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Riley-Day syndrome - Clinical Profile, Genes & Research | Kisho | Kisho

Features include: Orthostatic hypotension, Corneal ulceration, Pupillary hypersensitivity to parasympathomimetic agents, and Low muscle tone (hypotonia) and 28 more.

Organ System	Phenotype Count	Example Features
Digestive system	5	Gastroesophageal reflux, Feeding difficulties in infancy, Constipation
Eyes	3	Corneal ulceration, Recurrent corneal erosions, Decreased corneal reflex
Kidneys and urinary system	3	Abnormal renal physiology, Glomerular sclerosis, Elevated creatinine (kidney function marker) (elevated circulating creatinine concentration)
Brain and nerves	3	Emotional lability, Hyporeflexia, Neuropathic arthropathy
Muscles	2	Low muscle tone (hypotonia), Generalized hypotonia
Heart and blood vessels	2	Tachycardia, Hypertension
Lungs and breathing	1	Decreased sensitivity to hypoxemia
Skin	1	Episodic hyperhidrosis
Bones and joints	1	Sideways curvature of the spine (scoliosis)
Blood and immune system	1	Recurrent infections due to aspiration
Metabolism	1	Recurrent fever
Growth and development	1	Growth delay
Lab test results	1	Elevated creatinine (kidney function marker) (elevated circulating creatinine concentration)

GeneReviews

Clinical Guidance

Familial dysautonomia (FD) affects the development and survival of sensory, sympathetic, and parasympathetic neurons. It is a debilitating disease present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (I.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and cardiovascular instability. Hypotonia contributes to delay in acquisition of motor milestones. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased .

Table 2.

Clinical Manifestations of Familial Dysautonomia

Source: GeneReviews — "Familial Dysautonomia"

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

The five cardinal clinical diagnostic criteria for familial dysautonomia are absence of fungiform papillae on the tongue, absence of flare after injection of intradermal histamine, decreased or absent deep-tendon reflexes, absence of overflow emotional tears, and Ashkenazi Jewish descent . This last criterion, however, was rebutted after the discovery of three rare non-Jewish ELP1 variants .

Suggestive Findings

Clinical findings

Source: GeneReviews — "Familial Dysautonomia"

GeneReviews

Differential Diagnosis

Table 3. Genes and Disorders of Interest in the Differential Diagnosis

Gene(s)	Disorder	MOI	Clinical Characteristics / Comment
ATL1	HSN1D (See Spastic Paraplegia 3A.)	AD	Loss of pain temperature sensation; osteomyelitis; lancinating pain; distal motor involvement (variable); facultative deafness; no visceral signs of autonomic involvement
ATL3	HSN1F (OMIM 615632)

Genetic testing for ELP1 is available. Testing is considered confirmatory for diagnosis.

Biomarker and diagnostic research for Riley-Day syndrome has been reported in the published literature.

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for Riley-Day syndrome. An additional 3 compounds hold orphan drug designation.

Orphan Drug Designations

While no drugs are FDA-approved specifically for Riley-Day syndrome, some of the following designated compounds may be used off-label in clinical practice. Treatment decisions should be made in consultation with a specialist familiar with this condition.

The following drugs have received orphan drug designation from the FDA for Riley-Day syndrome. Orphan designation reflects regulatory interest and does not indicate approval for treatment.

Brand Name	Generic Name	Sponsor	Designated	Exclusivity End	Designation Status
2-[(2S)-2-aminopropyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine	2-[(2S)-2-aminopropyl]-3,5-dichloro-N-(2-thienylmethyl)thieno[3,2-b]pyridin-7-amine	Tikun Therapeutics Inc.	2024	—	Designated
Recombinant adeno-associated virus serotype 2 containing the human ELP1 gene, driven by the U1a promoter	Recombinant adeno-associated virus serotype 2 containing the human ELP1 gene, driven by the U1a promoter	Tikun Therapeutics Inc.	2024	—	Designated
O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic acid amidoxime dihydrochloride	O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic acid amidoxime dihydrochloride	Mitochon Technologies Kft.	2020	—	Designated

GeneReviews

Management Guidelines

Clinical practice guidelines have been published (full text). Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with familial dysautonomia, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Familial Dysautonomia

System/Concern	Evaluation	Comment
Growth	Measure height, weight, head circumference	—
Neurologic involvement	By pediatric neurologist	Comprehensive neurologic exam w/attn to sensory ataxia, abnormalities in proprioception; Positive Romberg sign; or absent deep tendon H-reflexes; Consider: (1) MRI if concerns re worsening gait ataxia /or balance; (2) EEG if concerns re seizures.

