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The Rarest of the Rare

In Europe, a rare disease is defined rare when it affects fewer than 1 in 2,000 people. However, this definition differs across the world.  There are over 7,000 known rare diseases, many of which appear early in life. Unfortunately, about 30% of children with rare diseases will die before reaching their fifth birthday. Early diagnosis in many cases can allow early intervention which can improve and/or extend the quality of life of patients. An accurate and early diagnosis can be supported by increased awareness of rare disease.

To celebrate Rare Disease Day on Sunday 28th February 2021 and to help raise awareness about rare diseases – we describe some of the rarest rare diseases that exist and the ongoing research (or lack of) that is happening.

Hutchinson-Gilford Progeria Syndrome (HGPS)

Frequency: Occurs in 1 in 4 million newborns worldwide.

HGPS or more commonly referred to progeria, is a rare and fatal progeroid syndrome, characterised by premature ageing. It was first described in the medical literature in 1886 (J. Hutchinson) and 1897 (H. Gilford). Children with progeria often have a normal appearance in early infancy and then at ~9-24 months they start to experience profound grow delays. They develop distinct facial features including a disproportionately small face in comparison to the head, an underdeveloped jaw, crowding of teeth, prominent eyes, small nose and also subtle blueness around the mouth. Progeria also causes alopecia, aged-looking skin, joint abnormalities, and a loss of fat under the skin. It does not affect intellectual development or motor skills. The average life expectancy for a child with progeria is about 13 years.

HGPS is an autosomal dominant genetic disorder. It is caused by de novo mutations in the gene that encodes lamin A – LMNA. Lamin A is a key component of the membrane surrounding the cell’s nucleus. The abnormal lamin A protein produced in HGPS is called progerin. It appears HGPS affects males and females and all races equally.

Late last year, the FDA approved Ionafarnib (a type of farnesyltransferase inhibitor), which helps prevent the build-up of defective progerin. In addition, there is ongoing research exploring inactivation of the ICMT gene in order to overcome senescence and increase proliferation of HGPS cells. However, majority of treatments are directed towards the specific symptoms that patients experience, e.g., complications with cardiovascular disease.

For more information visit the Progeria Research Foundation:


Frequency: Occurs in 1 in 250,000 -1,000,000 live births.

Alkaportonuria (also known as AKU or Black Bone Disease) is a rare inherited metabolic disorder characterised by the accumulation of homogentisic acid in the body. Affected individuals lack enough functional levels of the enzyme required to breakdown homogentisic acid. They often have dark urine or urine that turns black when exposed to air. Apart from dark urine, additional symptoms do not usually appear until adulthood. Due to the accumulation of homogentisic acid in connective tissue, individuals develop a condition called ochronosis in which the connective tissue turns blue, grey or black. Long-standing AKU leads to chronic joint pain and inflammation.

AKU is caused by mutations in the HGD gene – which encodes an enzyme known as homogentisate 1,2-dioxygenase. This enzyme is essential in converting homogentisic acid to maleylacetoacetic acid. AKU is inherited in an autosomal recessive manner and the risk for males and females is the same. Although symptoms tend to develop sooner and become more severe in males.

The main treatments for AKU are focussed on preventing other complications, such as preventing ochronosis. Pain management is tailored to each individual’s specific case. In October 2020, the European Commission granted marketing authorisation for nitisinone – an inhibitor of HPPD. HPPD is an enzyme that is part of the same metabolic pathway as that affected in AKU. AKU patients treated with nitisinone have been shown to produce far less HGA than those not treated.

For more information visit the AKU Society:

Also check out our recent article that explores advocate and fundraiser Nick Sireau’s talk at our recent Festival of Genomics and Biodata. Nick shares his experience having two children with AKU and his journey to find a treatment.

Ribose-5-phosphate isomerase deficiency

Frequency: Over a 27-year period only three cases have been reported – making it the rarest disease in the world.

Ribose-5-phosphate isomerase deficiency (RPID) is an extremely rare inborn error of metabolism in the pentose phosphate pathway.  It is characterised by progressive leukoencephalopathy and a highly increased ribitol and D-arabitol levels in the brain and body fluids. Individuals present with psychomotor delay, epilepsy, spasticity, cerebellar ataxia and also global developmental delay.

The molecular cause of pathology is not completely understood. Some believe that ribose-5-phosphate may not be present for RNA synthesis, whereas another hypothesis is that the accumulation of D-ribitol and D-arabitol may be toxic.

The first patient, a 14-year-old boy, with this disorder was compound heterozygous for a RPI frameshift and a missense allele. The second case, an 18-year-old man, had a novel homozygous missense mutation. Then the third case, a 7-year-old boy, was found to have compound heterozygous variants in the RPIA (the gene encoding ribose5-phosphate isomerase) gene. The first two cases were identified through magnetic resonance spectroscopy, whereas the final case was diagnosed by whole exome sequencing and biochemical confirmation after a 5-year diagnostic odyssey.

There is no current treatment for RIPD.

Ogden syndrome

Frequency: So far, there have been 85 diagnosed families.  

Ogden syndrome, also known as NAA10-related syndrome, is a rare neurodevelopmental disorder, originally described in 8 severely affected young boys in two unrelated families by Rope et al. in 2011. Since the initial report, the description of Ogden syndrome has broadened to include a variety of phenotypes categorised as NAA10-related syndrome. Patients present with a range of clinical symptoms due to the pleiotropic effects of NAA10 including postnatal growth failure, delayed psychomotor development, dysmorphic features and hypotonia.

It is an X-linked recessive condition affecting males more than females. It is caused by mutations in the NAA10 gene which encodes the catalytic subunit of NatA – the major enzyme heterodimer involved in the post-translational acetylation of protein. Mutations in this gene cause changes in the protein structure, making it less effective at N-terminal acetylation. This has a multitude of effects as N-terminal acetylation is one of the most common protein modifications in humans.

There is no cure or treatment specific to this condition. All treatment is symptomatic.

For more information visit the patient organisation for Ogden syndrome: 

KAT6A syndrome

Frequency: As of 2020, ~300 people have been diagnosed with this syndrome.

KAT6A syndrome is an extremely rare genetic neurodevelopmental disorder. It can cause a wide range of symptoms with each child affected differently to the other. Common symptoms however include intellectual disability, developmental delays, speech delays and hypotonia.

It is caused by variations in the KAT6A gene, which encodes a protein of the same name that functions as a histone acetyltransferase. This enzyme helps to regulate a wide variety of chemical processes in the body. Hence variation in the KAT6A gene can lead to a wide variety of issues. Most cases occur de novo. It is thought to affect females and males in equal numbers.

The treatment of KAT6A syndrome is directed toward the specific symptoms that are apparent in each individual.

For more information visit the KAT6A foundation:

Other resources:

Image credit: By Ivan-balvan –

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