Precision therapies for life-threatening ultra-rare genetic diseases in children

Project status: Active

Research areas: Genomic Medicine > Brain and Mitochondrial

Developing personalised medicines using genomics, stem cells and drug screening to restore brain function in children with specific ultra-rare, life-threatening genetic disorders.

Image: Dr Nicole Van Bergen, Team Leader, Brain and Mitochondrial Research

The challenge

Each year, around 15,000 Australian children are born with ultra-rare genetic diseases. Among these, TRAPPC4 deficiency, CDKL5 Deficiency Disorder (CDD) and NAXD deficiency are particularly devastating. Our team led the gene discovery for both NAXD and TRAPPC4 in 2019.

CDKL5 Deficiency Disorder (CDD)

CDD affects up to 1 in 40,000 births. CDD is a rare, severe neurological condition caused by genetic errors in the CDKL5 gene on the X-chromosome This condition causes:

Drug-resistant epilepsy
Severe intellectual disability
Dementia
Profound mobility issues

TRAPPC4 deficiency, or NEDESBA

Genetic coding mistakes in a gene called TRAPPC4 causes an ultra-rare and severe condition in young children that affects brain function. This condition is also called NEDESBA which stands for Neurodevelopmental Disorder with Epilepsy, Spasticity, and Brain atrophy.

TRAPPC4 deficiency is a rare neurodevelopmental condition characterised primarily by progressive brain damage. To date, the majority of the affected children with TRAPPC4 genetic errors have some or all of the following clinical features:

Seizures or fits
Slower learning of skills (developmental delay)
Smaller brain and head size (microcephaly)
Problems with limb movements
Facial appearance different to other family members (dysmorphism)

CDD and TRAPPC4 deficiency are devastating conditions that have health impacts comparable to quadriplegia, but treatment options are limited.

NAXD deficiency or PEBEL2

NAXD deficiency, also known as early-onset brain edema and/or leukoencephalopathy-2 (PEBEL2),is an ultra-rare neurometabolic genetic condition. Generally, affected individuals are born healthy, with disease progression being triggered by what would normally be a common fever associated childhood illness, or apparently minor injury/ trauma.

There are two main clinical subtypes of PEBEL2.

Affected individuals with the main clinical subtype present with a rapidly deteriorating brain condition, skin blisters, loss of bodily movement and seizures. Individuals with the major clinical subtype generally have rapid disease progression that is fatal in the majority of individuals.
Affected individuals with the less common clinical subtype present with a range of heart problems, some muscle weakness, numbness or pain. Generally, these individuals have a less severe condition and less aggressive disease.