GeneReviews

Clinical Guidance

Symptoms tend to be worse in hot or humid weather; affected individuals should try to avoid being outdoors in such conditions as much as possible. Other situations that can exacerbate disease manifestations include a full bladder; frequent visits to the lavatory are recommended . Since long car rides, coming out of a movie theater, or fatigue can also worsen symptoms, such situations should be avoided as much as possible . Episodic hypertension can occur in response to emotional stress or visceral pain, and therefore should be avoided when possible . Environmental situations associated with hypobaric hypoxia (e.g., aircraft flight or ascent to high altitude) pose a potential risk to individuals with daytime hypercapnia .

Source: GeneReviews — "Familial Dysautonomia"

GeneReviews

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Familial Dysautonomia"

Clinical Trials

3 trials found

Explore Trials

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

Table 6. Recommended Surveillance for Individuals with Familial Dysautonomia

System/Concern	Evaluation	Frequency
Constitutional	Assess height weight, head circumference.	Routinely in growing children Neurogenic
dysphagia	Assess weight, nutrition, safety of oral feeding.	In growing children: routinely; In adults: when respiratory function s or respiratory infections DD / Educational
issues	Assess developmental/educational progress.	At least annually
Behavior	Evaluate mental status.	Routinely during interim visits Respiratory
breathing	Full laboratory polysomnography incl end-tidal CO2 measurements	Annually regardless of previous normal studies; Before 6-8 weeks after starting growth hormone therapy Dysautonomic
crises	Frequency severity of hyperadrenergic crises	Annually Bradyarrhythmia
hypotension	Eval of symptoms orthostatic challenge tests	Perform during interim visits.
Blood pressure	Monitor BP to assure optimal mgmt of BP lability to help limit neurologic progression w/age (which can be assoc w/compromised cerebral perfusion)	Annual 24-hr BP monitoring
Kidney	Assess kidney function to assure early detection of renal disease	Persons w/normal kidney function: annually; Persons w/CKD: per treating nephrologist Monitor existing kidney disease.

Source: GeneReviews — "Familial Dysautonomia"

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

3 clinical trials registered, 1 recruiting. Interventions under study include drug therapy and other interventions. Pipeline includes 2 PHASE2. Research is primarily sponsored by academic and government institutions.

13 publications have been identified in PubMed for Riley-Day syndrome. Research spans Basic Science / Preclinical (31%), Case Report / Case Series (23%), and Diagnostic / Biomarker (15%).

Research Type	Count	% of Total
Laboratory research	4	31%
Patient case studies	3	23%
Testing and diagnosis research	2	15%
Disease patterns and progression	2	15%
Other research	1	8%
New treatment approaches	1	8%

Recent Publications

Peretto L (2026). [PMID: 41964038](https://pubmed.ncbi.nlm.nih.gov/41964038/). *Orphanet J Rare Dis*. [Other]
Ahmad R (2025). [PMID: 40938507](https://pubmed.ncbi.nlm.nih.gov/40938507/). *Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology*. [Case Report / Case Series]
Grobocopatel Marra M (2025). [PMID: 40580154](https://pubmed.ncbi.nlm.nih.gov/40580154/). *Expert review of neurotherapeutics*. [Basic Science / Preclinical]
González-Duarte A (2025). [PMID: 41385477](https://pubmed.ncbi.nlm.nih.gov/41385477/). *Annals of clinical and translational neurology*. [Diagnostic / Biomarker]
Fava M (2025). [PMID: 40607375](https://pubmed.ncbi.nlm.nih.gov/40607375/). *Frontiers in surgery*. [Case Report / Case Series]
Bar-Aluma BE (2025). [PMID: 40555858](https://pubmed.ncbi.nlm.nih.gov/40555858/). *Calcified tissue international*. [Epidemiology / Natural History]
Martínez-Lozano P (2025). [PMID: 40710871](https://pubmed.ncbi.nlm.nih.gov/40710871/). *Reports (MDPI)*. [Case Report / Case Series]
Schultz A (2024). [PMID: 39228100](https://pubmed.ncbi.nlm.nih.gov/39228100/). *Glia*. [Basic Science / Preclinical]
Chaverra M (2024). [PMID: 39138000](https://pubmed.ncbi.nlm.nih.gov/39138000/). *The Journal of neuroscience : the official journal of the Society for Neuroscience*. [Basic Science / Preclinical]
Wu HF (2024). [PMID: 38608707](https://pubmed.ncbi.nlm.nih.gov/38608707/). *Cell stem cell*. [Diagnostic / Biomarker]

Kisho

Riley-Day syndrome

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Differential Diagnosis

Treatment

Orphan Drug Designations

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Patient Support

Patient Advocacy Groups

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

Riley-Day syndrome

Overview

Clinical Presentation

Clinical Guidance

Explore clinical features

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Differential Diagnosis

Treatment

Orphan Drug Designations

Management Guidelines

Clinical Guidance

Therapies Under Investigation

Clinical Trials

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Patient Support

Patient Advocacy Groups

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team