Hutchinson-Gilford Progeria Syndrome
Children with HGPS age ~8x faster than normal. Growth failure, hair loss, skin changes, and premature atherosclerosis lead to death from heart attack or stroke at a median age of ~14.5 years.
Read the dossier →Friedreich Ataxia
Friedreich ataxia is the most common hereditary ataxia. Progressive gait and limb ataxia, dysarthria, and cardiomyopathy typically begin in adolescence. Most cases are caused by a GAA repeat expansion that silences frataxin, a mitochondrial protein needed for iron-sulfur cluster assembly.
Read the dossier →Lesch-Nyhan Syndrome
Lesch-Nyhan syndrome is an X-linked disorder of purine metabolism caused by complete HPRT1 deficiency. Affected boys develop uric acid overproduction (kidney stones, gout) alongside severe neurological disability and a striking, near-universal self-injurious biting behaviour. Allopurinol controls the uric acid but not the neurology.
Read the dossier →Huntington Disease
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. It causes progressive motor dysfunction (chorea), cognitive decline, and psychiatric symptoms, typically beginning in mid-adulthood. Mutant huntingtin forms toxic aggregates in striatal neurons. Current treatment is symptomatic only; allele-selective degradation and ASO silencing are the leading disease-modifying frontiers.
Read the dossier →Duchenne Muscular Dystrophy
Duchenne muscular dystrophy is the most common childhood muscular dystrophy, an X-linked disorder caused by dystrophin deficiency. Boys develop progressive muscle weakness from early childhood, losing ambulation in their teens and dying from respiratory or cardiac failure in young adulthood. Gene therapy and exon-skipping are the leading disease-modifying approaches.
Read the dossier →Gaucher Disease
Gaucher disease is the most common lysosomal storage disorder, an autosomal recessive deficiency of glucocerebrosidase. It causes glucocerebroside accumulation in macrophages, leading to enlarged spleen/liver, low blood counts, and bone disease. Enzyme replacement therapy is the standard disease-modifying treatment for the non-neuronopathic form.
Read the dossier →Fabry Disease
Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to globotriaosylceramide accumulation in the kidneys, heart, and vasculature. It causes progressive renal failure, cardiomyopathy, and neuropathic pain. Enzyme replacement and chaperone therapy are the standard disease-modifying approaches.
Read the dossier →Pompe Disease (Glycogen Storage Disease Type II)
Pompe disease is an autosomal recessive lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency, leading to glycogen accumulation in muscle. The infantile form causes severe cardiomyopathy and early death; the late-onset form causes progressive muscle weakness and respiratory failure. Enzyme replacement therapy is the standard disease-modifying treatment.
Read the dossier →Hereditary Transthyretin Amyloidosis
Hereditary transthyretin amyloidosis is an autosomal dominant disease in which mutant transthyretin misfolds and forms amyloid deposits in nerves and heart, causing progressive neuropathy and cardiomyopathy. It is a toxic gain-of-function amyloidosis; approved therapies silence or stabilise the amyloidogenic protein, and selective degraders are the next frontier.
Read the dossier →Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency is an autosomal co-dominant disorder caused by the SERPINA1 Z allele, whose protein product polymerizes and accumulates in the liver (causing cirrhosis) while deficient circulating antiprotease leaves the lungs vulnerable to emphysema. It is a dual gain-of-function (liver) and loss-of-function (lung) disease; augmentation therapy treats the lung component.
Read the dossier →Cystic Fibrosis (F508del)
Cystic fibrosis is an autosomal recessive disorder caused by CFTR mutations, most commonly F508del, which misfolds the chloride channel and prevents it reaching the cell surface. It causes progressive lung disease, pancreatic insufficiency, and male infertility. CFTR modulator drugs (correctors + potentiators) rescue the protein's folding and gating — a fundamentally different strategy from degradation or enzyme replacement.
Read the dossier →Angelman Syndrome
Angelman syndrome is a neurodevelopmental disorder caused by loss of the maternal UBE3A allele, leaving neurons without UBE3A because the paternal allele is normally silenced by imprinting. It causes severe developmental delay, ataxia, seizures, and a characteristic happy demeanor. The therapeutic frontier is antisense-mediated unsilencing of the intact paternal allele.
Read the dossier →Myotonic Dystrophy Type 1
Myotonic dystrophy type 1 is an autosomal dominant disorder caused by a CTG repeat expansion in DMPK, whose expanded CUG-repeat mRNA forms toxic nuclear foci that disrupt RNA splicing. It causes myotonia, progressive muscle weakness, cardiac conduction defects, and cataracts. Antisense therapy targeting the toxic RNA is the leading disease-modifying approach.
Read the dossier →Permanent Neonatal Diabetes Mellitus (KCNJ11)
Permanent neonatal diabetes due to KCNJ11 mutations is a gain-of-function channelopathy: an overactive ATP-sensitive potassium channel suppresses insulin secretion. The striking clinical result is that most patients can be switched from insulin injections to oral sulfonylurea tablets, which close the channel and restore insulin — a channel-blocker cure, not a degrader or replacement.
Read the dossier →Wilson Disease
Wilson disease is an autosomal recessive disorder of copper transport caused by ATP7B deficiency, leading to toxic copper accumulation in the liver, brain, and cornea. It presents with liver disease, neuropsychiatric symptoms, and Kayser-Fleischer rings. Treatment is copper chelation and zinc — removing the toxic metal, a strategy distinct from degradation or replacement.
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