Riley-Day Syndrome · Claude Code

1. Disease Information

Riley-Day syndrome, more commonly termed Familial Dysautonomia (FD), is a rare autosomal recessive congenital neurological disorder characterized by profound and progressive dysfunction of the sensory and autonomic nervous systems. It was first described by Conrad Milton Riley and Richard Lawrence Day in 1949, based on a case series of five Ashkenazi Jewish children with unexplained autonomic dysfunction, feeding difficulties, and alacrima (defective tearing). FD is now formally classified as Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III) within the wider HSAN family. The core disease process is a developmental failure and subsequent progressive degeneration of unmyelinated sensory neurons (nociceptors, autonomic afferents) and small autonomic (sympathetic/parasympathetic) neurons, producing early-life autonomic instability, absent overflow tears, insensitivity to pain and temperature, gastroesophageal reflux, aspiration pneumonia, and later development of ataxia, hypertensive vomiting crises, kyphoscoliosis, optic neuropathy, chronic kidney disease, and sleep-disordered breathing.

Key identifiers - OMIM: #223900 (Dysautonomia, familial; FD / HSAN III); gene entry OMIM 603722 (ELP1, previously IKBKAP) - Orphanet: ORPHA:1764 (Familial dysautonomia) - MONDO: MONDO:0009131 - ICD-10: G90.1 (Familial dysautonomia [Riley-Day]) - ICD-11: 8D87.Y - MeSH: D004402 (Dysautonomia, Familial) - GARD: 7581

Common synonyms/alternative names: Riley-Day syndrome, Hereditary Sensory and Autonomic Neuropathy Type III (HSAN III / HSAN3), Hereditary Sensory Neuropathy Type III, familial autonomic dysfunction, Riley-Day dysautonomia.

Data derivation: Because the disease has an extraordinarily narrow founder population and only ~700 living patients worldwide, most epidemiological, natural history, and treatment data derive from aggregated disease-level cohorts and registries — chiefly the New York University Dysautonomia Center registry (Kaufmann/Norcliffe-Kaufmann) and the Israeli Dysautonomia Center — rather than population EHR data. Molecular and mechanistic data derive from patient tissues, mouse models (Wnt1-Cre Ikbkap conditional knockouts, humanized TgFD/Elp1 mice), and iPSC-derived neurons. (Sources: GeneReviews, NBK1180; OMIM 223900; Norcliffe-Kaufmann 2023, Clin Auton Res, PMID 37000283.)

2. Etiology

2.1 Disease Causal Factors

FD is a monogenic autosomal recessive disorder. Bi-allelic pathogenic variants in ELP1 (formerly IKBKAP; HGNC:5959; NCBI Gene: 8518) on chromosome 9q31.3 cause tissue-specific reduction of the Elongator complex scaffolding subunit ELP1 (also called IκB kinase complex-associated protein, IKAP). The disease is therefore entirely genetic; environmental factors modulate crisis frequency and complication severity but do not cause the disease. (Sources: OMIM 603722; Anderson et al. 2001, Am J Hum Genet, PMID 11179016; Slaugenhaupt et al. 2001, Am J Hum Genet, PMID 11179017.)

2.2 Risk Factors

Genetic risk factors - Founder mutation c.2204+6T>C (IVS20+6T>C): A T→C transition at position +6 of the 5′ splice donor of intron 20 of ELP1 causes tissue-specific exon 20 skipping and reduced full-length ELP1. This variant accounts for >99.5% of pathogenic alleles in Ashkenazi Jewish (AJ) FD patients and is one of the strongest known founder alleles in medicine. (Anderson et al. 2001, PMID 11179016; Slaugenhaupt et al. 2001, PMID 11179017.) - Missense c.2087G>C (p.R696P): Accounts for the residual fraction (<0.5%) of pathogenic AJ alleles and a small number of non-AJ FD cases (e.g., Leyne et al. 2003, Am J Med Genet A, PMID 12687659). - Ashkenazi Jewish ancestry: The strongest population risk factor. Carrier frequency in AJ populations is approximately 1 in 27–36 (most commonly cited as ~1/30); still higher (~1/18) in Polish-descended AJ subgroups (Lehavi et al. 2003, PMID 12885336).

Environmental risk factors (for crises / complications, not the disease itself): - Emotional stress, anxiety, viral infections, meals, and dehydration precipitate hyperadrenergic autonomic crises. - Aspiration risk with feeding (due to abnormal oropharyngeal coordination and gastroesophageal reflux). - Recumbency for prolonged periods, high salt/fludrocortisone use, and hypokalemia elevate the risk of sudden death during sleep (Palma et al. 2017, Sleep, PMID 28521050).

2.3 Protective Factors

Heterozygosity: Heterozygous carriers of the c.2204+6T>C allele are clinically unaffected owing to the tissue-specific and dose-sensitive nature of the splicing defect (Slaugenhaupt et al. 2001, PMID 11179017).
No consistent genetic modifier or protective environmental exposure has been established, though avoidance of fludrocortisone and prompt initiation of non-invasive ventilation reduce SUDS (Palma et al. 2017, PMID 28521050).

2.4 Gene–Environment Interactions

Emotional/physical stress triggers a paradoxical, exaggerated peripheral catecholamine surge in FD due to a lesion of the afferent baroreflex (loss of glossopharyngeal/vagal chemo- and baroreceptor input); the efferent sympathetic limb remains intact, producing hypertensive vomiting crises. Feeding likewise triggers postprandial hypotension via unopposed splanchnic dilation. (Sources: Norcliffe-Kaufmann & Kaufmann 2012, Auton Neurosci; Palma et al. 2020, Hypertension, PMID 32623925.)

3. Phenotypes

Phenotypes are typically reported as >90% penetrant by adolescence in homozygotes; onset is neonatal for many. Frequencies below are drawn from the NYU FD registry and the GeneReviews/Orphanet expert summaries (Axelrod, GeneReviews NBK1180; MedLink Neurology - Familial Dysautonomia).

3.1 Neurological / Sensory

Absent overflow tears (alacrima) — ~100%, congenital (HP:0000522).
Absent fungiform papillae on the tongue (smooth glistening tip) — ~100%, congenital (HP:0000167 – atrophic fungiform papillae; HP:0100799 – smooth tongue).
Depressed / absent deep tendon reflexes — ~100% (HP:0001315).
Decreased pain sensation (nociceptor loss; palms, soles, neck, genital regions relatively spared) — ~100% (HP:0007021).
Decreased temperature sensation — ~90% (HP:0010829).
Proprioceptive ataxia and progressive gait ataxia — ~90% by adolescence (HP:0002066, HP:0002131).
Optic neuropathy / progressive vision loss, beginning ~age 5, legal blindness typically by 3rd decade (HP:0000632, HP:0000505). (Mendoza-Santiesteban et al. 2012.)

