MEN (General Swiss-German Mennonite)

Inheritance: autosomal recessive
Genes: BTD

Multiple carboxylase deficiency
BTD deficiency

Seizures
Hypotonia
Alopecia
Ataxia
Mental regression
Hearing loss
Optic atrophy
Dermatitis 

Biotin (Biotinidase) Deficiency

Clinical Characteristics

General description (for patients): 

Patients with this disorder have skin rashes, loss of hair, weak muscles and developmental delays. Seizures, hearing loss, vision loss, and unsteadiness may also occur.  Onset can be as early as the first month of life but not all patients have all signs.  Adults without symptoms have also been identified.  Early diagnosis is important since treatment with oral biotin can be highly effective.


Medical description: 

This disorder has both cutaneous and neurological manifestations.  Erythematous dermatitis, alopecia, hypotonia, mental regression and seizures are common and onset may be as early as the first month of life. Asymptomatic adults have also been identified.  Hearing loss and optic atrophy has also been observed.  High levels of 3-hydroxyisovaleric acid, beta-methylcrotonylglycine, and 3-hydroxypropionic acid may be present in the urine. Lactic acidosis, acute and intermittent ataxia and susceptibility to infections have been reported.  In fact, milder cases may not become symptomatic until stressed by a systemic infection.  Newborn screening programs are available.

Genetics: 

Biotin is an essential cofactor in all carboxylase reactions.  Biotin deficiency caused by a mutation(s) in the biotinidase gene (BTD) located on chromosome 3 (3p25) causes a late-onset multiple carboxylase deficiency.  It has been found among Mennonites in Pennsylvania.  (There is also an early onset form (#253270) resulting from a mutation in the holocarboxylase synthetase gene (HLCS) resulting in failure to utilize biotin).

Treatment:  

Oral biotin can lead to dramatic improvement in both clinical symptoms and metabolic imbalances. The latter can be demonstrated in cultured fibroblasts.  Treatment is recommended for all patients with biotin activity below 10%. 
PROGNOSIS: Variable depending on age at diagnosis and treatment.  Untreated asymptomatic adults have been reported.

Ancillary treatments and support:

Prompt treatment of infections is recommended.  Permanent neurologic damage needs to be managed with support and physical therapy.

Specialists and specialty centers: 

Pediatrician, neurologist, dermatologist.

References:

Wolf, B., Heard, G.S., Weissbecker, K.A., Secor McVoy, J.R., Grier, R.E., and Leshner, R.T.:  Biotinidase deficiency: initial clinical features and rapid diagnosis.  Ann. Neurol. 18: 614-617, 1985.  PubMed ID: 4073853

Swango, J,K, Demirkol, M., Huner, G., Pronicka, E., Sykut-Cegielska, J. Schulze, A., and Wolf, B.:  Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene.  Hum. Genet. 102: 571-575, 1998.  PubMed ID: 9654207

Suormala, T.M., Baumgartner, E.R., Wick, H., Scheibenreiter, S., and Schweitzer, S:  Comparison of patients with complete and partial biotinidase deficiency: biochemical studies.  J. Inherit. Metab. Dis. 13: 76-92, 1990.  PubMed ID: 2109151

Hymes, J., Stanley, C.M., and Wolf, B.:  Mutations in BTD causing biotinidase deficiency.  Hum. Mutat. 18: 375-381, 2001.  PubMed ID: 11668630

Resources:

Biotinidase Deficiency Family Support Group
 
Associated Graphics