Mandibuloacral Dysplasia Type B

Mendelian MONDO:0012074 Pathograph 22 Show in embeddings browser mandibuloacral dysplasia laminopathy progeroid syndrome

Mandibuloacral dysplasia with type B lipodystrophy (MADB) is an autosomal recessive progeroid disorder caused by biallelic ZMPSTE24 variants that leave partial activity of the zinc metalloprotease that cuts the farnesylated C-terminal tail off prelamin A. Farnesyl-prelamin A accumulates at the nuclear envelope, nuclei become misshapen, and cells show defective DNA damage responses, p53 activation and senescence. Clinically it presents in early childhood with mandibular and clavicular hypoplasia, acro-osteolysis of the distal phalanges, delayed cranial suture closure, dental crowding, mottled atrophic and sclerodermatous skin with calcified nodules, sparse brittle hair, short stature and lipoatrophy, often generalized. Focal segmental glomerulosclerosis with renal failure, osteoporosis with fractures, diabetes in a minority of patients, heart failure and, in one patient, a congenital myopathy have been reported. Underdevelopment of the occipital bone, present in every patient assessed, is the proposed sign distinguishing MADB from the LMNA-caused type A form. Cognition is usually normal. ZMPSTE24 deficiency is a severity spectrum ordered by residual enzyme activity: complete loss of function causes lethal restrictive dermopathy, while alleles retaining measurable activity cause MADB or a severe progeria. Restrictive dermopathy and the LMNA-caused type A form (MADA) are separate diseases and are not modelled here.

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1
Inheritance
9
Pathophys.
32
Phenotypes
2
Gaps
22
Pathograph
1
Genes
4
Medical Actions
1
Models
3
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Homozygous or compound heterozygous ZMPSTE24 variants; typically one null allele with one partially active missense allele, or two hypomorphic alleles. Heterozygous parents are healthy.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:31856865 SUPPORT Human Clinical
"MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24."
States the biallelic genetic basis.
PMID:18435794 SUPPORT Human Clinical
"Their parents and a brother, who were healthy, had heterozygous mutations."
Unaffected heterozygous relatives are consistent with recessive inheritance.
PMID:31856865 SUPPORT Human Clinical
"the patient and/or the parents should be informed about the 25% risk of siblings of the patient having the same condition"
Recurrence risk for siblings.
?

Discussions and Knowledge Gaps

2
Zmpste24-null mice lose almost all fat, but adipocyte-specific Zmpste24 deletion causes only a modest loss. Is the human lipodystrophy a direct effect of farnesyl-prelamin A in adipocytes, or secondary to systemic disease?
HUMAN MODEL MISMATCH OPEN madb_lipodystrophy_cell_autonomy
Attached to
pathophysiology#Adipose Tissue Loss
The answer decides whether adipose-targeted therapy could help, and whether lipodystrophy should sit downstream of the cell-autonomous prelamin A chain or of a systemic node.
Show evidence (1 reference)
PMID:31941672 SUPPORT Model Organism
"We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice."
The adipocyte-specific result that opens the question.
Is heart failure part of MADB? One patient died of heart failure at 44, and Zmpste24-null mice develop dilated cardiomyopathy, but no cardiac evaluation of MADB patients has been reported.
KNOWLEDGE GAP OPEN madb_heart_failure
Attached to
phenotypes#Congestive Heart Failure
If cardiac involvement is part of the disease, MADB patients would need cardiac surveillance as well as renal and metabolic checks.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Whether the heart failure in our patient is a solitary finding or this should be regarded part of mandibuloacral dysplasia requires further reports on MADB patients."
The authors state the open question.
⚙

Pathophysiology

9
ZMPSTE24 Partial Loss of Function
Biallelic ZMPSTE24 variants reduce, but do not abolish, the activity of the ER and inner nuclear membrane zinc metalloprotease. Missense alleles reduce catalytic activity, protein stability, or both. Residual activity orders the ZMPSTE24 disease spectrum: none in restrictive dermopathy, partial in MADB and severe progeria.
ZMPSTE24 hgnc:12877 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZMPSTE24 (hgnc:12877). hgnc:12877 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
metalloendopeptidase activity GO:0004222 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased metalloendopeptidase activity (GO:0004222). GO:0004222 is a molecular function from the Gene Ontology.
Downstream
Defective Prelamin A Endoproteolytic Maturation ZMPSTE24 performs the final cleavage that converts prelamin A to lamin A.
Show evidence (4 references)
PMID:12913070 SUPPORT Human Clinical
"We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy."
First identification of ZMPSTE24 as a cause of MAD.
PMID:12913070 SUPPORT In Vitro
"The ZMPSTE24 mutant construct, Phe361fsX379, was inactive in complementing the yeast a-factor but the mutant, Trp340Arg, was partially active compared to the wild type ZMPSTE24 construct."
One null and one partially active allele in the first MADB patient.
PMID:22718200 SUPPORT In Vitro
"Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria."
Places MADB at the partial-activity end of the ZMPSTE24 spectrum.
+ 1 more reference
Defective Prelamin A Endoproteolytic Maturation
The farnesylated, carboxymethylated C-terminal tail of prelamin A is not cleaved, so unprocessed farnesyl-prelamin A accumulates and mature lamin A is reduced. This is shown directly in patient lymphoblasts and fibroblasts.
LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee.
CAAX-box protein processing GO:0071586 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CAAX-box protein processing (GO:0071586). GO:0071586 is a biological process from the Gene Ontology.
nuclear lamina GO:0005652 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear lamina (GO:0005652). GO:0005652 is a cellular component from the Gene Ontology.
Animal models
Zmpste24 null mouse Mouse recapitulates Complete loss of Zmpste24 abolishes prelamin A processing.
Downstream
Nuclear Envelope Dysmorphology Farnesyl-prelamin A deforms the nucleus; halving its level in Zmpste24-null cells makes misshapen nuclei less frequent.
Defective DNA Damage Response and Genomic Instability Unprocessed prelamin A impairs recruitment of 53BP1 and RAD51 to DNA lesions, delaying checkpoint response and repair.
p53 Activation and Cellular Senescence A route independent of nuclear shape: farnesyl-methyl prelamin A at the nuclear rim suppresses AKT-mTOR signalling, promoting senescence.
Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation Defective prelamin A processing produces aging-like bone loss in the mouse; the cellular steps in between are not established.
Defective Intramembranous Ossification Proposed from the clinical pattern: the membranous interparietal bone fails to ossify while the endochondral supraoccipital forms normally.
Adipose Tissue Loss Farnesyl-prelamin A in adipocytes reduces fat stores only modestly in the mouse, so most of the fat loss may arise elsewhere.
Sparse Brittle Hair
Short Stature
Show evidence (2 references)
PMID:18435794 SUPPORT In Vitro
"Immunoblots demonstrated accumulation of prelamin A in the patients' cell lysates from lymphoblasts."
Prelamin A accumulates in patient cells.
PMID:21267004 SUPPORT In Vitro
"Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts."
Unprocessed prelamin A with reduced lamin A in patient fibroblasts.
Nuclear Envelope Dysmorphology
Patient fibroblasts have misshapen, structurally abnormal nuclei and a shortened replicative lifespan. Nuclear shape is a marker rather than a sufficient cause: fibroblasts from a restrictive dermopathy patient with only prelamin A had few nuclear abnormalities, and several rescues improve disease without normalizing nuclei.
dermal fibroblast CL:0002551 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with fibroblast of dermis (CL:0002551). CL:0002551 is a cell type from the Cell Ontology.
nuclear envelope organization GO:0006998 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nuclear envelope organization (GO:0006998). GO:0006998 is a biological process from the Gene Ontology.
Downstream
p53 Activation and Cellular Senescence The nuclear abnormalities activate a p53-dependent checkpoint.
Show evidence (3 references)
PMID:21267004 SUPPORT In Vitro
"These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure."
Nuclear shape defects in patient fibroblasts.
PMID:28050601 SUPPORT In Vitro
"In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors."
Independent confirmation of nuclear abnormalities in MADB fibroblasts.
PMID:28050601 SUPPORT In Vitro
"prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype"
Caveat that prelamin A and nuclear misshaping are not sufficient on their own.
Defective DNA Damage Response and Genomic Instability
Zmpste24-deficient cells accumulate DNA damage and chromosome aberrations, are sensitive to DNA-damaging agents, and fail to recruit 53BP1 and RAD51 to lesions, associated with hypoacetylation of histone H4 at lysine 16. Demonstrated in mouse cells; not yet measured in MADB patient cells.
double-strand break repair GO:0006302 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased double-strand break repair (GO:0006302). GO:0006302 is a biological process from the Gene Ontology.
Downstream
p53 Activation and Cellular Senescence Delayed DNA repair drives early cellular senescence.
Show evidence (2 references)
PMID:15980864 SUPPORT In Vitro
"We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents."
Genomic instability in cultured Zmpste24-null cells.
PMID:21746928 SUPPORT Model Organism
"Specifically, histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix."
A chromatin defect behind delayed repair-protein recruitment.
p53 Activation and Cellular Senescence
Zmpste24 deficiency upregulates p53 target genes with cellular senescence and organismal accelerated ageing; these are largely rescued by halving Lmna dosage and partly reversed by p53 loss. Patient fibroblasts show reduced proliferation and lifespan. Senescence is not simply a consequence of nuclear shape: reducing ICMT or RCE1 activity in Zmpste24-deficient cells relieves senescence through prelamin A-dependent AKT-mTOR signalling without correcting misshapen nuclei.
cellular senescence GO:0090398 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology.
Show evidence (4 references)
PMID:16079796 SUPPORT Model Organism
"We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level."
p53 activation and senescence in Zmpste24-null mice.
PMID:16079796 SUPPORT Model Organism
"These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice."
Genetic rescue places p53 downstream of prelamin A accumulation.
PMID:23686339 SUPPORT In Vitro
"The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts."
Senescence of Zmpste24-deficient cells depends on prelamin A signalling through AKT-mTOR.
+ 1 more reference
Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation
Zmpste24-null mice have fewer osteoblasts and osteocytes, more marrow fat, reduced cortical and trabecular bone and spontaneous fractures. Conditional deletion places the lesion upstream of mature osteoblasts: removing Zmpste24 from Prx1-lineage skeletal stem/progenitor cells causes bone loss, while removing it from Osx-lineage osteoblasts does not.
skeletal stem/progenitor cell CL:0020016 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal stem/progenitor cell, annotated with osteochondral skeletal stem cell (CL:0020016). CL:0020016 is a cell type from the Cell Ontology. osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology.
Animal models
Zmpste24 null mouse Mouse recapitulates Bone loss, fractures, micrognathia and osteolytic lesions.
Downstream
Osteoporosis
Show evidence (3 references)
PMID:19587107 SUPPORT Model Organism
"We found that defective prelamin A processing induced accelerated features of age-related bone loss including lower osteoblast and osteocyte numbers and higher levels of marrow adipogenesis."
Reduced osteoblast numbers in the mouse model.
PMID:12235369 SUPPORT Model Organism
"Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice."
Bone mass loss in the knockout.
PMID:37407584 SUPPORT Model Organism
"Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss."
Locates the bone defect in skeletal stem/progenitor cells rather than osteoblasts.
Defective Intramembranous Ossification
The interparietal part of the occipital squama, which forms by membranous ossification, fails to ossify, while the endochondral supraoccipital forms normally. Delayed suture closure and wide fontanelles fit the same membranous-bone pattern, but no study has tested that link.
intramembranous ossification GO:0001957 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intramembranous ossification (GO:0001957). GO:0001957 is a biological process from the Gene Ontology.
Downstream
Underdeveloped Occipital Bone
Show evidence (1 reference)
PMID:27410998 SUPPORT Human Clinical
"a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed"
The membranous-bone defect on radiographs.
Adipose Tissue Loss
Lipoatrophy is part of the defining phenotype, generalized in about half of patients. Zmpste24-null mice lose almost all adipose tissue by four months, but deleting Zmpste24 only in adipocytes reduces fat only modestly, so whether the lipodystrophy is cell-autonomous is unresolved.
adipocyte CL:0000136 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adipocyte (CL:0000136). CL:0000136 is a cell type from the Cell Ontology.
adipose tissue development GO:0060612 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal adipose tissue development (GO:0060612). GO:0060612 is a biological process from the Gene Ontology.
Animal models
Zmpste24 null mouse Mouse partially recapitulates Near-complete fat loss in the global knockout.
Downstream
Lipodystrophy
Show evidence (1 reference)
PMID:11923874 SUPPORT Model Organism
"Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy."
Lipodystrophy in the Zmpste24-null mouse.
Progressive Glomerulosclerosis
Two adults with ZMPSTE24 MAD developed focal segmental glomerulosclerosis (one collapsing) and died of renal failure at 27 and 37 years. How prelamin A accumulation injures the glomerulus has not been studied.
Downstream
Focal Segmental Glomerulosclerosis
Show evidence (1 reference)
PMID:17152860 SUPPORT Human Clinical
"Renal biopsies of both patients revealed focal segmental glomerulosclerosis, and the female patient had the collapsing variant."
Biopsy-proven FSGS in two ZMPSTE24 MAD patients.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Mandibuloacral Dysplasia Type B Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

