Novel Approaches to Diseases of Unknown Etiology¶

Chapter 505 | Emerging Topics in Clinical Medicine · Parts 19-20 – Consultative & Emerging Topics · Chapter 505

Key Clinical Points¶

Undiagnosed disease is an abnormal state affecting structure or function not due to external injury, where diagnosis is not determined after reasonable efforts.
Rare diseases have a high aggregate prevalence (6-10%) and include over 6,000 conditions affecting millions worldwide.
Factors leading to undiagnosed status include misleading information, unusual causes of common diseases, multi-morbidity, lack of characteristic symptoms, and geographic/temporal mismatches.
Comprehensive data collection (Table 505-2) is the critical first step in investigation.
Molecular testing can be Hypothesis-driven (targeted) or Agnostic (broad/unrestricted).
Advanced tools like Transcriptomics (RNA-Seq), Epigenetics, Metagenomics, Deep Sequencing, and Optical Genome Mapping offer new diagnostic avenues.
Symptomatic care and management of illness behaviors are essential when a definitive diagnosis is not reached.
The 'Exposome' concept considers the totality of human exposure (chemical, biological, etc.) over a lifetime.
Periodic reevaluation is necessary as medical knowledge and technology evolve.
Data sharing platforms like GeneMatcher and DECIPHER facilitate identification of ultra-rare conditions.

1. DEFINITION & OVERVIEW¶

• Disease:

Definition: An abnormal state that negatively affects the structure or function of all or part of an organism and that is not due to any immediate external injury. • Patient: Definition: The one who endures suffering. • Undiagnosed Disease: Definition: A condition for which a medical diagnosis is not discerned after reasonable efforts utilizing established methods and procedures. • Context of Diagnosis: Diagnosis involves hierarchical levels of information specificity: 1. Clinical: Based on signs and symptoms (e.g., Parkinson's features). 2. Therapeutic Response: Based on response to treatment (e.g., L-dopa in Parkinson's). 3. Mechanistic: Underlying biological processes (e.g., striatonigral degeneration). 4. Histopathologic: Cellular/tissue changes (e.g., Lewy body pathology). 5. Molecular: Genetic basis (e.g., SYNCA mutations).

2. EPIDEMIOLOGY¶

• Prevalence & Scale:

• Aggregate population prevalence of rare diseases: 6-10%. • Number of known rare diseases: >6,000 affecting millions worldwide. • Characteristics: • Many have a genetic basis and onset in childhood. • Impact of Diagnosis: Identification allows for specific counseling, targeted therapies, community engagement, and advocacy.

2.1 Factors Contributing to Undiagnosed Disease (Table 505-1)¶

• Misleading Information: False-negative or false-positive test results. • Unusual Causes of Common Diseases: e.g., Insulin-dependent diabetes mellitus as a presentation for autoimmune polyendocrinopathy syndrome, type I (OMIM 240300). • Presence of Multiple Disorders: Blended phenotypes masking the primary condition. • Lack of Characteristic Symptoms: Absence of pathognomonic signs; e.g., not all patients with Marfan's syndrome are tall. • Diseases Not Expected in Region/Population: e.g., Cystic fibrosis in persons of African ancestry; sickle cell disease in persons of northern European ancestry. • Diseases Thought to be Eradicated: e.g., Poliomyelitis. • Diseases in Unexpected Time of Life: e.g., Parkinson's in children, lysosomal storage disease in adults. • Rare Disease Mechanisms: e.g., Transmitted or sporadic prion disease; unusual zoonotic diseases. • Malingering: Feigned features for secondary gain (e.g., Munchausen syndrome).

3. ETIOLOGY & PATHOPHYYSOLOGY¶

• Core Mechanisms:

Interaction between genetic susceptibility and environmental exposures; protein aggregation, cellular stress responses, and mitochondrial proteome quality control. • Molecular Pathways: Mutations in genes such as SYNCA (synuclein) or AIRE (autoimmune regulator). • Categorization of Undiagnosed States: 1. New Disease: No prior knowledge/record; includes ultrarare conditions identified via data sharing. 2. Incorrect Affected Status: Misinformed family history leading to exclusion of heritable disorders. 3. Primary Disease: Masked by maladaptive behavior, medication effects, or secondary manifestations (e.g., somatoform disorders). 4. Rare Mechanisms: Transmitted/sporadic prion disease; unusual zoonotic diseases.

4. CLINICAL FEATURES¶

• Patient Motivation & Coping:

Patients seek to understand the 'what, when, where, how' of their condition. Identification of adaptive vs. maladaptive behaviors (e.g., sun avoidance in xeroderma pigmentosum). • Diagnostic Differentiation: Distinguishing 'functional' CNS or somatoform disorders from underlying organic diseases (e.g., pseudo-seizures vs. epilepsy). • Advanced Screening Tools: Use of exome/genome sequencing, RNA-Seq, and metabolomics to generate a fuller picture. • Validation of Findings: Reassessment of historical data; some older tests (e.g., transferrin isoelectric focusing for CDG) are no longer state-of-the-art. • Toxicant Exposure Clues: Pathognomonic signs: Mesothelioma/asbestos, clear cell adenocarcinoma of the vagina/IDET, chloracne/halogenated aromatic hydrocarbons. • Complex Environmental Interactions: Chemical exposure + lifestyle + host susceptibility → (1) common disease; (2) unusual phenotype (e.g., erethism/mercury); or (3) atypical presentation (e.g., manganese-induced parkinsonism).