3.2 Autonomic / Cardiovascular

Postural (orthostatic) hypotension — ~100% (HP:0001278).
Hyperadrenergic autonomic ("dysautonomic") crises with paroxysmal hypertension, tachycardia, cutaneous erythematous blotching, diaphoresis, retching/vomiting — ~40–65% (HP:0005112 - abnormal autonomic nervous system physiology; HP:0002326 – hypertension).
Blood pressure lability / baroreflex failure — ~100% (HP:0011169).
Excessive sweating with stress and red skin blotches — ~90% (HP:0000975).

3.3 Gastrointestinal

Gastroesophageal reflux — ~85% (HP:0002020).
Poor feeding / oropharyngeal dyscoordination in infancy — ~95% (HP:0011968).
Recurrent vomiting and cyclical vomiting crises — ~65% (HP:0002020, HP:0002572).
Gastroparesis and constipation — ~50%.

3.4 Respiratory

Recurrent aspiration pneumonia — ~90% (HP:0002102).
Blunted ventilatory responses to hypoxia and hypercapnia (chemoreflex failure) — ~100% (HP:0002098 – abnormal breathing regulation; HP:0002104 – apnea).
Sleep-disordered breathing (mixed obstructive/central) — >70% in adults (Palma et al. 2019, Sleep Med, PMID 30890343).

3.5 Musculoskeletal

Kyphoscoliosis — ~90% by adolescence (HP:0002751).
Reduced bone mineral density, growth retardation — common (HP:0004349, HP:0004322).
Charcot arthropathy / neuropathic joints — episodic.

3.6 Genitourinary

Progressive chronic kidney disease — >50% by 3rd decade (HP:0012622), driven by repeated hypoperfusion episodes and orthostatic hypotension.

3.7 Behavioral / Cognitive

Anxiety and emotional lability — very frequent (HP:0000739).
Intelligence is generally normal; developmental delay is often secondary to hospitalizations and hypoxic events rather than primary cognitive dysfunction.

3.8 Laboratory

Increased serum dopamine-to-norepinephrine ratio (HP:0011036) — supports diagnosis pre-DNA testing.
Blunted plasma catecholamine response to standing.
Elevated urinary VMA/HVA ratio (reflecting dysfunctional catecholamine metabolism).

3.9 Onset, Progression, Severity, QOL

Age of onset: Congenital / neonatal for feeding and alacrima; multisystem progression through childhood; sensory deficits and ataxia progress lifelong.
Severity: Uniformly severe; variable expressivity due to leaky splicing.
Progression: Progressive.
QOL impact: Severe. Cardinal drivers are ataxia/blindness (mobility loss), aspiration/pneumonia (repeated hospitalization), autonomic crises (medical emergencies), and dependence on gastrostomy feeding and nightly non-invasive ventilation in adulthood.

4. Genetic / Molecular Information

4.1 Causal Gene

ELP1 (previously IKBKAP), HGNC:5959, NCBI Gene 8518, UniProt O95163, chromosome 9q31.3, 37 exons spanning ~68 kb of genomic DNA, encoding a 1332-aa scaffolding subunit of the six-member Elongator complex.

4.2 Pathogenic Variants

Table (click to expand)

Variant (HGVS)	Type	Population	Frequency	Consequence
c.2204+6T>C (IVS20+6T>C)	Intronic splice-region (donor site +6)	Ashkenazi Jewish	>99.5% of AJ FD alleles	Tissue-specific skipping of exon 20 → frameshift, premature stop, ~79 kD truncated protein; leaky splicing preserves partial wild-type ELP1 in non-neural tissues
c.2087G>C (p.Arg696Pro; R696P)	Missense	AJ + occasional non-AJ	<0.5% AJ; small numbers non-AJ	Disrupts protein–protein binding of ELP1 in Elongator complex
Rare compound heterozygous private variants	Missense / nonsense	Non-AJ (rare)	Case reports	Reduced ELP1

ACMG classification: All confirmed FD alleles are Pathogenic. Both major variants are extensively curated in ClinVar (RCV000000541 for c.2204+6T>C).

Allele frequency in gnomAD: The founder variant c.2204+6T>C has a global heterozygote frequency of ~0.4%, concentrated in the AJ subpopulation (~1.5–2%).

Origin: Germline (recessive). No somatic FD is described.

Functional consequences: - Loss of function through drastically reduced full-length ELP1 protein in nervous tissue; the leaky splicing produces measurable — but insufficient — wild-type ELP1 in non-neural tissues, explaining tissue-specific pathology. - The Elongator complex catalyzes 5-carboxymethyl (cm5) modifications on uridine 34 (U34) of wobble tRNAs (tRNA-Lys, -Glu, -Gln, -Arg). Loss of Elongator activity impairs efficient decoding of AA-ending codons and disrupts the translation of codon-biased mRNAs (e.g., ATG9A, PCP4). (Karlsborn et al. 2014, RNA Biology.) - Elongator/ELP1 also plays roles in histone H3 acetylation, actin cytoskeleton regulation, and neurotrophin-dependent axonal transport of NGF.

4.3 Modifier Genes

No formally validated modifier gene is known, but variability in residual ELP1 expression (driven by cis regulatory context, PUF60/RBM24 splicing regulators, and cellular stress) correlates with clinical severity (Ohlen et al. 2017).

4.4 Epigenetic Information

No canonical epigenetic driver of FD is described. However, elongator complex loss changes histone H3K14ac at specific loci and secondarily alters transcriptional elongation in neurons.

4.5 Chromosomal Abnormalities

Not applicable — FD is a monogenic single-nucleotide variant disorder; chromosomal microarray is not indicated.

Ontology suggestions: GO:0033588 (Elongator holoenzyme complex); GO:0002098 (tRNA wobble uridine modification); GO:0006355 (regulation of DNA-templated transcription); GO:0000226 (microtubule cytoskeleton organization).

5. Environmental Information

Because FD is fully monogenic, environmental factors are triggers/modulators rather than causes.