32
Cardiovascular 2
Congestive Heart Failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Patient VIII died from heart failure at the age of 44 years."
Single case.
Hypertension HP:0000822 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertension (HP:0000822). HP:0000822 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Patients VI and VII developed hypertension for which antihypertensive medication was started."
Two of eight Surinamese patients.
Ear 1
Posteriorly Rotated Ears FREQUENT HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Posteriorly rotated ears | yes | no | no | no | yes | yes | yes | yes | 5/8 (63) | 3/7 (43) | 8/15 (53)"
8 of 15 patients (53%).
Endocrine 1
Diabetes Mellitus HP:0000819 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diabetes mellitus (HP:0000819). HP:0000819 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:21267004 SUPPORT Human Clinical
"Non-insulin-dependent diabetes mellitus was diagnosed but no treatment was administered."
Diabetes in one MADB patient.
PMID:20814950 REFUTE Human Clinical
"Acanthosis nigricans and other metabolic disturbances have not been reported so far in MAD due to ZMPSTE24 mutations."
Metabolic disease had not been seen in the ZMPSTE24 form as of 2010.
PMID:31856865 REFUTE Human Clinical
"None of the living patients developed diabetes mellitus."
No diabetes in the Surinamese cohort.
Eye 2
Proptosis FREQUENT HP:0000520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proptosis (HP:0000520). HP:0000520 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Proptosis | no | no | no | yes | yes | yes | no | no | 3/8 (38) | 7/10 (70) | 10/18 (56)"
10 of 18 patients (56%).
Gaze Palsy or Ptosis OCCASIONAL HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gaze palsy and/or ptosis, annotated with Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Gaze palsy and/or ptosis | no | no | no | no | no | no | yes (ptosis) | no | 1/8 (13) | 1/4 (25) | 2/12 (17)"
2 of 12 patients (17%).
Genitourinary 1
Focal Segmental Glomerulosclerosis HP:0000097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Focal segmental glomerulosclerosis (HP:0000097). HP:0000097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17152860 SUPPORT Human Clinical
"These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency."
FSGS in two adults with ZMPSTE24 MAD.
Head and Neck 8
Mandibular Hypoplasia VERY_FREQUENT Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular hypoplasia, annotated with Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Mandibular hypoplasia | yes | no | yes | yes | no | yes | yes | yes | 6/8 (75) | 12/12 (100) | 18/20 (90)"
18 of 20 patients (90%). Table 2 of the Suriname cohort plus literature review.
Delayed Cranial Suture Closure VERY_FREQUENT HP:0000270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed cranial suture closure (HP:0000270). HP:0000270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Delayed closure of cranial sutures | ? | yes | ? | yes | yes | yes | possible | ? | 5/5 (100) | 9/10 (90) | 14/15 (93)"
14 of 15 patients (93%). Table 2 of the Suriname cohort plus literature review.
High Palate VERY_FREQUENT HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"High palate | yes | yes | ? | yes | yes | yes | ? | yes | 6/6 (100) | 3/3 (100) | 9/9 (100)"
9 of 9 patients assessed (100%). Table 2 of the Suriname cohort plus literature review.
Dental Crowding VERY_FREQUENT HP:0000678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental crowding (HP:0000678). HP:0000678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Dental crowding | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 6/7 (86) | 14/15 (93)"
14 of 15 patients (93%). Table 2 of the Suriname cohort plus literature review.
Pinched Nose FREQUENT Narrow nasal ridge HP:0000418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pinched nose, annotated with Narrow nasal ridge (HP:0000418). HP:0000418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Pinched nose | yes | no | no | no | no/bifid | yes | yes | ? | 3/7 (43) | 9/11 (82) | 12/18 (67)"
12 of 18 patients (67%).
Hypoplastic Teeth OCCASIONAL Hypoplasia of teeth HP:0000685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic teeth, annotated with Hypoplasia of teeth (HP:0000685). HP:0000685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Hypoplastic teeth | yes | no | ? | no | no | yes | ? | ? | 2/6 (33) | 0/3 (0) | 2/9 (22)"
2 of 9 patients (22%).
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Head circumference-for-age (standard deviation) | −3.0 | −1.0 | −3.0 | −2.0 | −3.0 | − 1.5 | − 3.0 | −3.7 |"
Surinamese cohort only (8 patients).
Underdeveloped Occipital Bone VERY_FREQUENT Abnormality of skull ossification HP:0002703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure of ossification of the interparietal occipital bone, annotated with Abnormality of skull ossification (HP:0002703). HP:0002703 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31856865 SUPPORT Human Clinical
"Underdeveloped occipital bonea | yes | yes | yes | yes | yes | yes | yes | yes | 7/7 (100) | 2/2 (100) | 9/9 (100)"
Present in all 9 patients assessed.
PMID:27410998 SUPPORT Human Clinical
"a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed"
Radiographic description of the defect.
Integument 6
Hypoplastic Nails VERY_FREQUENT Hypoplastic fingernail HP:0001804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic nails, annotated with Hypoplastic fingernail (HP:0001804). HP:0001804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Hypoplastic nails | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 7/7 (100) | 15/15 (100)"
15 of 15 patients (100%). Table 2 of the Suriname cohort plus literature review.
Sparse Brittle Hair VERY_FREQUENT Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Brittle and/or sparse hair | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 9/12 (75) | 17/20 (85)"
17 of 20 patients (85%). Table 2 of the Suriname cohort plus literature review.
Mottled Pigmentation VERY_FREQUENT HP:0001070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mottled pigmentation (HP:0001070). HP:0001070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Mottled pigmentation | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 10/10 (100) | 18/18 (100)"
18 of 18 patients (100%). Table 2 of the Suriname cohort plus literature review.
Atrophic Skin VERY_FREQUENT Thin skin HP:0000963 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrophic thin skin, annotated with Thin skin (HP:0000963). HP:0000963 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31856865 SUPPORT Human Clinical
"Skin atrophy | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 11/11 (100) | 19/19 (100)"
19 of 19 patients (100%). Table 2 of the Suriname cohort plus literature review.
PMID:20814950 SUPPORT Human Clinical
"We conclude that in patients with MAD due to ZMPSTE24 mutations, the onset of disease manifestations such as thin skin and micrognathia occurs as early as 5 months of age."
Thin skin is among the earliest signs.
Sclerodermatous Skin VERY_FREQUENT HP:0100324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerodermatous skin, annotated with Scleroderma (HP:0100324). HP:0100324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Sclerodermic skin | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 8/9 (89) | 16/17 (94)"
16 of 17 patients (94%). Table 2 of the Suriname cohort plus literature review.
Alopecia FREQUENT HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Alopecia | no | no | no | yes | yes | yes | yes | yes | 5/8 (50) | 3/10 (33) | 8/18 (44)"
8 of 18 patients (44%).
Limbs 2
Acro-osteolysis of the Distal Phalanges VERY_FREQUENT Osteolytic defects of the distal phalanges of the hand HP:0009839 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acro-osteolysis of the distal phalanges of the hand, annotated with Osteolytic defects of the distal phalanges of the hand (HP:0009839). HP:0009839 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Acro-osteolysis of distal phalangesb | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 11/12 (92) | 19/20 (95)"
19 of 20 patients (95%). Table 2 of the Suriname cohort plus literature review.
Short Phalanges FREQUENT Short phalanx of finger HP:0009803 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shortened phalanges, annotated with Short phalanx of finger (HP:0009803). HP:0009803 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Shortened phalanges of the hands | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 7/11 (64) | 15/19 (79)"
15 of 19 patients (79%). Table 2 of the Suriname cohort plus literature review.
Musculoskeletal 6
Clavicular Hypoplasia VERY_FREQUENT Aplasia/Hypoplasia of the clavicles HP:0006710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clavicular hypoplasia, annotated with Aplasia/Hypoplasia of the clavicles (HP:0006710). HP:0006710 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Clavicular hypoplasiac | yes | yes | ? | yes | yes | yes | ? | yes | 6/6 (100) | 10/12 (83) | 16/18 (89)"
16 of 18 patients (89%). Table 2 of the Suriname cohort plus literature review.
Calcified Skin Nodules VERY_FREQUENT Calcinosis cutis HP:0025520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Calcified skin nodules, annotated with Calcinosis cutis (HP:0025520). HP:0025520 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31856865 SUPPORT Human Clinical
"Calcified skin nodules | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 5/7 (71) | 13/15 (87)"
13 of 15 patients (87%). Table 2 of the Suriname cohort plus literature review.
PMID:20814950 SUPPORT Human Clinical
"Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans."
Calcified nodules distinguish the ZMPSTE24 form from LMNA MAD.
Lipodystrophy FREQUENT HP:0009125 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lipodystrophy (HP:0009125). HP:0009125 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:31856865 SUPPORT Human Clinical
"Lipoatrophy of the extremities | yes | yes | no | yes | yes | yes | yes | yes | 7/8 (88) | 7/11 (64) | 14/19 (74)"
Extremity lipoatrophy in 14 of 19 patients (74%). Table 2 of the Suriname cohort plus literature review.
PMID:31856865 SUPPORT Human Clinical
"Truncal lipoatrophy | yes | yes | no | no | yes | yes | yes | ? | 5/7 (71) | 5/10 (50) | 10/17 (59)"
Truncal lipoatrophy in 10 of 17 patients (59%).
PMID:31856865 SUPPORT Human Clinical
"Generalized lipodystrophy | yes | yes | no | yes | yes | yes | yes | ? | 6/7 (86) | 4/11 (36) | 10/18 (56)"
Generalized lipodystrophy in 10 of 18 patients (56%).
Joint Contractures FREQUENT HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Joint contractures | no | no | no | yes | yes | yes | yes | yes | 5/8 (63) | 9/12 (82) | 14/20 (70)"
14 of 20 patients (70%). Table 2 of the Suriname cohort plus literature review.
Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital myopathy with fiber-type disproportion, annotated with Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21267004 SUPPORT Human Clinical
"combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion"
Single-patient report.
Osteoporosis HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20550970 SUPPORT Human Clinical
"The patient had typical skeletal changes of MAD, but in addition a number of unusual skeletal features including neonatal tooth eruption, amorphous calcific deposits, submetaphyseal erosions, vertebral beaking, severe cortical osteoporosis and delayed fracture healing."
Severe osteoporosis with impaired fracture healing in a ZMPSTE24 patient.
Prenatal and Birth 1
Premature Birth HP:0001622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature birth (HP:0001622). HP:0001622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20814950 SUPPORT Human Clinical
"Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans."
Premature birth reported as a feature of the ZMPSTE24 form.
Growth 2
Short Stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Short stature | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 10/10 (100) | 18/18 (100)"
18 of 18 patients (100%). Table 2 of the Suriname cohort plus literature review.
Small for Gestational Age FREQUENT HP:0001518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small for gestational age (HP:0001518). HP:0001518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Birth weight (percentile) | p5-p15 | p5-p15 | <p1 | <p1 | <p1 | <p1 | ? | <p1 |"
Surinamese cohort only (8 patients).
🧬

Genetic Associations

1
ZMPSTE24 (Biallelic hypomorphic variants, typically a null allele with a partially active missense allele, or a homozygous missense allele)
Gene: ZMPSTE24 hgnc:12877 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZMPSTE24 (hgnc:12877). hgnc:12877 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:12913070 SUPPORT Human Clinical
"We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy."
Gene discovery.
PMID:31856865 SUPPORT Human Clinical
"All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB."
A homozygous founder variant in eight related patients.
💊

Medical Actions

4
Lonafarnib
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lonafarnib CHEBI:47097 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lonafarnib (CHEBI:47097). CHEBI:47097 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
The farnesyltransferase inhibitor lonafarnib is FDA-approved for processing-deficient progeroid laminopathies. It corrects the nuclear phenotype of MADB patient fibroblasts. Another farnesyltransferase inhibitor, ABT-100, improves the Zmpste24-null mouse, while FTI-277 failed in one fibroblast study. No clinical outcome data in MADB patients are available.
Mechanism Target:
Defective Prelamin A Endoproteolytic Maturation
Show evidence (4 references)
PMID:38050983 SUPPORT In Vitro
"Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P)."
Lonafarnib corrects nuclear morphology in MADB fibroblasts.
PMID:38050983 SUPPORT In Vitro
"supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies"
Relates the cell findings to the approved indication.
PMID:16484451 SUPPORT INDIRECT Model Organism
"The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age."
The FTI tested was ABT-100, not lonafarnib.
+ 1 more reference
Rapamycin
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rapamycin CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses rapamycin, annotated with sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest. dimethyl sulfoxide CHEBI:28262 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dimethyl sulfoxide (CHEBI:28262). CHEBI:28262 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Experimental. Rapamycin with dimethylsulfoxide improved nuclear morphology and proliferation of MADB fibroblasts in culture; not tested in patients.
Mechanism Target:
Nuclear Envelope Dysmorphology
Show evidence (1 reference)
PMID:28050601 SUPPORT In Vitro
"We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts."
Cell-culture rescue only.
Bisphosphonate Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pamidronate CHEBI:7903 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pamidronate (CHEBI:7903). CHEBI:7903 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Pamidronate improved spinal bone density in one ZMPSTE24 patient but did not stop cortical bone loss.
Mechanism Target:
Osteoporosis
Show evidence (2 references)
PMID:20550970 SUPPORT Human Clinical
"Treatment with conventional doses of pamidronate improved estimated volumetric bone density in the spine but did not arrest cortical bone loss."
Partial response in a single patient.
PMID:18587406 SUPPORT INDIRECT Model Organism
"markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects"
In mice an aminobisphosphonate combined with a statin, acting on prelamin A prenylation rather than bone directly.
Metabolic and Renal Surveillance
Action: annual metabolic and renal surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is annual metabolic and renal surveillance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Annual blood glucose, blood pressure, and urine protein and glucose checks from diagnosis, with podiatric and dental review, as proposed from the Surinamese cohort.
Mechanism Target:
Focal Segmental Glomerulosclerosis
Diabetes Mellitus
Show evidence (2 references)
PMID:31856865 SUPPORT Human Clinical
"Urine protein and glucose levels; evaluation of renal failurea | following initial diagnosis | annually"
Proposed renal surveillance.
PMID:31856865 SUPPORT Human Clinical
"Blood glucose level; evaluation of diabetes mellitus | following initial diagnosis | annually"
Proposed glucose surveillance.
🔬

