Neurodevelopmental Disorder with Hearing Loss and Spasticity: Research Report

Executive summary

Neurodevelopmental disorder with hearing loss and spasticity (NEDHLS) is an ultra-rare, autosomal-recessive Mendelian disorder caused by biallelic germline variants in AFG2B, historically named SPATA5L1. Its defining phenotype comprises infantile-onset global developmental impairment, usually bilateral sensorineural hearing loss, and evolving motor dysfunction—most characteristically spasticity and/or dystonia. Epilepsy, microcephaly, cerebral or white-matter volume loss, delayed myelination, corpus-callosum hypoplasia, and dysmorphism are variable. The foundational report described 25 affected individuals; fewer than 30 had been reported before a detailed 2025 case, so robust prevalence, survival, penetrance, and genotype–phenotype estimates remain unavailable. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

The major recent advance is mechanistic. A 2024 Cell study established that AFG2B/SPATA5L1 participates with SPATA5, C1ORF109, and CINP in the 55LCC AAA+ ATPase complex, which maintains replisome proteostasis and genome integrity. Deficiency causes replication-fork stress first, followed by cohesion defects and micronucleation. This is strong biochemical and cellular evidence, but it does not yet prove exactly how particular neural and cochlear cell populations produce every clinical manifestation. (krishnamoorthy2024thespata5spata5l1atpase pages 1-3, krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

The following table provides a knowledge-base-oriented overview.

Table: This table summarizes high-confidence disease facts for AFG2B/SPATA5L1-related neurodevelopmental disorder with hearing loss and spasticity, including identifiers, phenotypes, mechanism, diagnostics, and current care gaps. It is designed as a compact knowledge-base artifact with suggested ontology mappings clearly labeled as suggestions.

1. Disease information

Definition and identifiers

• Preferred name: Neurodevelopmental disorder with hearing loss and spasticity.
• Abbreviation: NEDHLS.
• MONDO: MONDO:0859206.
• OMIM phenotype: 619616.
• Causal gene: AFG2B (current approved symbol in Open Targets; historical literature symbol SPATA5L1), Ensembl ENSG00000171763.
• Common names: AFG2B-related disorder; SPATA5L1-related neurodevelopmental disorder; SPATA5L1-related neurodevelopmental disorder with hearing loss and spasticity.
• Foundational publication: Richard et al., “Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss,” American Journal of Human Genetics 108:2006–2016, published October 2021; PMID 34626583; DOI 10.1016/j.ajhg.2021.08.003.
• Recent mechanism paper: Krishnamoorthy et al., Cell 187:2250–2268.e31, published April 2024; PMID 38554706; DOI 10.1016/j.cell.2024.03.002. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, krishnamoorthy2024thespata5spata5l1atpase pages 1-3, polczyk2025neurodevelopmentaldisorderwith pages 4-6)

No disease-specific MeSH descriptor or unique ICD-10/ICD-11 code was established in the retrieved evidence. In clinical coding, manifestations such as developmental disability, sensorineural hearing loss, epilepsy, dystonia, or spastic cerebral palsy would therefore generally require separate codes; this is not equivalent to a dedicated NEDHLS code.

The evidence is primarily aggregated disease-level evidence assembled from individually phenotyped patients, family segregation data, and experimental studies. It is not derived from a population-scale EHR cohort. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 9-10)

2. Etiology, risk, and protective factors

NEDHLS is caused by biallelic AFG2B/SPATA5L1 variants, usually homozygous or compound heterozygous, inherited in an autosomal-recessive pattern. The available data support loss of function or severe functional impairment—through truncation, impaired protein stability, defective complex assembly, or impaired ATPase/replisome-processing function—as the causal model. Patient-associated SPATA5L1 variants tested in the 2024 study compromised viability or 55LCC function; some behaved as partial-loss-of-function or hypomorphic alleles. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

