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Nonketotic Hyperglycinemia
Introduction
Nonketotic hyperglycinemia (NKH) is a rare genetic disease secondary to an inborn error of glycine metabolism.[1] Due to a mutation in the glycine cleavage enzyme system, the patient is unable to break down glycine, ultimately resulting in its accumulation throughout the body.[2][3][4] The buildup of glycine primarily occurs within the spinal cord and brain; thus, the initial clinical manifestations and the long-term sequelae from this condition are more often of neurological origin.[1][2][5]
No known interventions are effective in altering the natural history of nonketotic hyperglycinemia, but whatever therapeutic strategies are applied can potentially reduce the comorbidities associated with this condition. It is essential that the clinician recognizes this disease and initiates early evaluation and treatment to attain the best possible outcome.[4]
Etiology
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Etiology
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.[6]
Newer mutations were also reported in recent studies from Chinese and Turkish patients.[7] This is an autosomal recessive hereditary disease that usually presents at a very early age.
Epidemiology
Classic nonketotic hyperglycinemia is a rare disorder with a global incidence of 1 in 76,000.[8] The incidence may range between 1 in 12,000 to 1 in 63,000 cases in newborn babies in certain geographic areas.[9][10] This disease can occur in any population, but it is reportedly seen more frequently in individuals of Finnish descent.[10]
Pathophysiology
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.[11][12] Excessive activation of N-methyl-D-aspartate receptors can result in neuronal and axonal injury as well as potential impairment of neurogenesis.[13][14] Nonketotic hyperglycinemia occurs due to decreased activity of the glycine cleavage enzyme system, which is the system tasked with maintaining the appropriate glycine concentration.[2][3] This results in an accumulation of a significant quantity of glycine throughout the body, primarily within the brain and the spinal cord.[1][5] The pathophysiologic process of nonketotic hyperglycinemia likely begins as early in utero; thus, irreversible glycine-induced brain damage is also likely that has already occurred by the time of the patient symptom presentation.[15]
History and Physical
When a patient presents with signs and symptoms that cause concern for an inborn error of metabolism, the usual systematic approach of good history and physical examination are required.[16] Particular historical features that the clinician should investigate for nonketotic hyperglycinemia include a past medical history and a 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.[16]
Additional questions should focus on developmental delays (expressive language impairment), hyperactivity, and the progression of the patient's clinical manifestations as they become older children.[4][16] It is important to review a patient's family history, particularly for any evidence of stillbirth, unexplained neonatal death, and consanguinity.[16] Nonketotic hyperglycinemia is a disorder that begins in utero and commonly presents with abnormalities that are already present 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 asked directly.[1][17]
Physical examination findings that are suspicious for nonketotic hyperglycinemia are nonspecific but include lethargy and impaired mental status (like encephalopathy).[16] A complete neurologic examination should be performed on these patients. The exam should also focus on the respiratory system (evaluating for apnea, hiccuping, and/or irregular breathing, placing the patient at risk for respiratory failure), as well as a motor exam and an evaluation of muscle tone since patients may be hypotonic.[16]
Nonketotic hyperglycinemia is divided into two forms, severe and attenuated. Patients with severe NKH usually have intractable seizures and present no developmental progress, whereas those with the attenuated form of the disease present with varied developmental progress and no epilepsy (or easily controlled seizures).[18]
Evaluation
For patients with nonketotic hyperglycinemia, a systematic laboratory and diagnostic approach is 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.[16]
These tests are often followed by specialized testing in consultation with a metabolic specialist. For nonketotic hyperglycinemia, measurement of glycine within the plasma and the cerebral spinal fluid (evaluating for an abnormal CSF-to-plasma glycine ratio), a magnetic resonance imaging of the brain (evaluating for diffusion restriction in the infratentorial regions like the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum before the age of 3 months and generalized diffusion restriction of the supratentorial white matter after three months), a brain magnetic resonance spectroscopy, molecular genetic testing, and rarely, analysis of enzymatic activity should be performed, and they can help to establish the diagnosis as well as the extent of the systemic damage.[16][19][20]
If the patient has a seizure activity, additional testing may include an electroencephalogram.[16]
Treatment / Management
There are no effective treatment strategies that alter the natural history of nonketotic hyperglycinemia.[1][21] Thus, treatment focuses on reducing plasma glycine concentration by initiating sodium benzoate therapy and utilizing N-methyl-D-aspartate receptor site antagonists (i.e., dextromethorphan, oral ketamine) to reduce glycinergic stimulation.[21][22][23] These therapies have been shown to improve seizure control and neurodevelopmental outcomes in selected populations with nonketotic hyperglycinemia.[4](B2)
After establishing the diagnosis of nonketotic hyperglycinemia, the patient will require routine developmental assessments, frequent orthopedic evaluation for scoliosis and hip dislocation, especially as they age, and routine ophthalmologic evaluation to determine the presence of cortical blindness.[24][25][26] The patient may develop pulmonary hypertension, thus requiring cardiology evaluation to determine if they would benefit from pharmacological therapy.[27][28] A gastrointestinal referral may be necessary to determine if enteral access is needed for nutrition.[24] These patients often require long-term antiepileptic maintenance therapy with antiepileptic therapy, diet, and special surgical interventions (like vagal nerve stimulator placement).[27](B3)
