SUMMARY

 

1.  Mevalonate kinase deficiency causes a type of autosomal recessive periodic fever syndrome.  This mutation results in the accumulation of mevalonate in the serum and urine.  The exact mechanism for autoinflammation remains unclear.  The increase in mevalonate or the decrease in downstream products may be responsible.  

 

2.  The clinical spectrum of mevalonate kinase deficiency is broad, ranging from mild (Hyper IgD syndrome) to severe (mevalonic aciduria).  These two diseases were initially described separately but it is now clear that the underlying molecular cause is the same.  In HIDS the mevalonate kinase activity is 1-10% while the in MVA the kinase activity is completely absent.    

 

a.  Hyper IgD Syndrome (HIDS)  This disease is characterized by the onset of episodic fevers before the first year of life lasting 3-7 days and recurring every 2-8 weeks.  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly.  Attacks can be provoked by vaccinations, stress, and viral infections.  Serum IgD and IgA levels are increased during and between attacks.  

 

b.  Mevalonic Aciduria (MVA)  Patients with mevalonic aciduria are characterized by febrile episodes similar to hyper IgD syndrome.  However, patients also exhibit dysmorphic facial features (microcephaly, low-set posteriorly rotated ears, down-slanted palpebral fissures), neurologic abnormalities, mental retardation, and failure to thrive.  Patients have greatly elevated mevalonic acid levels in the urine during attacks and attack-free periods.   

 

3.  Diagnosis for both Hyper IgD syndrome and Mevalonic Aciduria is definitively established by mutation analysis of the MVK gene.  

 

4.  Currently there is no established treatment strategy for patients with HIDS or MVA.  Colchicine is not useful for the treatment of attacks.  Some patients may respond to oral steroids.    HMG-CoA reductase inhibitors (simvastatin, lovastatin) have had strikingly different effects on patients with HIDS and MVA:  

Hyper IgD Syndrome:  In one study, simvastatin decreased the number of febrile episodes in patients with HIDS without any significant side effects.  

Mevalonic Aciduria:  In contrast, a trial of lovastatin in 2 patients with MVA resulted in severe flares of disease.  

 

5.  Anakinra (an IL-1 receptor antagonist) and etanercept have been used with some success in patients.  Two patients with MVA have also been successfully treated with stem cell transplantation.  

 

6.  The overall prognosis for HIDS is quite good with relatively benign clinical course.  Amyloidosis can be a serious complication, but it has been reported in only 3% of HIDS patients.  However, patients with severe MVA can have premature mortality during infancy or early childhood (HSCT has been successfully performed in a small number of patients).  

 

 

 

                                                                                                               

OVERVIEW

 

     The periodic fever syndromes encompass a group of autoinflammatory disorders characterized by recurrent fevers and inflammation in the absence of infectious triggers.   Mevalonate kinase deficiency is an autosomal recessive form of periodic fever syndrome.  

 

     The clinical spectrum of mevalonate kinase deficiency is broad, ranging from mild (Hyper IgD syndrome) to severe (mevalonic aciduria).  These two diseases were initially described as two separate entities, but it is now clear that the underlying molecular cause is the same.  In HIDS the mevalonate kinase activity is 1-10% while in MVA the kinase activity is completely absent.    

 

Hyper IgD Syndrome (HIDS)  This disease is characterized by the onset of episodic fevers before the first year of life lasting 3-7 days and recurring every 2-8 weeks.  Attacks of fever are associated with skin rash, cervical lymphadenopathy, diarrhea, arthritis/arthralgia, oral ulcerations, abdominal pain, and hepatosplenomegaly.  Attacks can be provoked by vaccinations, stress, and viral infections.  Serum IgD are elevated (>100 IU/ml) in the majority of patients during and between attacks (20% of patients can have normal IgD levels).  IgA levels are also increased in 80% of patients.  

