ALys amyloidosis

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Discovery

Hereditary lysozyme (ALys) amyloidosis was first described in the medical literature by Professor Sir Mark Pepys and colleagues in 1993.  They discovered that lysozyme was the amyloid fibril protein in amyloid deposits found in members of 2 unrelated English families.  Genetic testing showed that affected members of each family carried a mutation in the lysozyme gene (a different mutation in each family).  Lysozyme is an enzyme produced by liver cells and blood cells.  It is present in various body secretions such as saliva and tears and is believed to play a role in fighting bacteria.

The mutations in the ALys gene associated with ALys amyloidosis cause the normally soluble lysozyme protein to fold abnormally and form amyloid fibrils which deposit in the body tissues causing illness.

ALys amyloidosis is extremely rare.  In 2012 the National Amyloidosis Centre doctors published a retrospective evaluation of all 16 patients with Alys amyloidosis followed at the NAC between 1998 and 2010.  This is the largest series reported in the medical literature.  Other cases described have usually been case reports or reports of several affected members of individual families.  Different families tend to carry different mutations in the lysozyme gene.

Inheritance

ALys amyloidosis is a hereditary condition described in Caucasian patients, of English, French and Italian origin.  It is caused by inheritance of an abnormal copy of a gene, known as a mutation, leading to life‑long production of an amyloidogenic form of lysozyme.

The condition is passed on by autosomal dominant inheritance.  This means that the presence of just one copy of a mutated gene can cause disease.  Each child of an affected parent has a 50% chance of inheriting the mutation.  The condition is highly penetrant, meaning that most, though not all, people who carry an amyloidogenic mutation in the lysozyme gene develop ALys amyloidosis.

Most people diagnosed with ALys amyloidosis are found to have a family history of amyloidosis, although the condition may not have been diagnosed in relatives.

For more information on autosomal dominant inheritance see:

Age of onset

The symptoms of ALys amyloidosis usually appear in middle age.  In the 2012 NAC review of 16 patients, ages at onset of symptoms ranged from 9 to 70 years.  Some patients remain well until old age.  One of the 16 patients was only diagnosed because she had been referred to the NAC for genetic screening and remained asymptomatic till her death at age 72.  Her sister developed symptoms of kidney failure at age 66.

Symptoms

ALys amyloidosis is associated with a wider and more diverse range of symptoms than the other hereditary types of amyloidosis.  ALys amyloidosis symptoms may mimic AL amyloidosis, the most common type of amyloidosis.

Gastrointestinal symptoms are frequent, including bleeding from the gastrointestinal tract, diarrhea, weight loss and fat malabsorption.  Amyloid deposits are almost always found in the liver and sometimes in the spleen.  Liver function tests often remain stable or only slightly abnormal, in contrast to AL amyloidosis where liver function tests are often abnormal.  There may be bleeding from the liver or rupture of the liver or spleen.  Soft tissue amyloidosis is recognized in both ALys and AL amyloidosis, often manifesting as sicca syndrome, in which the eyes and mouth become very dry.  In some patients with ALys amyloidosis in the NAC review, sicca syndrome appeared before other amyloidosis symptoms.  Other soft tissue amyloidosis manifestations seen in ALys and AL amyloidosis may include bruising and lymph node enlargement.  ALys amyloidosis may also affect the kidneys.

Treatment

Treatment of ALys amyloidosis is symptomatic.  The NAC doctors usually recommend lifelong prophylactic treatment with proton pump inhibitor drugs (drugs such as omeprazole, which suppress stomach acidity) for all patients with ALys amyloidosis who have gastrointestinal amyloid to try to reduce the risk of upper gastrointestinal bleeding.

Liver rupture in patients with ALys amyloidosis has been successfully treated with emergency liver transplantation in several patients, with good outcomes in terms of survival of the transplanted livers, despite evidence of amyloid recurrence after transplant.  One patient in the NAC series with extensive amyloid deposits in the liver and a family history of liver rupture underwent “prophylactic” liver transplantation successfully.

Artificial saliva or tears can help relieve the symptoms of dry mouth and eyes.

Patients with ALys amyloidosis who developed end stage kidney failure have undergone kidney transplants with excellent outcomes.

Outlook

The outlook for patients diagnosed with ALys amyloidosis is good, relative to many other types of amyloidosis.  ALys amyloidosis has a slower natural history than AL amyloidosis and other hereditary types of amyloidosis.  For example, in the NAC patient series, median survival from diagnosis of amyloidosis was nearly 18 years and only 4 of the 16 patients died over median follow up time of nearly 25 years from symptom onset.  The time from appearance of abnormal kidney function till development of end stage kidney disease was 11 years.

It is even possible that amyloid accumulation may abate in some patients once a large total body amyloid burden has accumulated.  The mechanism whereby this occurs is not understood.

Although at present there are no drugs in development specifically targeting ALys amyloidosis, it is hoped that the CPHPC plus anti SAP antibody approach will be beneficial for all types of amyloidosis.  This treatment approach was invented by Professor Sir Mark Pepys at the Wolfson Drug Discovery Unit and is being developed in partnership with GlaxoSmithKline.  It is currently undergoing a phase 2 clinical trial at the NAC and elsewhere.  Results of the initial phase 1 clinical trial showed very encouraging removal of amyloid deposits from the liver, spleen and kidneys.

ALys and AL amyloidosis are different diseases

Although the symptoms of ALys amyloidosis may mimic those of AL amyloidosis, they are very different diseases.  As discussed above, ALys amyloidosis is a hereditary condition where amyloid deposits are formed from misfolded abnormal lysozyme.  AL amyloidosis is a non-hereditary condition where amyloid deposits are formed from misfolded light chains (parts of antibodies) produced by abnormal plasma cells in the bone marrow.

Distinguishing between ALys and AL amyloidosis is critical for patients to be treated appropriately.  AL amyloidosis is treated with chemotherapy but there is no role for chemotherapy in treatment of ALys amyloidosis.

AL amyloidosis is the most common type of amyloidosis but ALys amyloidosis is extremely rare.  It is very important for doctors to exclude ALys amyloidosis before starting chemotherapy treatment for AL amyloidosis.

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