spondyloepimetaphyseal dysplasia, Bieganski type

disease

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Also known as H-SMDhypomyelination-spondyloepimetaphyseal dysplasia syndromeleukoencephalopathy with metaphyseal chondrodysplasialeukoencephalopathy-metaphyseal chondrodysplasia syndromeleukoencephalopathy-SEMD syndromeLKMCDSEMD X-linked with mental deteriorationspondyloepimetaphyseal dysplasia X-linked with mental deteriorationspondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, X-linked recessive

Summary

spondyloepimetaphyseal dysplasia, Bieganski type (MONDO:0010275) is a disease caused by AIFM1 (GenCC Strong), with 2 cohort genes.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: AIFM1 (GenCC Strong)
Cohort genes: 2
ClinVar variants: 19
Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0002352	Leukoencephalopathy	Very frequent (80-99%)
HP:0005871	Metaphyseal chondrodysplasia	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000587	Abnormal optic nerve morphology	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002062	Morphological abnormality of the pyramidal tract	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0003020	Enlargement of the wrists	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0012747	Abnormal brainstem MRI signal intensity	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0030866	Large knee	Frequent (30-79%)
HP:0100707	Abnormal astrocyte morphology	Frequent (30-79%)
HP:0000463	Anteverted nares	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0011800	Midface retrusion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia, Bieganski type
Mondo ID	MONDO:0010275
MeSH	C536671, C567065
OMIM	300232
Orphanet	83629, 168448
ICD-11	1073330593
UMLS	C1846148
MedGen	335350
GARD	0004891
Is cancer (heuristic)	no

Also known as: H-SMD · hypomyelination-spondyloepimetaphyseal dysplasia syndrome · leukoencephalopathy with metaphyseal chondrodysplasia · leukoencephalopathy-metaphyseal chondrodysplasia syndrome · leukoencephalopathy-SEMD syndrome · LKMCD · SEMD X-linked with mental deterioration · spondyloepimetaphyseal dysplasia X-linked with mental deterioration · spondyloepimetaphyseal dysplasia, X-linked, with hypomyelinating leukodystrophy, X-linked recessive

Data availability: 19 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia, Bieganski type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

19 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
694665	NM_004208.4(AIFM1):c.710A>G (p.Asp237Gly)	AIFM1	Pathogenic	no assertion criteria provided
694668	NM_004208.4(AIFM1):c.697-44T>G	AIFM1	Pathogenic	no assertion criteria provided
694667	NM_004208.4(AIFM1):c.705G>C (p.Gln235His)	RAB33A	Pathogenic	no assertion criteria provided
1327116	NM_004208.4(AIFM1):c.760G>A (p.Glu254Lys)	AIFM1	Likely pathogenic	criteria provided, single submitter
2412786	NM_004208.4(AIFM1):c.742G>A (p.Gly248Ser)	AIFM1	Likely pathogenic	criteria provided, single submitter
373913	NM_004208.4(AIFM1):c.1646C>T (p.Ala549Val)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
598756	NM_004208.4(AIFM1):c.720C>T (p.Asp240=)	AIFM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
932022	NM_004208.4(AIFM1):c.1770+12T>C	RAB33A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805860	NM_004208.4(AIFM1):c.649C>G (p.Leu217Val)	AIFM1	Uncertain significance	criteria provided, single submitter
2444375	NM_004208.4(AIFM1):c.1696T>A (p.Phe566Ile)	AIFM1	Uncertain significance	criteria provided, single submitter
642792	NM_004208.4(AIFM1):c.1693A>G (p.Ile565Val)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
836428	NM_004208.4(AIFM1):c.1586G>A (p.Arg529Gln)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
839040	NM_004208.4(AIFM1):c.253T>C (p.Tyr85His)	RAB33A	Uncertain significance	criteria provided, multiple submitters, no conflicts
136325	NM_004208.4(AIFM1):c.1833T>C (p.His611=)	AIFM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
543932	NM_004208.4(AIFM1):c.1227T>G (p.Thr409=)	AIFM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
136326	NM_004208.4(AIFM1):c.103C>T (p.Pro35Ser)	LOC130068679	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
367890	NM_004208.4(AIFM1):c.606-15C>T	RAB33A	Benign	criteria provided, multiple submitters, no conflicts
367892	NM_004208.4(AIFM1):c.273T>C (p.Asp91=)	RAB33A	Benign	criteria provided, multiple submitters, no conflicts
913255	NM_004208.4(AIFM1):c.597A>G (p.Lys199=)	RAB33A	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
AIFM1	Strong	X-linked	spondyloepimetaphyseal dysplasia, Bieganski type	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	gencc,clinvar
RAB33A	HGNC:9773	ENSG00000134594	Q14088	Ras-related protein Rab-33A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.
RAB33A	Ras-related protein Rab-33A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C
RAB33A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
apex of heart	1
heart left ventricle	1
C1 segment of cervical spinal cord	1
cortical plate	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle
RAB33A	207	ubiquitous	yes	cortical plate, C1 segment of cervical spinal cord, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIFM1	4,780
RAB33A	1,603

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAB33A	Q14088	81.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TBC/RABGAPs	1	259.6×	0.006	RAB33A
RAB geranylgeranylation	1	173.0×	0.006	RAB33A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein import into mitochondrial intermembrane space	1	2808.7×	0.003	AIFM1
protein import into the intermembrane space via the disulfide relay system	1	2808.7×	0.003	AIFM1
mitochondrial respiratory chain complex assembly	1	1404.3×	0.003	AIFM1
positive regulation of necroptotic process	1	1404.3×	0.003	AIFM1
cellular response to aldosterone	1	1203.7×	0.003	AIFM1
response to L-glutamate	1	842.6×	0.004	AIFM1
Rab protein signal transduction	1	495.6×	0.005	RAB33A
cellular response to nitric oxide	1	468.1×	0.005	AIFM1
antigen processing and presentation	1	351.1×	0.006	RAB33A
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.008	AIFM1
cellular response to estradiol stimulus	1	205.5×	0.009	AIFM1
positive regulation of neuron apoptotic process	1	135.9×	0.012	AIFM1
response to ischemia	1	125.8×	0.012	AIFM1
cellular response to hydrogen peroxide	1	117.0×	0.012	AIFM1
autophagosome assembly	1	112.3×	0.012	RAB33A
response to toxic substance	1	105.3×	0.012	AIFM1
cellular response to hypoxia	1	60.6×	0.019	AIFM1
neuron differentiation	1	50.1×	0.022	AIFM1
positive regulation of apoptotic process	1	28.4×	0.037	AIFM1
apoptotic process	1	14.3×	0.068	AIFM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AIFM1	0	0
RAB33A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AIFM1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	RAB33A

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
AIFM1	2	—
RAB33A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: AIFM1, RAB33A