Diagnosis

3
Clinical diagnostic criteria
MADB is highly likely with at least four major criteria, or three major and two minor criteria, defined from 20 genetically confirmed patients.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria."
Proposed clinical criteria.
Skull radiography for occipital ossification
An underdeveloped interparietal occipital bone was found in every MADB patient imaged and may separate MADB from MADA.
Show evidence (1 reference)
PMID:31856865 SUPPORT Human Clinical
"considered failure of ossification of the interparietal region of the occipital bone as a possible pathognomonic sign for MADB"
Proposed pathognomonic radiographic sign.
ZMPSTE24 sequencing and prelamin A immunoblot
Sequencing ZMPSTE24 confirms the diagnosis; prelamin A accumulation on immunoblot of patient cells supports pathogenicity of new variants.
Show evidence (1 reference)
PMID:18435794 SUPPORT In Vitro
"Immunoblots demonstrated accumulation of prelamin A in the patients' cell lysates from lymphoblasts."
Prelamin A immunoblot as a functional readout in patient cells.
📊

Prevalence

1
Genetically confirmed MADB patients in the literature
Cases In Literature Ultra Rare
Twenty genetically confirmed patients when the Suriname cohort was published in 2019: eight related Surinamese patients homozygous for the founder variant p.Tyr399Cys plus twelve earlier reports.
Show evidence (2 references)
PMID:31856865 SUPPORT Human Clinical
"We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features."
Twelve previously published cases.
PMID:31856865 SUPPORT Human Clinical
"All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB."
Eight further patients sharing a founder variant.
🐁

Animal Models

1
Zmpste24 null mouse
Species
Mouse
Genotype
Zmpste24-/-
Publication
PMID:11923874
Pathograph links
Defective Prelamin A Endoproteolytic Maturation recapitulates fidelity: high observes: molecular Complete loss of Zmpste24 abolishes prelamin A processing.
Limitations: The null mouse has no residual activity, unlike MADB, so it is closer to the complete-loss end of the human spectrum.
Show evidence (1 reference)
PMID:11923874 SUPPORT Model Organism
"In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A."
The processing defect in the model.
Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation recapitulates fidelity: moderate observes: tissue Bone loss, fractures, micrognathia and osteolytic lesions.
Limitations: Spontaneous fractures resemble osteogenesis imperfecta models, more severe than typical MADB.
Show evidence (1 reference)
PMID:15608054 SUPPORT Model Organism
"Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that..."
Skeletal phenotypes shared with human progeroid laminopathy.
Adipose Tissue Loss partially recapitulates fidelity: unknown observes: tissue Near-complete fat loss in the global knockout.
Limitations: Adipocyte-specific deletion reduces fat only modestly and only in males, so the global-knockout lipodystrophy may be secondary to systemic disease.
Show evidence (1 reference)
PMID:31941672 SUPPORT Model Organism
"We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice."
The conditional model separates cell-autonomous from systemic effects.
{ }

Source YAML

click to show 
name: Mandibuloacral Dysplasia Type B
creation_date: "2026-10-05T00:00:00Z"
category: Mendelian
description: >-
  Mandibuloacral dysplasia with type B lipodystrophy (MADB) is an autosomal
  recessive progeroid disorder caused by biallelic ZMPSTE24 variants that leave
  partial activity of the zinc metalloprotease that cuts the farnesylated
  C-terminal tail off prelamin A. Farnesyl-prelamin A accumulates at the nuclear
  envelope, nuclei become misshapen, and cells show defective DNA damage
  responses, p53 activation and senescence. Clinically it presents in early
  childhood with mandibular and clavicular hypoplasia, acro-osteolysis of the
  distal phalanges, delayed cranial suture closure, dental crowding, mottled
  atrophic and sclerodermatous skin with calcified nodules, sparse brittle hair,
  short stature and lipoatrophy, often generalized. Focal segmental
  glomerulosclerosis with renal failure, osteoporosis with fractures, diabetes
  in a minority of patients, heart failure and, in one patient, a congenital
  myopathy have been reported. Underdevelopment of the occipital bone, present
  in every patient assessed, is the proposed sign distinguishing MADB from the
  LMNA-caused type A form. Cognition is usually normal.

  ZMPSTE24 deficiency is a severity spectrum ordered by residual enzyme
  activity: complete loss of function causes lethal restrictive dermopathy,
  while alleles retaining measurable activity cause MADB or a severe
  progeria. Restrictive dermopathy and the LMNA-caused type A form (MADA) are
  separate diseases and are not modelled here.
disease_term:
  preferred_term: mandibuloacral dysplasia with type B lipodystrophy
  term:
    id: MONDO:0012074
    label: mandibuloacral dysplasia with type B lipodystrophy
parents:
- mandibuloacral dysplasia
- laminopathy
- progeroid syndrome
synonyms:
- MADB
- MAD-B
- mandibuloacral dysplasia type B
- ZMPSTE24-related mandibuloacral dysplasia
references:
- reference: PMID:12913070
  title: "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia."
- reference: PMID:22718200
  title: "Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity."
- reference: PMID:31856865
  title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."

inheritance:
- name: Autosomal recessive
  description: >-
    Homozygous or compound heterozygous ZMPSTE24 variants; typically one null
    allele with one partially active missense allele, or two hypomorphic
    alleles. Heterozygous parents are healthy.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24."
    explanation: States the biallelic genetic basis.
  - reference: PMID:18435794
    reference_title: "Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their parents and a brother, who were healthy, had heterozygous mutations."
    explanation: Unaffected heterozygous relatives are consistent with recessive inheritance.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient and/or the parents should be informed about the 25% risk of siblings of the patient having the same condition"
    explanation: Recurrence risk for siblings.

prevalence:
- population: Genetically confirmed MADB patients in the literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Twenty genetically confirmed patients when the Suriname cohort was
    published in 2019: eight related Surinamese patients homozygous for the
    founder variant p.Tyr399Cys plus twelve earlier reports.
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features."
    explanation: Twelve previously published cases.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB."
    explanation: Eight further patients sharing a founder variant.

pathophysiology:
- name: ZMPSTE24 Partial Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic ZMPSTE24 variants reduce, but do not abolish, the activity of the
    ER and inner nuclear membrane zinc metalloprotease. Missense alleles reduce
    catalytic activity, protein stability, or both. Residual activity orders
    the ZMPSTE24 disease spectrum: none in restrictive dermopathy, partial in
    MADB and severe progeria.
  genes:
  - preferred_term: ZMPSTE24
    term:
      id: hgnc:12877
      label: ZMPSTE24
  molecular_functions:
  - preferred_term: metalloendopeptidase activity
    modifier: DECREASED
    term:
      id: GO:0004222
      label: metalloendopeptidase activity
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:12913070
    reference_title: "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy."
    explanation: First identification of ZMPSTE24 as a cause of MAD.
  - reference: PMID:12913070
    reference_title: "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The ZMPSTE24 mutant construct, Phe361fsX379, was inactive in complementing the yeast a-factor but the mutant, Trp340Arg, was partially active compared to the wild type ZMPSTE24 construct."
    explanation: One null and one partially active allele in the first MADB patient.
  - reference: PMID:22718200
    reference_title: "Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria."
    explanation: Places MADB at the partial-activity end of the ZMPSTE24 spectrum.
  - reference: PMID:29794150
    reference_title: "ZMPSTE24 missense mutations that cause progeroid diseases decrease prelamin A cleavage activity and/or protein stability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All mutations show diminished prelamin A processing and fall into three classes, with defects in activity, protein stability or both."
    explanation: Disease missense alleles reduce activity and/or stability.
  downstream:
  - target: Defective Prelamin A Endoproteolytic Maturation
    causal_link_type: DIRECT
    description: ZMPSTE24 performs the final cleavage that converts prelamin A to lamin A.
    evidence:
    - reference: PMID:12913070
      reference_title: "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "ZMPSTE24 is involved in post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A in two steps to form mature lamin A."
      explanation: Names the processing step that a ZMPSTE24 defect blocks.

- name: Defective Prelamin A Endoproteolytic Maturation
  biological_scale: MOLECULAR
  description: >-
    The farnesylated, carboxymethylated C-terminal tail of prelamin A is not
    cleaved, so unprocessed farnesyl-prelamin A accumulates and mature lamin A
    is reduced. This is shown directly in patient lymphoblasts and fibroblasts.
  genes:
  - preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  biological_processes:
  - preferred_term: CAAX-box protein processing
    modifier: DECREASED
    term:
      id: GO:0071586
      label: CAAX-box protein processing
  cellular_components:
  - preferred_term: nuclear lamina
    term:
      id: GO:0005652
      label: nuclear lamina
  evidence:
  - reference: PMID:18435794
    reference_title: "Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblots demonstrated accumulation of prelamin A in the patients' cell lysates from lymphoblasts."
    explanation: Prelamin A accumulates in patient cells.
  - reference: PMID:21267004
    reference_title: "Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blot analysis revealed a major reduction of ZMPSTE24, together with the presence of unprocessed prelamin A and decreased levels of lamin A, in the patient's primary skin fibroblasts."
    explanation: Unprocessed prelamin A with reduced lamin A in patient fibroblasts.
  downstream:
  - target: Nuclear Envelope Dysmorphology
    causal_link_type: DIRECT
    description: >-
      Farnesyl-prelamin A deforms the nucleus; halving its level in
      Zmpste24-null cells makes misshapen nuclei less frequent.
    evidence:
    - reference: PMID:15608054
      reference_title: "Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "misshapen nuclei were less frequent in Zmpste24(-/-)Lmna(+/-) cells than in Zmpste24(-/-) cells"
      explanation: Lowering prelamin A dosage reduces nuclear misshaping in cultured cells.
  - target: Defective DNA Damage Response and Genomic Instability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Unprocessed prelamin A impairs recruitment of 53BP1 and RAD51 to DNA
      lesions, delaying checkpoint response and repair.
    evidence:
    - reference: PMID:15980864
      reference_title: "Genomic instability in laminopathy-based premature aging."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging."
      explanation: Shown in Zmpste24-null and prelamin A-expressing mouse cells, not MADB patient cells.
  - target: p53 Activation and Cellular Senescence
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A route independent of nuclear shape: farnesyl-methyl prelamin A at the
      nuclear rim suppresses AKT-mTOR signalling, promoting senescence.
    evidence:
    - reference: PMID:23686339
      reference_title: "Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "ICMT inhibition increased AKT-mTOR signaling and proliferation and delayed senescence in human HGPS fibroblasts but did not reduce the levels of misshapen nuclei in mouse and human cells."
      explanation: >-
        Senescence can be relieved without correcting nuclear shape; shown in
        cultured HGPS and Zmpste24-deficient cells, not MADB cells.
  - target: Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Defective prelamin A processing produces aging-like bone loss in the
      mouse; the cellular steps in between are not established.
    evidence:
    - reference: PMID:19587107
      reference_title: "Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "We found that defective prelamin A processing induced accelerated features of age-related bone loss including lower osteoblast and osteocyte numbers and higher levels of marrow adipogenesis."
      explanation: Ties the prelamin A defect to bone loss in mice.
  - target: Defective Intramembranous Ossification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed from the clinical pattern: the membranous interparietal bone
      fails to ossify while the endochondral supraoccipital forms normally.
    evidence:
    - reference: PMID:27410998
      reference_title: "Failure of ossification of the occipital bone in mandibuloacral dysplasia type B."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "This observation illustrates that ZMPSTE24 could play a specific role in membranous ossification in the interparietal part of the squama (Inca bone) but not in the intracartilaginous ossification of the supraoccipital."
      explanation: An inference from one patient's radiographs.
  - target: Adipose Tissue Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Farnesyl-prelamin A in adipocytes reduces fat stores only modestly in the
      mouse, so most of the fat loss may arise elsewhere.
    evidence:
    - reference: PMID:31941672
      reference_title: "Deficiency in ZMPSTE24 and resulting farnesyl-prelamin A accumulation only modestly affect mouse adipose tissue stores."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice."
      explanation: A modest adipocyte-autonomous effect.
  - target: Sparse Brittle Hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12235369
      reference_title: "Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Zmpste24(-/-) mice gain weight slowly, appear malnourished, and exhibit progressive hair loss."
      explanation: Hair loss in the knockout.
    - reference: PMID:18587406
      reference_title: "Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects"
      explanation: Blocking prelamin A prenylation reverses hair loss, placing it downstream of prelamin A.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18587406
      reference_title: "Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects"
      explanation: Growth retardation in the knockout is reversed by blocking prelamin A prenylation.

- name: Nuclear Envelope Dysmorphology
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts have misshapen, structurally abnormal nuclei and a
    shortened replicative lifespan. Nuclear shape is a marker rather than a
    sufficient cause: fibroblasts from a restrictive dermopathy patient with
    only prelamin A had few nuclear abnormalities, and several rescues improve
    disease without normalizing nuclei.
  cell_types:
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002551
      label: fibroblast of dermis
  biological_processes:
  - preferred_term: nuclear envelope organization
    modifier: ABNORMAL
    term:
      id: GO:0006998
      label: nuclear envelope organization
  evidence:
  - reference: PMID:21267004
    reference_title: "Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These cells exhibited significant reductions in lifespan associated with major abnormalities of the nuclear shape and structure."
    explanation: Nuclear shape defects in patient fibroblasts.
  - reference: PMID:28050601
    reference_title: "Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors."
    explanation: Independent confirmation of nuclear abnormalities in MADB fibroblasts.
  - reference: PMID:28050601
    reference_title: "Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype"
    explanation: Caveat that prelamin A and nuclear misshaping are not sufficient on their own.
  downstream:
  - target: p53 Activation and Cellular Senescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The nuclear abnormalities activate a p53-dependent checkpoint.
    evidence:
    - reference: PMID:16079796
      reference_title: "Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing."
      explanation: Links prelamin A nuclear abnormalities to a p53 checkpoint in mice.