A recent example is compound heterozygosity for c.1918C>T (p.Arg640Ter) and c.2066G>T (p.Gly689Val), inherited in trans from unaffected carrier parents. The reporting laboratory called p.Arg640Ter a VUS and p.Gly689Val likely pathogenic, while also noting ClinVar pathogenic classification for p.Gly689Val. The authors applied PVS1/PM2/PM3/PP4 reasoning to the truncating allele. These classifications should be re-evaluated against the current ClinVar record and ACMG/AMP specifications before clinical use. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

The p.Gly689Val allele is recurrent: it occurred in four people in the original 25-person cohort. Most other reported variants appear private, and the cohort is too small for reliable allele-specific prognosis. (polczyk2025neurodevelopmentaldisorderwith pages 6-7)

No validated susceptibility loci, modifier genes, protective alleles, environmental causes, lifestyle risks, infectious triggers, or gene–environment interactions are known. Consanguinity can increase the probability that partners carry the same rare allele but is not required; the 2025 case involved non-consanguineous parents. A de novo FRYL variant in that case was considered uncertain and potentially artifactual, not an established modifier. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

3. Phenotypes

The phenotype is congenital or infantile in biological origin, although clinical recognition usually occurs when developmental milestones or hearing are assessed. Exact cohort-wide percentages could not be verified from the accessible primary full text; qualitative frequencies below should not be converted into penetrance estimates.

• Global developmental/psychomotor delay and intellectual disability: core, often severe and persistent. Suggested HPO: HP:0001263, HP:0001249. In the 2025 patient, parental concern began at four months; at 14 months, motor organization approximated a 12-week developmental level. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
• Sensorineural hearing impairment: core and described as nearly universal in the literature summary. Suggested HPO: HP:0000407 and bilateral hearing impairment HP:0008619. The recent patient had bilateral 60-dBnHL loss diagnosed at seven months and received hearing aids. Hearing loss substantially affects speech-language acquisition and communication. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
• Motor disorder: spasticity and/or dystonia predominated in most members of the original cohort, producing a spastic-dystonic cerebral-palsy phenotype. Suggested HPO: HP:0001257, HP:0001332. Early hypotonia may precede hypertonia: the recent child remained centrally hypotonic at 14 months, later developing upper-limb stiffening. This supports age-dependent evolution rather than requiring spasticity in infancy. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
• Hypotonia: variable, particularly early. Suggested HPO: HP:0001252. It impairs antigravity posture, rolling, sitting, and mobility. (polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
• Epilepsy/EEG abnormality: common but not obligatory. Suggested HPO: HP:0001250, abnormal EEG HP:0010848. The recent child had no epileptiform activity at nine months; at approximately two years, bilateral sharp waves and other abnormalities appeared, but clinical epilepsy remained unconfirmed. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
• Microcephaly: variable. Suggested HPO: HP:0000252. The recent child’s head circumference was below the third percentile after age two. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
• MRI abnormalities: cerebral/cortical and white-matter volume loss, delayed myelination, periventricular T2 hyperintensity, mild ventriculomegaly, and thin/hypoplastic corpus callosum. Suggested HPO: HP:0002078, HP:0007058, HP:0002079, HP:0001273. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)
• Dysmorphism: variable and reported in roughly one-third according to the later literature summary; findings can include bitemporal narrowing, wide mouth, and epicanthal folds. Suggested HPO: HP:0001999, HP:0000286, and broad/wide mouth mapping after ontology validation. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
• Ophthalmic findings: strabismus, refractive errors, and occasionally cortical visual impairment. Suggested HPO: HP:0000486, hypermetropia HP:0000540, astigmatism HP:0000483. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 2-4)
• Primitive reflex persistence/abnormal postural reactions: potentially useful early motor signs, but not validated as disease-specific biomarkers. In one child, all seven Vojta postural reactions were abnormal at 11 and 14 months, and Moro, rooting, and Babkin reflexes persisted. (polczyk2025neurodevelopmentaldisorderwith pages 6-7)

No NEDHLS-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was found. Nevertheless, severe impairment of communication, mobility, self-care, education, and independent living is clinically foreseeable from the documented combined hearing and neurodevelopmental disabilities; this is an inference rather than a quantified disease-specific result.

