What is the presentation and management of biotinidase deficiency in children with cerebellar ataxia?

Presentation of Biotinidase Deficiency with Cerebellar Ataxia in Children

Ataxia occurs in approximately 50% of children with biotinidase deficiency and typically presents alongside other neurological symptoms between 2-5 months of age, though onset can be delayed until several years. 1

Clinical Presentation Pattern

Neurological Features

• Ataxia is part of a constellation of CNS symptoms that frequently appear first in biotinidase deficiency, with over 70% of symptomatic children exhibiting seizures, hypotonia, skin rash, or alopecia prior to diagnosis 1
• The ataxia can range from mild episodic episodes to severe progressive cerebellar dysfunction that may lead to metabolic compromise, coma, or death if untreated 1
• Episodic ataxia may be the initial presenting feature before progressing to persistent ataxia over weeks to months 2
• Approximately half of affected children develop ataxia along with developmental delay, conjunctivitis, and visual problems including optic atrophy 1

Associated Neurological Findings

• Seizures (present in >70% of symptomatic cases) - typically generalized tonic-clonic 1, 3
• Hypotonia - commonly accompanies ataxia 1
• Developmental delay or regression - occurs in approximately 50% 1
• Sensorineural hearing loss - develops in over 75% of symptomatic children and is often irreversible even with treatment 1, 4
• Visual abnormalities - including optic atrophy, loss of visual acuity, and scotomata 1

Cutaneous and Other Features

• Skin rash and alopecia - present in >70% of symptomatic cases 1
• Conjunctivitis - occurs in approximately 50% 1
• Dermatitis - may be prominent 5

Biochemical Abnormalities

• Metabolic ketoacidosis, lactic acidosis, and/or hyperammonemia may be present but are variable 1
• Elevated urinary organic acids including 3-hydroxyisovaleric acid, lactic acid, 3-hydroxypropionic acid, and 3-methylcrotonylglycine 1
• Important caveat: Symptomatic children do not always exhibit ketoacidosis or organic aciduria, so normal metabolic studies do not exclude the diagnosis 1, 2

Age-Related Presentation Variations

Infants and Young Children (2-5 months typical)

• Classic presentation with ataxia, seizures, hypotonia, and cutaneous findings 1

Older Children and Adolescents

• Atypical presentation with motor limb weakness, spastic paresis, and eye problems rather than the classic triad 1
• May present with myelopathy with or without vision abnormalities 1

Critical Management Principles

Immediate Treatment

• All symptomatic children with profound biotinidase deficiency must receive pharmacological doses of biotin at 5-20 mg daily 1, 6
• Ataxia resolves within hours to days of biotin initiation, making this a medical emergency requiring prompt diagnosis 1
• Seizures also resolve within hours to days, while cutaneous manifestations resolve within weeks 1

Prognosis and Irreversible Damage

• Hearing loss, visual abnormalities, and degrees of developmental delay are irreversible once they occur, even with biotin therapy 1
• Early treatment before symptom onset prevents all manifestations, including ataxia 6, 4
• Treatment delay is associated with permanent neurological damage, mental retardation, ataxia, paraparesis, and deafness 3

Lifelong Treatment Requirement

• Biotin therapy must be lifelong - children who discontinue therapy (intentionally or unintentionally) develop symptoms within weeks to months 1, 6
• Compliance monitoring is essential to prevent symptomatic relapse 6

Diagnostic Approach

When to Suspect Biotinidase Deficiency

• Any child presenting with episodic or progressive ataxia should be evaluated for biotinidase deficiency, even without typical cutaneous findings or organic aciduria 2
• Consider in children with ataxia plus any combination of seizures, hypotonia, developmental delay, hearing loss, or visual problems 1

Confirmatory Testing

• Serum biotinidase enzyme activity measurement is the gold standard using colorimetric biotin-4-amidobenzoic acid substrate method 6
• Profound deficiency defined as <10% of mean normal serum activity 1, 6
• Molecular testing can identify specific mutations and distinguish profound from partial deficiency 6

Key Clinical Pitfall

The most critical error is delayed diagnosis and treatment initiation - ataxia and seizures are rapidly reversible with biotin, but hearing loss, optic atrophy, and developmental delays become permanent if treatment is delayed 1, 4, 2. Therefore, biotinidase deficiency should be in the differential diagnosis of any child with unexplained ataxia, particularly when accompanied by other neurological symptoms, regardless of whether metabolic abnormalities or skin findings are present 2.