5. DIFFERENTIAL DIAGNOSIS¶

• Reevaluation Strategy:

Review of current evidence, inclusion of new clinical features over time, and consideration of age/progression. • Hypothesis-Driven Molecular Testing: Targeted panels; higher specificity for suspected categories. • Agnostic Molecular Testing: Broad platform (exome/genome); identifies new gene-disease associations regardless of pretest probability. • Exclusion Criteria: 1. Diseases thought to be eradicated. 2. Diseases in unexpected time of life. 3. Malingering. 4. Incorrect affected status (due to faulty family history).

6. INVESTIGATIONS & DIAGNOSIS¶

Comprehensive Data Collection (Table 505-2): • Narrative summaries of illness course. • Original test results (including names, dates, circumstances, normal ranges, and facility info). • Electronic copies of imaging studies. • Consultation notes and hospitalization intake/discharge summaries. • Accurate family history. • Optional but useful: Photos/videos of manifestations; longitudinal data (growth charts, serum labs); raw genomic data for re-analysis.
Clinically Available Tests (Table 505-3): • SNP Microarray / Karyotype: For dysmorphic features and neurodevelopmental disorders. • Exome or Genome Sequencing: For chronic, non-acquired conditions. • Lysosomal Storage Diseases (LSDs): Molecular/enzymatic tests; urine organic acids, sphingolipids, GAGs, oxysterols. • Biochemical Disorders: Ammonia, serum polyols, pyruvate, pyrimidine, plasma amino acids, very-long-chain fatty acids (VLAFs). • Mitochondrial Studies: Serum pyruvate, lactate, plasma amino acids, and GDF-15. • Cerebrospinal Fluid (CSF): Amino acids (AAs), lactate, methylpyridohydroxide (MTHF), or specific flow studies.
Emerging/Special Testing Strategies (Table 505-4): • Transcriptomics (RNA-Seq): Assess splice, regulatory, and noncoding variants; identify pathway changes. • Epigenetics: Identify methylation or parent-of-origin effects; interferon-inducible gene panels. • Metagenomics: Identify microbial fingerprints; resolve low-complexity regions (repeat expansions) and complex rearrangements. • Deep Sequencing: Resolve high-resolution chromosomal structure and low levels of mosaicism. • Optical Genome Mapping: High-resolution chromosomal structure analysis.

7. MANAGEMENT & TREATMENT¶

Symptomatic Care: • Provide immediate care for current symptoms. • Consider generic treatments when a specific etiology is unknown.
Consultative Assessment: • Engage in multi-disciplinary collaboration to explore hypotheses and identify rare/complex conditions.
Empiric Treatments: • Utilize evidence-based empirical approaches where definitive diagnosis is pending.
Managing Expectations: • Communicate limitations of current medical knowledge to patients and families.
Ongoing Management: • Manage illness behaviors. • Address psychological impact (stress, reduced quality of life). • Periodically reevaluate based on emerging science.

8. PROGNOSIS & COMPLICATIONS¶

• Impact of Undiagnosed State:

Prolonged lack of diagnosis leads to: 1. Personal and family uncertainty. 2. High stress levels. 3. Decreased productivity. 4. Limited access to specific counseling/resources. 5. Reduced quality of life. 6. Excessive utilization of medical services.

9. SPECIAL CONSIDERATIONS¶

• Reproductive Age: Impact on family planning and genetic counseling. • Pediatrics: Importance of early identification for neurodevelopmental disorders. • Aging: Consideration of how symptoms change or emerge as the patient ages.

10. KEY PEARLS & CLINICAL TRAPS¶

• The 'Exposome': Includes all environmental and internal factors (metabolism, microbiome) influencing health. • Data Integrity: Original test results are critical; second-hand reports often lead to missed diagnoses. • Agnostic vs. Hypothesis: Agnostic testing is the primary tool for identifying novel gene-disease associations. • Clinical Clues: Specific toxicant exposures (e.g., mercury, arsenic) can mimic rare genetic diseases.

FLOWCHARTS¶

Approach to the patient with an undiagnosed disease (Figure 505-1)¶

Initial State: No diagnosis after comprehensive evaluation.
Action: Parallel Assessment (Consultative/Iterative) → Reformulate differential diagnosis.
Decision Node: Diagnosis?
If YES:
Action: Document reasoning and supporting evidence.
If NO:
Action: Consider collaboration to explore hypotheses → Work with patient to define concrete follow-up.
Alternative Path (Concurrent/Direct):
Action: Symptommatic care, consider generic treatments.