4. Genetic and molecular information

AFG2B/SPATA5L1 encodes an AAA+ ATPase-family protein. Open Targets assigns an exact disease–target association score of approximately 0.726 and links the association to PMIDs 34626583 and 38554706. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity)

Reported pathogenic classes include missense, nonsense, frameshift, and likely splice-disrupting alleles, although a definitive exhaustive variant table and current gnomAD frequencies were not recoverable from the available primary text. Variants are germline, not somatic. The recessive inheritance and unaffected heterozygous parents are consistent with disease requiring two damaging alleles. (polczyk2025neurodevelopmentaldisorderwith pages 9-10, polczyk2025neurodevelopmentaldisorderwith pages 4-6)

Functional studies show several routes to pathogenicity:

1. reduced protein stability;
2. defective interaction or assembly within 55LCC;
3. reduced ATP binding/hydrolysis or pore-mediated unfoldase activity;
4. impaired replisome-substrate processing;
5. cellular replication stress and chromosome instability. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

Most patient mutants in the 2024 experiments were unstable after endogenous wild-type protein was removed. I466M and G689V were exceptions in retaining stability, although preserved abundance does not establish normal function. The patient-associated V245E allele severely compromised viability in CRISPR-rescue assays. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

No validated modifier gene, disease-specific methylation signature, chromosomal rearrangement, repeat expansion, mitochondrial-DNA defect, or somatic mechanism has been established. Large CNVs and uniparental disomy were specifically not explanatory in the recent patient. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

5. Environmental information

No toxin, radiation, pollution, occupation, diet, smoking, alcohol, exercise pattern, or infectious agent has been implicated causally. Prenatal history was uneventful in the detailed recent case. NEDHLS is not infectious, environmentally acquired, or zoonotic. Environmental and lifestyle measures may improve general health but are not known to alter the primary molecular defect. (polczyk2025neurodevelopmentaldisorderwith pages 2-4)

6. Mechanism and pathophysiology

Upstream molecular defect

SPATA5 and AFG2B/SPATA5L1 are type-II AAA+ ATPases related to the CDC48/p97 family. Together with C1ORF109 and CINP they form the stable four-member 55LCC complex. Cryo-EM and orthogonal interaction studies indicate a 4:2:2:2 stoichiometry—four SPATA5, two SPATA5L1, two C1ORF109, and two CINP subunits—forming a funnel/lid over a stacked-ring ATPase motor. ATP binding stabilizes the complex. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 5-7)

The complete complex has 3.6-fold greater ATP hydrolysis than SPATA5 alone, and replication-fork DNA specifically increases its ATPase activity. Mutating conserved Walker-B residues abolishes hydrolysis. Suggested annotations include ATP hydrolysis activity, DNA binding, protein unfolding, GO:0006260 DNA replication, GO:0005657 replication fork, and GO:0000785 chromatin. (krishnamoorthy2024thespata5spata5l1atpase pages 5-7)

Replisome proteostasis

55LCC interacts with POLD1/POLD3, RFC1, cohesin components, and other nuclear and cytoplasmic complexes. In S phase and after replication damage, its ATPase/pore activity appears to unfold replisome proteins, making them accessible to calpain-family or related cysteine proteases. Processed substrates include POLD3, RFC1, POLA1, POLD1, ATR, ATRIP, and RAD21. This turnover is largely ubiquitin- and proteasome-independent. The authors’ mechanistic conclusion was that 55LCC “acts as an unfoldase,” facilitating cleavage and removal of replisome proteins from chromatin. (krishnamoorthy2024thespata5spata5l1atpase pages 8-10, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

Downstream causal chain

Biallelic damaging AFG2B variants → impaired 55LCC abundance/assembly/ATPase activity → defective replisome-protein remodeling → replication-fork slowing, stalling, and defective restart → exposed single-stranded DNA and replication stress → later ATR checkpoint activation, cohesion loss, and micronuclei → impaired survival or development of vulnerable neural and auditory cells → developmental disability, motor-system dysfunction, epilepsy, and hearing loss.

