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. 2015 Jul 24;25:1–7. doi: 10.1007/8904_2015_421

Coenzyme Q10 and Pyridoxal Phosphate Deficiency Is a Common Feature in Mucopolysaccharidosis Type III

Dèlia Yubero 7, Raquel Montero 7,9, Mar O’Callaghan 7, Mercè Pineda 7, Silvia Meavilla 7, Veronica Delgadillo 7, Cristina Sierra 7, Laura Altimira 7, Plácido Navas 9,10, Simon Pope 11, Marcus Oppenheim 11, Viruna Neergheen 11, Arunabha Ghosh 12, Phillipa Mills 13, Peter Clayton 13, Emma Footitt 13, Maureen Cleary 13, Iain Hargreaves 11, Simon A Jones 12, Simon Heales 8,11,13, Rafael Artuch 7,9,✉
PMCID: PMC5059182  PMID: 26205433

Abstract

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs). Previously, we reported a secondary plasma coenzyme Q10 (CoQ) deficiency in MPS patients. For this study, nine MPS patients were recruited in the Hospital Sant Joan de Déu (HSJD, Barcelona) and two patients in the Neurometabolic Unit, National Hospital (NMU, London), to explore the nutritional status of MPS type III patients by analyzing several vitamins and micronutrients in blood and in cerebrospinal fluid. Plasma CoQ and plasma and cerebrospinal fluid pyridoxal phosphate (PLP) content were analyzed by high-pressure liquid chromatography (HPLC) with electrochemical and fluorescence detection, respectively. We found that most MPS-III patients disclosed low plasma pyridoxal phosphate (PLP) values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine). We observed significantly lower median values of PLP, tocopherol, and CoQ (Mann–Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients when compared with age-matched controls. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients. Cerebrospinal fluid PLP values were clearly deficient in the two patients studied. In conclusion, we report a combined CoQ and PLP deficiency in MPS-III patients. These observations could be related to the complexity of the physiopathology of the disease. If our results are confirmed in larger series of patients, CoQ and PLP therapy could be trialed as coadjuvant therapy with the current MPS treatments.

Introduction

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiencies of lysosomal enzymes catalyzing degradation of glycosaminoglycans (GAGs) (Neufeld and Muenzer 2001). Among them, MPS type III (MPS-III) or Sanfilippo syndrome is an autosomal recessive lysosomal storage disease caused by mutations in one of four genes which encode enzyme activities required for the lysosomal degradation of heparan sulfate. Four types have been recognized: heparan N-sulfatase is deficient in type A (OMIM #252900), α-N-acetylglucosaminidase in type B (OMIM #252920), acetyl-CoA α-glucosamide acetyltransferase in type C (OMIM# 252930), and N-acetyl glucosamine 6-sulfatase in type D (OMIM# 252940) (Neufeld and Muenzer 2001). This disorder primarily affects the central nervous system (Yogalingam and Hopwood 2001), being the only MPS with relatively minor somatic disease. It is characterized by speech delay, behavioral problems, progressive cognitive decline, dysmorphic facial features, loss of motor skills, and epilepsy. Due to the nonspecific clinical symptoms, a diagnostic delay is common in MPS-III (Neufeld and Muenzer 2001; de Ruijter et al. 2012). Over 300 mutations in the four genes (SGSH, NAGLU, HGSNAT, GNS) encoding for the enzymes have been described to date (Wijburg et al. 2013).

Coenzyme Q10 (CoQ) is an endogenously synthesized lipid present in all types of cells and in plasma associated with cholesterol transport lipoproteins. CoQ acts as an electron transporter inside the mitochondrial respiratory chain (MRC) and is necessary for ATP production. Among other biological properties, the reduced form of CoQ is an effective antioxidant for both cell membranes and plasma lipoproteins and also recycles α-tocopherol (Navas et al. 2007; Sohal 2004). Several secondary CoQ deficiencies related to different neurodegenerative conditions have been reported. In 2011, Delgadillo et al. reported for the first time plasma CoQ deficiency in different MPS patients monitored during genistein treatment (Delgadillo et al. 2011).

