What is the probable diagnosis for a 45-day-old male baby presenting with lethargy, hypoglycemia, seizures, and cerebral venous thrombosis (CVT)?

Probable Diagnosis: Inborn Error of Metabolism (Nonketotic Hyperglycinemia) with Secondary Cerebral Venous Thrombosis

The most probable diagnosis in this 45-day-old male infant presenting with lethargy, hypoglycemia, seizures, and cerebral venous thrombosis is an underlying inborn error of metabolism, specifically nonketotic hyperglycinemia (NKH), with CVT as a secondary complication.

Clinical Reasoning

Why Metabolic Disease is the Primary Diagnosis

• Nonketotic hyperglycinemia is an autosomal recessive error of glycine metabolism that characteristically presents in neonates with myoclonic jerks, hypotonia, hiccups, apnea, and progressive lethargy that may progress to encephalopathy or death 1
• The combination of hypoglycemia, seizures, and lethargy in a 45-day-old infant strongly suggests a metabolic disorder rather than primary CVT, as metabolic derangements are a known precipitant of thrombotic events in this age group 1
• A novel association has been documented between cerebral sinovenous thrombosis and nonketotic hyperglycinemia in neonates, where the metabolic disorder was confirmed after initial diagnosis of CVT 1

CVT as a Secondary Phenomenon

• CVT in neonates and young infants is typically secondary to underlying conditions rather than idiopathic, and metabolic disorders represent an important but underrecognized cause 1, 2
• Neonatal idiopathic CVT can present with lethargy or seizures, but the presence of hypoglycemia makes a primary metabolic etiology more likely 3
• Hyperglycemic hyperosmolar states and other metabolic derangements can precipitate cerebral venous thrombosis in pediatric patients 4

Diagnostic Workup Required

Immediate Metabolic Evaluation

• Obtain plasma and CSF amino acid analysis to evaluate for elevated glycine levels and calculate the CSF-to-plasma glycine ratio, which is diagnostic for nonketotic hyperglycinemia 1
• Measure serum glucose, electrolytes, ammonia, lactate, and blood gas to identify other metabolic abnormalities 1
• Obtain urine organic acids to exclude other inborn errors of metabolism 1
• Check complete blood count and iron studies, as severe iron deficiency anemia has been linked to CSVT formation in young children 5

Neuroimaging Confirmation

• MRI with MR venography is the preferred diagnostic modality for confirming CVT, showing both venous occlusion and parenchymal changes 6, 7
• MR phase imaging provides a powerful, noninvasive means of confirming the diagnosis of CVT in neonates 3
• Gradient echo T2 susceptibility-weighted images combined with MR venography improve diagnostic accuracy 6

Differential Considerations

Other Metabolic Causes to Consider

• Homocystinuria, which causes both arterial and venous occlusion and can present with seizures and mental status changes 8
• Hyperglycemic hyperosmolar state in new-onset diabetes, though less common at 45 days of age 4
• Other organic acidemias or urea cycle defects that can cause hypoglycemia and neurological deterioration 1

Non-Metabolic Causes (Less Likely Given Hypoglycemia)

• Primary idiopathic neonatal CVT, which typically presents with lethargy or seizures but without hypoglycemia 3
• Prothrombotic conditions such as inherited thrombophilias (protein C/S deficiency, antithrombin III deficiency, factor V Leiden), though these are less likely to cause hypoglycemia 6

Management Approach

Immediate Treatment

• Initiate anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin for the CVT, even in the presence of any hemorrhagic lesions 6, 7
• Correct hypoglycemia with appropriate glucose administration 1
• Treat seizures aggressively with antiepileptic medications 6

Metabolic-Specific Therapy

• If nonketotic hyperglycinemia is confirmed, initiate sodium benzoate and dextromethorphan therapy to reduce glycine levels 1
• Provide supportive care including respiratory support if apnea develops 1
• Genetic counseling for the family given the autosomal recessive inheritance pattern 1

Critical Pitfalls to Avoid

• Do not assume CVT is idiopathic in a neonate with systemic symptoms like hypoglycemia—always investigate for underlying metabolic disease 1
• Do not delay anticoagulation due to concerns about hemorrhagic transformation, as anticoagulation is indicated even with hemorrhagic lesions in CVT 6, 7
• Do not rely on D-dimer alone to exclude CVT, as normal D-dimers do not rule out CVT, particularly in patients with isolated symptoms 2
• Do not miss the diagnosis by relying solely on non-contrast CT, which has limited sensitivity (abnormal in only 30% of cases) 6, 7

Prognosis

• The prognosis depends primarily on the underlying metabolic disorder rather than the CVT itself 1
• Nonketotic hyperglycinemia typically has a poor prognosis with significant neurological impairment, though early diagnosis and treatment may improve outcomes 1
• CVT in neonates, when treated appropriately with anticoagulation, generally has a favorable outcome with low mortality 2, 3