Clinical Presentation of Biotinidase Deficiency in Children
Biotinidase deficiency in children typically presents between 2-5 months of age with seizures, hypotonia, skin rash, and alopecia as the most common initial features, though onset can be delayed until several years of age. 1
Age of Onset and Variability
- Symptoms in untreated patients usually appear between 2 and 5 months of age, but may not manifest until several years later 1
- The clinical presentation is highly variable, even within the same family 1
- Very early presentation can occur as early as 2-3 weeks of age with severe neurological symptoms 2
- Some children develop symptoms only later in childhood or during adolescence 1
Neurological Manifestations (Most Common Initial Features)
Central nervous system abnormalities are frequently the first features to occur: 1
- Seizures occur in more than 70% of clinically ascertained children, typically presenting as generalized tonic-clonic seizures 1, 3, 4
- Hypotonia is present in over 70% of symptomatic cases and often accompanies other neurological findings 1, 4
- Ataxia develops in approximately 50% of affected children 1, 5
- Developmental delay or regression occurs in about half of children 1, 4
Sensory and Visual Impairments
- Hearing loss develops in over 75% of symptomatic children and is irreversible once it occurs, even with biotin treatment 1, 5
- Visual problems affect approximately 50% of children, including optic atrophy, loss of visual acuity, and scotomata 1, 5, 4
- Conjunctivitis is present in about half of affected children 1, 5
Cutaneous Manifestations
- Skin rash appears in more than 70% of symptomatic children prior to diagnosis 1, 5
- Alopecia is present in over 70% of cases and is one of the characteristic early features 1, 5, 4
Biochemical Abnormalities
Untreated individuals may exhibit variable metabolic derangements: 1
- Metabolic ketoacidosis 1, 4
- Lactic acidosis 1, 4
- Hyperammonemia 1
- Elevated urinary excretion of 3-hydroxyisovaleric acid, lactic acid, 3-hydroxypropionic acid, and 3-methylcrotonylglycine 1
- Mildly elevated 3-hydroxyisovalerylcarnitine (C5-OH) on plasma acylcarnitine analysis 1
Important caveat: These metabolic abnormalities are variable, and affected children do not always exhibit ketoacidosis or organic aciduria, whether symptomatic or asymptomatic 1
Atypical Presentations in Older Children
Children with profound biotinidase deficiency who develop symptoms later in childhood or adolescence may present differently: 1
- Motor limb weakness 1
- Spastic paresis 1, 6
- Myelopathy (predominantly spinal cord disease) 1, 6
- Eye problems such as loss of visual acuity and scotomata, rather than the more characteristic symptoms seen in younger children 1
Severity Spectrum
The clinical spectrum ranges widely: 1
- Multiple mild episodes of seizures and ataxia on one end
- Severe metabolic compromise leading to coma or death on the other end 1
Critical Clinical Pitfalls
The most critical pitfall is delayed diagnosis, as hearing loss, visual abnormalities, and degrees of developmental delay are irreversible once they occur, even following initiation of biotin therapy. 1, 5 This makes biotinidase deficiency a medical emergency requiring prompt recognition and treatment. Seizures are often anticonvulsant-resistant until biotin is administered 3, 7, so any infant with refractory seizures plus hypotonia, skin rash, or alopecia should be immediately evaluated for biotinidase deficiency 4, 7.