Differential Diagnosis
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 (for example, hypoglycemia), hypoxia, intracranial hemorrhage, sepsis, thrombosis, neonatal epilepsy syndromes, or congenital brain malformations.[29][30][31][32][33]
During the 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:
- Medications (particularly valproate, which is known to decrease glycine cleavage enzyme system activity)[34]
- Artificial elevation due to laboratory sampling technique[34]
- Starvation[34]
- Use of glycine-containing fluids (i.e., bladder irrigation fluid)[34]
- Transient glycine encephalopathy due to intracerebral hemorrhage or hypoxic-ischemic injury[34][35]
- Transient glycine encephalopathy due to immaturity of the glycine cleavage enzyme system[36]
- Hyperglycinuria (due to defects in the renal transport of glycine, including familial iminoglycinuria or benign hyperglycinuria)[34]
There are inherited metabolic conditions that resemble nonketotic hyperglycinemia, but they have different pathophysiologic mechanisms, and they may require different treatment strategies. These include:
Prognosis
The prognosis depends on the amount of glycine cleavage enzyme system activity.[42] Severe deficiency in this enzyme results in the presentation of the disease during the neonatal period, which is associated with a poor prognosis due to life-threatening apnea.[42][43] In neonates where spontaneous breathing is reestablished, these patients may develop progressive lethargy, encephalopathy, or death. Other patients might be marred by a lifetime of severe developmental impairment and intractable epilepsy.[44][45] Patients who present later in life (defined as three months or later) are more likely to have attenuated glycine cleavage enzyme activity.[42] In those patients, the developmental progress and severity of epilepsy may vary depending on when the disease is recognized and if early treatment is initiated.[4][46]
Complications
When this disease presents in neonates, the patient may develop severe apnea resulting in acute hypoxemic respiratory failure requiring respiratory support.[42][44] In patients where respiratory failure resolves, the patient might likely develop progressive lethargy or encephalopathy. Some patients may live for several years, though death can occur at any time, depending on the severity of the disease.[28][42][44]
In those patients that survive or present later in life (mostly at three months or later), the severity of the disease varies.[42][44] They may be marred by a lifetime of no or limited developmental progress, intractable epilepsy, pulmonary hypertension, dysphagia and gastrointestinal dysmotility requiring surgical enteral access, scoliosis, hip dislocation due to spasticity, and even cortical blindness.[24][25][27][28] Different studies in infants also reported the presence of hydrocephalus [47] that required shunt placement.
Consultations
After the diagnosis of NKH has been made, most patients will benefit from evaluations by different specialists, including but not limited to a neurologist, a pulmonologist, a gastroenterologist, an orthopedic surgeon, and an ophthalmologist. Genetic counseling is essential in an effort also to help the families that have to take care of these patients. In the long run, for patients that survive, physical medicine and rehabilitation specialists should also be consulted to help with recovery from complications and, in particular physical disability, if any. Due to the need for multiple medical services, these patients will benefit from dedicated nursing teams and also social workers who can coordinate the care and alleviate some of the burden from parents and families.
Deterrence and Patient Education
Parents should be counseled on the prognosis of nonketotic hyperglycinemia, particularly the possibility of neurologic impairments in those who survive.[28] In patients who develop long-term epilepsy, the parents should have higher vigilance in situations (i.e., ensure adequate supervision) where the dangers can be compounded if seizure activity occurs.[48]
Genetic counseling may be required to help parents and siblings of a child with nonketotic hyperglycinemia understand the genetic risks to help them make informed future medical and personal decisions.[49]
Enhancing Healthcare Team Outcomes
Diagnosing and managing nonketotic hyperglycinemia require an interprofessional team approach that includes clinicians (including mid-level practitioners), nursing staff, and pharmacists to avoid complications like underrecognition of clinical seizures and ensure 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.[50] [Level 4] Specialists involved in the care of these patients may include:
- The pediatric neurologist should be consulted to evaluate the patient and confirm the diagnosis of seizures.[50] [Level 4]
- A metabolic specialist should be consulted to ensure that the patient receives an appropriate evaluation and initiation of therapy.[51] [Level 4]
- Genetic counseling specialists that the patient’s parents should be referred to determine the genetic risk for medical and personal reasons.[49] [Level 4]
- Pediatric palliative care specialists should be consulted in cases of patients with severe nonketotic hyperglycinemia, as these children have a poor neurologic prognosis, and families might need to get help for a difficult decision to be made about withdrawing critical care support.[28] [Level 4]
Nurses will be crucial in coordinating care between the various clinicians. In cases where anti-epileptic medications are necessary, the pharmacist will consult with clinicians to determine optimal dosing and agent selection and perform medication reconciliation. With this integrated and interprofessional coordination, timely and directed care coordination can improve patient outcomes. [Level 5]
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