- name: Defective DNA Damage Response and Genomic Instability
  biological_scale: CELLULAR
  conforms_to: "genomic_instability_aging#Declining Genome Maintenance and Erroneous Repair"
  description: >-
    Zmpste24-deficient cells accumulate DNA damage and chromosome aberrations,
    are sensitive to DNA-damaging agents, and fail to recruit 53BP1 and RAD51
    to lesions, associated with hypoacetylation of histone H4 at lysine 16.
    Demonstrated in mouse cells; not yet measured in MADB patient cells.
  biological_processes:
  - preferred_term: double-strand break repair
    modifier: DECREASED
    term:
      id: GO:0006302
      label: double-strand break repair
  evidence:
  - reference: PMID:15980864
    reference_title: "Genomic instability in laminopathy-based premature aging."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents."
    explanation: Genomic instability in cultured Zmpste24-null cells.
  - reference: PMID:21746928
    reference_title: "Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix."
    explanation: A chromatin defect behind delayed repair-protein recruitment.
  downstream:
  - target: p53 Activation and Cellular Senescence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Delayed DNA repair drives early cellular senescence.
    evidence:
    - reference: PMID:21746928
      reference_title: "Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "We have previously reported that Zmpste24 deficiency results in genomic instability and early cellular senescence due to the delayed recruitment of repair proteins to sites of DNA damage."
      explanation: Attributes senescence to the repair defect.

- name: p53 Activation and Cellular Senescence
  biological_scale: CELLULAR
  conforms_to: "cellular_senescence#Senescence-Associated Cell Cycle Arrest"
  description: >-
    Zmpste24 deficiency upregulates p53 target genes with cellular senescence
    and organismal accelerated ageing; these are largely rescued by halving
    Lmna dosage and partly reversed by p53 loss. Patient fibroblasts show
    reduced proliferation and lifespan. Senescence is not simply a consequence
    of nuclear shape: reducing ICMT or RCE1 activity in Zmpste24-deficient
    cells relieves senescence through prelamin A-dependent AKT-mTOR signalling
    without correcting misshapen nuclei.
  biological_processes:
  - preferred_term: cellular senescence
    modifier: INCREASED
    term:
      id: GO:0090398
      label: cellular senescence
  evidence:
  - reference: PMID:16079796
    reference_title: "Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level."
    explanation: p53 activation and senescence in Zmpste24-null mice.
  - reference: PMID:16079796
    reference_title: "Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice."
    explanation: Genetic rescue places p53 downstream of prelamin A accumulation.
  - reference: PMID:23686339
    reference_title: "Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts."
    explanation: Senescence of Zmpste24-deficient cells depends on prelamin A signalling through AKT-mTOR.
  - reference: PMID:32910507
    reference_title: "Targeting RAS-converting enzyme 1 overcomes senescence and improves progeria-like phenotypes of ZMPSTE24 deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results strengthen the idea that the presence of misshapen nuclei does not prevent phenotype improvement and suggest that targeting RCE1 might be useful for treating the rare progeroid disorders associated with ZMPSTE24 deficiency."
    explanation: Phenotype rescue without nuclear-shape correction.

- name: Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation
  biological_scale: TISSUE
  conforms_to: "osteoporosis_bone_resorption#Impaired Osteoblastic Bone Formation"
  description: >-
    Zmpste24-null mice have fewer osteoblasts and osteocytes, more marrow fat,
    reduced cortical and trabecular bone and spontaneous fractures. Conditional
    deletion places the lesion upstream of mature osteoblasts: removing
    Zmpste24 from Prx1-lineage skeletal stem/progenitor cells causes bone loss,
    while removing it from Osx-lineage osteoblasts does not.
  cell_types:
  - preferred_term: skeletal stem/progenitor cell
    term:
      id: CL:0020016
      label: osteochondral skeletal stem cell
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    modifier: DECREASED
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:19587107
    reference_title: "Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that defective prelamin A processing induced accelerated features of age-related bone loss including lower osteoblast and osteocyte numbers and higher levels of marrow adipogenesis."
    explanation: Reduced osteoblast numbers in the mouse model.
  - reference: PMID:12235369
    reference_title: "Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice."
    explanation: Bone mass loss in the knockout.
  - reference: PMID:37407584
    reference_title: "Premature aging of skeletal stem/progenitor cells rather than osteoblasts causes bone loss with decreased mechanosensation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we established models of premature aging by conditional depletion of Zmpste24 (Z24) in mice and found that Prx1-dependent Z24 deletion, but not Osx-dependent Z24 deletion, caused significant bone loss."
    explanation: Locates the bone defect in skeletal stem/progenitor cells rather than osteoblasts.
  downstream:
  - target: Osteoporosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:12235369
      reference_title: "Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta."
      explanation: Bone fragility in the knockout parallels human osteoporosis with fractures.

- name: Defective Intramembranous Ossification
  biological_scale: TISSUE
  description: >-
    The interparietal part of the occipital squama, which forms by membranous
    ossification, fails to ossify, while the endochondral supraoccipital forms
    normally. Delayed suture closure and wide fontanelles fit the same
    membranous-bone pattern, but no study has tested that link.
  biological_processes:
  - preferred_term: intramembranous ossification
    modifier: DECREASED
    term:
      id: GO:0001957
      label: intramembranous ossification
  evidence:
  - reference: PMID:27410998
    reference_title: "Failure of ossification of the occipital bone in mandibuloacral dysplasia type B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed"
    explanation: The membranous-bone defect on radiographs.
  downstream:
  - target: Underdeveloped Occipital Bone
    causal_link_type: DIRECT

- name: Adipose Tissue Loss
  biological_scale: TISSUE
  description: >-
    Lipoatrophy is part of the defining phenotype, generalized in about half of
    patients. Zmpste24-null mice lose almost all adipose tissue by four months,
    but deleting Zmpste24 only in adipocytes reduces fat only modestly, so
    whether the lipodystrophy is cell-autonomous is unresolved.
  cell_types:
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: adipose tissue development
    modifier: ABNORMAL
    term:
      id: GO:0060612
      label: adipose tissue development
  evidence:
  - reference: PMID:11923874
    reference_title: "Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histopathological analysis of the mutant mice revealed several abnormalities, including dilated cardiomyopathy, muscular dystrophy and lipodystrophy."
    explanation: Lipodystrophy in the Zmpste24-null mouse.
  downstream:
  - target: Lipodystrophy
    causal_link_type: DIRECT

- name: Progressive Glomerulosclerosis
  biological_scale: TISSUE
  description: >-
    Two adults with ZMPSTE24 MAD developed focal segmental glomerulosclerosis
    (one collapsing) and died of renal failure at 27 and 37 years. How prelamin
    A accumulation injures the glomerulus has not been studied.
  evidence:
  - reference: PMID:17152860
    reference_title: "Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsies of both patients revealed focal segmental glomerulosclerosis, and the female patient had the collapsing variant."
    explanation: Biopsy-proven FSGS in two ZMPSTE24 MAD patients.
  downstream:
  - target: Focal Segmental Glomerulosclerosis
    causal_link_type: DIRECT

phenotypes:
- name: Mandibular Hypoplasia
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Mandibular hypoplasia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mandibular hypoplasia | yes | no | yes | yes | no | yes | yes | yes | 6/8 (75) | 12/12 (100) | 18/20 (90)"
    explanation: 18 of 20 patients (90%). Table 2 of the Suriname cohort plus literature review.
- name: Clavicular Hypoplasia
  category: Skeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Clavicular hypoplasia
    term:
      id: HP:0006710
      label: Aplasia/Hypoplasia of the clavicles
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clavicular hypoplasiac | yes | yes | ? | yes | yes | yes | ? | yes | 6/6 (100) | 10/12 (83) | 16/18 (89)"
    explanation: 16 of 18 patients (89%). Table 2 of the Suriname cohort plus literature review.
- name: Acro-osteolysis of the Distal Phalanges
  category: Skeletal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Acro-osteolysis of the distal phalanges of the hand
    term:
      id: HP:0009839
      label: Osteolytic defects of the distal phalanges of the hand
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acro-osteolysis of distal phalangesb | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 11/12 (92) | 19/20 (95)"
    explanation: 19 of 20 patients (95%). Table 2 of the Suriname cohort plus literature review.
- name: Delayed Cranial Suture Closure
  category: Skeletal
  frequency: VERY_FREQUENT
  description: Includes enlarged fontanelles.
  phenotype_term:
    preferred_term: Delayed cranial suture closure
    term:
      id: HP:0000270
      label: Delayed cranial suture closure
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed closure of cranial sutures | ? | yes | ? | yes | yes | yes | possible | ? | 5/5 (100) | 9/10 (90) | 14/15 (93)"
    explanation: 14 of 15 patients (93%). Table 2 of the Suriname cohort plus literature review.
- name: Short Stature
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short stature | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 10/10 (100) | 18/18 (100)"
    explanation: 18 of 18 patients (100%). Table 2 of the Suriname cohort plus literature review.
- name: High Palate
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High palate | yes | yes | ? | yes | yes | yes | ? | yes | 6/6 (100) | 3/3 (100) | 9/9 (100)"
    explanation: 9 of 9 patients assessed (100%). Table 2 of the Suriname cohort plus literature review.
- name: Dental Crowding
  category: Dental
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental crowding | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 6/7 (86) | 14/15 (93)"
    explanation: 14 of 15 patients (93%). Table 2 of the Suriname cohort plus literature review.
- name: Hypoplastic Nails
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypoplastic nails
    term:
      id: HP:0001804
      label: Hypoplastic fingernail
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic nails | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 7/7 (100) | 15/15 (100)"
    explanation: 15 of 15 patients (100%). Table 2 of the Suriname cohort plus literature review.
- name: Sparse Brittle Hair
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brittle and/or sparse hair | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 9/12 (75) | 17/20 (85)"
    explanation: 17 of 20 patients (85%). Table 2 of the Suriname cohort plus literature review.
- name: Mottled Pigmentation
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Mottled pigmentation
    term:
      id: HP:0001070
      label: Mottled pigmentation
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mottled pigmentation | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 10/10 (100) | 18/18 (100)"
    explanation: 18 of 18 patients (100%). Table 2 of the Suriname cohort plus literature review.
- name: Atrophic Skin
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atrophic thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin atrophy | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 11/11 (100) | 19/19 (100)"
    explanation: 19 of 19 patients (100%). Table 2 of the Suriname cohort plus literature review.
  - reference: PMID:20814950
    reference_title: "Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that in patients with MAD due to ZMPSTE24 mutations, the onset of disease manifestations such as thin skin and micrognathia occurs as early as 5 months of age."
    explanation: Thin skin is among the earliest signs.
- name: Sclerodermatous Skin
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sclerodermatous skin
    term:
      id: HP:0100324
      label: Scleroderma
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sclerodermic skin | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 8/9 (89) | 16/17 (94)"
    explanation: 16 of 17 patients (94%). Table 2 of the Suriname cohort plus literature review.
- name: Calcified Skin Nodules
  category: Integumentary
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Calcified skin nodules
    term:
      id: HP:0025520
      label: Calcinosis cutis
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Calcified skin nodules | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 5/7 (71) | 13/15 (87)"
    explanation: 13 of 15 patients (87%). Table 2 of the Suriname cohort plus literature review.
  - reference: PMID:20814950
    reference_title: "Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans."
    explanation: Calcified nodules distinguish the ZMPSTE24 form from LMNA MAD.
- name: Lipodystrophy
  category: Metabolic
  frequency: FREQUENT
  description: >-
    Lipoatrophy of the extremities in 74%, generalized lipodystrophy in 56%,
    and facial lipoatrophy in 50% of 20 genetically confirmed patients.
  phenotype_term:
    preferred_term: Lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipoatrophy of the extremities | yes | yes | no | yes | yes | yes | yes | yes | 7/8 (88) | 7/11 (64) | 14/19 (74)"
    explanation: Extremity lipoatrophy in 14 of 19 patients (74%). Table 2 of the Suriname cohort plus literature review.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Truncal lipoatrophy | yes | yes | no | no | yes | yes | yes | ? | 5/7 (71) | 5/10 (50) | 10/17 (59)"
    explanation: Truncal lipoatrophy in 10 of 17 patients (59%).
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Generalized lipodystrophy | yes | yes | no | yes | yes | yes | yes | ? | 6/7 (86) | 4/11 (36) | 10/18 (56)"
    explanation: Generalized lipodystrophy in 10 of 18 patients (56%).
- name: Joint Contractures
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint contractures | no | no | no | yes | yes | yes | yes | yes | 5/8 (63) | 9/12 (82) | 14/20 (70)"
    explanation: 14 of 20 patients (70%). Table 2 of the Suriname cohort plus literature review.
- name: Short Phalanges
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Shortened phalanges
    term:
      id: HP:0009803
      label: Short phalanx of finger
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Shortened phalanges of the hands | yes | yes | yes | yes | yes | yes | yes | yes | 8/8 (100) | 7/11 (64) | 15/19 (79)"
    explanation: 15 of 19 patients (79%). Table 2 of the Suriname cohort plus literature review.
- name: Diabetes Mellitus
  category: Metabolic
  description: >-
    Variable and uncommon in the ZMPSTE24 form. Diabetes was diagnosed in one
    adult with a homozygous missense allele, and impaired glucose tolerance and
    diabetes are reported in a few patients, but other reports found no
    metabolic disturbance and none of the living Surinamese patients was
    diabetic. Metabolic complications are more typical of the LMNA type A form.
  phenotype_term:
    preferred_term: Diabetes mellitus
    term:
      id: HP:0000819
      label: Diabetes mellitus
  evidence:
  - reference: PMID:21267004
    reference_title: "Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-insulin-dependent diabetes mellitus was diagnosed but no treatment was administered."
    explanation: Diabetes in one MADB patient.
  - reference: PMID:20814950
    reference_title: "Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Acanthosis nigricans and other metabolic disturbances have not been reported so far in MAD due to ZMPSTE24 mutations."
    explanation: Metabolic disease had not been seen in the ZMPSTE24 form as of 2010.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the living patients developed diabetes mellitus."
    explanation: No diabetes in the Surinamese cohort.