Emotional and physical stress: Reliably triggers hypertensive autonomic crises via disinhibited catecholamine release (Norcliffe-Kaufmann 2010, PMID 20857273).
Meals: Postprandial hypotension is characteristic due to splanchnic redistribution unopposed by baroreflex.
Viral respiratory infections: Precipitate aspiration pneumonia and respiratory failure.
Fludrocortisone use, hypokalemia, and untreated obstructive sleep apnea: Increase risk of sudden unexpected death during sleep (SUDS) (Palma et al. 2017, Sleep, PMID 28521050).
Ambient temperature extremes: Cause temperature dysregulation (fever without infection; hypothermia).

Infectious agents: No causal role. Aspiration pneumonia (typically polymicrobial including anaerobes and Streptococcus pneumoniae) is a downstream complication rather than a primary etiology.

Ontology suggestions: ECTO:0001093 (exposure to psychosocial stress); ECTO:0000000-derived exposures related to meals/positional change (no exact term).

6. Mechanism / Pathophysiology

6.1 Ordered Causal Chain

Homozygous ELP1 c.2204+6T>C variant in the intron 20 donor splice site weakens U1 snRNP recognition →
Tissue-specific skipping of exon 20 occurs during ELP1 pre-mRNA splicing, most severely in the nervous system (partially retained in fibroblasts and other tissues; hence the "leaky" phenotype) (Cuajungco et al. 2003, PMID 12756454) →
Reduced full-length ELP1 protein in neurons (a hypomorphic loss of function) →
Loss of Elongator holoenzyme activity (Elp1–Elp6), leading to failure of tRNA wobble uridine cm⁵U/mcm⁵s²U modification on tRNA-Lys/Glu/Gln/Arg →
Impaired translation of AA-ending, codon-biased transcripts critical for neuronal function (e.g., ATG9A, PCP4, TrkA-pathway components); parallel effects on histone H3 acetylation, actin cytoskeleton, and NGF-dependent retrograde axonal transport (via HDAC6-mediated hyperacetylation deficiency and unstable microtubules) (Naftelberg et al. 2016, Trends Genet; Ohlen et al. 2017, PMID 28167615) →
Developmental failure of neural-crest–derived sensory and autonomic neuron populations: apoptosis of TrkA+ nociceptors and Pax3+ progenitors in dorsal root ganglia (DRG), sympathetic chain, trigeminal ganglion, and enteric plexus (George et al. 2013, PNAS, PMID 24007805; Jackson et al. 2014, eLife, PMID 25139957) →
Reduced neuron numbers at birth (DRG neuron counts ~10–20% of normal; C8 DRG normally 42,500–53,600 neurons, in FD patients 4,090–8,590; Pearson & Pytel 1978, PMID 624961) →
Slow, progressive postnatal degeneration of remaining sensory and autonomic neurons (unmyelinated fibers and small myelinated); loss of afferents from carotid/aortic baroreceptors and chemoreceptors; retinal ganglion cell degeneration in temporal papillomacular bundle →
Clinical manifestations:
Afferent baroreflex failure → hypertensive crises + orthostatic hypotension.
Afferent chemoreflex failure → blunted response to hypoxia/hypercapnia, paradoxical apnea, SUDS.
Nociceptor/thermoreceptor loss → pain and temperature insensitivity; Charcot joints.
Proprioceptor loss (dorsal columns) → ataxia.
Enteric autonomic loss → gastroparesis, reflux, dysmotility.
Lacrimal parasympathetic loss → alacrima.
Retinal ganglion cell degeneration → progressive optic neuropathy, blindness.
Recurrent hypotension → CKD; aspiration → chronic lung disease.

6.2 Molecular Pathways Involved

Elongator complex tRNA modification pathway (KEGG map03016 tRNA loading; Reactome R-HSA-6784531 tRNA modification in the nucleus and cytosol).
NGF/TrkA retrograde signaling and axonal transport (KEGG hsa04722, Reactome R-HSA-187037 NGF-stimulated transcription). HDAC6 hyperactivity in FD deacetylates α-tubulin, destabilizes microtubules, and impairs retrograde NGF trafficking (Naftelberg et al. 2016).
Autophagy (ATG9A) — reduced due to tRNA-mediated translation defect.
MAPK/ERK signaling downstream of TrkA — attenuated.
JNK stress signaling — activated; contributes to apoptosis of neural crest progenitors.

6.3 Cellular Processes

Neuronal apoptosis during development (GO:0006915).
Impaired axon guidance and target innervation in sensory neurons (GO:0007411).
Defective axonal transport — retrograde NGF endosome trafficking impaired (GO:0008090).
Cytoskeletal instability — decreased α-tubulin acetylation, microtubule dynamic instability (GO:0007010).
Mitochondrial dysfunction — described in Elp1-deficient retinal ganglion cells (Chekuri et al. 2018, Dis Model Mech).

6.4 Protein Dysfunction

ELP1 is a scaffolding subunit of the six-subunit Elongator holoenzyme (ELP1–ELP6). ELP3 provides the catalytic radical-SAM domain that modifies wobble U34. Truncated ELP1 (~79 kD) fails to nucleate a stable Elongator complex → loss of holoenzyme function (Karlsborn et al. 2014).

6.5 Metabolic / Biochemical Changes

Elevated dopamine/norepinephrine ratio — reflects loss of catecholaminergic autonomic neurons with residual central dopaminergic activity.
Elevated 3,4-dihydroxyphenylacetic acid (DOPAC) and reduced norepinephrine in plasma.
Altered urinary HVA/VMA ratio.
Mitochondrial oxidative-phosphorylation deficits in Elp1-deficient retinal cells.

6.6 Tissue Damage Mechanisms

Chronic hypoperfusion (orthostatic hypotension) → renal cortex ischemia → CKD.
Recurrent aspiration → bronchiectasis and chronic lung disease.
Oxidative stress in retinal ganglion cells → optic neuropathy.

6.7 Molecular Profiling

Transcriptomics in humanized TgFD9 Elp1 mice show tissue-specific dysregulation of neurotrophic and cytoskeletal genes, most severe in DRG and trigeminal ganglion (Morini et al. 2023, PMID 38168126).
Proteomics — trigeminal ganglion in Elp1-deficient mice shows down-regulation of NGF, BDNF signaling and mitochondrial metabolism (Leonard et al. 2025 bioRxiv).

