[CIS PIDD] [CIS-PAGID] 8 year old girl with mitochondrial disorder and severe infections

[Bodo Grimbacher]

Dear all,

not as a differential for this girl, but
I would not be surprised if inherited primary mitochondrial disorders have
an immunodeficiency.
The pathophysiology of Kostmann's disease (Hax1 deficiency) points towards
the primary involvement of the mitochondria in neutropenia.
(Klein et al., Nat Genet. 2007)


also not as a differential for this case, but in general in the adult PID
field,
PROMM, also called Curshman-Steinert, or muscular dystropy type 2, caused
by a quatruple repeat expansion in ZNF9,
can manifest as PID (mainly antibody deficiency) and also has autoimmunity
and endocrinopathies.

PROMM (DM2)
 
Mutation: Extension of CCTG-repeat in intron 1 of the ZNF9 zinc finger
transcription factor
 
Epidemiology: most patients come from Poland or Germany, all derive from
Europe, in Germany DM2 is as common as DM1, approx. 380 patients with DM2
reported
 

Clinical manifestation: electrical myotonia              90%, weakness
                        82%, low IgG                                  65%,
high gGT                               64%, musclepain
                62%, cataracts                               61%, diabetes
                               23%, cardiac involvement
    19%, low IgM                                  11%, muscle atrophy
              9%, normal IgA                            (!), mental
retardation         (!)
 


A good review is attached.


Best, 
Bodo

CCI - Centre of Chronic Immunodeficiency
University Hospital Freiburg
GERMANY

Am 30.05.12 13:56 schrieb "Dewton Vasconcelos" unter <dmvascon at usp.br>:


>

>  

>    

>  

>  

>    Dear Tom, good morning

>    

>    A long time ago I have followed a highly consanguineous family with

>    7 siblings. Five of them presented signs of mitocondrial disorder,

>    with muscular (striated and cardiac) manifestations, low carnitine

>    etc, and two of these five presented severe skin and respiratory

>    infections (abscesses). These two patients presented very low levels

>    of oxidative burst (evaluated by NBT at that time), without evident

>    immunoglobulin disorder.

>    

>    Nowadays I am following a 15 years-old girl with a probable

>    mitochondrial disease (waiting for the muscular biopsy), with

>    dysautonomia, cardiac arrythmia, intolerance to exercises, severe

>    gastrointestinal delayed emptying and familial autoimmunity, with

>    just a few infections that seem to be related to the muscular

>    disturbance.

>    

>    Good luck with your patient.

>    

>    Best,

>    

>    Dewton Vasconcelos

>    University of Sao Paulo School of Medicine

>    

>    Boyce, Thomas G., M.D. wrote:

>    

>      

>      

>      8 year old girl with mitochondrial disorder and severe

>        infections

>      

>      Do any of you see poorly

>          characterized immune deficiencies in patients with

>          mitochondrial disorders?

>      

>      This is an 8 year old girl born at

>          32 weeks' gestation who spent 5 weeks in the NICU with

>          multiple chest tubes for chylous effusions and pneumothoraces

>          and mechanical ventilation for 14 days.  She had severe bowel

>          motility problems and is now TPN dependent.  She has

>          neurogenic bladder and has a vesicostomy.  She has a poorly

>          characterized mitochondrial disorder with complex deficiencies

>          in the electron transport chain.

>      Despite getting the inactivated

>          influenza vaccine each year, twice she has developed severe

>          ARDS and DIC with influenza, first in October 2009 and then in

>          March 2011.  She will sometimes go into DIC with other

>          infections as well, such as line infections with coagulase

>          negative staph.  I measured her response to vaccine and she

>          does make an immune response to influenza vaccine (and the

>          infection).  After the second episode of severe complications

>          associated with influenza, we have placed her on oseltamivir

>          for the duration of the local flu season.  This year she did

>          not get influenza (although it was a very mild flu year here).

>      Most of her other infections are

>          recurrent UTIs which are presumably more anatomical in

>          predisposition.

>      

>      When she gets infection, she

>          generally does not mount much of a febrile response.  She also

>          does not develop leukocytosis.

>      Her labs are as follows (not during

>          an episode of DIC):

>      

>      Hb 11.9

>        

>        WBC 3.7 (1.92N, 1.45L, 0.22M, 0.12E,

>          0.03B)

>        

>        PLT 78

>        

>        ESR 3

>        

>        CD3 1161

>        

>        CD19 107

>        

>        NK 146

>        

>        CD4 503

>        

>        CD8 478

>        

>        H/S ratio 1.1

>      

>      B cell subsets essentially normal.

>        

>        CD4 RTEs were adequate 119 (38%)

>      

>      Igs are normal (IgG is supranormal

>          as she gets IVIG monthly for autoimmune neuropathy)

>      

>      Slightly decreased (but not absent)

>          NK cell function.

>      

>      Normal neutrophil oxidative burst.

>      

>      Normal lymphocyte proliferative

>          response to PHA but no response to tetanus toxoid.

>      

>      Adequate tetanus and diphtheria

>          serology (prior to starting on IVIG).

>      

>      Very poor response to

>          polysaccharide pneumococcal vaccine (postvaccination, she has

>          titers >1.3 mcg/mL to only 6 of 23 serotypes).

>      Her specific mitochondrial defect

>          remains undefined.  She clearly seems prone to severe

>          manifestations of certain infections.  Are there other

>          investigations that might characterize her immune

>          susceptibility?

>      Thanks.

>      

>      Tom

>      

>      Thomas G. Boyce, MD, MPH

>        

>        Pediatric Infectious Diseases and

>          Immunology

>        

>        Mayo Clinic

>        

>        Rochester, MN 55905

>        

>        phone: 507-255-8464

>        

>        fax: 507-255-7767

>        

>        Boyce.Thomas at mayo.edu

>      

>    

>

>  


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