- name: Pinched Nose
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pinched nose
    term:
      id: HP:0000418
      label: Narrow nasal ridge
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pinched nose | yes | no | no | no | no/bifid | yes | yes | ? | 3/7 (43) | 9/11 (82) | 12/18 (67)"
    explanation: 12 of 18 patients (67%).
- name: Proptosis
  category: Ocular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Proptosis
    term:
      id: HP:0000520
      label: Proptosis
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proptosis | no | no | no | yes | yes | yes | no | no | 3/8 (38) | 7/10 (70) | 10/18 (56)"
    explanation: 10 of 18 patients (56%).
- name: Posteriorly Rotated Ears
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Posteriorly rotated ears | yes | no | no | no | yes | yes | yes | yes | 5/8 (63) | 3/7 (43) | 8/15 (53)"
    explanation: 8 of 15 patients (53%).
- name: Alopecia
  category: Integumentary
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alopecia | no | no | no | yes | yes | yes | yes | yes | 5/8 (50) | 3/10 (33) | 8/18 (44)"
    explanation: 8 of 18 patients (44%).
- name: Hypoplastic Teeth
  category: Dental
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypoplastic teeth
    term:
      id: HP:0000685
      label: Hypoplasia of teeth
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypoplastic teeth | yes | no | ? | no | no | yes | ? | ? | 2/6 (33) | 0/3 (0) | 2/9 (22)"
    explanation: 2 of 9 patients (22%).
- name: Gaze Palsy or Ptosis
  category: Ocular
  frequency: OCCASIONAL
  description: >-
    Gaze palsy and/or ptosis, recorded together in the table; bound to ptosis, the finding in the Surinamese patient.
  phenotype_term:
    preferred_term: Gaze palsy and/or ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gaze palsy and/or ptosis | no | no | no | no | no | no | yes (ptosis) | no | 1/8 (13) | 1/4 (25) | 2/12 (17)"
    explanation: 2 of 12 patients (17%).
- name: Small for Gestational Age
  category: Growth
  frequency: FREQUENT
  description: >-
    Birth weight below the 1st percentile in 5 of 7 Surinamese patients with data; the literature cases were not tabulated for this.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Birth weight (percentile) | p5-p15 | p5-p15 | <p1 | <p1 | <p1 | <p1 | ? | <p1 |"
    explanation: Surinamese cohort only (8 patients).
- name: Microcephaly
  category: Growth
  frequency: FREQUENT
  description: >-
    Head circumference 2 SD or more below the mean in 6 of 8 Surinamese patients; not tabulated for the literature cases.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Head circumference-for-age (standard deviation) | −3.0 | −1.0 | −3.0 | −2.0 | −3.0 | − 1.5 | − 3.0 | −3.7 |"
    explanation: Surinamese cohort only (8 patients).
- name: Underdeveloped Occipital Bone
  category: Skeletal
  frequency: VERY_FREQUENT
  description: >-
    Failure of ossification of the interparietal (membranous) part of the
    occipital squama. Proposed as the sign that distinguishes MADB from MADA,
    although few MADA skulls have been imaged. Bound to the ossification term
    rather than HP:0012294 Abnormal occipital bone morphology because the
    finding is a failure of ossification; neither term names both.
  phenotype_term:
    preferred_term: Failure of ossification of the interparietal occipital bone
    term:
      id: HP:0002703
      label: Abnormality of skull ossification
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Underdeveloped occipital bonea | yes | yes | yes | yes | yes | yes | yes | yes | 7/7 (100) | 2/2 (100) | 9/9 (100)"
    explanation: Present in all 9 patients assessed.
  - reference: PMID:27410998
    reference_title: "Failure of ossification of the occipital bone in mandibuloacral dysplasia type B."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a striking failure of ossification of the interparietal region of the occipital bone, up to the position where transverse occipital suture can be observed"
    explanation: Radiographic description of the defect.
- name: Myopathy
  category: Musculoskeletal
  description: >-
    Congenital myopathy with fiber-type disproportion, reported in one patient
    homozygous for p.Leu94Pro.
  phenotype_term:
    preferred_term: Congenital myopathy with fiber-type disproportion
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: PMID:21267004
    reference_title: "Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion"
    explanation: Single-patient report.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    One Surinamese patient died of heart failure at 44 with an enlarged heart;
    whether this belongs to MADB is unsettled.
  phenotype_term:
    preferred_term: Heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient VIII died from heart failure at the age of 44 years."
    explanation: Single case.
- name: Hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients VI and VII developed hypertension for which antihypertensive medication was started."
    explanation: Two of eight Surinamese patients.
- name: Osteoporosis
  category: Skeletal
  description: >-
    Severe cortical osteoporosis with fractures and delayed fracture healing;
    these and other unusual skeletal features are more prevalent with ZMPSTE24
    than with LMNA mutations.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:20550970
    reference_title: "Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had typical skeletal changes of MAD, but in addition a number of unusual skeletal features including neonatal tooth eruption, amorphous calcific deposits, submetaphyseal erosions, vertebral beaking, severe cortical osteoporosis and delayed fracture healing."
    explanation: Severe osteoporosis with impaired fracture healing in a ZMPSTE24 patient.
- name: Focal Segmental Glomerulosclerosis
  category: Renal
  description: >-
    Progressive renal disease reaching end-stage renal failure and early death
    in reported adults.
  phenotype_term:
    preferred_term: Focal segmental glomerulosclerosis
    term:
      id: HP:0000097
      label: Focal segmental glomerulosclerosis
  evidence:
  - reference: PMID:17152860
    reference_title: "Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency."
    explanation: FSGS in two adults with ZMPSTE24 MAD.
- name: Premature Birth
  category: Perinatal
  phenotype_term:
    preferred_term: Premature birth
    term:
      id: HP:0001622
      label: Premature birth
  evidence:
  - reference: PMID:20814950
    reference_title: "Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans."
    explanation: Premature birth reported as a feature of the ZMPSTE24 form.

genetic:
- name: ZMPSTE24
  gene_term:
    preferred_term: ZMPSTE24
    term:
      id: hgnc:12877
      label: ZMPSTE24
  association: Biallelic hypomorphic variants, typically a null allele with a partially active missense allele, or a homozygous missense allele
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:12913070
    reference_title: "Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now show compound heterozygous mutations, Phe361fsX379 and Trp340Arg, in the zinc metalloproteinase (ZMPSTE24) gene in one of the four patients who had severe MAD associated with progeroid appearance and generalized lipodystrophy."
    explanation: Gene discovery.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB."
    explanation: A homozygous founder variant in eight related patients.

diagnosis:
- name: Clinical diagnostic criteria
  description: >-
    MADB is highly likely with at least four major criteria, or three major and
    two minor criteria, defined from 20 genetically confirmed patients.
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria."
    explanation: Proposed clinical criteria.
- name: Skull radiography for occipital ossification
  description: >-
    An underdeveloped interparietal occipital bone was found in every MADB
    patient imaged and may separate MADB from MADA.
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "considered failure of ossification of the interparietal region of the occipital bone as a possible pathognomonic sign for MADB"
    explanation: Proposed pathognomonic radiographic sign.
- name: ZMPSTE24 sequencing and prelamin A immunoblot
  description: >-
    Sequencing ZMPSTE24 confirms the diagnosis; prelamin A accumulation on
    immunoblot of patient cells supports pathogenicity of new variants.
  evidence:
  - reference: PMID:18435794
    reference_title: "Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblots demonstrated accumulation of prelamin A in the patients' cell lysates from lymphoblasts."
    explanation: Prelamin A immunoblot as a functional readout in patient cells.

treatments:
- name: Lonafarnib
  description: >-
    The farnesyltransferase inhibitor lonafarnib is FDA-approved for
    processing-deficient progeroid laminopathies. It corrects the nuclear
    phenotype of MADB patient fibroblasts. Another farnesyltransferase
    inhibitor, ABT-100, improves the Zmpste24-null mouse, while FTI-277 failed
    in one fibroblast study. No clinical outcome data in MADB patients are
    available.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lonafarnib
      term:
        id: CHEBI:47097
        label: lonafarnib
  target_mechanisms:
  - target: Defective Prelamin A Endoproteolytic Maturation
  evidence:
  - reference: PMID:38050983
    reference_title: "The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P)."
    explanation: Lonafarnib corrects nuclear morphology in MADB fibroblasts.
  - reference: PMID:38050983
    reference_title: "The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies"
    explanation: Relates the cell findings to the approved indication.
  - reference: PMID:16484451
    reference_title: "A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "The FTI-treated mice exhibited improved body weight, grip strength, bone integrity, and percent survival at 20 weeks of age."
    explanation: The FTI tested was ABT-100, not lonafarnib.
  - reference: PMID:28050601
    reference_title: "Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide."
    supports: REFUTE
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "FTI-277 treatment failed to inhibit these features in the patients with MAD."
    explanation: A different FTI, FTI-277, did not improve MADB fibroblasts.
- name: Rapamycin
  description: >-
    Experimental. Rapamycin with dimethylsulfoxide improved nuclear morphology
    and proliferation of MADB fibroblasts in culture; not tested in patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rapamycin
      term:
        id: CHEBI:9168
        label: sirolimus
    - preferred_term: dimethyl sulfoxide
      term:
        id: CHEBI:28262
        label: dimethyl sulfoxide
  target_mechanisms:
  - target: Nuclear Envelope Dysmorphology
  evidence:
  - reference: PMID:28050601
    reference_title: "Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts."
    explanation: Cell-culture rescue only.
- name: Bisphosphonate Therapy
  description: >-
    Pamidronate improved spinal bone density in one ZMPSTE24 patient but did
    not stop cortical bone loss.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pamidronate
      term:
        id: CHEBI:7903
        label: pamidronate
  target_mechanisms:
  - target: Osteoporosis
  evidence:
  - reference: PMID:20550970
    reference_title: "Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with conventional doses of pamidronate improved estimated volumetric bone density in the spine but did not arrest cortical bone loss."
    explanation: Partial response in a single patient.
  - reference: PMID:18587406
    reference_title: "Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects"
    explanation: In mice an aminobisphosphonate combined with a statin, acting on prelamin A prenylation rather than bone directly.

- name: Metabolic and Renal Surveillance
  description: >-
    Annual blood glucose, blood pressure, and urine protein and glucose checks
    from diagnosis, with podiatric and dental review, as proposed from the
    Surinamese cohort.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: annual metabolic and renal surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Focal Segmental Glomerulosclerosis
  - target: Diabetes Mellitus
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urine protein and glucose levels; evaluation of renal failurea | following initial diagnosis | annually"
    explanation: Proposed renal surveillance.
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blood glucose level; evaluation of diabetes mellitus | following initial diagnosis | annually"
    explanation: Proposed glucose surveillance.

animal_models:
- name: Zmpste24 null mouse
  species: Mouse
  genotype: Zmpste24-/-
  publication: PMID:11923874
  modeled_mechanisms:
  - target: Defective Prelamin A Endoproteolytic Maturation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Complete loss of Zmpste24 abolishes prelamin A processing.
    limitations: >-
      The null mouse has no residual activity, unlike MADB, so it is closer to
      the complete-loss end of the human spectrum.
    evidence:
    - reference: PMID:11923874
      reference_title: "Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In agreement with this finding, Zmpste24-null mice are defective in the proteolytic processing of prelamin A."
      explanation: The processing defect in the model.
  - target: Skeletal Stem/Progenitor Cell Loss and Impaired Bone Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Bone loss, fractures, micrognathia and osteolytic lesions.
    limitations: >-
      Spontaneous fractures resemble osteogenesis imperfecta models, more
      severe than typical MADB.
    evidence:
    - reference: PMID:15608054
      reference_title: "Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Zmpste24-deficient (Zmpste24(-/-)) mice exhibit retarded growth, alopecia, micrognathia, dental abnormalities, osteolytic lesions in bones, and osteoporosis, which are phenotypes shared with Hutchinson-Gilford progeria syndrome, a human disease caused by the synthesis of a mutant prelamin A that cannot undergo processing to lamin A."
      explanation: Skeletal phenotypes shared with human progeroid laminopathy.
  - target: Adipose Tissue Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: Near-complete fat loss in the global knockout.
    limitations: >-
      Adipocyte-specific deletion reduces fat only modestly and only in males,
      so the global-knockout lipodystrophy may be secondary to systemic disease.
    evidence:
    - reference: PMID:31941672
      reference_title: "Deficiency in ZMPSTE24 and resulting farnesyl-prelamin A accumulation only modestly affect mouse adipose tissue stores."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice."
      explanation: The conditional model separates cell-autonomous from systemic effects.

discussions:
- discussion_id: madb_lipodystrophy_cell_autonomy
  prompt: >-
    Zmpste24-null mice lose almost all fat, but adipocyte-specific Zmpste24
    deletion causes only a modest loss. Is the human lipodystrophy a direct
    effect of farnesyl-prelamin A in adipocytes, or secondary to systemic
    disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Adipose Tissue Loss
  rationale: >-
    The answer decides whether adipose-targeted therapy could help, and
    whether lipodystrophy should sit downstream of the cell-autonomous
    prelamin A chain or of a systemic node.
  evidence:
  - reference: PMID:31941672
    reference_title: "Deficiency in ZMPSTE24 and resulting farnesyl-prelamin A accumulation only modestly affect mouse adipose tissue stores."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We conclude that ZMPSTE24 deficiency in adipocytes, and the accompanying accumulation of farnesyl-prelamin A, reduces adipose tissue stores, but only modestly and only in male mice."
    explanation: The adipocyte-specific result that opens the question.

