Rare Diseases

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A rare disease is a condition that affects fewer than one in 2000 people. It is often reported that there are approximately 7000 rare diseases, of which about 80% are genetic. This figure is an underestimate if you include cancers and infectious diseases. In New Zealand only 24 rare diseases are tested in the Newborn Metabolic Screening Programme.

Key Observations for Rare vs Common disease

Features	Rare Diseases	Common Diseases
Age	Young people - Occam's razor more likely to be true	Older people - Hickam's dictum more likely to be true.
Pattern of inheritance	Mendelian (because there is one cause)	May cluster in families however none of the common diseases are monogenic (because there are multiple causes)
Syndromic?	Often syndromic	Usually non-syndromic
Environmental factors	Environmental factors generally play less of a role	Environmental factors play a stronger role
Prevalence	1 in 2000 or less	One thousand to one million times more common
Number of diseases	>7000 rare disease	<100

Common diseases are considered complex diseases. They exhibit a limited set of clinical phenotypes that result from derangement of various pathways. The micro-effects leading to the disease are distinct from each other, but the macro-effect is commonplace. On the other hand, in rare diseases, a specific phenotype is produced due to a single gene mutation activating a particular pathway. Unlike common diseases, the pathways leading to these phenotypes are more defined and distinct.

Family GENES

It is not humanely possible for an individual doctor to attain knowledge and experience with anything more than a tiny fraction of all rare diseases. Therefore, an important cognitive step is suspecting that the patient might have a rare disease of some kind. The following are clinical indicators of a possible undiagnosed rare disease.

Family history: multiple affected siblings or individuals in multiple generations. Remember that lack of a family history does NOT rule out genetic causes.

G: group of congenital anomalies: Common anatomic variations are, well, common; but two or more anomalies are much more likely to indicate the presence of a syndrome with genetic implications.

E: extreme or exceptional presentation of common conditions: Early onset cardiovascular disease, cancer, or renal failure. Unusually severe reaction to infectious or metabolic stress. Recurrent miscarriage. Bilateral primary cancers in paired organs, multiple primary cancers of different tissues

N: neurodevelopmental delay or degeneration: Developmental delay in the paediatric age group carries a very high risk for genetic disorders. Developmental regression in children or early onset dementia in adults should similarly raise suspicion for genetic etiologies

E: extreme or exceptional pathology: Unusual tissue histology, such as pheochromoctyoma, acoustic neuroma, medullary thyroid cancer, multiple colon polyps, plexiform neurofibromas, multiple exostoses, most paediatric malignancies.

S: surprising laboratory values: Markedly abnormal pathology results

Rare Causes of Chronic Pain

Some examples of rare diseases that can cause pain

• Brachial Neuritis
• Facioscapulohumeral Dystrophy
• Myotonic Dystrophy
• Pompe Disease
• McArdle Disease
• Charcot Marie Tooth
• Progressive External Ophthalmoplegia
• Limb Girdle Muscular Dystrophies
• Chronic Inflammatory Demyelinating Polyneuropathy
• Ehlers Danlos Syndrome (note: the hypermobile EDS subtype should not be considered a rare disease because the prevalence is 1 in 500)

Resources

There are many sources to assist with the diagnostic process.

• Rare Disease 101 course: https://learn.m4rd.org/
• https://www.findzebra.com/: Open access, web-based tool specifically to assist rare disease diagnosis. Start with two most specific terms.
• http://www.omim.org/: The OMIM database is a comprehensive compendium of human genes and genetic phenotypes
• http://www.orpha.net/: Search keywords such as a disease or genes. tutorial
• https://compbio.charite.de/phenomizer/: An open access, web-based tool to assist diagnosis
• https://rarediseases.org/: NORD (national organisation for rare diseases)
• https://www.eurordis.org/: Rare Diseases Europe

Rare Diseases - Members Subpage

See Also

Diagnosis