Owing to these preliminary findings, our aim was to explore the nutritional status of different MPS-III patients by analyzing several vitamins and micronutrients in blood. Additionally, we were able to analyze the CSF of two further MPS-III patients.

Material and Methods

Subjects

Patient samples were received by Hospital Sant Joan de Déu (HSJD, Barcelona) and the Neurometabolic Unit (NMU), National Hospital, Queen Square, London. In HSJD, nine MPS type III patients were studied (range age: 5–17 years; average 11 years) for nutritional assessment. Five out of nine patients were MPS-IIIA, three were MPS-IIIB, and one patient was type IIIC. At the time of the study, no patient was receiving a vitamin or CoQ supplement. Four out of nine patients were on treatment with genistein (100–150 mg/kg/day) following a previously reported protocol (Delgadillo et al. 2011). In five of them, seizures were being treated with a combination of different antiepileptics (lamotrigine, carbamazepine, and phenobarbital). Due to new onset movement disorders, cerebrospinal fluid (CSF) neurotransmitters and pyridoxal phosphate (PLP) concentration was assessed, by the NMU, from two patients with MPS-IIIA (4 and 16 years old).

Control population: All blood analyses results were compared with the age-dependent reference values established for each biochemical parameter in HSJD laboratory. Moreover, we selected an age-matched healthy pediatric population (n = 9; range age: 5–17 years; average = 11 years) to asses biochemical data in parallel with MPS patients. All controls were healthy subjects who came to the hospital for routine analysis: exclusion criteria were the diagnosis of inborn errors of metabolism or any other genetic or chronic condition, pharmacological treatments, or special diets. For assessment of pyridoxal phosphate status in CSF, results were compared to the NMU-established age-related reference intervals (Ormazabal et al. 2008).

Ethical issues: The study was approved by the Ethical Committee of the Hospital Sant Joan de Déu, and samples from patients and controls were obtained according to the Helsinki Declaration of 1964, as revised in 2001. CSF analysis was performed after informed consent and at the request of the clinical team.

Nutritional Study

Dietary questionnaires were completed by patient’s parents and were performed to the 9 MPS-III patients selected. Nutritional status was followed up by the gastroenterology and nutrition department of the HSJD.

Laboratory Studies

Blood and urine samples were collected in the fasting state. Blood samples were centrifuged to 1,500 × g for 10 min at 4°C and the plasma/serum samples obtained were stored at −80°C up to the day of the analysis. Urine samples were collected and stored at −20°C until the moment of the analysis. CSF PLP was collected, stored at −80°C, and processed as previously described (Ormazabal et al. 2008).

In blood samples, routine parameter analyses (blood count, ions, glucose, hepatic and renal function, lipid and iron metabolism markers) were performed by standardized automated analysis. Amino acids were measured by ion-exchange chromatography with spectrophotometric detection after ninhydrin derivatization in a Biochom 30 analyzer (Chromsystems UK). For nutritional markers in blood (plasma/serum), we analyzed plasma CoQ content by reversed-phase high-pressure liquid chromatography (HPLC) with electrochemical detection (Montero et al. 2005), and vitamin E, vitamin A, vitamin B1, and pyridoxal phosphate (PLP) were measured by HPLC with UV and fluorescence detection following previously reported procedures (Ormazabal et al. 2008; Moyano et al. 1997; Lu and Frank 2008). Serum folate and vitamins B12 and D were quantified by automated chemoimmunoluminescence procedures in an ARCHITECT analyzer (Abbot, USA). For trace element analysis (zinc, copper, and selenium), inductively coupled plasma mass spectrometry (ICP-MS) was applied, as reported (Tondo et al. 2010). Urinary total GAGs excretion in patients during the study was done by the automated-DMB spectrophotometric assay.

All patients were diagnosed with MPS-IIIA, B, or C on the basis of the demonstration of enzymatic activity deficiency of particular lysosomal hydrolases in leukocytes or skin fibroblasts (sulfamidase, α-N-acetylglucosaminidase, and heparin-α-glucosaminido-acetyltransferase). In all cases molecular studies were performed for identification of pathogenic mutations by automated DNA Sanger sequencing method (data available on request).