- discussion_id: madb_heart_failure
  prompt: >-
    Is heart failure part of MADB? One patient died of heart failure at 44, and
    Zmpste24-null mice develop dilated cardiomyopathy, but no cardiac
    evaluation of MADB patients has been reported.
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Congestive Heart Failure
  rationale: >-
    If cardiac involvement is part of the disease, MADB patients would need
    cardiac surveillance as well as renal and metabolic checks.
  evidence:
  - reference: PMID:31856865
    reference_title: "Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whether the heart failure in our patient is a solitary finding or this should be regarded part of mandibuloacral dysplasia requires further reports on MADB patients."
    explanation: The authors state the open question.

notes: >-
  Psychomotor development was normal in 14 of 16 patients assessed in the
  Suriname cohort and literature review (PMID:31856865, Table 2). No
  GeneReviews chapter exists for mandibuloacral dysplasia. Lonafarnib is
  approved in the United States for processing-deficient progeroid
  laminopathies, which include ZMPSTE24 deficiency, but MADB-specific clinical
  outcome data are lacking.
📚

References & Deep Research

References

3
PMID:12913070
Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.
No top-level findings curated for this source.
PMID:22718200
Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity.
No top-level findings curated for this source.
PMID:31856865
Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines.
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 (1)

Create: Mandibuloacral_Dysplasia_Type_B · 2026-10-05T16:04:11Z · View source

Created the ZMPSTE24-related mandibuloacral dysplasia with type B lipodystrophy entry (MONDO:0012074). Phenotype frequencies are taken item by item from Table 2 of the Suriname cohort plus literature review (PMID:31856865, n=20); FSGS, osteoporosis, myopathy, diabetes and heart failure come from individual reports. The pathograph runs from partial ZMPSTE24 loss of function (residual-activity spectrum, PMID:22718200, 29794150) through failed prelamin A processing (patient cells, PMID:18435794, 21267004) to nuclear dysmorphology, DNA repair failure, p53 activation and senescence, with a nuclear-shape-independent AKT-mTOR route (PMID:23686339, 32910507), skeletal stem/progenitor cell bone loss (PMID:37407584), intramembranous ossification failure, adipose loss and glomerulosclerosis. Mouse-derived links are marked INDIRECT. Insulin resistance was deliberately not asserted; diabetes is recorded with REFUTE items because the ZMPSTE24 form is usually metabolically spared. Two open questions are recorded as discussions: whether the lipodystrophy is adipocyte-autonomous, and whether heart failure belongs to the disease. Deep research: OpenScientist (24/24 references resolved, preflight-dr PASS); its citations 37407584, 21746928, 23686339 and 32910507 were taken into the entry. An internal fresh-context review before the PR led to replacing grouped criteria snippets with per-feature table rows, correcting FTI evidence (ABT-100 and FTI-277 are not lonafarnib), re-routing edges whose snippets supported a neighbouring node, adding the occipital ossification phenotype, and regrading cultured mouse cell evidence as IN_VITRO. No GeneReviews chapter exists.

OpenScientist ▸
Mandibuloacral Dysplasia Type B (MAD-B): Comprehensive Disease Characteristics Report
openscientist-autonomous 24 citations 2026-10-05T11:48:43.827365

Mandibuloacral Dysplasia Type B (MAD-B): Comprehensive Disease Characteristics Report

Disease: Mandibuloacral Dysplasia Type B (MAD-B / MADB) MONDO ID: MONDO:0012074 · OMIM: #608612 · Causal gene: ZMPSTE24 (FACE1), OMIM 606480, HGNC:12877, chromosome 1p34.2 Category: Mendelian, autosomal recessive progeroid laminopathy

Summary

Mandibuloacral dysplasia type B (MAD-B) is an ultra-rare, autosomal recessive progeroid laminopathy caused by biallelic hypomorphic (residual-activity) mutations in ZMPSTE24 (FACE1), the zinc metalloprotease that performs the final endoproteolytic maturation of prelamin A into mature lamin A. When ZMPSTE24 activity is reduced, toxic farnesylated, carboxymethylated prelamin A accumulates at the inner nuclear membrane, disrupting nuclear lamina architecture and triggering a cascade of downstream pathology: defective DNA-damage repair, epigenetic/chromatin dysregulation (H4K16 hypoacetylation, aberrant H3K9me3), AKT–mTOR pathway activation, oxidative/mitochondrial stress, and premature cellular senescence. These converge on the characteristic multisystem clinical picture of growth failure, craniofacial and skeletal dysplasia (mandibular and clavicular hypoplasia, delayed cranial suture closure, acro-osteolysis of distal phalanges), generalized (type B) lipodystrophy with insulin resistance and metabolic complications, and progeroid skin/hair changes (mottled atrophic skin, sparse brittle hair, hypoplastic nails).

A central organizing principle of this disease is a gene-dosage/enzyme-activity severity gradient shared with its allelic disorder restrictive dermopathy (RD): complete ZMPSTE24 loss-of-function (biallelic null) causes neonatally lethal RD, whereas variants that preserve residual prelamin A-processing activity cause the milder, survivable MAD-B. This genotype–phenotype correlation is quantitatively supported across case series and is biologically mirrored in Zmpste24-deficient mouse models, which recapitulate the bone, muscle, lipodystrophy, immune, and epigenetic phenotypes and have supported mechanism-targeted therapeutic proof-of-concept (isoprenylcysteine methylation inhibition, RCE1/ICMT targeting, SUV39H1 depletion, RANKL inhibition).

There is no approved disease-modifying therapy for MAD-B. Management is multidisciplinary and symptomatic, targeting the disease components: metabolic control of the lipodystrophy/diabetes/hypertriglyceridemia (including leptin replacement with metreleptin, the only approved therapy for generalized lipodystrophy), bone/orthopedic care, and dermatologic and dental surveillance. Prenylation-targeted drugs borrowed from the Hutchinson–Gilford progeria (HGPS) paradigm — notably the farnesyltransferase inhibitor lonafarnib, which rescues nuclear morphology in MAD-B patient fibroblasts — represent the most mechanistically rational experimental strategy.

Evidence-source key: [H] human clinical · [M] model organism · [V] in vitro · [C] computational/database. Primary citations are given as PMIDs; database-level identifiers are aggregated resource knowledge.

1. Disease Information

Overview. MAD-B is a rare autosomal recessive progeroid disorder of the mandibuloacral dysplasia (MAD) spectrum, defined molecularly by mutations in ZMPSTE24 and clinically by the combination of mandibular and clavicular hypoplasia, acro-osteolysis, delayed cranial suture closure, generalized lipodystrophy, and progeroid skin features. It belongs to the laminopathies — disorders of the nuclear lamina — and specifically to the subgroup caused by defective post-translational processing of prelamin A.

Key identifiers.

Resource Identifier
MONDO MONDO:0012074
OMIM (phenotype) #608612 (Mandibuloacral dysplasia with type B lipodystrophy; MADB)
Causal gene ZMPSTE24 / FACE1 (OMIM 606480, HGNC:12877, 1p34.2)
Disease class Autosomal recessive progeroid laminopathy

Synonyms / alternative names. Mandibuloacral dysplasia with type B lipodystrophy; MADB; MAD type B; MAD-B; ZMPSTE24-related mandibuloacral dysplasia; mandibuloacral dysplasia with generalized lipodystrophy.

Information source. The knowledge base here derives from aggregated resources plus individual patient case reports and small case series — MAD-B is ultra-rare, and the strongest clinical dataset is an aggregate of 20 genetically confirmed patients, anchored by an 8-patient Suriname founder cohort [H] (PMID: 31856865).

2. Etiology

Primary cause — genetic. MAD-B is caused by biallelic (homozygous or compound heterozygous) mutations in ZMPSTE24, reducing zinc-metalloprotease activity and impairing prelamin A processing. This is a Mendelian, monogenic disease; it is not infectious, and there is no primary environmental cause.

"MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24." — [H] PMID: 31856865

"Mutation in ZMPSTE24 gene, encoding a major metalloprotease, leads to defective prelamin A processing and causes type B mandibuloacral dysplasia, as well as the lethal neonatal restrictive dermopathy syndrome." — [H] PMID: 21267004

Genetic risk factors. The causal variants themselves are the risk determinant. Severity depends on the residual enzyme activity conferred by the specific genotype (Finding F002). Consanguinity and founder effects increase recurrence risk — the Suriname cohort (n=8) is homozygous for a single founder allele, c.1196A>G p.(Tyr399Cys).

Environmental / iatrogenic modifiers. Although MAD-B is genetic, the same enzymatic pathway can be inhibited pharmacologically: HIV protease inhibitors (notably lopinavir) inhibit ZMPSTE24 and phenocopy prelamin A pathology, causing acquired lipodystrophy (Finding F009). This is an acquired/iatrogenic analogue rather than a cause of Mendelian MAD-B, but it establishes a key gene–environment convergence on ZMPSTE24.

Protective factors. No established genetic or environmental protective alleles are documented for MAD-B. Mechanistically, interventions that reduce prelamin A prenylation/methylation (e.g., ICMT or RCE1 loss, FTIs) are protective in models — a therapeutic inference, not a naturally occurring protective factor.

3. Phenotypes

The phenotype is a multisystem progeroid syndrome. Major clinical criteria were defined across all 20 genetically confirmed patients, each present in 85–100% of affected individuals [H] (PMID: 31856865).

"Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmen[tation]..." — PMID: 31856865

"MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges." — PMID: 31856865

Phenotype Type Suggested HPO term Frequency Onset / course
Short stature / growth failure Physical HP:0004322 High (major, 85–100%) Childhood; progressive
Mandibular hypoplasia Clinical sign HP:0000347 High (major) Childhood
Clavicular hypoplasia Clinical sign HP:0006660 High (major) Childhood
Delayed cranial suture closure Clinical sign HP:0000270 High (major) Childhood
High/narrow palate Clinical sign HP:0000218 High (major) Congenital/childhood
Dental crowding Clinical sign HP:0000678 High (major) Childhood
Acro-osteolysis of distal phalanges Radiographic HP:0009771 High (major) Childhood; progressive
Hypoplastic nails Physical HP:0001792 High (major) Childhood
Brittle / sparse hair Physical HP:0002213 / HP:0008070 High (major) Childhood
Mottled pigmentation / atrophic skin Physical HP:0001000 / HP:0000963 High (major) Childhood; progressive
Generalized (type B) lipodystrophy Physical/metabolic HP:0009125 Core feature Childhood; progressive
Insulin resistance / diabetes mellitus Laboratory HP:0000855 / HP:0000857 Common Childhood–adolescence
Hypertriglyceridemia Laboratory HP:0002155 Common Childhood–adolescence
Congenital myopathy (reported) Clinical sign HP:0003198 Variable/rare Homozygous missense case (PMID: 21267004)

Severity / progression. Features are generally progressive and chronic (bone resorption, lipodystrophy, skin atrophy worsen over time), but the overall course is slowly progressive and survivable into adulthood (contrast lethal RD — Section 8). Expressivity is variable, even within the same genotype.

Quality-of-life impact. Short stature, craniofacial/orthopedic abnormalities, and skin/hair changes affect appearance, dentition, and mobility; metabolic complications (diabetes, hypertriglyceridemia) impose chronic disease burden. Disease-specific validated QoL instruments for MAD-B are not available; impact is inferred from the lipodystrophy and progeroid literature.

4. Genetic / Molecular Information

Causal gene. ZMPSTE24 (also FACE1; zinc metallopeptidase STE24), encoding a membrane-bound zinc metalloprotease of the inner nuclear/ER membrane that cleaves farnesylated prelamin A. Gene OMIM 606480; phenotype OMIM #608612.

Variant spectrum (Finding F007). MAD-B variants span missense, frameshift, and splice-site classes, unified by preservation of some residual enzyme activity:

Variant (cDNA) Protein Type Note Source
c.1196A>G p.(Tyr399Cys) Missense Suriname homozygous founder allele (n=8) PMID: 31856865
c.281T>C p.(Leu94Pro) Missense Reported MAD-B literature spectrum
c.794A>G p.(Asn265Ser) Missense Compound het with frameshift PMID: 30919593
c.1085dup p.(Leu362Phefs*19) Frameshift Compound het (Chile case) PMID: 30919593
c.1077dupT p.(Leu362fsX18) Frameshift Mosaic UPD chr1; intermediate phenotype PMID: 29341437
c.28_29insA p.(Leu10Tyrfs*37) N-terminal frameshift Rescued by downstream alternative start codon PMID: 35597529
c.378+1G>A — Splice-site Homozygous (Chinese MAD case report) PMID: 38544690

A notable molecular phenomenon is alternative translation initiation rescue: N-terminal frameshifts predicted to be null instead use a downstream in-frame start codon, yielding a hypomorphic (residual-activity) protein that produces survivable MAD-B rather than lethal RD.

