Read on Twitter
The understanding of rare disease results in treatment for common disease: two examples.
A rare disease affects less than 1 in 2000 people but there are tons of them, meaning 1 in 17 people are actually affected by a rare disease.
8 out of 10 rare diseases have a genetic cause, although this can be difficult to establish owing to genetic and phenotypic heterogeneity, as well as access to and limitations of current technologies.
The rarity of individual conditions can also lead to a lack of impetus from a pharmaceuticals standpoint for drug discovery.
But can the understanding of rare disease lead to tangible benefits for people with common disease also?
Case 1: Glanzmann’s thrombasthenia (GT) is...
Glanzmann’s thrombasthenia is caused by biallelic mutations in GpIIb/IIIa subunits (ITGA2B and ITGB3), which are expressed on platelets and act, together, as a receptor for vWF and fibrinogen (amongst other ligands). The condition affects about 1 in a million people.
These patients present in early life with mucocutaneous bleeding and spontaneous bruising. For those haematologists reading (I apologise already), FBC will usually be normal and so will aPTT and PT. It’s the bleeding time that’s prolonged.
So it’s not that platelets are low, it’s that they’re not sticking together like they should do.
Phillips et al 1977 found GT patients’ platelets displayed reductions in two major glycoproteins: IIb and IIIa . This got people thinking about platelet aggregation in other conditions.
The first murine monoclonal antibody described to act against GpIIb/IIIa was reported in 1983. GpIIb/IIIa was felt an attractive candidate as patients with GT rarely had intracranial haemorrhage, which may be a benefit over other available anti-platelets.
The first GpIIb/IIIa antagonist approved by the FDA was abciximab in 1994. There are now three GpIIb/IIIa antagonists available including Tirofiban and Eptifibatide.
Although their use is somewhat centre-specific, I have prescribed Tirofiban in the setting of PPCI fairly recently. Still the story of their discovery is interesting and shows how rare disease research can have far-reaching implications.
Case 2: Familial hypercholesterolaemia (FH), the inheritance of which is...
There are multiple types of FH but the most common is due to mutations in LDLR. Heterozygotes become symptomatic in 4th or 5th decade of life, whereas homozygotes present within the 1st and 2nd decade of life.
Some patients don’t have mutations in LDLR and that’s a little confusing. But humans have plenty of other genes that could be to blame.
Abifadel et al 2003 looked at individuals with FH but no LDLR mutations using linkage analysis (finding blocks of chromosomes that are shared, having not recombined, in affected individuals from several generations).
They narrowed down a region on chromosome 1p which included 41 genes. Within this list was PCSK9 and they found rare mutations in this gene in all 3 families they studied and they were absent from controls.
Interestingly, these mutations were missense changes (amino acid substitutions) and lead to a gain-of-function. PCSK9 actually degrades LDLR in the liver, increasing plasma LDL. ‘Gain of function’ means it is degrading more than it should.
Loss-of-function mutations (I.e. frameshifts, nonsense and some missense) in PCSK9 are found in healthy populations and are actually known to reduce cholesterol levels and protect against coronary heart disease.
With this in mind, PCSK9-inhibitors, such as evolucumab, have been developed which are used in statin-resistant (or intolerant) hypercholesterolaemia. They’re hella expensive at the moment so you might not see them that often.
So just a couple of examples of how finding a genetic diagnosis in rare disease can, not only have a positive effect for those affected, but also pave the way for new treatments in common disease.
I’ll get back in my box now.
