); learning support needs. No disease-specific QoL instrument has been published.

4. Genetic/Molecular Information

Causal gene: INPP5K (SKIP), 17p13.3, OMIM 607875, HGNC:21940, UniProt Q9BT40. Variant classes: missense, nonsense, frameshift, splice-site, deletions, and splice-altering synonymous variants (e.g., c.261G>A causing exon 3 skipping). Functional consequence: loss of function / hypomorphic — either loss of catalytic phosphatase activity (catalytic-domain alleles) or altered subcellular localization (SKICH-domain alleles) (PMID: 28190456). Allele frequency: individual pathogenic alleles are ultra-rare/absent in gnomAD; summed pLoF q ≈ 1×10⁻³. Origin: germline. Classification examples: c.274C>T p.(Arg92Cys) likely pathogenic; c.261G>A p.(Lys87=) pathogenic (ACMG) (PMID: 42467360). Chromosomal abnormalities / epigenetics: none established as causal (note: Inpp5k* appears in a rat 17p tumor-suppressor deletion region — not relevant to CMD — PMID: 26170120).

5. Environmental Information

Not applicable — no environmental, lifestyle, or infectious contributors are known for this Mendelian disorder.

6. Mechanism / Pathophysiology

See Mechanistic Model above (ordered causal chain, branches A–D, ontology terms).

7. Anatomical Structures Affected

Primary organs: skeletal muscle (UBERON:0001134), ocular lens (UBERON:0000965). Nervous system: brain/cerebellum (subset; UBERON:0002037) — cognition; MRI usually normal. Body systems: musculoskeletal, ocular/visual, nervous. Tissue/cell: skeletal muscle fibers, lens fiber cells, neurons. Subcellular: endoplasmic reticulum membrane (GO:0005789), plasma membrane, cytosol, nucleus. Lateralization: bilateral/symmetric (cataracts and muscle involvement).

8. Temporal Development

Onset: congenital to childhood (insidious/chronic); cataracts often congenital/early childhood; weakness from birth in classic cases, adolescent in milder cases. Progression: slowly progressive to relatively stable; selective muscle fatty infiltration pattern over time. Course: chronic, lifelong. Critical period: prenatal/early postnatal development (myogenesis, lens formation, neurodevelopment) — the window where L-serine/phosphoinositide pathways are most active and, potentially, most therapeutically relevant.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: reduced/incomplete for individual features (muscular dystrophy, ID); expressivity: highly variable. Epidemiology: ultra-rare, ~30–40 reported patients; predicted biallelic-pLoF birth prevalence ~1 per million (lower bound); carrier frequency ~1 in 500 (gnomAD-derived, this investigation). Consanguinity: major contributor to homozygous cases (Middle Eastern, South Asian families reported). Founder/recurrent alleles: a recurrent European variant reported (PMID: 33193651). Sex ratio: no sex bias expected (autosomal). No genetic anticipation (not a repeat-expansion disorder).

10. Diagnostics

Laboratory: elevated serum creatine kinase (HP:0003236). Electrophysiology: EMG may show myopathic/irritable myopathy changes. Imaging: cranial MRI typically normal (key differentiator); muscle MRI shows characteristic selective fatty infiltration (severe gluteal/thigh, sparing rectus femoris, sartorius, gracilis — PMID: 42467360); muscle ultrasound is a useful bedside tool (PMID: 39133882). Biopsy/IHC: dystrophic features; reduced α-dystroglycan glycosylation on IHC. Ophthalmology: slit-lamp for cataracts. Genetic testing (definitive): WES or WGS, or CMD/limb-girdle gene panels including INPP5K; single-gene testing confirms candidate variants. RNA studies can confirm splice-altering variants. Differential diagnosis: classic dystroglycanopathies (abnormal brain MRI), Marinesco-Sjögren syndrome (SIL1; cerebellar atrophy), other congenital muscular dystrophies and congenital cataract syndromes.

11. Outcome/Prognosis

Survival: no reported reduction in life expectancy from the muscular dystrophy itself; the disorder is non-lethal and slowly progressive in reported cases. Morbidity: motor disability (ambulation), visual impairment (surgically treatable cataracts), learning/cognitive support needs. Complications: potential orthopedic (contractures), respiratory monitoring as in other CMDs (not specifically quantified). Prognostic factors: variant severity (null vs hypomorphic) and genotype likely influence phenotype severity, though formal correlations are limited by small numbers. No validated prognostic biomarker.