Ontology suggestions: GO:0002098 (tRNA wobble uridine modification); GO:0033588 (Elongator holoenzyme complex); GO:0007411 (axon guidance); GO:0008089 (anterograde axonal transport); GO:0006915 (apoptotic process); GO:0007628 (adult walking behavior); GO:0031982 (vesicle); GO:0090128 (regulation of synaptonemal complex assembly). Cell types: CL:0011003 (peripheral autonomic neuron); CL:0000103 (bipolar neuron); CL:0000198 (nociceptor); CL:0000101 (sensory neuron); CL:0000740 (retinal ganglion cell).

7. Anatomical Structures Affected

7.1 Organ Level

Primary organs: Peripheral nervous system (dorsal root ganglia, sympathetic chain ganglia, cranial nerve ganglia, enteric nervous system).
Secondary organ involvement: Kidneys (progressive CKD), lungs (chronic aspiration lung disease/bronchiectasis), heart (baroreflex failure → BP lability), retina and optic nerve, skeletal system (kyphoscoliosis, Charcot joints), tongue (absent fungiform papillae), lacrimal glands (alacrima), gastrointestinal tract (dysmotility).
Body systems: Autonomic nervous, sensory nervous, cardiovascular, respiratory, gastrointestinal, ocular, musculoskeletal, urinary.

7.2 Tissue and Cell Level

Dorsal root ganglion (UBERON:0000044) sensory neurons — small pseudounipolar neurons (CL:0000101), especially unmyelinated nociceptors (CL:0000198) and proprioceptors.
Sympathetic chain ganglia (UBERON:0002440) autonomic neurons (CL:0011003).
Enteric nervous system (UBERON:0002393) neurons.
Trigeminal ganglion (UBERON:0001675) neurons.
Retinal ganglion cells (CL:0000740), particularly in the papillomacular bundle.
Lissauer's tract, dorsal columns (fasciculus gracilis/cuneatus) — progressive axonal loss in spinal cord (Pearson & Pytel 1978, PMID 624961).
Lacrimal gland parasympathetic innervation.
Tongue fungiform papillae (UBERON:0002205) — congenitally absent.

7.3 Subcellular Level

Cytoplasmic Elongator complex (GO:0033588).
Microtubule cytoskeleton (GO:0005874) — hypoacetylated α-tubulin.
Mitochondria (GO:0005739) — dysfunctional in retinal cells.
Vesicular retrograde transport machinery.

7.4 Localization

Lateralization: Bilateral, symmetric.
Specific sites: UBERON:0000044 (dorsal root ganglion), UBERON:0001675 (trigeminal ganglion), UBERON:0002440 (sympathetic ganglion), UBERON:0002393 (enteric nervous system), UBERON:0000970 (eye), UBERON:0000970/UBERON:0001782 (retina), UBERON:0001291 (lacrimal gland), UBERON:0002205 (fungiform papilla).

8. Temporal Development

8.1 Onset

Congenital / neonatal. Presentation typically begins at birth or within the first weeks: hypotonia, feeding difficulties, absent tears with crying, poor thermoregulation.
Onset pattern: Insidious (developmental) with superimposed acute autonomic crises beginning in infancy/toddlerhood.

8.2 Progression / Stages

Infancy: Feeding difficulty, aspiration pneumonia, alacrima, hypotonia, unstable temperature.
Childhood (2–10 y): Cyclical vomiting/autonomic crises emerge; delayed motor milestones; ataxia becomes apparent.
Adolescence: Kyphoscoliosis; early optic neuropathy; hypertensive lability worsens.
Adulthood (>18 y): Progressive ataxia, blindness (by 20s–30s), CKD, chronic lung disease, sleep-disordered breathing, sudden death risk.
Progression rate: Slow, monotonically progressive (no true remitting phase).
Duration: Lifelong.

8.3 Patterns

No spontaneous or treatment-induced remission.
Critical developmental windows: Prenatal and early postnatal periods are the key windows for neural-crest-derived neuron survival; disease-modifying therapy is hypothesized to work best if administered before massive neuronal loss (relevant to newer splicing-modulator therapeutics).

9. Inheritance and Population

9.1 Epidemiology

Prevalence: Extremely rare overall (<1/1,000,000 in general non-AJ populations). Incidence in Ashkenazi Jewish population: ~1 in 3,600 live births (ranges 1/3,600–1/3,700). Worldwide living FD patients: ~500–700 (Axelrod 2004, PMID 15277940; Orphanet ORPHA:1764).
Carrier frequency (AJ): ~1 in 30 (1 in 27–36 across studies; higher, ~1/18, in Polish-descended AJ subgroups; Lehavi et al. 2003, PMID 12885336).

9.2 Genetic Etiology Details

Inheritance pattern: Autosomal recessive (HP:0000007). Compatible with founder effect and consanguinity in isolated non-AJ pedigrees.
Penetrance: Effectively 100% in biallelic homozygotes/compound heterozygotes for known pathogenic variants.
Expressivity: Variable — largely dictated by residual "leaky" full-length ELP1 expression.
Anticipation: Not observed (not a repeat expansion disorder).
Germline mosaicism: Not reported as a significant source of new cases.
Founder effect: Yes — a single ancestral c.2204+6T>C haplotype, estimated to have originated ~500–1000 years ago in Eastern European Ashkenazi Jewish populations, drives >99.5% of AJ cases.
Consanguinity role: Contributes in non-AJ pedigrees; incidence in AJ populations is driven by founder-allele frequency rather than consanguinity.

9.3 Population Demographics

Affected populations: Ashkenazi Jews (predominant); rare cases in non-AJ populations (Puerto Rican, English, Mexican described).
Geographic distribution: Highest incidence in Israel and North American AJ communities; sporadic elsewhere.
Sex ratio: ~1:1 (autosomal recessive, no sex predilection).
Age distribution: All ages; the surviving population increasingly includes adults >20 due to improved supportive care.

10. Diagnostics

10.1 Clinical Diagnostic Criteria (Historical Cardinal Five)

Per Axelrod et al., diagnosis is supported by all of: 1. Absent overflow tears (alacrima). 2. Absent fungiform papillae on tongue (smooth glistening tip). 3. Absent axon flare after intradermal histamine (loss of C-fiber response). 4. Decreased or absent deep tendon reflexes. 5. Ashkenazi Jewish ancestry. (Sources: Axelrod 2004, PMID 15277940; GeneReviews NBK1180.)