 

Mevalonic Aciduria (MVA)  Patients with mevalonic aciduria are characterized by recurrent febrile episodes similar to hyper IgD syndrome.  However, patients also exhibit dysmorphic facial features (microcephaly, low-set posteriorly rotated ears, down slanted palpebral fissures), ataxia, mental retardation, cataracts, and failure to thrive.  Patients have greatly elevated mevalonic acid levels in the urine during and between attacks.

  

     The overall prognosis for HIDS is quite good with a relatively benign clinical course.  Amyloidosis can be a serious complication, but it has been reported in only 3% of HIDS patients.  However, patients with severe early onset MVA can have significant premature mortality during infancy or early childhood.  

       

 

 

PATHOGENESIS

 

     Mutations in the mevalonate kinase (MVK) gene result in the accumulation of mevalonate in the serum and urine.  Mevalonate is part of the cholesterol synthesis pathway and is generated by HMG CoA Reductase.   MVK converts mevalonate to 5-phosphomevalonate.  The exact mechanism for autoinflammation remains unclear.  There is debate as to whether it is the increase in mevalonate or the decrease in downstream products that are responsible for causing the febrile episodes. .  

         

 

 

DIFFERENTIAL DIAGNOSIS

 

 

1. FMF
2.TRAPS
3.Crypopyrin associated periodic fevers (muckle wells, FCAS, NOMID) 
4.PFAPA
5.Cyclic neutropenia

 

 

 

                                 

EVALUATION

 

Step 1:  Screening Studies

 

-Serum IgD and IgA levels
-Urine mevalonic acid levels
-C reactive protein / Erythrocyte sedimentation rate

 

-Serum IgD and IgA levels are typically elevated during and between disease flares in HIDS.  However, as discussed previously, normal levels of IgD can be present in 22% of patients. 
-Urine MVA  may be mildly elevated in HIDS during attacks but may be absent between attacks.  Urine MVA levels are typically persistently elevated in mevalonic aciduria.   
-CRP and ESR are often elevated during and between attacks.  

 

 

Step 2:  Genetic confirmation


-MVK gene sequencing

-This is the definitive test for establishing a diagnosis of HIDS or MVA and is commercially available.  

 

 

 

                                                                   

MANAGEMENT

 

1.  Hyper IgD Syndrome  Patients should receive symptomatic treatment of febrile episodes.  Due to the relatively benign course (except for rare amyloidosis) for most patients, more aggressive therapies such as stem cell transplantation are not typically considered.  Colchicine appears to have very little effect in the therapy of HIDS in contrast to FMF.  A number of pharmacologic options are listed below:


Nonsteroidal anti-inflammatory drugs (NSAIDs)
Oral steroids 
HMG-CoA reductase inhibitors (statins) 
Etanercept
Anakinra

 

2.  Mevalonic Aciduria  The treatment strategy is similar to Hyper IgD syndrome with symptomatic treatment of febrile episodes.   The administration of HMG-CoA reductase inhibitors should be avoided in patients with MVA (two patients who received this medication developed severe flares of disease).  Stem cell transplantation has been successfully performed in small number of patients with MVA. 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources     

 

Gene Dx:  Offers sequencing for MVK.   
A sample submission and informed consent form is required.  
Testing typically takes 4-6 weeks.   
www.genedx.com/services/dis_cg.php
Phone 301-519-2100     Fax 301-519-2892

 

 

 

Literature Resources

 

1.   Gattorno 2008 
      Diagnosis and management of autoinflammatory diseases in childhood (review)
      

2.  Drenth 1999 
     Mutations in mevalonate kinase cause Hyper IgD syndrome
     

3.  Haas 2006 
     Mevalonic kinase deficiency review
     

4.  Haas 2007 
     Mevalonate kinase deficiency and autoinflammatory disorders NEJM
     

5.  Van der Hilst 2008 
     Long term follow up and clinical features of 103 patient with Hyper IgD
     

6. Simon 2004 
    Simvastatin treatment for attacks in Hyper IgD syndrome


7.  Nevyjel 2007 
     The use of anakinra in a patient with Mevalonic Aciduria
     

8.  Neven 2007 
     Allogenic bone marrow transplantation in mevalonic aciduria