Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 6 Issue: 1

Biotinidase Deficiency Presenting as Hyperventilation Syndrome

Iwanicka-Pronicka K1*, Pajdowska M2, Dariusz Rokicki3, Piekutowska-Abramczuk D4, Kozłowski D2, Wiśniewska-Ligier D5, Ksiazyk JB3, Krajewska-Walasek M4, Wolf B6 and Pronicka E3,4
1Department of Audiology and Phoniatrics, The Children’s Memorial Health Institute, Warsaw, Poland
2Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, Warsaw, Poland
3Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, Warsaw, Poland
4Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland
5Department of Pediatrics, Immunology and Nephrology, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
6Department of Research Administration, Henry Ford Hospital, Detroit, MI, 48202, USA and Center for Molecular Medicine and Genetics, Wayne State University, School of Medicine, Detroit, MI 48201, USA
Corresponding author : Iwanicka-Pronicka K, MD, PhD
Department of Audiology and Phoniatrics, The Children’s Memorial Health Institute, Aleja Dzieci Polskich 20 04-730, Warsaw, Poland
Tel: +48 22 815 17 61
Fax: +48 22 815 16 14
E-mail: [email protected]
Received: December 12, 2016 Accepted: January 05, 2017 Published: January 05, 2017
Citation: Iwanicka-Pronicka K, Pajdowska M, Rokicki D, Piekutowska-Abramczuk D, Kozłowski D, et al. (2017) Biotinidase Deficiency Presenting as Hyperventilation Syndrome. J Genet Disor Genet Rep 6:1. doi: 10.4172/2327-5790.1000149

Abstract

Biotinidase is responsible for recycling the vitamin, biotin, and making the free biotin available to activate the biotin-dependent carboxylases, including pyruvate carboxylase, which is involved in mitochondrial energy metabolism. Individuals with untreated biotinidase deficiency usually exhibit lethargy, hypotonia, ataxia, cutaneous abnormalities, vision and hearing impairment and developmental delay.
We recently observed a child who presented with hyperventilation syndrome and lactic acidemia who was thought to have a mitochondrial disorder. After six months of multiple hyperventilation episodes in the absence of the usual neurocutaneous features of biotinidase deficiency, the child was determined to be homozygous for a likely pathogenic variant of the biotinidase, BTD, gene. This case prompted us to evaluate retrospectively the presence of respiratory alkalosis and hypocapnia, indicative of hyperventilation syndrome, in other symptomatic individuals with biotinidase deficiency.
The results showed statistically significant hypocapnia at the onset of symptoms which rapidly resolved upon administration of biotin (pCO2 27.2 ±11.6 vs. 41.5 ± 3.5; normal >35 mmHg).
Selective screening for biotinidase deficiency should be considered in individuals with hypocapnia and respiratory alkalosis. This is particularly important in locations where newborn screening for this disorder is not performed.

Keywords: Biotinidase deficiency; Hyperventilation syndrome; Hypocapnia; Respiratory alkalosis

Keywords

Biotinidase deficiency; Hyperventilation syndrome; Hypocapnia; Respiratory alkalosis

Case Study

The boy is the only child of non-consanguineous parents. He was delivered by caesarean section because of threatened asphyxia. His birth weight was 2970g and his Apgar scores at 1, 3, 5 minutes were all 10. His development was normal at age of 22 months, when he developed shortness of breath that was attributed to a lower respiratory tract infection. Over the next three months, he required three hospitalizations to the local paediatric ward for recurring respiratory disturbances, characterized by tachypea, choking and drooling.
Chest X-rays revealed bronchitis or pneumonia on each occasion. He consistently exhibited respiratory alkalosis with severe hypocapnia (pCO2 11.0-19.5 mmHg; normal >35), hyperglycemia 6.06 mmol/l (109 mg/dl), lactic acidemia 3.33 mmol/l (30 mg/dl), mild hyperchloremia (113 mmol/l), and hyperuricemia 392.5 μmol/l (6.6 mg/dl), with a normal white blood cell count and no other evidence of an infection. Neurological examination revealed deep breathing, hyperactivity, limited eye contact, slightly unsteady gait, decreased social behaviour (did not obey simple commands) and mild developmental delay, specifically speech delay. EEG, computerized tomography of the brain, ophthalmological examination and nasofiberoscopy of the upper respiratory tract were normal.
Five months after the first symptoms, the boy was referred to our mitochondrial reference centre due to increase plasma lactate concentration, with the suspicion of Leigh disease [1]. Screening for common pathogenic SURF1, SCO2, and MTATP6 variants was negative [2,3]. An intravenous glucose test was performed as described [4] and revealed an increase in plasma lactate concentration in response to the glucose load (Figure 1) as observed in pyruvate dehydrogenase deficiency. The parents refused to perform brain MRI and muscle biopsy, but agreed to have Next Generation Sequencing of his DNA to search a targeted panel of 2,741 Mendelian disorders (performed in a laboratory in Berlin). This testing revealed homozygosity status for a probable pathogenic variant in the BTD gene, c.643C>T; p.Leu215Phe).
Figure 1: Lactate response to an intravenous glucose load in our study case with a high pH and hypocapnia (7.543 and 15,7 mmHg; normal: 7.35- 7.43, 35-45 mHg) compared to that in another child (historical case) with biotinidase deficiency who had a normal pH and pCO2 (7.346 and 36.2 mmHg).
At 30 months of age, biotin treatment was started at home. His hyperpnea diminished and his general status improved during the next few days.
The boy returned to our mitochondrial reference centre in 9th day of biotin administration. Serum biotinidase activity was undetectable. He had complete reversal of his previous acid-base abnormalities in blood gases, with pCO2 43.3mmHg, HCO3 21.1 mmol/l and pH 7.33 and plasma lactate concentration was 2.7 mmol/l (24.3 mg/dl). Gas chromatography-mass spectrometry of archive urine sample, obtained before biotin therapy was started, revealed increased excretion of 3-hydroxyisovaleryl acid and tiglyl acid.
The boy’s breathing pattern normalized and he did not have hyperpnea. Neurological examination showed only increased tendon reflexes and marked articulatory muscle weakness. Hearing tests, including DPOAE (distortion products otoacoustic emission), tympanometry and the brain stem auditory evoked potentials, were normal. He did not exhibit any of the other neurological or cutaneous features usually observed in untreated individuals with profound biotinidase deficiency [5,6].

