Nonketotic Hyperglycinemia: Symptoms, Types, Causes and Treatment

Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare but serious inherited metabolic disorder. It disrupts how the body processes glycine, a vital amino acid, leading to its accumulation in tissues and especially in the brain. This buildup has profound neurological consequences. In this comprehensive article, we explore the symptoms, types, causes, and treatment options for NKH, providing a clear and detailed overview based on current research evidence.

Symptoms of Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia affects individuals differently, but its hallmark is the excessive accumulation of glycine, causing a range of neurological and developmental symptoms. Recognizing these symptoms early is crucial for prompt diagnosis and management.

Symptom	Age of Onset	Severity/Outcome	Source(s)
Lethargy	Neonatal	Progressive, can lead to coma	3 5
Hypotonia	Neonatal	Weak muscle tone, severe in classic NKH	3 5
Seizures	Neonatal/Infant	Difficult to control; refractory	3 5 7 10 11
Apnea/Breathing	Neonatal	Life-threatening, central apnea	3 5
Feeding Difficulty	Neonatal/Infant	Poor sucking, failure to thrive	3 5
Developmental Delay	Neonatal/Infant	Profound, often do not reach milestones	3 5 7 10
Spasticity	Later Infancy	Abnormal muscle stiffness	3 5
Behavioral Issues	Infant/Late	Heterogeneous, especially in attenuated	2 10

Table 1: Key Symptoms

Overview of Common Symptoms

NKH typically presents in the first days or weeks of life, especially in its classic (severe) form. The most common early symptoms are lethargy (extreme sleepiness), weak muscle tone (hypotonia), feeding difficulties, and seizures that are often resistant to standard treatments. Many infants develop life-threatening breathing problems, such as central apnea, which can lead to rapid decline or death if not managed promptly 3 5.

In children who survive the neonatal period, severe developmental delays become evident. These children often do not achieve basic milestones like sitting up, grabbing objects, or drinking from a bottle. Over time, they may lose previously acquired skills. Spasticity (increased muscle tone and stiffness) and refractory seizures are frequent, further impairing quality of life 3 5 7.

Symptom Progression and Variation

• Classic (Severe) NKH: Symptoms are most pronounced and appear within days of birth. Nearly all affected infants show progressive encephalopathy, with myoclonic jerks, hiccups, and frequent apnea. Many die in the neonatal period; survivors face profound disability 3 5 7.
• Attenuated (Milder) Forms: Some children have a less severe disease course. Symptoms may appear later and be less intense, with variable developmental delay, behavior problems, and uncoordinated movements 2 10.
• Atypical Variants: These may present with more heterogeneous symptoms, including behavioral abnormalities and psychiatric manifestations, especially in late-onset forms 2 10.

Impact on Brain Development

Brain imaging studies show that NKH primarily affects brain growth, with the corpus callosum (a major brain structure connecting the two hemispheres) being notably underdeveloped in severe cases. While microspongiosis (tissue changes seen on MRI) is common, it does not predict severity 7.

Types of Nonketotic Hyperglycinemia

NKH is not a single, uniform disease. Instead, it encompasses several types, classified by age at onset, clinical severity, and underlying genetic mechanisms. Recognizing the type is essential for prognosis and management.

Type/Variant	Onset	Clinical Features	Source(s)
Classic/Severe	Neonatal	Profound encephalopathy, poor outcome	2 3 5 6
Attenuated	Neonatal/Infant	Milder delays, possible milestones	2 3 6 10
Atypical	Neonatal-Late	Variable, behavioral/psychiatric signs	2 4 10
Variant (Enzyme Def.)	Variable	Spastic paraplegia, optic atrophy	1

Table 2: Types of Nonketotic Hyperglycinemia

Classic (Severe) NKH

The classic form is the most common and most severe. It usually presents in the first days of life with rapidly worsening neurological symptoms: lethargy, hypotonia, seizures, apnea, and often death or profound disability. Most children do not achieve developmental milestones and may lose skills over time 3 5 6.

Attenuated (Milder) NKH

The attenuated form generally manifests later than the classic type and is less severe. Children may develop symptoms in infancy, such as developmental delays and seizures, but some attain limited milestones, and the overall prognosis is better. Early diagnosis and intervention can improve outcomes, especially if some residual enzyme activity is present 2 3 10.

Atypical Variants

Atypical NKH includes neonatal, infantile, and late-onset forms, each with differing presentations. Neonatal atypical NKH resembles the classic form but has a significantly better outcome. Infantile and late-onset forms may present with mental retardation, behavioral issues, or movement disorders, and are more heterogeneous in presentation 2 4 10.

Variant NKH (Enzyme Cofactor Deficiencies)

A subset of patients have "variant NKH," which is not due to mutations in the main glycine cleavage system genes but to defects in genes involved in lipoate synthesis or iron-sulfur cluster biogenesis (e.g., LIAS, BOLA3, GLRX5). These patients may have symptoms such as spastic paraplegia, optic atrophy, neurodegeneration, leukodystrophy, and sometimes cardiac involvement. The clinical course is variable and depends on the specific gene affected 1.

Causes of Nonketotic Hyperglycinemia

Understanding the causes of NKH is vital for diagnosis, genetic counseling, and ongoing research into potential therapies. NKH is fundamentally a disorder of glycine metabolism, mostly due to inherited genetic mutations affecting specific enzymes.

