| Domain | Summary | Ontology / Identifier Suggestions | Evidence |
|---|---|---|---|
| Identity / OMIM | **Autosomal recessive spastic ataxia 9 (SPAX9)**; Mendelian, neurogenetic complex spastic ataxia. OMIM **#618438**. Do **not** infer MONDO/Orphanet/ICD identifiers from current evidence; **unknown/not confirmed here**. | OMIM: **618438**; disease label: **SPAX9**; MONDO/Orphanet/ICD: **unknown/not established in retrieved evidence** | (pqac-00000001, pqac-00000016) |
| Causal gene and variant | Causal gene: **CHP1** (*calcineurin-like EF-hand protein 1*). Founding human family carried homozygous **NM_007236.4:c.52_54del, p.Lys19del (p.K19del)**. Variant segregated with disease in a consanguineous Moroccan pedigree; absent from public databases in the discovery study. | Gene: **CHP1**; variant class: **in-frame 3-bp deletion**; inheritance origin: **germline** | (pqac-00000000, pqac-00000016, pqac-00000008) |
| Inheritance | **Autosomal recessive**; disease established in one consanguineous family with affected homozygous siblings and heterozygous parents. | Inheritance: **AR** | (pqac-00000001, pqac-00000016, pqac-00000008) |
| Human evidence size | Extremely limited evidence base: **2 affected siblings** in the index report; no additional pathogenic **CHP1** variants found in screening cohorts (**ARCA n=319**; **NeurOmics n=657**), supporting rarity. | Evidence status: **ultra-rare / sparse human evidence** | (pqac-00000001, pqac-00000016) |
| Onset / course | Onset **during the first decade of life**; chronic **progressive** neurodegenerative course with gait instability, spastic ataxia, and cerebellar involvement. | HPO (inferred): **Childhood onset** HP:0011463; **Progressive neurologic deterioration** HP:0002344 | (pqac-00000000, pqac-00000016) |
| Core phenotypes | Core reported phenotype: gait instability / ataxia, **spastic paraparesis**, **upper and lower motor neuron involvement**, **motor neuropathy**, **slow ocular saccades**, **intellectual disability**, **growth retardation**; ovarian failure reported in the female proband, but likely not clearly attributable to CHP1 alone. | HPO (inferred): **Ataxia** HP:0001251; **Spastic paraplegia / paraparesis** HP:0001258 or HP:0002313; **Peripheral neuropathy** HP:0009830; **Abnormal pyramidal signs** HP:0002493; **Slow saccadic eye movements** HP:0001276; **Intellectual disability** HP:0001249; **Short stature / growth delay** HP:0004322; **Primary ovarian insufficiency** HP:0008209 (uncertain disease attribution) | (pqac-00000000, pqac-00000001, pqac-00000015, pqac-00000016) |
| MRI / anatomy | Brain MRI in one affected individual showed **moderate cerebellar atrophy** with **hypoplasia of posterior and nodular regions of the cerebellar vermis**, while cerebellar hemispheres were not hypoplastic; no evident white-matter abnormalities on the cited axial FLAIR image. | UBERON (inferred): **cerebellum** UBERON:0002037; **cerebellar vermis** UBERON:0002245; nervous system: UBERON:0001016 | (pqac-00000000, pqac-00000008, pqac-00000016) |
| Molecular causal chain | **Upstream:** biallelic **CHP1 p.Lys19del** → reduced soluble CHP1, increased insoluble fraction, aggregation propensity, abnormal higher-molecular-weight complexes. **Intermediate:** impaired CHP1 support of **NHE1/SLC9A1** maturation and membrane targeting. **Downstream:** reduced NHE1 membrane localization/function → disturbed intracellular **pH/ion homeostasis** → Purkinje-neuron and motor-system dysfunction → spastic ataxia phenotype. | GO (inferred): **protein folding** GO:0006457; **protein complex assembly** GO:0065003; **protein localization to plasma membrane** GO:1903076; **sodium:hydrogen antiporter activity / regulation** GO:0015385-related; **intracellular pH reduction/homeostasis** GO:0051453 / GO:0055078; **neuron degeneration** GO:0070997 | (pqac-00000001, pqac-00000003, pqac-00000013, pqac-00000014, pqac-00000015) |
| Affected cell types | Human phenotype and model data implicate **Purkinje neurons** and **motor neurons / motor axons** as key vulnerable populations; additional CNS regions may be sensitive to NHE1 depletion in animal models. | CL (inferred): **Purkinje cell** CL:0000121; **motor neuron** CL:0000100; broader: **neuron** CL:0000540 | (pqac-00000002, pqac-00000004, pqac-00000015) |
| Diagnostic strategy | Recommended current approach: clinical recognition of **childhood-onset progressive spastic ataxia** plus MRI evidence of cerebellar involvement, followed by **exome/genome sequencing or ataxia/spastic paraplegia gene panel** including **CHP1**; confirm by segregation testing. No disease-specific biomarker is established. | Testing modalities: **WES/WGS/panel sequencing**; family segregation; MRI. Biomarker status: **unknown/not established** | (pqac-00000001, pqac-00000016) |
| Epidemiology | No prevalence or incidence estimates identified in retrieved evidence. Present evidence supports an **ultra-rare** disorder. Geographic signal from current human data: one **consanguineous Moroccan family**. | Epidemiology: **unknown**; founder effect: **not established**; sex ratio: **unknown** | (pqac-00000001, pqac-00000016) |
| Treatment / status | **No SPAX9-specific approved disease-modifying therapy** and no relevant registered clinical trial found in retrieved evidence. Current real-world management is expected to be **supportive/multidisciplinary** (rehabilitation, spasticity and mobility management, genetic counseling). **PLS3 overexpression** is a **preclinical modifier** only, not a human therapy. | NCIT (inferred supportive care): **Physical Therapy** C15329; **Occupational Therapy** C15231; **Genetic Counseling** C15709; disease-modifying therapy: **none established** | (pqac-00000004, pqac-00000005, pqac-00000006) |
| Model organisms | **Zebrafish:** chp1 morphants show motor-axon defects, cerebellar hypoplasia, increased spontaneous contractions, and spastic-like trunk movements; rescued by WT but not mutant human **CHP1** mRNA. **Mouse:** **Chp1 vacillator** mutants develop early balance deficits, progressive ataxic gait, Purkinje axon hypertrophy/swellings, later Purkinje-cell loss; **PLS3** overexpression delays early but not late phenotype and trends toward improved NHE1 membrane localization. | Species/models: **Danio rerio** chp1 knockdown; **Mus musculus** Chp1 vacillator; evidence class: **in vivo functional / modifier** | (pqac-00000002, pqac-00000004, pqac-00000007, pqac-00000015) |


*Table: This table condenses the currently retrievable evidence for autosomal recessive spastic ataxia 9, emphasizing the very small human evidence base, the CHP1→NHE1 mechanistic model, and practical knowledge-base fields with clearly marked inferred ontologies and unknowns.*