10.2 Confirmatory Testing

Molecular genetic testing — targeted ELP1 c.2204+6T>C testing (Sanger or specific PCR assay) — is the standard of care and confirms nearly all AJ cases. Rare non-AJ cases require full ELP1 sequencing.
Elevated plasma dopamine/norepinephrine ratio.
Postural blood pressure testing — orthostatic BP drop >20 mmHg without appropriate HR increase.
Blunted response to intradermal histamine — absent axon flare.
Sural nerve biopsy (rarely used now) — reduced unmyelinated fibers.

10.3 Imaging / Functional Tests

Chest CT — bronchiectasis in adults.
Ophthalmic OCT — thinning of retinal nerve fiber layer (especially temporal papillomacular bundle) as early as childhood.
Ambulatory blood pressure monitoring — extreme BP variability.
Polysomnography — high prevalence of sleep-disordered breathing (>70% adults).
Renal ultrasound / eGFR — progressive CKD.
Ventilatory response tests — blunted hypoxic/hypercapnic ventilatory response.

10.4 Screening

Preconception carrier screening for the ELP1 c.2204+6T>C variant is standard-of-care in Ashkenazi Jewish populations and included in the ACMG/ACOG expanded AJ panels and commercial screens (JScreen, Myriad Foresight, Natera).
Prenatal diagnosis (CVS or amniocentesis with targeted ELP1 mutation testing) available for known-carrier couples; PGT-M (preimplantation genetic testing) is commonly used.
Newborn screening is not standard because the genotype is essentially always confirmed in couples-at-risk before conception.

10.5 Differential Diagnosis

Other HSANs (HSAN I–VIII), particularly HSAN II (WNK1/HSN2), HSAN IV (NTRK1), HSAN V (NGF).
Congenital insensitivity to pain with anhidrosis (CIPA).
Central hypoventilation syndrome (PHOX2B).
Chronic inflammatory demyelinating polyneuropathy (autonomic variant).
Multiple system atrophy (in adult presentations).
POTS / pure autonomic failure (adult onset).

11. Outcome / Prognosis

11.1 Survival and Mortality

Historical (pre-1960): ~50% mortality by age 5.
Current (2020s): ~50% probability of reaching age 40; some patients survive into their 60s–70s. Approximately 40% of the surviving FD cohort is >20 years old (Palma et al. 2017, Sleep; MedLink Neurology).
Leading causes of death:
Sudden Unexpected Death During Sleep (SUDS) — most common; annual incidence ~3.4 per 1,000 person-years (Palma et al. 2017, PMID 28521050).
Chronic lung disease / respiratory failure — from repeated aspiration.
Renal failure.
Autonomic crises with severe hypertension — cerebral hemorrhage.

11.2 Morbidity and Function

Severe cumulative disability: blindness, ataxia, feeding-tube dependence, ventilator dependence, dialysis in late-stage CKD.
QOL measures show substantial impairment across physical and mental domains; anxiety is prominent.

11.3 Complications

Aspiration pneumonia and bronchiectasis.
Chronic kidney disease.
Kyphoscoliosis with restrictive lung disease.
Optic neuropathy → legal blindness.
Charcot joints, unrecognized fractures.
Severe hypertensive crises with end-organ damage.

11.4 Prognostic Factors

Younger age at first crisis / more frequent crises → worse prognosis.
Sleep-disordered breathing (untreated OSA), fludrocortisone use, low-normal potassium — independent risk factors for SUDS (Palma et al. 2017, PMID 28521050).
Residual full-length ELP1 protein levels (measurable in blood or fibroblasts) may correlate with severity and are being explored as biomarkers (González-Duarte et al. 2025 Ann Clin Transl Neurol, PMID 41385477).

12. Treatment

All currently approved therapy is symptomatic; disease-modifying therapy is investigational.

12.1 Pharmacotherapy (Symptomatic)

Autonomic crises:
Diazepam IV/rectal (0.2 mg/kg every 3 hours, max 10 mg) — first line to abort vomiting and reduce catecholamine surges (NCIT:C29435).
Clonidine oral/transdermal — for persistent hypertension (α₂-agonist; NCIT:C505). Combined diazepam+clonidine is standard.
Dexmedetomidine — refractory crises, more selective α₂-agonist with shorter half-life (Krajewski et al. 2022 Cureus, PMID 36381719); sublingual formulation being trialed (NCT06148311).
Baroreflex failure / BP lability: Carbidopa (peripheral DOPA-decarboxylase inhibitor) reduces peripheral catecholamine surges and BP variability in a double-blind crossover trial (Palma et al. 2020, Hypertension, PMID 32623925).
Orthostatic hypotension: Midodrine (α₁-agonist), high salt intake, compression stockings; fludrocortisone is now avoided given SUDS association.
Gastrointestinal: Proton pump inhibitors, prokinetics, Nissen fundoplication, gastrostomy tube.
Alacrima: Artificial tears, punctal plugs.
Anxiety: Benzodiazepines, SSRIs.

12.2 Disease-Modifying / Advanced Therapies (Investigational)

Kinetin (N⁶-furfuryladenine) — small-molecule splicing corrector; increases exon 20 inclusion and full-length ELP1 mRNA/protein in patient cells and in vivo (Slaugenhaupt et al. 2004 Hum Mol Genet; Axelrod et al. 2011, Pediatr Res, PMID 21725277).
PTC258 / PTC-related oral splicing modulators (PTC Therapeutics) — kinetin-derivative small molecules that cross the blood–brain barrier and restore correct ELP1 splicing in Elp1 mouse brain and prevent gait ataxia and retinal degeneration (Sinha et al. 2023, PMID 36809767). Clinical development ongoing.
BPN-14477 / other splice modulators in preclinical stages.
Phosphatidylserine — FDA-approved food supplement that elevates ELP1 expression and, combined with kinetin, is additive; ameliorated neurodegeneration in mouse models (Bochner et al. 2013, PLOS Genet).
Exon-specific U1 snRNA (ExSpeU1) delivered by AAV2 intravitreally — rescues optic neuropathy in mouse models (Romani et al. 2025 bioRxiv).
AAV2-ELP1 gene augmentation intravitreally — restores retinal function in humanized FD mice; first demonstration that visual function can be recovered pharmacologically (Yesilyurt et al. 2026, Molecular Therapy).
Antisense oligonucleotides (ASOs) targeting the ELP1 splice defect — under preclinical development.

12.3 Surgical/Interventional

Nissen fundoplication + gastrostomy tube — for severe GERD and aspiration risk.
Spinal fusion for progressive scoliosis.
Punctal plugs / lateral tarsorrhaphy for severe alacrima.
Tracheostomy and non-invasive ventilation — for severe SDB or respiratory failure.

