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Biotinidase deficiency is a rare disorder with a wide spectrum of neurological, dermatological, and immunological dysfunction. Identification of this disorder is important as it is easily treatable and the patients show dramatic response to therapy, besides the fact that it can prove fatal if not diagnosed. We report a case of biotinidase deficiency who presented with quadriparesis, highlighting all these issues.
Keywords: Biotin, biotinidase
A 3 year 10-month-old girl child was referred to our hospital with complaints of episodes of rapid breathing and progressive weakness of all four limbs. Her complaints had started about 3 months prior when she was admitted for a “lower respiratory tract infection” with predominant complaints of rapid breathing. Subsequent to which, she continued to have episodes of rapid breathing, for which she received treatment on OPD basis. Over the period of time, she developed weakness of all four limbs, predominately of the proximal muscle group, manifesting as unsteady gait and inability to self-feed. The weakness progressed and she was bedridden at the time of admission. There was also history of one episode of generalized clonic–tonic seizures 2 weeks prior. She was a product of a nonconsanguineous marriage, with no remarkable delay in attaining the target developmental milestones. Her elder brother had died following similar clinical manifestations of progressive weakness at 4 years of age. In fact, this heightened the parental anxiety to seek medical help. Clinically, she was alert and had silent tachypnea. Skin manifestations in form of candidal lesions of the axilla and the toe clefts along with alopecia were present. The bilateral plantars were extensor with gross hypotonia and the power in the proximal muscles of both limbs being Grade II (as per Medical Research Council Grading System of United Kingdom). Baseline investigations revealed partially compensated metabolic acidosis. MRI studies showed mild cerebral atrophy with hypoplasia of cerebellar vermis. MRI of spine was suggestive of myelopathy. CSF study and ophthalmologic and audiological evaluations were normal. In view of family history and the episodic nature of respiratory complaints suggestive of metabolic acidosis, along with the skin manifestations, possibility of neurometabolic syndrome was considered. Serum lactate was elevated [31 mg/dL (4.5–19.8 mg/dL)] and the biotinidase activity was 0 nmol/min/mL. The child was started on daily oral biotin 20 mg and made significant recovery. Hyperventilation subsided in 12 h; the child could sit without support in 2 days and started walking in the second week of treatment. Skin lesions healed in the third week and there was hair growth.
Biotinidase is an essential enzyme required for recycling biotin by lysing lysine moiety from biocytin, as elucidated in the biotin cycle.2,3 Deficiency of biotinidase results in the deficiency of biotin, which is required as a catalyst for the carboxylase systems in the body. The four main carboxylase systems being: (1) pyruvate carboxylase (required for glucose production; inactivity lowers blood sugar resulting in hypoglycemia and lactic acidosis); (2) acetyl-CoA carboxylase (required for biosynthesis of fatty acids by liver and fat cells; inactivity results in reduced availability of stored fatty acids for exercise resulting in hypotonia); (3) propionyl-CoA carboxylase (required for breakdown of amino acids with an odd number of carbons; inactivity results in propionic academia and reduced activity of citric acid cycle resulting in reduced energy production in the brain, resulting in developmental delays); and (4) methylcrotonyl-CoA carboxylase (required for breakdown of leucine; inactivity results in lowered carnitine levels and methylcrotonylglycinuria).4
Although individual deficiencies of all four carboxylases have been reported, the clinical spectrum varies widely from a severe form presenting early (multiple carboxylase deficiency, holocarboxylase synthase deficiency) to milder varieties presenting late (biotinidase deficiency).5,6 The clinical presentation of repeated episodes of hyperventilation, progressive neurological deterioration with skin lesions, and corroborating with laboratory features of lactic acidosis suggested the diagnosis of biotinidase deficiency in this case.
The clinical spectrum of biotinidase deficiency depends on the severity of the defect. The clinical manifestations predominately include neurological and skin and respiratory manifestations. The neurological spectrum includes seizures, hypotonia, and developmental delay in the early period. Some older children present with progressive spastic quadriparesis and hearing and visual impairment.7 The present case had muscle weakness. In view of the clinical presentation and previous case reports of recurrent myelopathy,7 MRI of spine was done, which was suggestive of myelopathy (Fig. 5). Seborrheic dermatitis, alopecia, and candidal infections due to immunological dysfunction are the predominant skin manifestations and our patient had most of these features. Metabolic acidosis resulting in hyperventilation often masquerades as a primary respiratory illness, as in this patient.
Identification of this disorder is important as it can be treated with supplementation of biotin. Lifelong supplementation up to 40 mg/day is needed that results in both clinical and radiological improvement.
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- Frank Y, Ashwal S. Neurologic disorders associated with gastrointestinal diseases, nutritional deficiencies and fluid-electrolyte disorders. In: Swaiman K, Ashwal S, Ferriero D (editors). Pediatric Neurology: Principles and Practice, 4th ed. Philadelphia: Elsevier 2006:2317.
- Enns G, Cowan T, Klein O, Packman S. Aminoacidemias and organic acidemias. In: Swaiman K, Ashwal S, Ferriero D (editors). Pediatric Neurology: Principles and Practice, 4th ed. Philadelphia: Elsevier 2006:590e1.
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