Nonketotic hyperglycinemia is a rare, genetic, inborn error of glycine metabolism. Due to a mutation in the glycine cleavage enzyme system, the patient is unable to breakdown glycine, resulting in its accumulation throughout the body. The buildup of glycine primarily occurs within the spinal cord and brain; thus, the initial clinical manifestations and long-term sequelae from this condition are often neurological.
There are no known interventions effective in altering the natural history of nonketotic hyperglycinemia, but there are therapeutic strategies that can reduce the co-morbidities associated with this condition. Thus, the clinician needs to recognize this disease and initiate early evaluation and treatment to try to attain the best possible outcome.
Classic nonketotic hyperglycinemia commonly occurs due to defects in the genes (GLDC and AMT) that encode the protein components of the glycine cleavage enzyme system resulting in decreased enzyme activity.
Classic nonketotic hyperglycinemia is a rare disorder with a global incidence of 1:76,000. In certain geographic areas, the incidence may range between 1:12,000 to 1:63,000 in newborn babies. This disease can occur in any population but is reportedly seen more in individuals with Finnish descent.
Glycine is an amino acid that is primarily an inhibitory neurotransmitter but also serves as a co-agonist (excitation modulator) of N-methyl-D-aspartate (NMDA) (glutamatergic) receptors. Excessive activation of N-methyl-D-aspartate receptors can result in neuronal and axonal injury as well as potentially impair neurogenesis. Nonketotic hyperglycinemia occurs due to decreased activity of the glycine cleavage enzyme system; it is a system tasked with maintaining appropriate glycine concentration. This results in an accumulation of a significant quantity of glycine throughout the body, primarily within the brain and spinal cord. The pathophysiologic process of nonketotic hyperglycinemia likely begins in utero; thus, irreversible glycine-induced brain damage likely has already occurred by the time of patient presentation.
When a patient presents with signs and symptoms concerning for an inborn error of metabolism, the usual systematic approach to history and physical examination are required. Particular historical features that clinician should investigate for nonketotic hyperglycinemia include a past medical history and review of systems that focus on the presence of lethargy, poor feeding, hypotonia, refractory seizures, encephalopathy (particularly if there are unexplained episodes), and apnea (if the patient presents during the neonatal period). It is essential for the clinician to fully investigate the patient's dietary history, growth, and development. In older children, additional questions should focus on developmental delays (expressive language impairment), hyperactivity, and progression of the patient's clinical manifestations. It is important to review a patient's family history, particularly for any evidence of stillbirth, unexplained neonatal death, and consanguinity. Nonketotic hyperglycinemia is a disorder that begins in utero and commonly presents with abnormalities often at birth; thus, the maternal history should be thoroughly reviewed. Inquiries regarding fetal movement, particularly neonatal hiccups, are suspicious for nonketotic hyperglycinemia and should be directly asked.
Physical examination findings that are suspicious for nonketotic hyperglycinemia are nonspecific but include the presence of lethargy and impaired mental status (encephalopathy). A full neurologic examination should be performed in these patients along with particularly focusing on the respiratory system (evaluating for apnea, hiccuping, and/or irregular breathing placing the patient at risk for respiratory failure), motor exam, and tone (which may be hypotonic in patients with nonketotic hyperglycinemia).
For patients with nonketotic hyperglycinemia, a systematic laboratory and diagnostic approach are often undertaken when the patient first presents as the etiology is often unknown. This may include a CBC with differential, blood glucose, electrolytes, blood urea nitrogen, creatinine, uric acid, arterial blood gas, ammonia level, and liver enzymes. These tests are often followed by specialized testing in consultation with a metabolic specialist. For nonketotic hyperglycinemia, measurement of glycine within the plasma and cerebral spinal fluid (evaluating for an abnormal CSF-to-plasma glycine ratio), magnetic resonance imaging of the brain (evaluating for diffusion restriction in the infratentorial regions (posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, cerebellum) before the age of 3 months and generalized diffusion restriction of the supratentorial white matter after 3 months; brain magnetic resonance spectroscopy; molecular genetic testing; and rarely, analysis of enzymatic activity. If the patient has a seizure activity, additional testing may include an electroencephalogram.