Cause/Mechanism	Gene(s) Involved	Inheritance Pattern	Source(s)
Glycine cleavage system defect	GLDC, AMT, GCSH	Autosomal recessive	5 6 8 9
Variant lipoate synthesis defect	LIAS, BOLA3, GLRX5	Autosomal recessive	1
Unknown (atypical late-onset)	?	?	2

Table 3: Genetic Causes

The Glycine Cleavage System

The main cause of NKH is a defect in the glycine cleavage system (GCS), a multi-enzyme complex responsible for breaking down glycine. This complex consists of four proteins (P, H, T, L) encoded by different genes:

• GLDC (P-protein): The most common site of mutation, accounting for about 80% of cases 6 9.
• AMT (T-protein): The second most frequent site of mutation 6 8.
• GCSH (H-protein): Rarely involved.
• L-protein: Very rarely implicated 6 8.

Mutations in any of these genes impair the breakdown of glycine, resulting in its accumulation in the body—most significantly in the central nervous system. The inheritance is autosomal recessive, meaning both copies of the gene must be mutated for the disease to manifest 5 6 8 9.

Variant Forms: Lipoate and Iron-Sulfur Cluster Deficiency

Some patients with clinical and biochemical features of NKH do not have mutations in the main GCS genes. Instead, they may have defects in genes responsible for producing cofactors necessary for GCS function, such as lipoate or components of iron-sulfur clusters. Key genes include:

• LIAS (lipoate synthase)
• BOLA3 (BolA family member 3)
• GLRX5 (glutaredoxin 5)

These variant forms present with unique features, such as spastic paraplegia and optic atrophy, and may have a slightly different clinical course 1.

Genetic Diversity and Population Differences

There are hundreds of unique mutations described worldwide, with some populations (e.g., Finns) having a high prevalence due to founder mutations 6 9. In some cases, residual enzyme activity from certain mutations can lead to milder (attenuated) phenotypes 2 10.

Unresolved Causes

In late-onset atypical NKH, the precise cause of glycine elevation is not always known, and research is ongoing 2.

Treatment of Nonketotic Hyperglycinemia

While there is currently no cure for NKH, early and aggressive treatment can improve outcomes, particularly in milder (attenuated) forms. Management focuses on reducing glycine levels and blocking its neurotoxic effects.

Treatment Option	Mechanism/Goal	Effectiveness	Source(s)
Sodium benzoate	Binds glycine, promotes excretion	Reduces plasma glycine; some benefit	10 11 12
Dextromethorphan	NMDA receptor antagonist	Seizure reduction; variable outcomes	10 11 12 13
Ketamine	NMDA receptor antagonist	Some improvement in select cases	14
Early intervention	Start therapy in neonatal period	Better developmental outcomes	10 13
Supportive care	Seizure control, respiratory support	Essential for survival	3 5 13
Experimental treatments	Lipoate supplementation, etc.	Not yet successful	1

Table 4: Treatment Options

Mainstay Therapies

• Sodium Benzoate: This compound binds to glycine, facilitating its excretion in urine. It is consistently shown to reduce plasma glycine levels and can lead to improved alertness and, in some cases, seizure reduction. However, it is less effective in reducing central nervous system (CSF) glycine, which is critical for neurological outcomes 10 11 12.
• Dextromethorphan: An NMDA receptor antagonist, it blocks the excitatory effects of glycine in the brain. Dextromethorphan can help control seizures and improve arousal, though its effectiveness varies between patients 11 12 13.
• Ketamine: Another NMDA antagonist, ketamine has been used in isolated cases with some improvement seen in neurological symptoms 14.

Importance of Early Diagnosis and Intervention

• Early Initiation: Starting treatment in the neonatal period, especially in children with some residual enzyme activity (attenuated forms), significantly improves developmental outcomes and reduces the likelihood of seizures 10 13.
• Aggressive Management: Normalizing plasma glycine levels and early seizure control are linked to better adaptive behavior and higher developmental quotients in affected children 10.

Supportive and Adjunctive Therapies

• Seizure Management: Seizures in NKH are often refractory and require careful management with anti-epileptic drugs, in addition to NMDA antagonists 3 5 11.
• Respiratory and Nutritional Support: Many infants require intensive care to manage apnea and feeding difficulties 3 5 13.

Experimental and Investigational Approaches

• Lipoate Supplementation: In variant NKH due to lipoate deficiency, efforts to supplement lipoate have so far been unsuccessful in correcting the underlying enzyme deficiency 1.
• Gene Therapy and Novel NMDA Blockers: These are areas of active research but not yet available for clinical use 1 13 14.

Prognosis and Long-term Management

Despite treatment, many children with classic NKH have severe neurological impairment. Outcomes are better in attenuated and variant forms, especially with early diagnosis and intervention 3 5 10 11 13. Genetic counseling is vital for affected families, including the possibility of prenatal diagnosis in known cases 4 8.

Conclusion

Nonketotic hyperglycinemia is a complex and challenging disorder with a spectrum of clinical presentations. Prompt recognition and early intervention are crucial for optimizing outcomes, especially in milder forms. Ongoing research is expanding our understanding of its genetic and biochemical diversity, paving the way for more targeted therapies in the future.

Main Points:

• NKH is a rare inherited disorder causing glycine accumulation and severe neurological symptoms.
• Symptoms include lethargy, hypotonia, seizures, apnea, feeding difficulties, and profound developmental delays.
• Types include classic (severe), attenuated (milder), atypical, and variant forms, each with distinct clinical and genetic features.
• Most cases result from mutations in the glycine cleavage system genes (GLDC, AMT, GCSH); some variants are linked to cofactor synthesis defects (LIAS, BOLA3, GLRX5).
• Treatment focuses on reducing glycine levels (sodium benzoate) and blocking neurotoxicity (dextromethorphan, ketamine), with best outcomes seen when started early.
• Prognosis remains poor in classic NKH, but early and aggressive therapy can improve the quality of life and development in attenuated and variant forms.

Understanding NKH requires a multidisciplinary approach involving clinicians, geneticists, and researchers, aiming for improved diagnostics, counseling, and, ultimately, more effective treatments.