12. Treatment

No approved disease-modifying therapy. Management is supportive/multidisciplinary (NCIT: Supportive Care; Physical Therapy; Occupational Therapy): cataract extraction surgery (NCIT: Cataract Surgery), physiotherapy to maintain mobility, developmental/educational support, low-vision support, orthopedic management. Experimental/mechanism-based: L-serine supplementation (CHEBI:17115) is a rationally supported candidate — it rescued neuronal phenotypes in inpp5k, sil1, and phgdh zebrafish models (PMID: 33792664) — but has not been tested in INPP5K-CMD patients (no NCT identifier). Pharmacogenomics / gene / cell / RNA / targeted / immunotherapies: none established. Treatment algorithm: symptom-directed, following general congenital muscular dystrophy care standards.

13. Prevention

No primary prevention (Mendelian). Genetic counseling is central: 25% recurrence risk for carrier couples; carrier/cascade testing for at-risk relatives; prenatal diagnosis and preimplantation genetic testing are available once familial variants are identified. Consanguinity counseling in affected populations. No vaccine, behavioral, public-health, or prophylactic interventions apply. Not part of standard newborn screening.

14. Other Species / Natural Disease

Orthologs: mouse Inpp5k (NCBI Gene 19062), rat Inpp5k, zebrafish inpp5ka/inpp5kb, pig SKIP. No naturally occurring companion-animal/wildlife disease attributable to INPP5K is catalogued (not in OMIA to the knowledge base). Comparative biology: evolutionary conservation is high — the zebrafish model faithfully reproduces muscle, eye, and brain phenotypes (see Finding 4), and porcine/rodent SKIP studies recapitulate the muscle-differentiation and insulin-signaling roles. No zoonotic potential (genetic disease).

15. Model Organisms

Zebrafish (NCBI Taxon 7955): morpholino inpp5k knockdown → shortened body axis, microphthalmia/disorganized lens, microcephaly, reduced motility, disorganized myofibers (PMID: 28190459, PMID: 28190456); inpp5ka mutants show variable skeletal muscle abnormalities (PMID: 28940338); double inpp5ka+b model used for L-serine rescue (PMID: 33792664). Mouse N2A neuroblastoma cells: INPP5K knockdown impairs neuronal differentiation and glycosylation (PMID: 38559586). C2C12 myoblasts (mouse): SKIP knockdown/overexpression define insulin-PI3K-AKT regulation (PMID: 19250614). Porcine SKIP: muscle-development and MyoD-regulation studies (PMID: 20336382, PMID: 22682687). Phenotype recapitulation: zebrafish captures the muscle/eye/brain triad well; limitation — no published mammalian (mouse) Inpp5k-null disease model recapitulating the full human tetrad, and cataract/short-stature phenotypes are less characterized across models.

Evidence Base

PMID	Title (abbrev.)	Role / contribution	Evidence type
28190459	Mutations in INPP5K cause a CMD overlapping MSS & dystroglycanopathy	Landmark; establishes causality, zebrafish model, dystroglycan/BiP	Human + zebrafish
28190456	Mutations in INPP5K cause CMD with cataracts & cognitive impairment	Landmark; defines tetrad, normal MRI, two mutational mechanisms	Human + functional
33792664	INPP5K & SIL1 converge through PHGDH dysregulation	MSS overlap; PHGDH/L-serine mechanism; L-serine rescue	Human + zebrafish proteomics
38559586	Knockdown of INPP5K compromises N2A differentiation	Links to dystroglycan hypoglycosylation & neuronal differentiation	In vitro
28940338	INPP5K variant causes recessive congenital cataract	Reduced penetrance/variable expressivity; modifiers	Human
42467360	INPP5K-MD from synonymous splicing variant (China)	Expands variant spectrum; muscle MRI pattern; ACMG	Human + functional
33060052	INPP5K: gene structure to in vivo functions	Enzymatic/structural basis; domains; functions	Review
19250614	SKIP knockdown enhances insulin glycogen signaling (C2C12)	Insulin-PI3K-AKT-GSK3β regulation in muscle	In vitro
20336382	MyoD control of SKIP during muscle development	SKIP is a MyoD-regulated myogenesis gene	Model (pig)
22403078	Phosphoinositide phosphatases	Family context; SKIP negatively regulates insulin signaling	Review
19272022	Role of 5-phosphatases in disease	Family of 10; OCRL/INPP5E/SHIP2 disease links	Review
33193651	Recurrent pathogenic INPP5K variant	Recurrent/founder allele in a cohort	Human
39133882	Muscle ultrasound in INPP5K-MD	Diagnostic tool	Human case
22682687	Porcine SKIP in muscle development	Muscle development/insulin role	Model (pig)
26170120	Inpp5k/Myo1c as candidate tumor suppressors	Tangential (cancer context, not CMD)	Model (rat)

Computational evidence generated in this investigation: gnomAD v2.1.1 constraint (Findings 7, 9) and GTEx v8 expression (Finding 8), retrieved via the gnomAD GraphQL and GTEx APIs.

