Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Summary

Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome (MONDO:0014725) is a disease caused by SLC1A4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC1A4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 31
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0011451	Congenital microcephaly	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000664	Synophrys	Occasional (5-29%)
HP:0000733	Abnormal repetitive mannerisms	Occasional (5-29%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002828	Multiple joint contractures	Occasional (5-29%)
HP:0003739	Myoclonic spasms	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0006808	Cerebral hypomyelination	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012167	Hair-pulling	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
Mondo ID	MONDO:0014725
OMIM	616657
Orphanet	447997
DOID	DOID:0070537
UMLS	C4225254
MedGen	900192
GARD	0013425
Is cancer (heuristic)	no

Also known as: ASCT1 deficiency · spastic quadriplegia-thin corpus callosum-progressive postnatal microcephaly syndrome · spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome · SPATCCM

Data availability: 31 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn serine deficiency › neurometabolic disorder due to serine deficiency › spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Related subtypes (4): PSAT deficiency, PSPH deficiency, 3-phosphoglycerate dehydrogenase deficiency, serine biosynthesis pathway deficiency, infantile/juvenile form

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

31 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 8 pathogenic, 6 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1699944	NM_003038.5(SLC1A4):c.971del (p.Asn324fs)	SLC1A4	Pathogenic	no assertion criteria provided
1699945	NM_003038.5(SLC1A4):c.542C>T (p.Ser181Phe)	SLC1A4	Pathogenic	no assertion criteria provided
1878540	NM_003038.5(SLC1A4):c.964C>T (p.Arg322Ter)	SLC1A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2499988	NM_003038.5(SLC1A4):c.2T>C (p.Met1Thr)	SLC1A4	Pathogenic	no assertion criteria provided
265259	NM_003038.5(SLC1A4):c.766G>A (p.Glu256Lys)	SLC1A4	Pathogenic	criteria provided, multiple submitters, no conflicts
372157	NM_003038.5(SLC1A4):c.944_945del (p.Leu315fs)	SLC1A4	Pathogenic	no assertion criteria provided
372158	NM_003038.5(SLC1A4):c.1369C>T (p.Arg457Trp)	SLC1A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
488671	NM_003038.5(SLC1A4):c.1035-381_1230-73del	SLC1A4	Pathogenic	criteria provided, single submitter
587615	NM_003038.5(SLC1A4):c.1364+1G>A	SLC1A4	Pathogenic	criteria provided, single submitter
932143	NM_003038.5(SLC1A4):c.1358G>A (p.Trp453Ter)	SLC1A4	Pathogenic	no assertion criteria provided
932144	NM_003038.5(SLC1A4):c.1141G>A (p.Gly381Arg)	SLC1A4	Pathogenic/Likely pathogenic	no assertion criteria provided
1723373	NM_003038.5(SLC1A4):c.885dup (p.Lys296fs)	SLC1A4	Likely pathogenic	criteria provided, single submitter
2500887	NM_003038.5(SLC1A4):c.925G>T (p.Gly309Ter)	SLC1A4	Likely pathogenic	criteria provided, single submitter
3024238	NM_003038.5(SLC1A4):c.344G>A (p.Gly115Asp)	SLC1A4	Likely pathogenic	criteria provided, single submitter
3586846	NM_003038.5(SLC1A4):c.807_810del (p.Pro270fs)	SLC1A4	Likely pathogenic	criteria provided, single submitter
3780612	NM_003038.5(SLC1A4):c.805_808dup (p.Pro270fs)	SLC1A4	Likely pathogenic	criteria provided, single submitter
800961	NM_003038.5(SLC1A4):c.1357T>C (p.Trp453Arg)	SLC1A4	Likely pathogenic	no assertion criteria provided
2575108	NM_003038.5(SLC1A4):c.1120G>A (p.Gly374Arg)	LINC02245	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1499237	NM_003038.5(SLC1A4):c.1439del (p.Lys480fs)	SLC1A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1685441	NM_003038.5(SLC1A4):c.1370G>A (p.Arg457Gln)	SLC1A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435984	NM_003038.5(SLC1A4):c.172_193del (p.Leu58fs)	SLC1A4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2435983	NM_003038.5(SLC1A4):c.570G>A (p.Thr190=)	SLC1A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2435985	NM_003038.5(SLC1A4):c.442C>T (p.Leu148Phe)	SLC1A4	Uncertain significance	criteria provided, single submitter
2585351	NM_003038.5(SLC1A4):c.1010C>A (p.Ala337Glu)	SLC1A4	Uncertain significance	criteria provided, single submitter
2684392	NM_003038.5(SLC1A4):c.1280G>A (p.Gly427Glu)	SLC1A4	Uncertain significance	criteria provided, single submitter
2690000	NM_003038.5(SLC1A4):c.1040C>A (p.Ala347Glu)	SLC1A4	Uncertain significance	criteria provided, single submitter
4080067	NM_003038.5(SLC1A4):c.1229T>G (p.Leu410Arg)	SLC1A4	Uncertain significance	criteria provided, single submitter
436740	NM_003038.5(SLC1A4):c.1520C>A (p.Ser507Ter)	SLC1A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
587616	NM_003038.5(SLC1A4):c.1316G>A (p.Gly439Glu)	SLC1A4	Uncertain significance	criteria provided, multiple submitters, no conflicts
801718	NM_003038.5(SLC1A4):c.272T>C (p.Leu91Pro)	SLC1A4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
SLC1A4	Definitive	Autosomal recessive	spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC1A4	Orphanet:447997	Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC1A4	HGNC:10942	ENSG00000115902	P43007	Neutral amino acid transporter A	gencc,clinvar
LINC02245	HGNC:53134	ENSG00000237638		long intergenic non-protein coding RNA 2245	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC1A4	Neutral amino acid transporter A	Sodium-coupled antiporter of neutral amino acids.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC1A4	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
LINC02245	Other/Unknown	no

