Hereditary systemic amyloidosis

The hereditary amyloidoses are adult-onset systemic diseases characterised by autosomal dominant inheritance with variable penetrance. Single amino acid substitutions or small deletions/insertions in one of 12 different genes result in destabilisation of the native protein structure and predispose affected individuals to atypical protein refolding and extracellular accumulation of amyloid fibrils. The presentation depends on the tissues and organs predominantly affected.

The clinical features of amyloidosis can include:

• proteinuria that usually progresses to kidney failure;
• cardiomyopathy;
• autonomic or peripheral neuropathy;
• enlarged liver and spleen;
• corneal lattice dystrophy, facial motor neuropathy and skin laxity; and 
• sicca syndrome, pleomorphic rashes and easy bruising. 

Autosomal dominant inheritance is usual but penetrance and expressivity vary.

There is considerable individual variation in age of onset and organs affected. Manifestations can vary depending on the genetic variant and the protein affected, with intrafamilial variation being common. 

Amyloidosis is caused by aberrant folding of protein molecules of normal or variant sequence that auto aggregate into a characteristic fibrillar structure. In hereditary amyloidosis, variant sequence causes or increases fibril formation. 

The table below summarises the different types of amyloidoses and their associated genes and typical manifestations.

• Amyloidoses are most commonly identified when a patient presents with cardiomyopathy, nephrotic range proteinuria or neuropathy. But the presentation varies between types and some rare forms can present without any of these common features.
• Genetic types constitute approximately 10% of new diagnoses, but are often mistaken for more common forms, particularly for AL amyloidosis. Investigations can be focused if there is a suggestive family history, which commonly prompts genomic testing. But family history may be negative in genetic amyloidoses because of variable penetrance/expressivity or a new (de novo) variant. 
• Amyloidosis affecting the kidney is usually diagnosed after renal biopsy to investigate proteinuria or unexplained renal disease. AL amyloid (caused by clonal immunoglobulin light chains) is most common, followed by AA amyloid secondary to prolonged acute phase response. The presence of low or moderate levels of circulating clonal light chains or intact immunoglobulin should not be accepted as proof of a diagnosis of AL amyloid without positive findings on biopsy by immunohistochemistry. If there are negative immunohistochemical findings, particularly with unusual presentation or appearance, laser mass spectroscopy analysis and genomic testing for familial amyloid variants (National Genomic Test Directory R204 Hereditary systemic amyloidosis) may be appropriate. 
• Some characteristic presentations and echocardiographic appearances of cardiomyopathy should now lead to genomic testing. For more information, see ‘Adult with hypertrophic cardiomyopathy’, ‘Patient with neuropathy’ and ‘Patient with a family history of cardiomyopathy’.
• With other presentations, diagnosis often relies on characteristic clinical features and on following up the appearance of amyloid on tissue biopsies. 
• For more information about genomic testing, see ‘Patient with unclassified amyloidosis’.

Hereditary systemic amyloidosis is an autosomal dominant condition. It is almost always adult-onset, with variable penetrance and expressivity.

• Individuals affected by an autosomal dominant condition have one unaltered copy of the gene and one with a pathogenic variant.
• The chance of a child inheriting the pathogenic gene variant from an affected parent is 1 in 2 (50%).
• Incomplete penetrance can occur, meaning that not everyone who has the variant develops the disease.
• If biallelic amyloid-associated variants are found (very rare), the phenotype is likely to be more severe. 

Management of hereditary systemic amyloidosis is usually supportive. Disease-specific treatments are approved, and becoming available, for ATTRv. Check the links below for up-to-date information.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) signed off panels resource
• NHS England: National Genomic Test Directory
• Specific types of inherited systemic amyloidosis:
  • GeneReviews: Familial Mediterranean Fever
  • GeneReviews: TNF Receptor-Associated Periodic Fever Syndrome
  • GeneReviews: Transthyretin (TTR) amyloidosis  
  • OMIM: ApoA1 amyloidosis 
  • University College London: Amyloidosis Overview

For patients

• University College London: Amyloidosis Overview
• University College London: Amyloidosis patient information leaflets