Mitochondrial disease, hypertrophic cardiomyopathy and cutaneous lupus in an infant with food hypersensitivity

This paper describes a 4 month-old-girl with food allergies, mitochondrial disease, cutaneous lupus, and hypertrophic cardiomyopathy. She suffered from infectious pericarditis due to Coxsakie virus as a complication. She additionally presented bicytopenia (hemoglobin levels 8.9 g/dL, platelets 127 x 103 / μL), high lactate levels (5mmol/L), seizures, hypertrophic cardiomyopathy. This was suggestive of mitochondrial disease. Specifi c IgE levels were positive for milk, patch tests were positive for milk and soy, with a persistency of symptoms with extensively hydrolyzed formula as well as an amino acid-based formula. A chicken-based formula was well tolerated. Coenzyme Q10 levels were low (0.29L). Low Coenzyme Q10 levels in mitochondrial patients have been found as well as in allergic diseases. We suggest that food hypersensitivity should be ruled out in mitochondrial patients with low Coenzyme Q10 levels. Case Report


Introduction
Food allergies have dramatically increased although the reasons are unclear. In the developed world, this prevalence is approaching 10%. Many food allergies which start in early childhood are outgrown later in childhood [1]. Dermatologic and systemic manifestations of a food allergy are well recognized but we should not forget digestive tract manifestations [2].
Food hypersensitivity is a complex immune-mediated disease consisting of two mechanisms, IgE mediated and non IgE mediated [3].
Mitochondrial diseases are a group of genetic disorders that are characterized by defects in oxidative phosphorylation that encode structural mitochondrial proteins or proteins involved in mitochondrial function [4,5]. These are characterized by a wide variety of symptoms, such as: musculoskeletal and neurological symptoms, sensorial organs symptoms (sight and hearing disorders), organ and system damage: heart (cardiomyopathy or conductive defects), liver (hepatomegaly or development of liver failure), kidney (tubular diseases), gastro intestinal (vomit, diarrhea), blood (anemia, pancytopenia), and damage to the endocrine system [6] (Table 1). Coenzyme Q 10 is a lipid that acts in the mitochondrial respiratory chain, regardless of the cause. The impairment of CoQ10 status can result in profound defi cits to mitochondrial function [7]. There is strong evidence that suggests mitochondrial dysfunction and allergy [8].
In this report, we describe the case of an infant who had a combination of food allergies, mitochondrial disease, cutaneous lupus, and Coenzyme Q 10 low levels.

Case description
The patient was a 4 month-old-girl with a family history of atopy, and a sibling with atopic dermatitis and food allergies.
Her mother suffers from Sjögren syndrome and hypothyroidism. During pregnancy, the mother suffered with a threatened miscarriage. She was delivered by cesarean section at 40 weeks of gestation, the baby was born with a body weight 2.59 kg, and a height of 49cm, with a screening showing normal metabolic and hearing. Hidden bottle with milk formula. The Umbilical cord dropped after 2 weeks. The mother tried to breastfeed but was unsuccessful due to baby refl ux events.
In the fi rst few days after birth, the patient presented the following symptoms. She suffered from gastroesophageal refl ux, diarrhea, and blood in her stools. Physical examination revealed skin with red lesions in a ring shape on the face, scalp, chest, and abdomen ( Figure 1).
The patient was referred to Hospital Angeles Metropolitano at the age of 3 months. The growth retardation was evident, with a weight of 3360gms (<3) and body length of 51.1 (<3) percentiles. A delay on neurological development was observed.
Her skin, with red lesions in a ring shape were displayed on her face, thorax and abdomen. ENT exploration was normal, with grade 3-4, systolic murmur, louder over the second right intercostal space, no clicks were heard. Respiratory sounds were normal, hepatic border at 3cm. She reacted to any milk formula even with extensively hydrolyzed formula and amino acid-based formulas. She presented vomit, diarrhea and blood in her stools.
We performed an atopy patch test: milk positive (13 p) soy (20 p) (Heine R Score) [9]. Due to a soy and milk allergy, we started a chicken-based formula which showed good tolerance, less vomit, diarrhea and blood in the stools. Her karyotype was normal. (Table 2) A skin biopsy reported: perivascular and interstitial vacuolar dermatitis, which is suggestive of cutaneous lupus