Statistical Studies

De Mann–Whitney U test was used to compare data for all the variables analyzed between MPS patients and age-matched controls. Chi-square test was applied to search for categorical association among the different biochemical parameters included in the study. Statistical differences were considered when p was <0.05. Statistical analysis was done with the SPSS 22.0 program.

Results

Nutritional Studies

Dietary assessments of the MPS patients confirmed that dietary intake was correct for their age according to recommended dietary allowances (data not shown). Moreover, all of them were able to feed normally and none required enteral feeding by gastric button or other feeding device.

Biochemical Results

Routine parameters (blood count, ions, glucose, hepatic and renal function makers, alkaline phosphatase, lipid and iron metabolism) and other nutritional biomarkers (amino acids; vitamins B1, B12, and A; folate and trace elements) were within the reference ranges in all MPS patients (data not shown). The urinary GAGs excretion was altered in all MPS patients at the time of the study (range 12.6–24.2 mg/mmol creat).

Main biochemical results are stated in Tables 1 and 2. The results of MPS patients and age-matched controls are expressed as range and average and as range for reference values established in our laboratory. Most MPS patients showed low plasma PLP values (seven out of nine) and also low plasma CoQ concentrations (eight out of nine) (Table 2). The other parameters stated in Table 1 were normal or slightly impaired in a minority of cases. Interestingly, CSF PLP values were below the appropriate reference range for both patients studied (Table 1).

Table 1.

Main plasma biochemical data of MPS patients and control subjects are stated. The results of MPS patients and age-matched controls are expressed as range and average and as range for reference values established in our laboratory. The number of patients displaying impaired results is also indicated

MPS patients (n = 9)
(5–17) 11 years		 Age-matched controls (n = 9)
(5–17) 11 years		 Reference values
Alkaline phosphatase (UI/L) (72–315) 207
0/9		 (37–277) 167
0/9		 <365
Total homocysteine (μmol/L) (5.9–24.8) 9.6
3/9		 (3.1–10.0) 5.5
0/9		 <9.2 (12–20 years)
<7.5 (5–11 years)
Total cholesterol (mmol/L) (3.1–5.6) 4.3
1/9		 (3.3–5.9) 4.4
2/9		 2.4–5.2
Retinol (μmol/L) (1.0–2.1) 1.3
0/9		 (0.8–1.4) 1.1
1/9		 0.9–2.1
Tocopherol (μmol/L) (12–26) 17.3
1/9		 (18–34) 25.4
0/9		 13–36
Pyridoxal phosphate (nmol/L) (8–99) 27
7/9		 (32–105) 69
0/9		 30–169
Coenzyme Q10 (μmol/L) (0.20–0.53) 0.32
8/9		 (0.41–0.76) 0.53
0/9		 0.41–1.15
Coenzyme Q10/cholesterol ratio (mmol/mol) (47–102) 74
9/9		 (100–141) 120
2/9		 115–316
CSF PLP values (nmol/L) 9 (4 years)
7 (16 years)		 Not available 16–44
10–37
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CSF cerebrospinal fluid

Table 2.

Individual plasma biochemical data of the nine MPS patients, age-matched controls, and reference values are stated. Results of age-matched controls are expressed as range and average and as range for reference values