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
buccal mucosa cell	1
gluteal muscle	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
monocyte	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC1A4	294	ubiquitous	marker	buccal mucosa cell, sperm, gluteal muscle
LINC02245	159	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC1A4	1,412
LINC02245	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC1A4	P43007	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Amino acid transport across the plasma membrane	1	300.5×	0.013	SLC1A4
R-HSA-425393	1	129.8×	0.015	SLC1A4
SLC-mediated transmembrane transport	1	59.2×	0.023	SLC1A4
Transport of small molecules	1	25.1×	0.040	SLC1A4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
threonine transport	1	16852.0×	4e-04	SLC1A4
hydroxyproline transport	1	16852.0×	4e-04	SLC1A4
L-serine import across plasma membrane	1	4213.0×	8e-04	SLC1A4
L-serine transport	1	3370.4×	8e-04	SLC1A4
L-alanine import across plasma membrane	1	3370.4×	8e-04	SLC1A4
L-cystine transport	1	2808.7×	8e-04	SLC1A4
L-aspartate import across plasma membrane	1	2808.7×	8e-04	SLC1A4
L-alanine transport	1	2407.4×	8e-04	SLC1A4
L-glutamine transport	1	1404.3×	0.001	SLC1A4
proline transport	1	1296.3×	0.001	SLC1A4
L-glutamate transmembrane transport	1	802.5×	0.002	SLC1A4
synaptic transmission, glutamatergic	1	358.6×	0.003	SLC1A4
amino acid transport	1	312.1×	0.004	SLC1A4
cognition	1	285.6×	0.004	SLC1A4
transport across blood-brain barrier	1	179.3×	0.006	SLC1A4

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
SLC1A4	0	0
LINC02245	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC1A4	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC1A4, LINC02245

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)
SLC1A4	2	—
LINC02245	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.