Hartnup Disease and Glycine Metabolic Effects

Brief Introduction to Hartnup Disease

• Hartnup disorder was named after the first family that was diagnosed with the disease. 
• It belongs to the category of neutral amino acid metabolism defect. Tryptophan is the prominent amino acid involved. 
• It is a genetic disorder that follows autosomal recessive inheritance. 
• It causes defective transport of neutral monoamine-monocarboxylic acid across the intestinal mucosa and renal tubules, leading to a tryptophan deficiency. 
• The causative mutation occurs in the SLC6A19 gene located at chromosome 5p15.33, which expresses the B⁰-AT1 transporter.

Symptoms of Hartnup disease

• Most patients are asymptomatic. 
• Symptomatic patients present the following symptoms.
  • Cutaneous photosensitivity with pellagra-like manifestations, typically a Casal necklace, on the skin exposed to light
  • Intermittent or episodic ataxia is associated with intermittent behavioral impairment, which appears during the episodes.

Investigations in Hartnup Disease

• Analysis of symptoms is the primary investigation.
• The differential diagnosis is the biochemical analysis of urine for aminoaciduria involving neutral amino acids. Urinary excretion of proline, hydroxyproline, and arginine remains normal.
• This finding helps to differentiate Hartnup disorder from other causes of generalized aminoaciduria, such as Falconi syndrome.
• The confirmatory test is a genetic analysis of the SLC6A19 gene.

Diagnosis Of Hartnup Disease

• The intermittent nature of symptoms and characteristic findings on urine amino acid analysis establish the diagnosis of Hartnup disorder.

Treatment  Of Hartnup Disease

• The treatment is the administration of nicotinic acid or nicotinamide at a high dose of 50-300 mg/day with high protein nutrition.

GLYCINE METABOLISM DEFECTS

Introduction to Gline Metabolic Disorders

Glycine is a nonessential neutral amino acid that functions as a neurotransmitter in the CNS. Its metabolism is related to serine metabolism. Impaired glycine metabolism most commonly arises due to a defective cleavage system, which includes four proteins. 

• P-protein (glycine decarboxylase)
• T protein
• H protein
• L protein. 

The diagnosis looking for an abnormal amount of neutral amino acid helps differentiate Hartnup disease from Fanconi disease, which is generalized aminoaciduria.

Hyperglycinemia is of two types: ketotic and non-ketotic hyperglycinemia.

Ketotic Hyperglycinemia

• The ketotic type is also known as secondary hyperglycemia, which results from various organic acidemias that induce inhibition of the glycine cleavage enzyme system. 
• Propionic acidemia and methylmalonic acidemia are a few examples. 
• It is called ketotic type because it is associated with ketoacidosis. 

Non-Ketotic Hyperglycinemia OR Primary Hyperglycinemia

• It is considered the true form of hyperglycinemia due to the defective protein expression in the glycine enzyme cleavage system. 
• Defects in P protein are seen in about 75% of the incidence.
• Defective T and H proteins cause about 20 and 1% of cases.
• There are four types of non-ketotic hyperglycinemia.

1. The neonatal form is the most common and severe.
   • The disease onset begins at the 6th hour of life to the 8th day of birth. The presentations include vomiting, feeding inability, episodes of apnea, myoclonic seizures, and progressive coma.
   • The blood pH is found to be normal, and ketoacidosis is absent. 
   • The survival rate of neonates with hyperglycinaemia is 70%. Infants that survive the defect exhibit intellectual disabilities and retardation. 
2. Infantile form presents at infancy beyond the neonatal period, and the features are similar but less severe. Here also, mental retardation and infantile disability does develop. 
3. The late-onset form can manifest between the ages of 1 and 32. Clinical features in the late-onset include episodic choreoathetosis movements, ataxia, and behavioral changes, which become more severe during an intercurrent illness. 
4. The transient form is due to an immature cleavage enzyme system. It presents similar to neonatal form but improves without therapy. 

Investigational Findings  In Glycine Metabolic Effects:

• Blood levels of serum glycine are elevated up to eight times the normal level. 
• CSF levels of serum glycine rise to 30 times the normal. 
• The ratio of glycine level in CSF to plasma rises beyond 0.08 as opposed to the normal value of 0.02.
• In addition, the CSF serine level is found to be low. 

Treatment Of  Glycine Metabolic Effects

Currently, there is no cure for the disease. But Enteral sodium benzoate may help improve milder conditions. Certain drugs, such as dextromethorphan and felbamate, counteract the effect of glycine on neuronal cells. These have shown great benefit in the treatment of milder forms of Glycine Metabolic Disorders. 

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