Patient MPS type Age (years) Coenzyme Q10 (μmol/L) Pyridoxal phosphate (nmol/L) Tocopherol (μmol/L) Total cholesterol (mmol/L) Glycosaminoglycans (mg/mmol creatinine)
1. IIIA 10 0.31 19 17 5.0 13.3
2. IIIA 8 0.35 20 19 4.2 14.1
3. IIIA 10 0.31 22 14 4.3 24.2
4. IIIA 5 0.21 35 12 3.1 22.5
5. IIIA 16 0.20 15 26 4.3 15.9
6. IIIB 14 0.31 8 17 3.4 17.5
7. IIIB 11 0.53 22 15 5.2 16.5
8. IIIB 9 0.36 99 21 5.7 14.2
9. IIIC 17 0.29 8 15 3.5 12.6
Age-matched controls (5–17) 11 (0.41–0.76) 0.53 (32–105) 69 (18–34) 25 (3.3–5.9) 4.4
Reference values 0.41–1.15 30–169 13–36 2.5–5.2 <6.4 (5–12 years)
<4.5 (13–17 years)
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When we compared the blood biochemical parameters in the two groups of subjects (MPS vs age-matched controls), we observed significantly lower median values of PLP, tocopherol, and CoQ (Mann–Whitney U test, p = 0.006, p = 0.004, and p = 0.001, respectively) in MPS patients (Table 1, Fig. 1). No differences were observed in total cholesterol values, alkaline phosphatase activity, total homocysteine, and the other parameters between the two groups. Chi-square test showed a significant association between the fact of having low plasma PLP and CoQ values in the whole cohort of patients and controls studied (χ2 = 7.137; p = 0.008), but not with other parameters analyzed. No association was found between both CoQ and PLP deficiency and the antiepileptic treatment.

Fig. 1.

Fig. 1

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The box plot represents PLP and CoQ values in group 1 (MPS patients) versus group 2 (age-matched controls). The spot line represents the minimum PLP and CoQ values in the reference population

Discussion

In a previous report, we studied 30 patients (2–23 years; 9.8 average) with diagnosis of different MPS (19 of them MPS-III) during the monitoring of genistein treatment (Delgadillo et al. 2011). In that report, decreased plasma CoQ values were a common feature. Thus, we have done a nutritional study in nine selected MPS-III patients, and CoQ deficiency was detected in most of them. Furthermore, not only plasma CoQ was decreased, but also a PLP deficiency was present in seven out of nine cases studied. Other nutritional parameters were assessed as normal or showed only minor differences when compared to reference values.

Concerning CoQ deficiency, we do not have yet an explanation for this finding. Total cholesterol values were normal, suggesting that the cause of such deficiency is probably unrelated to impaired cholesterol biosynthesis (and consequently CoQ biosynthesis). This statement would be supported by the data of Matalonga et al., who demonstrated a normal CoQ biosynthesis rate in cultured skin fibroblast from MPS patients (Matalonga et al. 2014). Plasma CoQ values depend on dietary sources (around 20% of total CoQ) and liver biosynthesis, but dietary CoQ deficiency is unlikely considering the adequate nutritional status of our patients and the normality of most of the other vitamins and trace elements analyzed. However, an absorption problem in the gut for CoQ cannot be ruled out at this stage. Diarrhea is common in children with MPS-III and may be severe, and the mouse model has increased submucosal thickness with lysosomal storage of GAG in this region and in the lamina propria of the villus tip (Roberts et al. 2009). Increased CoQ consumption may also be a factor explaining this deficiency, since some authors suggested the possible involvement of the reactive oxygen species in the MPS type IIIB disease pathogenesis (Villani et al. 2009). Recently a positive effect has been observed in cultured fibroblasts from Sanfilippo A and B treated with CoQ and other antioxidants (Matalonga et al. 2014). Moreover, since CoQ participates in tocopherol recycling (Navas et al. 2007), the significantly lower median tocopherol values observed in our MPS patients when compared with age-matched controls might be related with the CoQ deficiency. The importance of these lower median tocopherol values is probably limited since in absolute values, most of the tocopherol results were normal when compared with the reference range.

As regards PLP deficiency, the explanation also remains elusive. The alkaline phosphatase activity (ALP) maintains the equilibrium needed to dephosphorylate PLP to pass through cell membranes. Increased ALP activity in plasma may lead to a secondary PLP deficiency. However, in our MPS patients, biochemical data supported a real PLP deficiency, since no increment of plasma ALP activity was demonstrated. The finding of PLP deficiency in both plasma and CSF might support a hypothesis of a transport defect affecting PLP movement across both the gut and the blood–brain barrier. Heparan sulfate and phosphorylated B6 vitamers both bind to divalent cations, so it is conceivable that phosphorylated B6 vitamers could become bound to HS.

