Synonyms: Late onset multiple carboxylase deficiency

Biotinidase (BTD) is a widely distributed enzyme involved in recycling biotin. This is an essential water-soluble vitamin co-factor, sometimes called vitamin H, used by human carboxylase enzymes in the metabolism of fats, carbohydrates and proteins.

Pathogenesis

Severe or partial deficiency of biotinidase causes late-onset multiple carboxylase deficiency, which causes a wide spectrum of disorders, but if recognised early these problems can be avoided with oral supplementation.

Mutations in the BTD gene cause biotinidase deficiency. Many mutations that cause the enzyme to be nonfunctional or to be made at extremely low levels have been identified. It is inherited as an autosomal recessive condition. The gene that encodes biotinidase is localised at 3p25.¹

Epidemiology

Incidence is less than 1 in 60,000 babies - no more than 12 cases per year.²

Presentation

Usually presents aged 1 week to 2 years (earlier onset carboxylase deficiency is more likely to be caused by holocarboxylase synthetase deficiency). About half the cases are only mildly affected.³
Untreated children with partial biotinidase deficiency do not exhibit symptoms unless they are stressed eg by prolonged infection.⁴

• Gastroenterological:
  • Feeding difficulties
  • Vomiting
  • Diarrhoea
  • Hepatomegaly
  • Splenomegaly
• Respiratory:
  • Laryngeal stridor
  • Tachypnoea
  • Apnoea
• Neurological:
  • Optic atrophy (visual loss)
  • Hypotonia
  • Seizures
  • Ataxia
  • Developmental delay
  • Neuropathy
  • Sensorineural deafness
  • Bulbar palsies
  • Spastic paraparesis (rarely)
• Dermatology:
  • Alopecia
  • Peri-oral or peri-anal dermatitis
  • Recurrent and chronic fungal infections

Differential diagnosis

• Meningitis
• Sepsis

Investigations

• FBC, U&E, creatinine, LFT, ±blood gases, urinalysis (for organic acids and ketones)
• Biotinidase, carnitine, and acylcarnitine levels
• MRI (demonstrates cerebral oedema, cerebral atrophy, low attenuation of white matter)
• Ophthalmological and audiological assessment ±auditory evoked potentials

Management

All patients with less than 10% biotinidase activity should receive biotin supplements.⁵

• Dietary supplementation e.g. oral biotin 10 mg daily. Some patients require higher dosages - up to 40 mg/d.^3,6
• Treatments may also be required for developmental delay, spasticity, and bulbar dysfunction. Newer treatments for spasticity and dystonia associated with inborn errors of metabolism have been reported, including intrathecal baclofen and neurotoxins.

Screening

Newborn screening on blood spot would be straightforward to perform.
Incidence considered too low for the UK National Screening Committee to recommend at present.⁷In a population of 700,000 births per year, the number of potentially adverse events that a national screening programme could prevent would be 3-43.⁸