GPT2 Deficiency

 GPT2 Deficiency

OVERVIEW

GPT2 deficiency (glutamate pyruvate transaminase 2 deficiency) is a genetic, neurological and metabolic disorder that results in intellectual disability and progressive motor dysfunction. This deficiency disrupts important biological processes necessary for proper brain growth. The developing brain relies on the creation and reinforcement of synapses, or connections, between neurons. This disease compromises those connections, resulting in fewer synapses and weaker brain circuits. GPT2 deficiency ultimately hinders brain development, causes metabolic abnormalities including deficiencies in metabolites that protect the nervous system, so patients tend to become more severely affected over time (neurodegenerative course).

SYNONYMS

alanine transaminase 2 (ALT2) deficiency

neurodevelopmental disorder with spastic paraplegia and microcephaly

autosomal recessive intellectual disability associated with GPT2 gene

glutamate pyruvate transaminase 2 deficiency

SYMPTOMS

Individuals with GPT2 deficiency have been reported to have varying levels of intellectual disability. Most affected infants have low muscle tone (hypotonia) at birth and too much muscle tone (hypertonia) later in childhood. Most individuals experience progressive coordination and movement problems, including spastic paraplegia or diplegia around 8-10 years of age. Below is a list of reported and researched symptoms:

• mild, moderate or severe intellectual disability

• global developmental delay

• postnatal microcephaly (small head)

• failure to thrive

• low percentiles for weight and height

• poor feeding, including frequent vomiting

• ataxia (poor muscle control causing clumsy movements)

• apraxia (difficulty performing learned skills or movements)

• dysarthria (muscle disorder causing difficulty speaking)

• hyperreflexia (overactive reflexes)

• oral-motor dysfunction (muscle disorder causing difficulty speaking and eating)

• hypotonia during infancy

• hypertonia later in childhood

• progressive spastic diplegia or paraplegia (weakness or paralysis of legs or lower half of body)

• seizures

CAUSES

GPT2 deficiency is caused by loss-of-function variants (mutations) in the GPT2 gene. This gene codes for the important mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Loss-of-function mutations reduce the capacity of important enzymes and proteins to carry out normal operation, sometimes with total inactivation. The GPT2 gene is expressed in the brain and helps regulate levels of metabolites central to proper development. Metabolites are tiny molecules that are responsible for proper cell growth, defense and function.

The GPT2 enzyme, which is localized to the mitochondria, is responsible for the regulation of important metabolic processes, such as amino acid metabolism and the TCA (tricarboxylic acid) cycle, and is also responsible for encoding a mitochondrial alanine transaminase. Glutamate is a particularly important neurotransmitter as it helps brain cells connect and interact, thereby ensuring proper neuronal development and health. GPT2 deficiency undermines all of these processes, resulting in reduced postnatal brain development as well as cognitive and motor disability.

It is important that intermediates of this cycle are replenished and that the cycle is rebuilt through a process called anaplerosis. When the cycle-building process of anaplerosis is disrupted due to GPT2 deficiency, subsequent metabolic pathways are disrupted as well. There is a chain reaction effect resulting first in altered alanine, reduced TCA cycle intermediates and reduced pyruvate, followed by elevations in glycolytic intermediates and amino acids. These disruptions severely compromise neuronal growth and survival – causing various levels of intellectual disability and developmental delays – and seem to lead to neurodegeneration expressed as progressive spastic paraplegia or diplegia.

GPT2 deficiency is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

AFFECTED POPULATIONS

GPT2 deficiency seems to affect males and females equally. Individuals with this condition are from a variety of countries across the globe and from many different ethnic backgrounds. GPT2 deficiency is currently considered an ultra-rare disease with a very small number of individuals reported with the mutations and it is often unrecognized or misdiagnosed. As genetic testing, specifically whole exome sequencing (WES), becomes more accessible, it will be possible to gain more information about affected populations.

DISORDERS WITH SIMILAR SYMPTOMS

GPT2 deficiency may appear in a differential diagnosis with other disorders that may be defined by intellectual and developmental disability, postnatal microcephaly and spastic paraplegia. This includes several different genetic forms of intellectual disability or complex spastic paraplegias.

DIAGNOSIS

Diagnosis of GPT2 deficiency must be confirmed through genetic testing. The GPT2 gene is included in certain genetic diagnostic panels and whole exome sequencing.

STANDARD THERAPIES

Treatment

While there are no guidelines for the treatment of GPT2 deficiency, standard therapies can address the specific symptoms of this disease. Early intervention is especially important for young children exhibiting symptoms. Ongoing therapies may include but are not limited to physical therapy, occupational therapy, feeding therapy and speech therapy.

Comprehensive interdisciplinary care is helpful for managing symptoms and improving patient outcomes. Specialists that may be consulted include geneticists, gastroenterologists, neurologists, ear nose and throat specialists (ENTs), physical therapists, occupational therapists, feeding and speech pathologists as well as developmental pediatricians. It is important to consult with a pediatrician or primary care physician regarding the treatment of any concerning symptoms.

Genetic counseling is recommended for affected individuals and their family members.

Type of Doctor Department : pediatrician or primary care physician