In engineered cells, phosphorylated RPA and fork shortening appeared within 18–24 hours; mitotic abnormalities emerged around 48–72 hours; approximately 25% of cells had micronuclei after 72 hours of induced depletion. Thus, replication stress is experimentally upstream of chromosomal instability. (krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

An unfolded-protein response, including increased CHOP and spliced XBP1, also followed 55LCC loss. Earlier work additionally links complex members to late ribosome assembly, but the 2024 study found the replication/genome-instability phenotype separable from the reported ribosomal function. No disease-specific patient tissue transcriptome, proteome, metabolome, lipidome, single-cell atlas, spatial transcriptome, or integrated multi-omic signature has yet been established. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

Suggested cell terms are neuron, glial cell, and inner-ear sensory hair cell; these should be mapped to exact CL identifiers during curation. The evidence for enrichment in neurons, glial nuclei, and neurosensory hair cells comes from later synthesis, whereas the causal replication experiments used cultured cells rather than patient neural tissue. (polczyk2025neurodevelopmentaldisorderwith pages 1-2)

7. Anatomical structures affected

The primary systems are the central nervous system and auditory system. Brain structures implicated by imaging include cerebral cortex, white matter, corpus callosum, periventricular regions, and anterior temporal regions. Motor manifestations implicate corticospinal and extrapyramidal networks, although tract-specific pathology has not been demonstrated. Suggested UBERON mappings include brain, cerebral cortex, cerebral white matter, corpus callosum, inner ear, and cochlea. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

Hearing loss is bilateral in the reported detailed case and generally sensorineural, supporting cochlear hair-cell and/or auditory-neural involvement. At the subcellular level, the relevant compartments include nucleus, chromatin, replication fork, and the 55LCC macromolecular complex. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

No consistent primary cardiovascular, pulmonary, renal, hepatic, gastrointestinal, endocrine, immune, or hematologic phenotype has been established for NEDHLS. Thrombocytopenia appears in the broader SPATA5/55LCC disease discussion but should not be assigned to AFG2B-related NEDHLS without patient-level confirmation. (krishnamoorthy2024thespata5spata5l1atpase pages 12-14)

8. Temporal development

Onset is infantile and insidious, not acute. Developmental delay and hypotonia can be evident by four months; hearing loss may be recognized within the first year; spasticity/dystonia and EEG abnormalities may emerge later. (polczyk2025neurodevelopmentaldisorderwith pages 6-7, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

The course is chronic and lifelong. A practical—not formally validated—staging model is:

1. Early infancy: hypotonia, abnormal visual/social engagement, delayed motor milestones, hearing impairment.
2. Later infancy/childhood: persistent global delay, abnormal postural control, possible microcephaly and MRI abnormalities.
3. Evolving course: spastic-dystonic motor disorder and possible epilepsy/EEG abnormalities.

No relapsing-remitting pattern, spontaneous remission, or disease-defined end stage is known. Early auditory and developmental intervention is rational because infancy is a critical period for language and motor development, but no study has quantified a disease-specific window for modifying the underlying disorder. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous carrier parents, standard Mendelian recurrence expectations are 25% affected, 50% carrier, and 25% unaffected/non-carrier per pregnancy, subject to confirmation that both alleles are truly pathogenic. No anticipation is expected, and no founder effect, germline mosaicism rate, carrier frequency, ethnic enrichment, geographic concentration, or sex bias has been demonstrated.