"the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS)" — [H/V] PMID: 35597529

"mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype" — [H/V] PMID: 37270786

Variant classification. Reported MAD-B alleles are classified pathogenic/likely pathogenic (ACMG/AMP), supported by segregation, recessive genotype, functional reduction in prelamin A processing, and phenotype concordance. Allele frequencies in population databases (gnomAD) are very low/absent, consistent with recessive disease.

Functional consequence. Loss of function of ZMPSTE24 protease activity → toxic accumulation of farnesylated prelamin A (a gain-of-toxic-function at the substrate level). Severity scales inversely with residual activity (Finding F002).

Origin. Germline, biallelic. One reported patient had an unusual mosaic uniparental isodisomy of chromosome 1 unmasking a ZMPSTE24 variant (PMID: 29341437).

Modifier genes / epigenetics. In models, modifiers of the prelamin A pathway alter severity: SUV39H1 (H3K9 methyltransferase) depletion improves DNA repair and lifespan; ICMT and RCE1 (prenyl-processing enzymes) modulate prelamin A toxicity. Epigenetic changes downstream of ZMPSTE24 loss include H4K16 hypoacetylation and altered H3K9me3 (Section 6).

5. Environmental Information

MAD-B is a monogenic genetic disease; no environmental, lifestyle, or infectious agent causes it. However, the ZMPSTE24 enzyme is a documented pharmacologic target: HIV protease inhibitors inhibit ZMPSTE24 and phenocopy prelamin A disease (acquired lipodystrophy, accelerated cellular senescence), establishing an environmental/iatrogenic analogue of the genetic defect (Finding F009).

"lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability, which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway" — [M/H] PMID: 40461512

No infectious agents are implicated.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic hypomorphic ZMPSTE24 mutation reduces zinc-metalloprotease activity (demonstrated).
  2. This results in defective endoproteolytic maturation of prelamin A → lamin A (demonstrated).
  3. Which leads to accumulation of farnesylated, carboxymethylated prelamin A anchored at the inner nuclear membrane (demonstrated).
  4. Accumulated prelamin A disrupts nuclear lamina architecture / nuclear morphology (misshapen nuclei) (demonstrated in patient fibroblasts; rescued by FTI).
  5. Lamina disruption branches into several downstream effects:
  6. 5a. Impaired DNA-damage repair via H4K16 hypoacetylation (reduced Mof association with nuclear matrix) and aberrant H3K9me3 (SUV39H1-dependent) → genomic instability (demonstrated in mouse).
  7. 5b. Prelamin A–dependent activation of AKT–mTOR signaling (prelamin A–AKT interaction) → altered proliferation/senescence balance (demonstrated).
  8. 5c. Mitochondrial dysfunction and oxidative stress, prominent in adipose tissue (demonstrated proteomically).
  9. These converge on premature cellular senescence and tissue-specific stem/progenitor depletion (demonstrated).
  10. Senescence + progenitor depletion in skeletal stem/progenitor cells, adipocytes, osteocytes, and other lineages results in the clinical phenotype: bone dysplasia/acro-osteolysis, generalized lipodystrophy with insulin resistance, progeroid skin/hair, and growth failure (inferred from model + human concordance).

Detailed mechanism

Molecular pathways. The central lesion is in the prelamin A post-translational processing pathway (farnesylation → –AAX cleavage → carboxymethylation → ZMPSTE24-mediated 15-residue upstream cleavage to mature lamin A). Downstream signaling nodes include AKT–mTOR (activated by prelamin A), the Usp7/Mdm2/p53 senescence axis (shown pharmacologically with lopinavir), and NF-κB (B-lymphopoiesis in marrow).

"triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts." — [M/V] PMID: 23686339

Cellular processes. Premature cellular senescence (GO:0090398), cell-cycle dysregulation, DNA-damage response (GO:0006974), and stem/progenitor cell depletion are core. scRNA-seq of conditional Zmpste24 deletion shows loss of skeletal stem/progenitor cell populations drives bone loss [M] (PMID: 37407584).

Protein dysfunction. Loss of ZMPSTE24 catalytic function → persistent farnesyl/methyl modification of prelamin A, which anchors it to the nuclear envelope as a toxic species (gain-of-toxic-function at the substrate).

Epigenetic changes. H4K16 hypoacetylation (reduced Mof HAT at nuclear matrix) and SUV39H1-dependent H3K9me3 dysregulation link lamina disruption to defective DNA repair.

"histone H4 was hypoacetylated at a lysine 16 residue (H4K16), and this defect was attributed to the reduced association of a histone acetyltransferase, Mof, to the nuclear matrix" — [M] PMID: 21746928

Metabolic / mitochondrial. Adipose-tissue proteomics in Zmpste24-/- mice reveal major mitochondrial changes and vimentin processing alterations, tying defective prelamin A processing to lipoatrophy and oxidative damage.

"support the relationship between defective prelamin A processing and mitochondrial dysfunction and highlight the relevance of oxidative damage in lipoatrophy and aging" — [M] PMID: 21828285

Immune involvement. Prelamin A accumulation compromises NF-κB-regulated B-lymphopoiesis via the bone-marrow microenvironment in the progeria mouse model [M] (PMID: 24764515).

Ontology suggestions. Biological processes: GO:0006508 (proteolysis), GO:0006974 (DNA damage response), GO:0090398 (cellular senescence), GO:0006629 (lipid metabolic process). Cell types: CL:0000136 (adipocyte), CL:0000062 (osteoblast), CL:0000137 (osteocyte), CL:0000057 (fibroblast), skeletal stem/progenitor cell. Cellular components: GO:0005637 (nuclear inner membrane), GO:0005635 (nuclear envelope), GO:0005739 (mitochondrion). Chemicals: CHEBI:24017 (farnesyl group); farnesyltransferase inhibitor class.

Mechanistic schematic

ZMPSTE24 biallelic hypomorphic mutation
    │ (reduced zinc-metalloprotease activity)
    ▼
Defective prelamin A → lamin A maturation
    │
    ▼
Accumulation of FARNESYLATED PRELAMIN A at inner nuclear membrane
    │
    ▼
Nuclear lamina disruption / abnormal nuclear morphology ──► (rescued by lonafarnib)
     │              │                 │
     ▼              ▼                 ▼
 Impaired       AKT–mTOR          Mitochondrial
 DNA repair     activation        dysfunction &
 (H4K16↓,                         oxidative stress
 H3K9me3 dysreg)                  (adipose)
     │              │                 │
     └──────────────┴─────────────────┘
    ▼
 PREMATURE CELLULAR SENESCENCE +
 stem/progenitor depletion
    ▼
 ┌──────────────┬──────────────────┬─────────────────┐
 ▼              ▼                  ▼                 ▼
Bone dysplasia  Generalized       Progeroid         Growth
acro-osteolysis lipodystrophy +   skin/hair         failure
insulin resistance

7. Anatomical Structures Affected

  • Skeletal system (primary). Mandible (UBERON:0001684), clavicle (UBERON:0001105), cranial sutures (UBERON:0007842), distal phalanges (acro-osteolysis; UBERON:0004248), skull/palate. Bone loss is driven by skeletal stem/progenitor cell senescence and osteocyte–RANKL signaling.
  • Adipose tissue (primary). Generalized loss of subcutaneous and visceral adipose tissue (UBERON:0001013); mitochondrial dysfunction in adipocytes.
  • Skin and appendages. Skin (UBERON:0002097) — mottled, atrophic; hair (brittle/sparse); nails (hypoplastic).
  • Endocrine/metabolic (secondary). Insulin resistance, diabetes mellitus, hypertriglyceridemia — consequences of lipodystrophy and leptin deficiency.
  • Muscle. Congenital myopathy reported in a homozygous missense case (PMID: 21267004); muscle wasting prominent in Zmpste24-/- mice.
  • Hematopoietic/immune (model-level). Impaired B-lymphopoiesis in the marrow microenvironment (mouse).
  • Subcellular. Nuclear envelope / inner nuclear membrane (GO:0005637), nuclear lamina, mitochondria (GO:0005739).
  • Lateralization. Skeletal features are generally bilateral/symmetric.

8. Temporal Development

Onset. Postnatal / childhood onset; chronic, insidious course (Finding F011). This contrasts sharply with the allelic restrictive dermopathy (RD), the ZMPSTE24-null disorder with congenital taut translucent skin, joint contractures, and death usually within the first month of life.

"death usually occurring within the first month of life" (lethal neonatal RD) — [H] PMID: 41877632

Progression. Slowly progressive and chronic/lifelong; skeletal resorption, lipodystrophy, and skin atrophy worsen over time. A 30-year longitudinal clinical survey of a ZMPSTE24-mutant progeroid patient documents survival into and through adulthood.

"we report a 30-year longitudinal clinical survey of a patient" — [H] PMID: 21267004

Severity continuum. Position on the RD ↔ MAD-B continuum is set by residual ZMPSTE24 activity / prelamin A burden (Finding F002). An "intermediate form" genocopying severe progeria has been described (PMID: 29341437).

Critical window. Mechanism-targeted interventions in models work best when started early (e.g., Rce1 knockout at postnatal week 4–5 doubled median survival), suggesting an early-childhood window of opportunity.

9. Inheritance and Population

  • Inheritance. Autosomal recessive (biallelic ZMPSTE24).
  • Penetrance. Effectively complete for biallelic pathogenic genotypes; expressivity is variable across (and within) genotypes.
  • Prevalence/incidence. Ultra-rare; precise prevalence not established. Only ~20 genetically confirmed patients form the aggregate clinical dataset; reported as isolated cases and small series worldwide.
  • Founder effects / consanguinity. A homozygous founder mutation (c.1196A>G, p.Tyr399Cys) underlies the 8-patient Suriname cohort — a clear founder effect. Consanguinity increases recurrence risk; several reported cases arise from consanguineous or isolated-population backgrounds.
  • Geographic distribution. Reported globally (Suriname, Chile, China, and others); no single endemic region beyond founder clusters.
  • Sex ratio. Autosomal recessive — expected 1:1 male:female.
  • Carrier frequency. Not formally established; expected very low given rarity.

10. Diagnostics

Clinical/imaging. Diagnosis is suspected from the characteristic constellation: short stature, mandibular/clavicular hypoplasia, delayed cranial suture closure, high palate, dental crowding, radiographic acro-osteolysis of distal phalanges, hypoplastic nails, sparse brittle hair, mottled atrophic skin, and generalized lipodystrophy. Skeletal survey/radiography demonstrates clavicular hypoplasia and acro-osteolysis. Metabolic labs show insulin resistance, hyperglycemia/diabetes, and hypertriglyceridemia.

Cellular/functional. Skin fibroblasts show abnormal nuclear morphology (misshapen nuclei) from prelamin A accumulation — a supportive in vitro finding reversible with FTI (lonafarnib).

Genetic testing (confirmatory, gold standard). - Single-gene sequencing of ZMPSTE24 confirms the diagnosis. - Gene panels (lipodystrophy / laminopathy / progeroid panels including LMNA, ZMPSTE24, POLD1, MTX2) and whole-exome sequencing (WES) are effective when phenotypes overlap other MAD/progeroid syndromes. - WGS/WES also detect unusual mechanisms (e.g., mosaic uniparental isodisomy of chromosome 1 unmasking a ZMPSTE24 allele — PMID: 29341437). - Functional confirmation: reduced prelamin A processing / prelamin A accumulation on immunoblot.

Clinical diagnostic criteria. Formal major/minor criteria and management guidelines were proposed from the 20-patient aggregate (PMID: 31856865; Finding F003).

Differential diagnosis (Finding F006).

Disorder Gene Distinguishing feature
MAD type A LMNA Partial (type A) lipodystrophy
MAD type B ZMPSTE24 Generalized (type B) lipodystrophy
Restrictive dermopathy ZMPSTE24 (null) Neonatal lethal; taut translucent skin, contractures
Hutchinson–Gilford progeria LMNA (progerin) Severe vascular disease; distinct skeletal pattern
MDPL POLD1 Deafness, male hypogonadism
MDPS MTX2 (null) Arterial calcification, renal glomerulosclerosis, hypertension
MDP syndrome unknown Sensorineural deafness; no clavicular hypoplasia/acro-osteolysis (PMID: 20631028)
Hallermann–Streiff syndrome unknown (not a laminopathy) Congenital cataracts; no ZMPSTE24/LMNA pathogenic variants (PMID: 22570643)

"The molecular defects associated with MAD are mutations in LMNA or ZMPSTE24 (FACE1) gene, causing type A or type B MAD, respectively." — [H] PMID: 29208544

"We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia" — [H] PMID: 32917887

Screening. Carrier screening / cascade testing in affected families (especially founder populations); prenatal / preimplantation genetic diagnosis is feasible once familial variants are known.

11. Outcome / Prognosis

  • Survival. Unlike lethal neonatal RD, MAD-B is survivable into adulthood; a 30-year longitudinal survey documents long-term survival (PMID: 21267004). Prognosis is set by residual enzyme activity.
  • Morbidity. Substantial chronic morbidity from skeletal dysplasia (acro-osteolysis, fractures, deformity), lipodystrophy-driven metabolic disease (diabetes, severe hypertriglyceridemia with pancreatitis risk, hepatic steatosis), and progeroid skin/dental problems.
  • Complications. Metabolic complications of generalized lipodystrophy; orthopedic complications; potential cardiac repolarization abnormalities reported in prelamin A disorders (progeroid models/HGPS) warrant surveillance.
  • Prognostic factors. Degree of residual ZMPSTE24 activity / prelamin A accumulation (molecular prognostic axis); severity of metabolic complications.
  • Recovery. No cure; recovery is not expected, but metabolic management substantially modifies morbidity.

12. Treatment

No disease-modifying therapy is approved for MAD-B; management is multidisciplinary and symptomatic (Finding F010). Management guidelines accompany the diagnostic criteria (PMID: 31856865).

