Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis.
OBJECTIVE
To search for biochemical and molecular markers for the diagnosis of patients and carriers with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency.


METHODS
Organic acids in urine, MHBD activity in fibroblasts, immunoblotting and molecular studies were performed in seven patients. Seven carriers were also studied.


RESULTS
Under low protein diet or poor feeding all the patients showed only a slightly altered organic acid profile. Measurement of 2-methyl-3-hydroxybutyric acid and tiglylglycine after an isoleucine loading test, failed to demonstrate the carrier status of one patient. However, measurement of 2-ethylhydracrylic acid (EHA) was positive in all the carriers tested. MHBD activity was clearly deficient in males and in one female patient. We identified four missense mutations, two of them were novel.


CONCLUSIONS
Quantification of EHA may be of help for the diagnosis of the heterozygous condition. The carrier females showed the classical biochemical variability of X-linked diseases due to random X-chromosome inactivation.
García-Villoria
Judit
J
Sección de Errores Congénitos del Metabolismo (IBC), Servicio de Bioquímica y Genética Molecular, and CIBER de Enfermedades Raras, Hospital Clínic, Barcelona, Spain.
Navarro-Sastre
Aleix
A
Fons
Carme
C
Pérez-Cerdá
Celia
C
Baldellou
Antonio
A
Fuentes-Castelló
Miguel Angel
MA
González
Inmaculada
I
Hernández-Gonzalez
Arturo
A
Fernández
Cristina
C
Campistol
Jaume
J
Delpiccolo
Carina
C
Cortés
Nuria
N
Messeguer
Angel
A
Briones
Paz
P
Ribes
Antonia
A
D015094:3-Hydroxyacyl CoA Dehydrogenases; D000429:Alcohol Oxidoreductases / Q000172:deficiency*; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006885:Hydroxybutyrates / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D014631:Valerates / Q000378:metabolism
D006885:Hydroxybutyrates; D014631:Valerates; C003603:tiglylglycine; C007674:2-ethylhydracrylic acid; C016579:2-methyl-3-hydroxybutyric acid; D000429:Alcohol Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; C419903:2-methyl-3-hydroxybutyryl-coenzyme A dehydrogenase; D005998:Glycine