The foundational cohort contained 25 patients, and a 2025 report described the total literature as fewer than 30 affected individuals. Prevalence, incidence, mortality, and population carrier frequency are unknown; absence from epidemiologic registries should not be interpreted as zero prevalence. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

Penetrance among individuals with clearly pathogenic biallelic genotypes appears high for neurodevelopmental impairment, but exact penetrance is not calculable. Expressivity is variable, particularly for epilepsy, microcephaly, imaging abnormalities, and the timing of hypertonia. (polczyk2025neurodevelopmentaldisorderwith pages 7-9)

10. Diagnostics

Clinical workup

The recognizable combination is developmental delay plus bilateral sensorineural hearing loss and hypotonia or evolving spastic-dystonic motor dysfunction. Evaluation should include detailed neurologic/developmental examination, formal audiology or auditory brainstem response, ophthalmology, brain MRI, and EEG when seizures or episodic unresponsiveness are suspected. Serial assessment is important because EEG and tone abnormalities may evolve. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

There is no validated blood, urine, enzyme, metabolite, proteomic, epigenetic, biopsy, or liquid-biopsy biomarker. Replication-stress measurements remain research assays.

Molecular diagnosis

Preferred testing is trio WES or WGS with copy-number calling and confirmation of two rare, plausibly damaging AFG2B variants in trans. A neurodevelopmental/hearing-loss/spasticity panel that includes AFG2B is reasonable when rapid targeted testing is preferred. Sanger or equivalent orthogonal confirmation and parental segregation are appropriate. The recent real-world workflow used trio WES, mitochondrial-genome analysis, noncoding ClinVar-variant analysis, CNV assessment, and UPD assessment. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

WGS may identify noncoding, structural, or poorly captured variants missed by WES, although NEDHLS-specific incremental yield is unknown. RNA sequencing may help resolve suspected splice variants, but no validated disease-specific RNA diagnostic was identified. CMA can exclude alternative pathogenic CNVs but cannot reliably detect most causal single-nucleotide or small indel alleles. Karyotype, FISH, mitochondrial testing, and repeat-expansion testing are not first-line disease-specific tests unless the phenotype suggests another diagnosis.

Differential diagnosis

Key genetic differentials include SPATA5/AFG2A-related neurodevelopmental disorder, HPDL-related neurodegeneration/spasticity, hereditary spastic paraplegias, mitochondrial disorders, congenital infections, and other syndromic hearing-loss/epileptic encephalopathies. SPATA5-related disease reportedly has earlier seizures, more marked microcephaly, and frequent movement disorders, while AFG2B disease more consistently features sensorineural hearing loss and spastic-dystonic cerebral palsy; substantial overlap prevents clinical distinction without molecular testing. (polczyk2025neurodevelopmentaldisorderwith pages 7-9)

No population or newborn genetic screening program exists. Audiologic newborn screening may detect hearing loss but is neither sensitive nor specific for NEDHLS.

11. Outcome and prognosis

No 5- or 10-year survival estimates, life-expectancy data, mortality rates, or validated prognostic biomarkers exist. Available reports support persistent developmental and motor disability rather than recovery to typical development. Hearing amplification can improve sound access but does not reverse the genetic neurodevelopmental disorder. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

Potential long-term morbidity includes severe communication impairment, limited mobility, contractures from spasticity, epilepsy, feeding or nutritional difficulty secondary to neurologic disability, and caregiver burden, although NEDHLS-specific complication rates are unavailable. Younger age without seizures or spasticity cannot be assumed to predict a mild course because these features may emerge later. (polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 6-7)

12. Treatment and current implementation

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, cell therapy, or genotype-guided drug. No relevant disease-specific interventional trial was identified by searching the disease name and AFG2B/SPATA5L1.

Current treatment is multidisciplinary and phenotype-directed:

• hearing aids; cochlear-implant assessment if hearing loss meets standard audiologic criteria;
• early communication intervention, including speech-language and hearing rehabilitation;
• physical and occupational therapy, positioning, mobility devices, and contracture prevention;
• standard spasticity management where needed, potentially including oral antispastic medication, botulinum toxin, orthoses, or specialist procedures;
• standard antiseizure medication selected according to seizure type if epilepsy is confirmed;
• nutritional/feeding, ophthalmologic, orthopedic, and psychosocial support.