12.4 Supportive / Rehabilitative

Nutritional support via G-tube.
Physical therapy for ataxia and orthopedic complications.
Occupational therapy for adaptive tools (blindness, ataxia).
Speech-language therapy for dysphagia.
Multidisciplinary care at specialized dysautonomia centers (NYU, Israel FD Center).

Ontology suggestions (NCIT): NCIT:C505 (Clonidine); NCIT:C29435 (Diazepam); NCIT:C471 (Carbidopa); NCIT:C61708 (Dexmedetomidine); NCIT:C935 (Midodrine); NCIT:C874 (Fludrocortisone – avoid); NCIT:C15986 (Pharmacotherapy); NCIT:C15238 (Gene Therapy); NCIT:C15329 (Surgical Procedure); NCIT:C15302 (Physical Therapy).

13. Prevention

13.1 Primary Prevention

Preconception carrier screening for the ELP1 c.2204+6T>C variant is the cornerstone of primary prevention. Included in expanded AJ carrier screening panels (ACMG-recommended).
PGT-M (preimplantation genetic testing for monogenic disorders) for carrier couples.
Prenatal diagnosis (CVS/amniocentesis + targeted mutation testing).

13.2 Secondary Prevention (Early Detection & Complications)

Routine polysomnography and initiation of non-invasive ventilation for sleep-disordered breathing (reduces SUDS incidence).
Regular renal function and ophthalmological monitoring.
Aspiration precautions: G-tube feeding, thickened liquids.

13.3 Tertiary Prevention

Prophylactic pulmonary hygiene / chest physiotherapy.
Vaccinations (influenza, pneumococcal, RSV as indicated).
Aggressive management of GERD and treatment of pneumonia early.

13.4 Genetic Counseling

Recurrence risk for carrier couples is 25%.
Genetic counseling is offered routinely to AJ couples before conception; JScreen and hospital-based counseling widely accessible.

14. Other Species / Natural Disease

FD is a human-only disease; no naturally occurring counterpart has been reported. Animal disease modeling is entirely experimental.

NCBI Taxon: NCBITaxon:9606 (Homo sapiens).
Orthologous genes: ELP1 is highly conserved. Orthologs: mouse Ikbkap/Elp1 (MGI:1927169); rat Elp1; zebrafish elp1; S. cerevisiae IKI3/ELP1. Elongator complex components are present from yeast to mammals.
Comparative pathology: Elongator loss in yeast and C. elegans causes translation/tRNA modification defects but obviously no neuropathy phenotype. Mouse conditional knockouts and humanized TgFD9 models faithfully recapitulate DRG, sympathetic, and retinal degeneration (see §15).
Zoonotic potential: Not applicable.

15. Model Organisms

15.1 Mouse Models

Global Ikbkap knockout (Ikbkap⁻/⁻) — early embryonic lethal by E12.5 due to cardiovascular and neural tube defects (Chen et al. 2009; Dietrich et al. 2011).
Wnt1-Cre;Ikbkap^flox/flox (neural-crest conditional knockout) — apoptosis of Pax3⁺ progenitors, sensory and sympathetic neurons; recapitulates DRG loss and phenotypic FD (George et al. 2013 PNAS, PMID 24007805).
Tyrp2-Cre;Ikbkap^flox/flox — retinal-specific loss; slow, progressive RGC and photoreceptor degeneration mimicking FD optic neuropathy (Ueki et al. 2016 eNeuro; Chekuri et al. 2018 Dis Model Mech).
TgFD9 (humanized) mouse — carries human ELP1 with the c.2204+6T>C variant on a mouse Elp1-null background; produces tissue-specific ELP1 reduction paralleling human disease and shows progressive gait ataxia and RGC degeneration. Used as the primary preclinical platform for testing kinetin/PTC258 splice modulators and gene therapies (Sinha et al. 2018 Am J Hum Genet, PMID 30827494; Sinha et al. 2023, PMID 36809767).
Elp1 CNS-conditional knockouts (Nestin-Cre) — CNS role for ELP1 in oligodendrocyte and neuron survival (Chaverra et al. 2017, Dis Model Mech, PMID 28167615).

15.2 Cellular / In Vitro Models

Patient-derived fibroblasts — standard for splicing assays; leaky wild-type ELP1 splicing measurable.
iPSC-derived sensory / sympathetic / retinal ganglion neurons — from FD patients or CRISPR-edited controls; used to model developmental apoptosis and screen small-molecule splicing correctors (Zeltner et al. 2016, Nat Med, PMID 27295489).
HEK293/HeLa cell lines with ELP1 minigene constructs — high-throughput splice-modulator screens.

15.3 Zebrafish

elp1 morphants and mutants — recapitulate peripheral neurogenesis defects; useful for high-throughput drug screens (Cheishvili et al. 2011).

15.4 Model Applications and Limitations

Applications: Small-molecule and gene therapy preclinical testing, mechanistic dissection of splicing, elucidation of Elongator's tissue-specific role.
Limitations: No mouse model reproduces the full multisystem autonomic crisis phenotype (BP lability, gastrointestinal dysmotility); most models focus on sensory/retinal degeneration. The humanized TgFD9 mouse is the most faithful but retains partial wild-type Elp1 in some tissues.

15.5 Resources

MGI (Mouse Genome Informatics) for Ikbkap/Elp1 alleles.
NYU Langone Dysautonomia Center Biorepository — patient fibroblasts, iPSCs, tissue samples.
JAX and academic labs (Slaugenhaupt lab; Kaufmann/Palma group) — humanized mouse lines.
Familial Dysautonomia Foundation — funding and biobank coordination.