Metabolic / lipodystrophy management. - Metreleptin (recombinant leptin; NCIT: leptin replacement therapy / metreleptin) — the only approved therapy for generalized lipodystrophy and mechanistically applicable to MAD-B's leptin-deficient generalized lipodystrophy. In generalized lipodystrophy cohorts it produced significant reductions in HbA1c and triglycerides.

"Significant short-term median reductions from baseline were observed for HbA1c (- 1.4%; n = 26), fasting plasma glucose (- 0.5 mmol/L; n = 21); fasting triglycerides (TG; -1.5 mmol/L; n = 26)" — [H] PMID: 42507316

  • Standard metabolic agents (insulin sensitizers, lipid-lowering agents), diet, and exercise for diabetes/hypertriglyceridemia.

Mechanism-targeted / experimental (prenylation-directed). - Lonafarnib (farnesyltransferase inhibitor; NCIT: farnesyltransferase inhibitor) improves abnormal nuclear morphology in ZMPSTE24-deficient MAD-B patient fibroblasts, providing direct in vitro rationale.

"Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A..." — [V] PMID: 38050983

  • The HGPS triple-therapy paradigm (lonafarnib + pravastatin + zoledronic acid) improved bone mineral density and weight gain in trial, supporting translation to prelamin A disorders.

"Secondary improvements included increased areal (P=0.001) and volumetric (P<0.001-0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (P<0.001)." — [H] PMID: 27400896

  • Model-level strategies with translational promise: ICMT inhibition (delays senescence), RCE1 targeting (doubled median survival in mice), SUV39H1 depletion (~60% lifespan extension in mice), RANKL inhibition (antiresorptive; improves bone, muscle, lifespan in progeroid mice), and mTOR modulation.

Supportive / surgical. Orthopedic/dental surveillance and intervention; physical therapy; dermatologic care; growth and nutritional management.

Pharmacovigilance. Avoid HIV protease inhibitors where alternatives exist, since they inhibit ZMPSTE24 and could worsen prelamin A pathology (Finding F009).

13. Prevention

  • Primary prevention. Not possible for a Mendelian disease; prevention centers on genetic counseling and reproductive options.
  • Genetic counseling / carrier & cascade testing. Autosomal recessive recurrence risk of 25% for carrier couples; cascade testing in founder populations (e.g., Suriname). Prenatal diagnosis and preimplantation genetic testing available once familial variants are known.
  • Secondary prevention. Early detection and management of metabolic complications (diabetes, hypertriglyceridemia) and bone disease.
  • Tertiary prevention. Multidisciplinary surveillance to prevent complications (orthopedic, metabolic, dental, cardiac).
  • Iatrogenic avoidance. Caution with ZMPSTE24-inhibiting drugs (HIV protease inhibitors).

14. Other Species / Natural Disease

  • Orthology. ZMPSTE24 is evolutionarily conserved (yeast Ste24 ortholog); mouse Zmpste24 is the functional ortholog used to model the disease. The prelamin A processing pathway is conserved across mammals.
  • Natural disease in other species. No well-characterized naturally occurring animal analogue of MAD-B is documented; disease knowledge comes from engineered mouse models rather than spontaneous veterinary cases.
  • Comparative biology. Zmpste24-/- mice recapitulate core human features (progeroid phenotype, osteoporosis, lipodystrophy, muscle wasting), supporting strong cross-species mechanism conservation.
  • Zoonotic potential. Not applicable (non-infectious genetic disease).

15. Model Organisms

The principal model is the Zmpste24-deficient (knockout) mouse, which accumulates prelamin A and develops progeroid features closely paralleling human prelamin A disorders (Finding F008).

Model Type Key phenotype / finding Source
Zmpste24-/- mouse Global knockout Prelamin A accumulation; osteoporosis/fractures, muscle wasting, lipodystrophy, short lifespan multiple
Suv39h1-depleted Zmpste24-/- Compound genetic Improved DNA repair; ~60% lifespan extension PMID: 23695662
Rce1-knockout Zmpste24-/- Compound genetic Delayed senescence; doubled median survival PMID: 32910507
RANKL-targeted progeroid mice Therapeutic Prevented bone loss, improved muscle function, extended lifespan PMID: 42572248
Prx1-Cre; Zmpste24 conditional Conditional KO SSPC depletion drives bone loss (scRNA-seq) PMID: 37407584
Zmpste24-/- B-lymphopoiesis Global KO Prelamin A impairs NF-κB-dependent B-lymphopoiesis via marrow niche PMID: 24764515
MAD-B patient fibroblasts In vitro Abnormal nuclear morphology; rescued by lonafarnib PMID: 38050983

"loss of Suv39h1 in Zmpste24(-/-) mice delays body weight loss, increases bone mineral density and extends lifespan by ∼60%" — [M] PMID: 23695662

"Lack of Zmpste24, a metalloproteinase responsible for prelamin A processing, leads to progeroid features resembling HGPS." — [M] PMID: 24764515

"an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice" — [M] PMID: 42572248

Recapitulation / limitations. The mouse recapitulates bone, muscle, lipodystrophy, immune, and epigenetic phenotypes and supports therapeutic proof-of-concept. Limitations include species differences in lifespan and that complete-null mouse models represent the more severe end of the ZMPSTE24-deficiency spectrum (closer to RD) rather than hypomorphic MAD-B; patient fibroblasts better capture the residual-activity MAD-B state.

Key Findings (with evidence)

  1. MAD-B is an autosomal recessive laminopathy caused by biallelic ZMPSTE24 mutations reducing prelamin A processing (F001). Case series and reviews consistently attribute MAD-B to compound heterozygous/homozygous ZMPSTE24 mutations reducing zinc-metalloprotease activity and causing accumulation of unprocessed farnesylated prelamin A; the Suriname founder cohort (n=8) all carried homozygous c.1196A>G p.(Tyr399Cys). [PMID: 31856865, 21267004]

  2. Residual ZMPSTE24 activity sets an allelic severity gradient from lethal RD to MAD-B (F002). Complete LoF (biallelic null) → neonatally lethal restrictive dermopathy; residual-activity variants → survivable MAD-B; severity correlates with residual activity and prelamin A burden. [PMID: 41877632, 21267004]

  3. Clinical diagnostic criteria defined from a 20-patient aggregate (F003). Major criteria present in 85–100%: short stature, clavicular hypoplasia, delayed suture closure, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis, hypoplastic nails, brittle/sparse hair, mottled pigmentation, plus generalized lipodystrophy and metabolic complications. [PMID: 31856865]

  4. Prelamin A accumulation drives downstream AKT–mTOR activation, senescence, DNA-repair defects, and oxidative/mitochondrial stress (F004). [PMID: 23686339, 21746928, 21828285]

  5. Lonafarnib (FTI) rescues nuclear morphology in MAD-B fibroblasts, supporting prenylation-targeted therapy; HGPS triple-therapy trial improved bone density and weight (F005). [PMID: 38050983, 27400896]

  6. MAD-B sits within a gene-defined classification of mandibuloacral dysplasias/progeroid differentials (F006). [PMID: 29208544, 32917887]

  7. ZMPSTE24 variant spectrum spans missense, frameshift, and splice variants, with N-terminal frameshifts rescued by alternative translation initiation (F007). [PMID: 37270786, 35597529, 30919593]

  8. The Zmpste24-/- mouse is the principal model, recapitulating bone, muscle, lipodystrophy, immune, and epigenetic defects and supporting therapeutic targets (F008). [PMID: 23695662, 24764515, 42572248, 37407584]

  9. Pharmacologic ZMPSTE24 inhibition (HIV protease inhibitors) phenocopies prelamin A disease (F009). [PMID: 40461512]

  10. Management is multidisciplinary/symptomatic; metreleptin addresses the leptin-deficient generalized lipodystrophy and metabolic complications (F010). [PMID: 42507316, 31856865]

  11. MAD-B has postnatal/childhood onset with a chronic, slowly progressive course and survival into adulthood, unlike lethal neonatal RD (F011). [PMID: 41877632, 21267004]

Evidence Base (selected literature)

PMID Role Contribution
31856865 Anchor clinical Suriname cohort, founder mutation, diagnostic criteria & management
21267004 Clinical/mechanism MAD-B with congenital myopathy; genotype–severity correlation; 30-yr survey
41877632 Allelic contrast RD vs MAD-B activity gradient; lethal neonatal course of RD
37270786 / 35597529 Variant biology Alternative translation initiation rescue converting null→hypomorph
30919593 Variant Compound het variants (Chile)
29341437 Variant/mechanism Mosaic UPD chr1; phenotypic heterogeneity; intermediate form
23686339 Mechanism AKT–mTOR activation by prelamin A; ICMT targeting
21746928 Mechanism H4K16 hypoacetylation and DNA-repair defect
21828285 Mechanism Adipose mitochondrial dysfunction/oxidative stress
38050983 Therapy Lonafarnib rescues nuclear morphology in MAD-B fibroblasts
27400896 Therapy HGPS triple-therapy trial outcomes
23695662 / 32910507 / 42572248 / 24764515 / 37407584 Models Zmpste24-/- mouse mechanisms & therapeutic modifiers
40461512 Environmental HIV protease inhibitor ZMPSTE24 inhibition phenocopy
42507316 Therapy Metreleptin metabolic benefit in generalized lipodystrophy
29208544 / 32917887 Classification MAD A/B gene definitions; MTX2/MDPS differential

Evidence source types. Human clinical (case series/reports, diagnostic-criteria aggregate), in vitro (patient fibroblasts, FTI rescue), and model organism (mouse genetic/therapeutic studies) all contribute. Mechanistic depth is strongest from mouse models and shared prelamin A/HGPS biology; MAD-B-specific clinical data are limited by rarity.

Limitations and Knowledge Gaps

  • Small clinical denominator. The strongest clinical dataset is ~20 genetically confirmed patients; frequencies, QoL, and natural-history metrics carry wide uncertainty. No formal prevalence/incidence exists.
  • Mechanism extrapolation. Much mechanistic detail (AKT–mTOR, H4K16, mitochondrial, immune) derives from Zmpste24-/- null mice and HGPS, which model the severe end; the hypomorphic residual-activity state specific to MAD-B is less directly studied in vivo.
  • No MAD-B-specific therapeutic trials. Metreleptin and FTI evidence is extrapolated from generalized lipodystrophy and HGPS cohorts, not MAD-B trials.
  • Genotype–phenotype quantitation. The activity gradient is well-supported qualitatively but lacks systematic quantitative mapping of residual activity to specific phenotype severity across the full variant spectrum.
  • Cardiac risk in MAD-B specifically (vs HGPS/model repolarization data) is under-characterized.
  • Validated QoL instruments for MAD-B are absent.

Proposed Follow-up Experiments / Actions

  1. Patient-derived iPSC and organoid models (bone, adipose) carrying defined MAD-B hypomorphic alleles (e.g., p.Tyr399Cys) to study the residual-activity state and test prenylation-targeted drugs in a disease-specific context.
  2. Quantitative residual-activity assays across the reported ZMPSTE24 variant spectrum, correlated to clinical severity scores, to formalize genotype–phenotype prediction.
  3. Prospective registry / natural-history study (leveraging founder populations such as Suriname) to establish prevalence, progression rates, metabolic outcomes, cardiac surveillance needs, and validated QoL metrics.
  4. Pilot trials of metreleptin specifically in MAD-B generalized lipodystrophy, with metabolic endpoints (HbA1c, triglycerides, hepatic fat).
  5. Mechanism-targeted combination testing (FTI ± statin ± bisphosphonate; RANKL inhibition; mTOR/senolytic approaches) in MAD-B models, prioritizing early-window intervention informed by mouse survival data.
  6. Cardiac phenotyping (ECG/repolarization, imaging) in MAD-B patients given prelamin A cardiac electrical defects seen in progeroid models.
  7. Pharmacovigilance guidance formalizing avoidance of ZMPSTE24-inhibiting drugs (HIV protease inhibitors) in patients with prelamin A disorders.

Report compiled from 11 confirmed findings and 47 reviewed papers across 5 investigation iterations. Evidence spans human clinical case series, in vitro patient-fibroblast studies, and mouse model work; claims are cited to primary literature by PMID.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 24
On topic 21
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 37
Resolved 36
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 24
Terms named correctly 12
Terms named as a different term 11
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:

  • MONDO:0012074 (2 mentions) - the report calls it "MONDO"; MONDO calls it mandibuloacral dysplasia with type B lipodystrophy
  • HP:0004322 (1 mention) - the report calls it "Physical"; HP calls it Short stature
  • HP:0000347 (1 mention) - the report calls it "Clinical sign"; HP calls it Micrognathia
  • HP:0006660 (1 mention) - the report calls it "Clinical sign"; HP calls it Aplastic clavicle
  • HP:0000270 (1 mention) - the report calls it "Clinical sign"; HP calls it Delayed cranial suture closure
  • HP:0000218 (1 mention) - the report calls it "Clinical sign"; HP calls it High palate
  • HP:0000678 (1 mention) - the report calls it "Clinical sign"; HP calls it Dental crowding
  • HP:0009771 (1 mention) - the report calls it "Radiographic"; HP calls it Osteolytic defects of the phalanges of the hand
  • HP:0009125 (1 mention) - the report calls it "Physical/metabolic"; HP calls it Lipodystrophy
  • HP:0002155 (1 mention) - the report calls it "Laboratory"; HP calls it Hypertriglyceridemia
  • HP:0003198 (1 mention) - the report calls it "Clinical sign"; HP calls it Myopathy

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:

  • HP:0001792 (1 mention) - the report calls it "Physical"; HP calls it Small nail, and lists "Hypoplastic nail" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0006974 - called "DNA-damage response", "DNA damage response"