The detailed 2025 case used hearing aids and early reflex-locomotion/Vojta-oriented rehabilitation. The report documented persistent abnormalities, not a controlled treatment-response estimate. Suggested NCIT concepts include hearing-aid intervention, physical therapy, occupational therapy, speech therapy, rehabilitation, anticonvulsant therapy, and botulinum-toxin treatment; exact NCIT identifiers require terminology-service validation. (polczyk2025neurodevelopmentaldisorderwith pages 4-6, polczyk2025neurodevelopmentaldisorderwith pages 7-9, polczyk2025neurodevelopmentaldisorderwith pages 2-4)

The 2024 mechanism identifies 55LCC, calpain-linked processing, replication stress, and proteostasis as research targets, but directly inhibiting this essential complex would be biologically risky: all four components were pan-essential across several cell lines. Mechanistic rescue or gene-replacement approaches remain preclinical concepts, not current clinical applications. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

13. Prevention

There is no vaccine, behavioral prevention, environmental prophylaxis, or medication that prevents disease in a person with a causal biallelic genotype.

Primary genetic prevention/reproductive options include carrier testing of parents and adult relatives, genetic counseling, partner testing, preimplantation genetic testing for monogenic disease, and prenatal diagnosis by chorionic-villus sampling or amniocentesis once familial variants are established. Secondary prevention consists of early molecular diagnosis, audiology, developmental surveillance, and seizure monitoring. Tertiary prevention targets complications through rehabilitation, hearing support, spasticity management, orthopedic surveillance, and epilepsy treatment.

Variant interpretation must be finalized before using a familial allele for reproductive testing, particularly when one allele remains a VUS. (polczyk2025neurodevelopmentaldisorderwith pages 4-6)

14. Other species and natural disease

No naturally occurring AFG2B-equivalent syndrome in a companion animal, livestock species, or wildlife population was identified. Consequently, breed ontology identifiers, veterinary prevalence, and zoonotic transmission are not applicable. The disorder is inherited rather than transmissible.

AFG2B/SPATA5L1 orthologs and the ATPase/proteostasis machinery are evolutionarily conserved, enabling experimental modeling, but conservation alone does not establish a spontaneous veterinary disease.

15. Model organisms and experimental systems

The strongest disease-relevant models currently retrieved are in vitro biochemical and engineered human-cell systems, not a fully validated organismal NEDHLS model.

• Recombinant 55LCC supported ATPase, nucleic-acid-binding, thermal-stability, mass-photometry, native-mass-spectrometry, and cryo-EM studies.
• HeLa S3 and engineered degron/CRISPR-rescue systems established complex essentiality, patient-variant effects, replication-fork defects, stress responses, cohesion loss, and micronucleation.
• DNA-fiber assays, iPOND, chromatin fractionation, co-immunoprecipitation, and mass spectrometry defined replisome interactions and temporal effects. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 41-46, krishnamoorthy2024thespata5spata5l1atpase pages 3-5, krishnamoorthy2024thespata5spata5l1atpase pages 8-10)

These models reproduce the molecular defect—impaired replisome proteostasis and genome stability—but cannot by themselves reproduce cognition, spastic-dystonic cerebral palsy, hearing behavior, or developmental trajectories. No retrieved evidence established a stable Afg2b-knockout mouse, rat, zebrafish, Drosophila, patient-derived iPSC neuron, cochlear organoid, or cerebral organoid that recapitulates NEDHLS. Such models are priorities for resolving tissue selectivity and testing allele-specific rescue.