There are no effective treatment strategies that alter the natural history of nonketotic hyperglycinemia. Treatment is thus focused on reducing plasma glycine concentration by initiating sodium benzoate and utilizing N-methyl-D-aspartate receptor site antagonists (i.e., dextromethorphan, oral ketamine) to reduce glycinergic stimulation. These therapies have resulted in an improvement in seizure control and neurodevelopmental outcomes in selected populations with nonketotic hyperglycinemia.
After establishing the diagnosis of nonketotic hyperglycinemia, the patient will require routine developmental assessments, orthopedic evaluation for scoliosis and hip dislocation as they age, and routine ophthalmologic evaluation to determine the presence of cortical blindness. The patient may develop pulmonary hypertension, thus requiring cardiology evaluation to determine if the patient requires pharmacological therapy. A gastrointestinal referral may be necessary to determine if enteral access is needed for nutrition. These patients often need long-term antiepileptic maintenance therapy with antiepileptic therapy, diet, and surgical interventions (i.e., vagal nerve stimulator).
The clinical manifestations guide the differential diagnosis of this condition during the presentation. Inborn errors of metabolism do not represent the most common cause of confirmed seizures or encephalopathy. Thus, the clinician should first consider acute metabolic disturbances (i.e., hypoglycemia), hypoxia, intracranial hemorrhage, sepsis, thrombosis, neonatal epilepsy syndromes, congenital brain malformations.
During newborn screening or when a clinician suspects an inborn error of metabolism, laboratory features of nonketotic hyperglycinemia may be present. The following conditions, therefore, must be differentiated from nonketotic hyperglycinemia. These include:
There are inherited metabolic conditions that resemble nonketotic hyperglycinemia, but have different pathophysiologic mechanisms and may require different treatment strategies. These include:
Prognosis is dependent on the amount of glycine cleavage enzyme system activity. Severe deficiencies in this enzyme result in the presentation during the neonatal period, which is associated with a poor prognosis due to life-threatening apnea. In neonates where spontaneous breathing is reestablished, these patients may develop progressive lethargy, encephalopathy, and death. Others are marred by a lifetime of severe developmental impairment and intractable epilepsy. Patients who present later in life (3 months or later) likely have attenuated glycine cleavage enzyme activity. There developmental progress and severity of epilepsy vary depending on when it is recognized and if early treatment is initiated.
When this disease presents in neonates, the patient may develop severe apnea resulting in acute hypoxemic respiratory failure requiring respiratory support. In patients where respiratory failure resolves, the patient will likely develop progressive lethargy, encephalopathy. Some patients may live for several years though death can occur depending on the severity of the disease. In those that survive or present later in life (3 months or later), the severity of the disease varies. They may be marred by a lifetime of no or limited developmental progress, intractable epilepsy, pulmonary hypertension, dysphagia, and dysmotility requiring surgical enteral access, scoliosis, and hip dislocation due to spasticity, cortical blindness.
Parents should be counseled on the prognosis of nonketotic hyperglycinemia, particularly the possibility of neurologic impairments in patients who survive.
In patients who develop long-term epilepsy, the parents should have higher vigilance in situations (i.e., ensure adequate supervision) where if seizure activity occurs, the dangers can be compounded.
Genetic counseling may be required to help parents and siblings of a child with nonketotic hyperglycinemia understand the genetic risks to help make informed future medical and personal decisions.
The diagnosis and management of nonketotic hyperglycinemia require an interprofessional approach to avoid the complications from underrecognition of clinical seizures and ensuring that early and proper diagnostic testing is performed.
Referral to critical care services (neonatal or pediatric) should be performed early to place the patient under the care of neurocritical care experts and to ensure that the patient is stabilized from a neurocritical care standpoint. [Level 4]
Pediatric neurology should be consulted to evaluate the patient and confirm the diagnosis of seizures. [Level 4]
A metabolic specialist should be consulted to ensure the patient receives an appropriate evaluation and initiation of therapy. [Level 4]
The patient’s parents should be referred to genetic counseling to determine the genetic risk for medical and personal reasons. [Level 4]
Finally, patients with severe nonketotic hyperglycinemia should be referred to a pediatric palliative care specialist as these children have a poor neurologic prognosis, and families may let to withdraw critical care support. [Level 4]
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