Study of Archival Cases

We reviewed archival records of 16 individuals diagnosed with profound biotinidase deficiency in our centre between 1994 and 2016. Some of them have been reported previously [7-9]. We selected those with blood gases and plasma lactate concentrations at the time of diagnosis. A comparison of the parameters before and after biotin therapy is shown in Table 1.
Table 1: Acid-base parameters in children with profound biotinidase deficiency before and after biotin administration.

Discussion

Hyperventilation syndrome [10,11] characterized by hypocapnia and respiratory alkalosis, was the major clinical feature in our child. Similar laboratory findings were also present in other biotinidasedeficient children for whom laboratory details were available for this retrospective analysis (Table 1).
The child in this report was only identified as having biotinidase deficiency when Next-Generation Sequencing was performed for Leigh and he was to be homozygous for a likely pathogenic variant of BTD. Subsequent serum enzyme testing revealed that this child had undetectable biotinidase activity about eight months after the child’s first episode of hyperventilation. Therefore, appropriate biotin treatment was delayed and put the child at risk for developing irreversible neurological abnormalities [6].
The mean and median partial pressures of carbon dioxide (pCO2) were markedly decreased before the initiation of biotin treatment. They increased from 25.2 to 41.8 mmHg, (normal: 35-50 mmHg). These results indicate permanent hyperventilation expressed by acute and chronic respiratory alkalosis. The other acid-base parameters show secondary metabolic compensation (Table 1).
The range of pCO2 in individual assays exceeds not only the lower, but also the upper limit of the normal range (Table 1), reflecting respiratory center impairment. Although the mean and median pCO2 values indicate predominance of hyperventilation, the CO2 retention in individual assays (max. 61.8 mmHg; normal <50 mmHg) corresponds to these periods of hypoventilation. There is also a mild increase in lactate and pyruvate concentrations and hyperglycemia, up to 8.5 mmol/l (153 mg/dl) (Table 1).
Breathing abnormalities in children with biotinidase deficiency has been known since its discovery [7]. About 25-50% of symptomatic children with biotinidase deficiency exhibited breathing dysfunction [12]. However, we could not find any acid-base data, before or after biotin administration studied in these children, except for a single description in a child initially diagnosed with Leigh disease [13]. The patient’s capillary gases showed very low pCO2 (14.0-29.5 mmHg; normal >35 mmHg) and high pH, up to 7.56 (7.38-7.56; normal <7.43). Increase in 3-hydroxylisovalerate, (230 and 210 mmol/mol creatine; normal <50) excretion was the only metabolic finding in that boy. Specific extra-cerebral symptoms, typical of biotinidase deficiency, were lacking, thereby delaying the correct diagnosis. The symptomatology and the laboratory findings of this child are similar to those in our case. Interestingly, both of these children had initial lactate response to glucose load similar to individuals with Leigh syndrome having homozygous mutations in SURF1 [3].
Considering the pathological mechanism of respiratory alkalosis in individuals with biotinidase deficiency, it is likely that inhibition of pyruvate carboxylase (PC) activity in the biotin-depleted brain is responsible for neurological symptoms [7,12-14] and persistent hyperpnea. Rapid restoration of PC activity in the biotinidase-deficient individuals after biotin administration, even at physiological doses, appears adequate to resolve the symptoms. We speculate that differences in PC inhibition and activation in the brain explains the development of hyperventilation in some individuals with biotinidase deficiency.
The response to a glucose load examined in two individuals with biotinidase deficiency (Figure 1) is consistent with this mechanism. A substantial difference is seen between our historical case, with a normal pH blood at testing, and the study case with increased pH value. In our interpretation, the declining lactate curve pattern (Figure 1) observed in the historical biotin-deficient case, indicates exclusively a mitochondrial involvement, the PC inhibition. On the other hand, the pattern found in the study case, with increasing lactate curve (Figure 1), may reflect an inhibition of glycolysis pathway due to respiratory alkalosis. We observed similar patterns of lactate response to glucose in individuals with various causal mutations of Leigh syndrome [1,15,16].

Conclusions

Most symptomatic individuals with untreated profound biotinidase deficiency exhibit the usual neurological and cutaneous abnormalities that prompt the clinician to consider an organic aciduria or specifically biotinidase deficiency [6]. However, when an individual only exhibits breathing abnormalities and has blood gas alterations consistent with hyperventilation syndrome, the clinician is less likely to consider biotinidase deficiency in the differential diagnosis and, thereby, delays the appropriate treatment. This becomes most important in locations that do not perform newborn screening for the disorder. Moreover, selective screening for inborn errors of metabolism by gas chromatography-mass spectrometry/ tandem mass spectrometry should be considered in the evaluation of mitochondrial disorders.

Informed Consent

All procedures followed were in accordance with the ethical standards of the Bioethic Commitee of the Children’s Memorial Health Institute and with the Helsinki Declaration of 1975, as revised in 2000.
Informed consent was obtained from the patient for being included in the study (available upon request).

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