Evidence appraisal and principal knowledge gaps

The human disease association is strong because multiple unrelated patients carry recessive biallelic variants with compatible phenotypes and familial segregation. The molecular mechanism is supported by high-quality structural, biochemical, and cell-biological experiments published in 2024. However, the bridge from replication stress to selective human brain and cochlear pathology remains inferential. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, krishnamoorthy2024thespata5spata5l1atpase pages 7-8, krishnamoorthy2024thespata5spata5l1atpase pages 1-3)

The most important gaps are: reliable phenotype frequencies from expanded cohorts; longitudinal natural history; variant-level penetrance and functional calibration; population carrier frequency; validated neural/cochlear models; patient-derived multi-omics; quantitative quality-of-life outcomes; treatment-response data; and disease-specific clinical trials.

Key abstract-supported statements

The foundational paper’s title itself states the principal human conclusion: “Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.” PMID 34626583; October 2021; DOI URL. (OpenTargets Search: Neurodevelopmental disorder with hearing loss and spasticity, polczyk2025neurodevelopmentaldisorderwith pages 9-10)

The 2024 mechanistic study concluded that the complex processes replisome substrates and regulates genome stability, proposing that “55LCC acts as an unfoldase” and facilitates subsequent cysteine-protease cleavage and removal of replisome proteins from chromatin. PMID 38554706; April 2024; DOI URL. (krishnamoorthy2024thespata5spata5l1atpase pages 10-12)

A 2025 detailed case report concluded that integrating genomic sequencing with structured motor assessment can refine recognition and management; it also documented that biallelic disease may initially present with hypotonia and no confirmed epilepsy, illustrating age-dependent and variable expression. Published November 2025; DOI 10.3390/jcm14238442. (polczyk2025neurodevelopmentaldisorderwith pages 1-2, polczyk2025neurodevelopmentaldisorderwith pages 7-9)

References

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3. (polczyk2025neurodevelopmentaldisorderwith pages 6-7): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.

4. (krishnamoorthy2024thespata5spata5l1atpase pages 1-3): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

5. (krishnamoorthy2024thespata5spata5l1atpase pages 8-10): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

6. (krishnamoorthy2024thespata5spata5l1atpase pages 10-12): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

7. (polczyk2025neurodevelopmentaldisorderwith pages 4-6): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.

8. (polczyk2025neurodevelopmentaldisorderwith pages 7-9): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.

9. (polczyk2025neurodevelopmentaldisorderwith pages 9-10): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.

10. (polczyk2025neurodevelopmentaldisorderwith pages 2-4): Artur Polczyk, Ewelina Wolańska, Anna Zimny, Agnieszka Zubkiewicz-Kucharska, Mateusz Biela, Agnieszka Pawelak, and Robert Śmigiel. Neurodevelopmental disorder with psychomotor delay, hearing loss, and spasticity caused by compound heterozygous spata5l1 variants—expanding phenotype. Journal of Clinical Medicine, 14:8442, Nov 2025. URL: https://doi.org/10.3390/jcm14238442, doi:10.3390/jcm14238442. This article has 1 citations.

11. (krishnamoorthy2024thespata5spata5l1atpase pages 5-7): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

12. (krishnamoorthy2024thespata5spata5l1atpase pages 3-5): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

13. (krishnamoorthy2024thespata5spata5l1atpase pages 7-8): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

14. (krishnamoorthy2024thespata5spata5l1atpase pages 12-14): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

15. (krishnamoorthy2024thespata5spata5l1atpase pages 41-46): Vidhya Krishnamoorthy, Martina Foglizzo, Robert L. Dilley, Angela Wu, Arindam Datta, Parul Dutta, Lisa J. Campbell, Oksana Degtjarik, Laura J. Musgrove, Antonio N. Calabrese, Elton Zeqiraj, and Roger A. Greenberg. The spata5-spata5l1 atpase complex directs replisome proteostasis to ensure genome integrity. Cell, 187:2250-2268.e31, Apr 2024. URL: https://doi.org/10.1016/j.cell.2024.03.002, doi:10.1016/j.cell.2024.03.002. This article has 18 citations and is from a highest quality peer-reviewed journal.

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