An association between CoQ and PLP status has been reported (Spinneker et al. 2007). PLP is a versatile coenzyme and it is the essential cofactor for multiple reactions. It is involved in the transsulfuration pathway of homocysteine (and, although nonsignificant, some of our MPS patients showed some evidence of increased total homocysteine values at the time of the study), as well as in the metabolism of amino acids, neurotransmitters, and other substrates (Spinneker et al. 2007). Furthermore, PLP is required for the formation of 4-hydroxyphenylpyruvic acid from tyrosine, the essential precursor of the benzoquinone ring of CoQ. In fact, it has been demonstrated that PLP deficiency is associated with low CoQ concentrations (Willis et al. 1999), which could explain CoQ deficiency as a secondary condition of low precursor availability.

The pathophysiology of the MPS disorders is complex, and the molecular basis and the sequence of events leading to neurodegeneration in MPS remain to be clarified. Several treatments have been designed for different types of MPS including enzyme replacement therapy, gene therapy, or substrate reduction therapy (Kakkis et al. 2001; Wraith et al. 2004; Piotrowska et al. 2006). These treatments lead the partial restoration of the enzyme activity or inhibition of GAG synthesis. However, such approaches have not been completely successful. PLP is the active form of vitamin B6 and the cofactor of many enzyme reactions including neurotransmitter metabolism (dopamine, serotonin, and GABA among others). Primary and secondary PLP metabolism disturbances can produce refractory seizures in the newborn period and infancy that respond to this vitamin supplementation. Thus, PLP treatment seems advisable in this condition. On the other hand, the antioxidant properties of CoQ are well recognized. A chronic CoQ deficiency may lead to an increased oxidative stress that might in turn participate in neurodegeneration in MPS. Moreover, the demonstration of a beneficial effect of CoQ in GAGs accumulation in fibroblast further support that this therapy in combination with PLP would be advisable as coadjuvant treatment in MPS patients presenting PLP and CoQ deficiency.

Conclusions

We report for the first time a combined CoQ and PLP deficiency in MPS-III patients. These observations could contribute to the complexity of the physiopathology of the disease. After a careful evaluation of nutritional status in large series of MPS patients, both CoQ and PLP could be trialed as coadjuvant therapy with the current MPS treatments.

Acknowledgments

This research was partially funded by grants PI11/02350, PI11/00078, PI1400028, and PI14-01962 from the Spanish Ministry of Health (Fondo de Investigación Sanitaria, Instituto de Salud Carlos III). We are very grateful for the support of the “MPS España” association.

Synopsis

Combined CoQ and PLP deficiency is common in MPS-III patients.

Compliance with Ethics Guidelines

Conflict of Interest

Dèlia Yubero, Raquel Montero, Mar O’Callaghan, Mercè Pineda, Silvia Meavilla, Veronica Delgadillo, Cristina Sierra, Laura Altimira, Plácido Navas, Simon Pope, Marcus Oppenheim, Viruna Neergheen, Arunabha Ghosh, Phillipa Mills, Peter Clayton, Emma Footitt, Maureen Cleary, Iain Hargreaves, Simon A. Jones, Simon Heales, and Rafael Artuch declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study. Informed consent was obtained and must be available upon request.

Author Contributions

All co-authors have peer-reviewed the manuscript and there is a consensus agreement to submission. Thus, we confirm the absence of previous similar and simultaneous publications. Dr. Yubero, Montero, O’Callaghan, Heales, and Artuch had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

  • Study concept and design: Yubero, Montero, O’Callaghan, Pineda, Hargreaves, Heales, and Artuch

  • Acquisition of data: Yubero, Montero, O’Callaghan, Pineda, Meavilla, Delgadillo, Sierra, Altimira, Pope, Oppenheim, Neergheen, Ghosh, Mills, Clayton, Footitt, Cleary, Jones, and Heales

  • Analysis and interpretation of data: Yubero, Montero, O’Callaghan, Navas, Mills, Clayton, Hargreaves, Heales, and Artuch

  • Drafting of the manuscript: All authors

  • Critical revision of the manuscript for important intellectual content: All authors

  • Study supervision: Artuch

Footnotes

Competing interests: None declared

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