نقص البيوتينيداز

مقدمة

Synonyms: late-onset multiple carboxylase deficiency

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

Multiple carboxylase deficiency was described in 1971 and causes problems in the neonatal period. BTD deficiency presents in infancy.¹

التسبب في المرض¹²

Biotin is used in the synthesis of the carboxylase enzymes pyruvate carboxylase, propionyl-coenzyme A (CoA) carboxylase, beta-methylcrotonyl-CoA carboxylase and acetyl-CoA carboxylase. In order to function, these enzymes need to be bound with biotin, which is subsequently cleaved off by BTD. Lack of BTD prevents this cleavage and leads to biotin deficiency.

Severe or partial deficiency of BTD is termed late-onset multiple carboxylase deficiency: strictly speaking, a separate biochemical entity because the early-onset form seen in neonates is thought to be due to a deficiency of another enzyme, another biotin-responsive biochemical abnormality, holocarboxylase synthetase deficiency . It causes a wide spectrum of disorder but, if recognised early, these problems can be avoided with oral supplementation.

Mutations in the BTD gene cause BTD 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 BTD is localised at 3p25.

علم الأوبئة

Incidence is less than 1 in 60,000 babies - no more than 12 cases per year.³ The carrier frequency in the general population is 1 in 120.⁴

عرض¹²

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.⁵

Untreated children with partial biotinidase (BTD) deficiency do not exhibit symptoms unless they are stressed, eg by prolonged infection.⁶

• Gastroenterological:
  

  • Feeding difficulties

  • التقيؤ

  • إسهال

  • تضخم الكبد

  • Splenomegaly

• الجهاز التنفسي:
  

  • Laryngeal stridor

  • تسرع التنفس

  • Apnoea

• عصبي:
  

  • ضمور العصب البصري (visual loss)

  • Hypotonia

  • Seizures⁷

  • Ataxia

  • Developmental delay

  • Neuropathy

  • Sensorineural deafness

  • Bulbar palsies

  • Spastic paraparesis (rarely)

• Dermatology:
  

  • الثعلبة

  • Perioral or perianal dermatitis

  • Recurrent and chronic fungal infections

التشخيص التفريقي¹⁴

• التهاب السحايا.

• تعفن الدم.

• Isolated carboxylase deficiency.

• Holocarboxylase synthetase deficiency.

• Other causes of ataxia.

• Other causes of sensorineural hearing loss.

التحقيقات¹⁴

• FBC, U&E, creatinine, LFTs, ± blood gases, urinalysis (for organic acids and ketones).

• Biotinidase (BTD),⁸ carnitine, and acylcarnitine levels.

• MRI (demonstrates cerebral oedema, cerebral atrophy, low attenuation of white matter).

• CT scan may be necessary if MRI is equivocal.

• Ophthalmological and audiological assessment ± auditory evoked potentials.

• Pre-treatment EEG may show characteristic changes but may be normal after treatment.

الإدارة¹⁹

• All patients with less than 10% biotinidase (BTD) activity should receive biotin supplements. British National Formulary for Children (BNFC) recommended doses are:¹⁰

  • Neonate: 5 mg once daily, usual maintenance 10-50 mg daily, higher doses may be required.

  • 1 month-18 years: 10 mg once daily, usual maintenance 10-50 mg daily but up to 100 mg daily may be required.

• Treatments may also be required for developmental delay, spasticity and bulbar dysfunction. Newer treatments for spasticity and خلل التوتر العضلي associated with inborn errors of metabolism have been reported, including intrathecal baclofen and neurotoxins.

التكهن¹

If the condition is treated promptly, no symptoms may arise. Delayed treatment may result in neurological complications, including mental retardation, seizures and coma. Profound biotinidase (BTD) deficiency may result in death if untreated and the condition should be considered in cases of sudden infant death syndrome; seizure or brain stem dysfunction is thought to be the cause.

الفحص⁵

فحص حديثي الولادة on blood spot would be straightforward to perform but is associated with substantial cost. The UK National Screening Committee decided in 2009 that the incidence was too low to recommend national screening. This decision is due to be reviewed.⁵ However, the authors of a Welsh study pointed out that less than one patient a year is diagnosed with biotinidase (BTD) deficiency. Even when restricting the patient population to those suffering from developmental delay, screening is not justified.¹¹