Ontology Term Summary

Table (click to expand)

Feature	Suggested Term
Disease	MONDO:0009131 (Familial Dysautonomia); ICD-10 G90.1
Gene	HGNC:5959 (ELP1); UniProt O95163
Inheritance	HP:0000007 (Autosomal recessive)
Alacrima	HP:0000522
Absent fungiform papillae	HP:0000167
Areflexia	HP:0001315
Nociceptor loss / pain insensitivity	HP:0007021
Ataxia (proprioceptive)	HP:0002131
Optic neuropathy	HP:0000632
Autonomic crises	HP:0005112
Orthostatic hypotension	HP:0001278
Kyphoscoliosis	HP:0002751
Gastroesophageal reflux	HP:0002020
Recurrent aspiration	HP:0002100
Sudden death in sleep	HP:0001700-related
Elongator complex	GO:0033588
tRNA wobble modification	GO:0002098
DRG	UBERON:0000044
Sympathetic ganglion	UBERON:0002440
Nociceptor	CL:0000198
Retinal ganglion cell	CL:0000740
Clonidine	NCIT:C505
Diazepam	NCIT:C29435
Carbidopa	NCIT:C471

Key References (selected, primary literature)

Anderson SL, Coli R, Daly IW, et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am J Hum Genet. 2001;68(3):753-758. PMID: 11179016.
Slaugenhaupt SA, Blumenfeld A, Gill SP, et al. Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. 2001;68(3):598-605. PMID: 11179017.
Cuajungco MP, Leyne M, Mull J, et al. Tissue-specific reduction in splicing efficiency of IKBKAP due to the major mutation associated with familial dysautonomia. Am J Hum Genet. 2003;72(3):749-758. PMID: 12756454.
Pearson J, Pytel BA. Quantitative studies of dorsal root ganglia and neuropathologic observations on spinal cords in familial dysautonomia. J Neurol Sci. 1978;39(1):47-59. PMID: 624961.
Axelrod FB. Familial dysautonomia. Muscle Nerve. 2004;29(3):352-363. PMID: 15277940.
Lehavi O, Aizenstein O, Bercovich D, et al. Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews. Genet Test. 2003;7(2):139-142. PMID: 12885336.
Leyne M, Mull J, Gill SP, et al. Identification of the first non-Jewish mutation in familial dysautonomia. Am J Med Genet A. 2003;118A(4):305-308. PMID: 12687659.
Axelrod FB, Liebes L, Gold-Von Simson G, et al. Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr Res. 2011;70(5):480-483. PMID: 21725277.
George L, Chaverra M, Wolfe L, et al. Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3+ progenitors and peripheral neurons. PNAS. 2013;110(46):18698-18703. PMID: 24007805.
Ueki Y, Ramirez G, Salcedo E, et al. Loss of Ikbkap causes slow, progressive retinal degeneration in a mouse model of familial dysautonomia. eNeuro. 2016;3(5). PMID: 27822501.
Chekuri A, Bhagavath Chandran G, Yesilyurt HG, et al. Retina-specific loss of Ikbkap/Elp1 causes mitochondrial dysfunction that leads to selective retinal ganglion cell degeneration. Dis Model Mech. 2018;11:dmm033746.
Palma JA, Norcliffe-Kaufmann L, Kaufmann H. Sudden Unexpected Death During Sleep in Familial Dysautonomia: A Case-Control Study. Sleep. 2017;40(8):zsx083. PMID: 28521050.
Palma JA, Norcliffe-Kaufmann L, Fuente-Mora C, et al. Chemoreflex failure and sleep-disordered breathing in familial dysautonomia. Sleep Med. 2019;54:34-40. PMID: 30890343.
Palma JA, Norcliffe-Kaufmann L, Martinez J, Kaufmann H. Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia. Hypertension. 2020;76(3):724-731. PMID: 32623925.
Sinha R, Kim YJ, Nomakuchi T, et al. Development of an oral treatment that rescues gait ataxia and retinal degeneration in a phenotypic mouse model of familial dysautonomia. Am J Hum Genet. 2023;110(4):531-547. PMID: 36809767.
Krajewski KJ et al. Experience With Dexmedetomidine Use in the Treatment of Dysautonomic Crisis in Familial Dysautonomia: An Off-Label Use. Cureus. 2022. PMID: 36381719.
Jackson MZ, Gruner KA, Qin C, Tourtellotte WG. A neuron autonomous role for the familial dysautonomia gene ELP1 in sympathetic and sensory target tissue innervation. Development. 2014. PMID: 25139957.
Bochner R, Ziv Y, Zeevi D, et al. Phosphatidylserine increases IKBKAP levels in a humanized knock-in IKBKAP mouse model. Hum Mol Genet. 2013. PMID: 23824189.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Table (click to expand)

Outcome	Count
References checked	38
Resolved	38
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	38
On topic	7
Off topic	8

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:37000283 (1 mention) - An assessment of vegetation cover of Mysuru City, Karnataka State, India, using deep convolutional neural networks.
shared terms: model
PMID:32623925 (3 mentions) - Genetically Predicted Blood Pressure Across the Lifespan: Differential Effects of Mean and Pulse Pressure on Stroke Risk.
shared terms: disease
PMID:20857273 (3 mentions) - [Psychotherapy of Asperger syndrome in adults].
shared terms: none
PMID:24007805 (3 mentions) - The effect of color priming on infant brain and behavior.
shared terms: none
PMID:38168126 (1 mention) - A 3-year follow-up clinical study on the preservation for vitality of involved tooth in jaw cysts through an innovative method.
shared terms: none
PMID:21725277 (4 mentions) - Myocardial dysfunction in neonatal sepsis: a tissue Doppler imaging study.
shared terms: none
PMID:23824189 (1 mention) - A calcineurin-dependent switch controls the trafficking function of α-arrestin Aly1/Art6.
shared terms: cell, model
DOI:10.1161/HYPERTENSIONAHA.120.15267 (4 mentions) - Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia
shared terms: failure

Weighed against this report's own most characteristic terms: elp1, autonomic, loss, crise, disease, gene, elongator, retinal, aspiration, sensory, neuron, failure, progressive, palma, ataxia, cell, neuropathy, complex, model, ganglion.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Table (click to expand)

Outcome	Count
Terms checked	74
Resolved	68
Unresolved (possible confabulation)	3
Obsolete	0
Unverifiable	3
Terms whose name was checked	57
Terms named correctly	21
Terms named as a different term	19
Terms whose name is worth a second look	17

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:

