Manifesting Heterozygotes in APBD
APBD is often caused by a deficiency of glycogen brancher enzyme. This disease is inherited
by an autosomal recessive mode. This means that both copies (or alleles) of the brancher
enzyme gene are mutated (have an error). Since we all have two copies of the brancher
enzyme gene, both parents of an APBD patient are carriers (or heterozygotes) of a mutated
copy but are not affected by the disease since the normal copy of the brancher enzyme gene
protects them. In order to have APBD, both copies of the brancher enzyme have to be
mutated. Therefore, APBD patients inherit one mutated copy from each parent.
The mutations in both copies of the brancher enzyme gene are identified in most APBD
patients. However, using standard methods of gene sequencing, in about 40% of the
patients we can identify only one mutation. A patient with this result is sometimes referred
to as a ‘manifesting heterozygote’. However, such APBD patients have the same degree of
brancher enzyme deficiency and the same disease severity as those with mutations of both
copies of the gene identified. Therefore, according to Dr Salvatore DiMauro’s work, we think
that the other copy, or allele, of the brancher gene is also abnormal but the abnormality
cannot be detected using the common sequencing techniques. The ‘mysterious’ abnormality
of the other copy of the brancher enzyme gene can be either a complete absence (deletion)
of the gene, a mutation in a part of the gene that controls transcription or more likely a
mutation in a part of the gene that is responsible for the assembly of its messenger RNA.
The messenger RNA is the nucleic acid that is “translated” by the cell to make the brancher
enzyme protein. An incorrect assembly of the messenger RNA usually leads to absence of
glycogen brancher enzyme produced by the affected copy of the gene.
Dr. Mochel graduated from the Medical school of the University of Montpellier III, France in 2001 and
received her Doctor of Medicine Degree (M.D.) from University of Paris Descartes in France in 2005.
She subsequently obtained an inter-university diploma in Inborn Errors of Metabolism in 2004 from
the University of Paris Descartes and earned her Master’s Degree in Molecular and Cellular Biology
from the University of Pierre and Marie Curie in Paris in 2006. Dr Mochel is board certified in
genetics. She worked with Dr Schiffmann as a research fellow at the Developmental and Metabolic
Neurology Branch in the National Institute of Neurological Disorders and Stroke at the NIH. She
currently works at the Department of Genetics at La Salpêtrière hospital in Paris and is completing
her PhD in neuroscience at the University of Pierre and Marie Curie.
Dr. Mochel’s research has focused on neurogenetic and neurometabolic disorders. In particular Dr
Mochel has developed new biochemical diagnostic tools using nuclear magnetic resonance
spectroscopy of body fluids in order to identify new complex neurological diseases or biomarkers for
known neurological diseases. Dr Mochel has also built an expertise on energy metabolism in the
brain and developed therapies addressing cerebral energy deficit in inborn errors of metabolism as
well as neurodegenerative diseases such as Huntington disease. Dr. Mochel has authored more than
30 peer-reviewed publications, reviews and book chapters and has presented her research in
numerous national and international meetings.
a