Limitations and Knowledge Gaps

Extremely small patient numbers (~30–40 worldwide) preclude formal epidemiology, robust genotype–phenotype correlation, and natural-history/prognosis quantification. All clinical content derives from case reports/small series with inherent ascertainment bias.
No formal prevalence/incidence estimate exists. The ~1 per million figure is a computational lower bound from gnomAD pLoF alleles only and excludes the pathogenic missense/hypomorphic variants that cause most reported cases — true prevalence is uncertain.
Mechanistic branches are partially inferred. The BiP/HSPA5 ER-stress arm and the precise route from phosphoinositide dysregulation to dystroglycan hypoglycosylation are supported by interaction/association data rather than fully resolved causal demonstration in human muscle.
No mammalian (mouse) disease model recapitulating the full human tetrad has been published; zebrafish and cell models dominate, limiting translational and cataract/growth-phenotype study.
L-serine therapy is unproven in humans — efficacy shown only in zebrafish; no clinical trial (no NCT) exists. Optimal dose, timing (critical developmental window), and which phenotypes might respond are unknown.
Modifier genes and epigenetic factors invoked to explain variable expressivity/reduced penetrance are hypothesized but not identified.
Quality-of-life and functional-outcome data are absent; no disease-specific instruments.

Proposed Follow-up Experiments / Actions

Establish an international patient registry/natural-history study to quantify penetrance, progression rate, muscle-MRI evolution, and genotype–phenotype correlations across the mutational spectrum (null vs hypomorphic; catalytic vs SKICH alleles).
Generate a conditional/knock-in mouse model (e.g., patient-specific missense knock-in) to test whether the full tetrad is recapitulated in a mammal and to serve as a preclinical therapeutic platform.
Pilot clinical evaluation of L-serine supplementation in INPP5K-CMD patients, guided by metabolomic PHGDH/serine biomarkers, with careful attention to the developmental critical window suggested by the zebrafish rescue.
Define the glycosylation defect mechanistically — quantify α-dystroglycan glycosylation and map the phosphoinositide→glycosylation link in patient-derived myotubes/iPSC-myocytes, integrating lipidomics (PtdIns species) with proteomics.
Patient-derived iPSC models (myocytes, lens epithelial cells, cortical neurons) to dissect tissue-specific vulnerability despite ubiquitous expression (Finding 8) and to screen for small molecules correcting ER stress, PI3K-AKT dysregulation, or serine deficiency.
Systematic variant functional assays (phosphatase activity, localization, splicing) to resolve VUS and build an ACMG-aligned variant interpretation resource for INPP5K.
Search for modifier loci via whole-genome analysis of discordant family members (e.g., the reduced-penetrance Pakistani family) to explain variable expressivity.

Report compiled from 9 confirmed findings and 15 reviewed papers across a 5-iteration autonomous investigation. Evidence types are distinguished throughout as human clinical, model organism (zebrafish/pig/mouse cell), in vitro, or computational (gnomAD/GTEx).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	15
On topic	9
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	32
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	6
Terms named correctly	4
Terms named as a different term	1
Terms whose name is worth a second look	1

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:0001251 (1 mention) - the report calls it "Ataxia (subset, MSS-overlap)"; HP calls it Ataxia

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006486 (obsolete protein glycosylation) (1 mention) - replaced by GO:0009101

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

CHEBI:17115 (2 mentions) - the report calls it "L-serine supplementation"; CHEBI calls it L-serine

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Imaging Findings

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

INPP5K-Related Congenital Muscular Dystrophy: A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — Biallelic INPP5K mutations are causal (autosomal recessive)

Finding 2 — Clinical tetrad with marked variable expressivity

Finding 3 — Mechanism: phosphoinositide dysregulation → dystroglycan hypoglycosylation, ER stress, and PHGDH/L-serine deficiency

Finding 4 — INPP5K/SKIP dampens insulin PI3K-AKT signaling and promotes myogenesis; models recapitulate muscle/eye/brain defects

Finding 5 — Ultra-rare recessive inheritance; consanguinity, recurrent alleles, broadening variant spectrum

Finding 6 — Clinical overlap with Marinesco-Sjögren syndrome

Finding 7 — gnomAD constraint confirms LoF tolerance (recessive mechanism)

Finding 8 — GTEx shows ubiquitous expression → vulnerability, not restriction

Finding 9 — gnomAD-derived prevalence estimate: ~1 per million (lower bound)

Mechanistic Model / Interpretation

Causal chain (initiating lesion → clinical manifestation)

Upstream vs downstream

Cell types and biological processes (ontology suggestions)

Section-by-Section Content

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

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look