Discussion
This child underwent an extensive clinical and laboratory examination to establish an association between food allergies, mitochondrial diseases and low levels of Coenzyme Q 10 .
Although we must not forget the onset of dermatitis (cutaneous lupus) since the fi rst days of life (10); differential diagnosis of skin disorders in the newborn were considered, particularly atopic dermatitis which is highly associated with food allergies.
However, the topography and morphology of the skin lesions are different in atopic dermatitis. These can take many forms (papules, vesicles, plaques, nodules and excoriations) [11].
Mitochondrial diseases have a wide spectrum of symptoms; the fi rst systems affected are the muscular and nervous systems, and later, organs show symptoms of damage (Table 1).
In the case we have described, the child presented neurological delay and seizures as nervous system damage, followed by cardiomyopathy, gastrointestinal symptoms and bicytopenia, and growth delay due to the damage in organs and systems [5,6].
Although it is described "phenomena of irregular red fi bers" as a main marker of mitochondrial diseases, there are other morphologic characteristics in mitochondrial diseases,     such as: the signifi cant increase in the size of mitochondria, accumulation of glycogen, lipids and calcium conglomerates in the subsarcolemmal, and a decrease in the activity of mitochondrial enzymes. This is the biopsy description of our patient. The phenomenon of irregular red fi bers can develop in other diseases such as: Duchene myodystrophy, dermatomyositis or by drugs such as clofi brate [6,12,13].
Compelling evidence has recently suggested that mitochondria in mammals, have multiple roles in immunity, and that in addition to being the powerhouse of the cell, they also represent the powerhouse of immunity [14]. In this light, increasing evidence strongly suggests a relevant role for mitochondrial dysfunction, and consequent excessive generation of reactive oxygen species (ROS) in an allergy. Mitochondrial dysfunction and elevated ROS have been reported in atopic dermatitis, allergic rhinitis and asthma [15]. Studies in a murine model suggest that the liver could act as a source of CD4 + T cells and could play an important role in the IgE response to dietary antigens [8]. These features could link the symptoms and evolution in the patient.  [16].
The prevalence of food allergies may vary from 0.3% to 10% worldwide and milk formulas have high allergenic potential for infants. We can choose extensively hydrolyzed formulas or amino acid-based formulas, but there are more culprit proteins such as soy, corn, wheat, and egg. In the patient our choice was a chicken-based formula. Patients with food allergies may have gastrointestinal, respiratory, and cutaneous symptoms.
In our patient, the food allergy background led us to suspect this [17,18].

Conclusion
patients with mitochondrial disease suspicion, Coenzyme Q 10 low levels should be evaluated as well for food hypersensitivity. In order to treat them with early CoQ10 supplementation and it can result in clinical improvement in conjunction with an avoidance diet. A number of disorders associated with CoQ10 defi ciency have been successfully treated via CoQ10 supplementation [19]. CoQ10 has a central role in the metabolism of all cells, and its defi ciency is linked to the pathogenesis of a range of disorders. Primary CoQ10 defi ciency results from genetic defects in the multi-step CoQ10 biosynthetic pathway. Brain, muscle and kidney tissues are particularly susceptible to the metabolic consequences of a defi cit in the status of this isoprenoid, presenting clinically with disorders such as ataxia, myopathy and nephrotic syndrome, respectively. Early identifi cation in CoQ10 defi ciency is essential, since patients may show remarkable clinical improvement following CoQ10 supplementation when administered at an early stage of disease [19][20][21][22].