Reference Tables¶

TABLE 505-1 Factors Contributing to the Presence of an Undiagnosed Disease FACTOR Misleading information Rare disorder¶

Harrison's 22e, p.3995

FACTOR	EXAMPLE
Misleading information	False-negative and false-positive test results
Unusual causes of common diseases, including atypical course of illness	Insulin-dependent diabetes mellitus may be the presenting feature for the relatively rare autoimmune polyendocrinopathy syndrome, type I (OMIM 240300).
505	Novel Approaches to Diseases of Unknown Etiology David R. Adams, Camilo Toro, Joseph Loscalzo
Lack of characteristic symptoms of known disease	Diseases are commonly ascertained via cardinal signs or symptoms leading to incomplete ascertainment of all possible disease presentations. For instance, not all persons with Marfan’s syndrome are tall relative to other family members. For progressive diseases, pathognomic signs and symptoms may be missing in early stages of disease.
Incorrect affected status assignments in family history	A heritable disorder may be inappropriately excluded if family history information is incorrect.
Disease not expected in region or population	Cystic fibrosis in persons of African ancestry, sickle cell disease in persons of northern European ancestry; infectious agents with marked geographical incidence patterns
Diseases occurring in unexpected time of life	Parkinson’s disease in children, lysosomal storage disease in adults
Rare disease mechanisms	Transmitted or sporadic prion disease, unusual zoonotic diseases

TABLE 505-2 Essential Records for Undiagnosed Disease Patients 1. Any narrative summaries that detail the course of the…¶

Harrison's 22e, p.3996

1. Any narrative summaries that detail the course of the illness
  2. Copies of original test results with names, dates, testing circumstances,
  normal ranges, and test facility information
  3. Electronic copies of imaging studies
  4. Consultation notes
  5. Hospitalization intake and discharge summaries
  6. Accurate family history accounts and family relations
  Optional but potentially useful records include:
  1. Photographs and/or videos of disease manifestations
  2. Longitudinal data (growth charts, symptom logs, serial lab measurements)
  3. Data or specimens that could be reanalyzed, including pathology specimens
  and genomic sequencing of raw data

TABLE 505-3 Clinically Available Tests with Notable Utility for Undiagnosed Cases

TEST	TARGET PHENOTYPES	RATIONALE
Single nucleotide polymorphism microarray and/or karyotype	Dysmorphic features, cognitive impairment, neurodevelopmental disorders	Genomic structure abnormalities may be missed by other testing
	Any undiagnosed disease that is chronic and not clearly acquired
Lysosomal storage diseases (LSDs), molecular or enzymatic tests. urine organic acids, urinary glycosaminoglycans (GAGs), oxysterols	Progressive neurologic disorders, psychiatric disorders	Some LSDs have nonspecific presentations, and adult- onset cases are often missed
	Pediatric-onset disorders, cognitive impairment, neurologic phenotypes
Biochemical disorders, ammonia, serum polyols, urine purines and pyrimidines, plasma amino acids, very-long- chain fatty acids	Neurologic phenotypes, especially with waxing and waning course, selective speech involvement, or patients with unusual self- selected diets	Metabolic disorders may have nonspecific symptoms, and adult- onset cases are often missed
	Complex multisystem disorders with neurometabolic, endocrine, and gastrointestinal symptoms, muscle dysfunction, and waxing and waning or progressive course
Cerebrospinal fluid (CSF) studies including amino acids (AAs), lactate, pterins, methyltetrahydrofolate (MTHF), or special CSF flow studies	Synthetic neurotransmitter defects in patients with unexplained fluctuating encephalopathy/ movement disorders or patients with atypical neuroinflammatory syndromes	Patterns of profiles point to particular enzymatic deficits in neurotransmitter synthesis or characterization of unique immunologic profiles of inflammatory central nervous system diseases

Harrison's 22e, p.3997

TESTING STRATEGY	RELATED DIAGNOSTIC QUESTION	AVAILABLE CLINICALLYa
Transcriptomics, RNA-Seq	Relevance of splice, regulatory, and other noncoding variants; correlated changes in gene expression within pathways	Yes
	Hypothesis generation via nontargeted approaches, correlated pathway changes, correlation with molecular findings
Epigenetics	Diseases known or suspected to be caused by methylation or parent-of-origin effects	Yes
	Search for profile particular to certain disease states, e.g., interferon-inducible gene panels (interferon signature) in certain autoinflammatory disorders
Specialized, disease- specific testing	Prion-related diseases, metabolic diseases, and many other assays	Some
	Model organisms, cell biology, and other approaches to validating a hypothesized gene-disease association
Metagenomics	Search for molecular fingerprints of other organisms (e.g., infectious agents) within human samples	Yes
	Accurate resolution of low-complexity regions of the human genome (repeat expansion disorders) and complex genome structural rearrangements
Deep sequencing	Accurate resolution of low levels of mosaicism	Some
	High-resolution chromosomal structure