HP:0100799 (1 mention) - the report calls it "smooth tongue"; HP calls it Neoplasm of the middle ear
HP:0001315 (2 mentions) - the report calls it "Depressed / absent deep tendon reflexes — ~100%", "Areflexia"; HP calls it Diminished deep tendon reflex**
HP:0002131 (2 mentions) - the report calls it "Ataxia (proprioceptive)"; HP calls it Episodic ataxia
HP:0000632 (2 mentions) - the report calls it "Optic neuropathy"; HP calls it Lacrimation abnormality
HP:0005112 (2 mentions) - the report calls it "abnormal autonomic nervous system physiology", "Autonomic crises"; HP calls it Abdominal aortic aneurysm
HP:0002326 (1 mention) - the report calls it "hypertension"; HP calls it Transient ischemic attack
HP:0011169 (1 mention) - the report calls it "Blood pressure lability / baroreflex failure — ~100%"; HP calls it Generalized clonic seizure**
HP:0002102 (1 mention) - the report calls it "Recurrent aspiration pneumonia — ~90%"; HP calls it Pleuritis**
HP:0000739 (1 mention) - the report calls it "Anxiety and emotional lability — very frequent"; HP calls it Anxiety**
HP:0011036 (1 mention) - the report calls it "Increased serum dopamine-to-norepinephrine ratio"; HP calls it Abnormality of renal excretion
CL:0011003 (2 mentions) - the report calls it "peripheral autonomic neuron"; CL calls it magnocellular neurosecretory cell
UBERON:0002393 (2 mentions) - the report calls it "Enteric nervous system", "enteric nervous system"; UBERON calls it pharyngotympanic tube
UBERON:0002205 (2 mentions) - the report calls it "Tongue fungiform papillae", "fungiform papilla"; UBERON calls it manubrium of sternum
UBERON:0001291 (1 mention) - the report calls it "lacrimal gland"; UBERON calls it thick ascending limb of loop of Henle
NCIT:C29435 (3 mentions) - the report calls it "Diazepam"; NCIT calls it DNA Minor Groove Binding Agent SG2000
NCIT:C505 (3 mentions) - the report calls it "Clonidine"; NCIT calls it Fluorouracil
NCIT:C471 (2 mentions) - the report calls it "Carbidopa"; NCIT calls it Enzyme Inhibitor
NCIT:C61708 (1 mention) - the report calls it "Dexmedetomidine"; NCIT calls it Dextroamphetamine Saccharate
NCIT:C874 (1 mention) - the report calls it "Fludrocortisone – avoid"; NCIT calls it Thiamine

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0000167 (2 mentions), reported as "atrophic fungiform papillae", "Absent fungiform papillae" - HP does not contain this term
ECTO:0001093 (1 mention), reported as "exposure to psychosocial stress" - ECTO does not contain this term
ECTO:0000000 (1 mention) - ECTO does not contain this term

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:0007021 (2 mentions) - the report calls it "Nociceptor loss / pain insensitivity"; HP calls it Pain insensitivity
HP:0010829 (1 mention) - the report calls it "Decreased temperature sensation — ~90%"; HP calls it Impaired temperature sensation**
HP:0002020 (3 mentions) - the report calls it "Gastroesophageal reflux — ~85%", "Gastroesophageal reflux"; HP calls it Gastroesophageal reflux**
HP:0002098 (1 mention) - the report calls it "abnormal breathing regulation"; HP calls it Respiratory distress, and lists "Labored breathing" among its other names
HP:0002751 (2 mentions) - the report calls it "Kyphoscoliosis — ~90% by adolescence", "Kyphoscoliosis"; HP calls it Kyphoscoliosis**
GO:0033588 (4 mentions) - the report calls it "Elongator holoenzyme complex", "Cytoplasmic Elongator complex", "Elongator complex"; GO calls it elongator holoenzyme complex, and lists "Elongator core complex" among its other names
GO:0002098 (3 mentions) - the report calls it "tRNA wobble uridine modification", "tRNA wobble modification"; GO calls it tRNA wobble uridine modification
GO:0006915 (2 mentions) - the report calls it "Neuronal apoptosis during development", "apoptotic process"; GO calls it apoptotic process**, and lists "induction of apoptosis by p53" among its other names
GO:0090128 (1 mention) - the report calls it "regulation of synaptonemal complex assembly"; GO calls it regulation of synapse maturation
UBERON:0000044 (3 mentions) - the report calls it "Dorsal root ganglion", "dorsal root ganglion", "DRG"; UBERON calls it dorsal root ganglion, and lists "DRG" among its other names
UBERON:0002440 (3 mentions) - the report calls it "Sympathetic chain ganglia", "sympathetic ganglion", "Sympathetic ganglion"; UBERON calls it inferior cervical ganglion, and lists "stellate ganglion" among its other names
GO:0005874 (1 mention) - the report calls it "Microtubule cytoskeleton"; GO calls it microtubule
GO:0005739 (1 mention) - the report calls it "Mitochondria"; GO calls it mitochondrion, and lists "mitochondria" among its other names
UBERON:0001782 (1 mention) - the report calls it "retina"; UBERON calls it pigmented layer of retina, and lists "pigmented retina" among its other names
HP:0000007 (2 mentions) - the report calls it "Autosomal recessive", "Inheritance pattern: Autosomal recessive"; HP calls it Autosomal recessive inheritance
NCIT:C935 (1 mention) - the report calls it "Midodrine"; NCIT calls it Vindesine Sulfate, and lists "Gesidine" among its other names
HP:0002100 (1 mention) - the report calls it "Recurrent aspiration"; HP calls it Recurrent aspiration pneumonia

Terms named inconsistently

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

HP:0000167 - called "atrophic fungiform papillae", "Absent fungiform papillae"
HP:0001315 - called "Depressed / absent deep tendon reflexes** — ~100%", "Areflexia"
HP:0005112 - called "abnormal autonomic nervous system physiology", "Autonomic crises"
HP:0002020 - called "Gastroesophageal reflux** — ~85%", "Gastroesophageal reflux"
HP:0002751 - called "Kyphoscoliosis** — ~90% by adolescence", "Kyphoscoliosis"
GO:0033588 - called "Elongator holoenzyme complex", "Cytoplasmic Elongator complex", "Elongator complex"
GO:0002098 - called "tRNA wobble uridine modification", "tRNA wobble modification"
GO:0006915 - called "Neuronal apoptosis** during development", "apoptotic process"
CL:0000198 - called "nociceptor", "Nociceptor"
CL:0000740 - called "retinal ganglion cell", "Retinal ganglion cells", "Retinal ganglion cell"
UBERON:0000044 - called "Dorsal root ganglion", "dorsal root ganglion", "DRG"
UBERON:0002440 - called "Sympathetic chain ganglia", "sympathetic ganglion", "Sympathetic ganglion"
UBERON:0002393 - called "Enteric nervous system", "enteric nervous system"
UBERON:0001675 - called "Trigeminal ganglion", "trigeminal ganglion"
UBERON:0002205 - called "Tongue fungiform papillae", "fungiform papilla"
HP:0000007 - called "Autosomal recessive", "Inheritance pattern: Autosomal recessive"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.