Sulfocysteine

Sulfocysteine is a naturally occurring compound formed in humans when sulfur metabolism is disrupted, often due to conditions like molybdenum cofactor deficiency (MoCD) and sulfite oxidase deficiency (SOD). 

During the breakdown of sulfur-containing amino acids cysteine and methionine, sulfite is produced. This sulfite can react with cystine, forming S-sulfocysteine (SSC). 

Normally, the mitochondrial enzyme sulfite oxidase converts sulfite to sulfate, which is then excreted in the urine. Elevated levels of urinary sulfite, thiosulfate, and SSC are key diagnostic markers for MoCD and SOD. 

SSC is structurally similar to glutamate and acts as an NMDA receptor agonist, leading to neurotoxic effects through calcium influx and downstream cell signaling. 

This neurotoxicity is a significant factor in the severe neurological impairments seen in these conditions, emphasizing the importance of understanding SSC's role in these metabolic disorders.

What is Sulfocysteine?

Sulfocysteine is a naturally occurring compound formed in humans when sulfur metabolism pathways are slowed, which tends to occur in conditions such as molybdenum cofactor deficiency (MoCD) and sulfite oxidase deficiency [4.].

Sulfite is produced during the catabolism of sulfur-containing amino acids cysteine and methionine. Accumulated sulfite reacts with cystine, leading to the formation of S-sulfocysteine (SSC) [2., 4.].

Normally, endogenous sulfite levels are maintained at low concentrations by a mitochondrial enzyme called sulfite oxidase, which converts sulfite to sulfate, which is then subsequently excreted in the urine [5., 7.].

Elevated urinary levels of sulfite, thiosulfate, and SSC are all diagnostic markers for both MoCD and sulfite oxidase deficiency [2.].

Sulfocysteine in the Central Nervous System

S-sulfocysteine (SSC) is a structural analog of glutamate that accumulates in the plasma and urine of patients with certain genetic disorders affecting sulfur metabolism [4.].

It acts as an N-methyl-D-aspartate receptor (NMDA-R) agonist, leading to calcium influx, downstream cell signaling, and neurotoxicity [4.].

SSC activates the protease calpain, resulting in the degradation of the inhibitory synaptic proteins which exacerbates excitotoxicity and promotes the loss of GABAergic synapses [4.].

Clinical Significance of Sulfocysteine

Sulfite Oxidase Deficiency 

Isolated sulfite oxidase deficiency (SOD) is a rare autosomal recessive disorder characterized by severe neurologic dysfunction, ectopia lentis, and increased urinary excretion of sulfite, thiosulfate, and S-sulfocysteine [6.].

This deficiency is often due to mutations in the SUOX gene, which renders the enzyme less effective and allows for the buildup of sulfur-containing metabolites including sulfocysteine. 

Diagnosis is often missed due to variability in urine screening tests [6.].

Sulfite oxidase deficiency ranges from severe early-onset to milder late-onset forms. 

Classic sulfite oxidase deficiency manifests within hours to days of life with intractable seizures, feeding difficulties, and rapidly progressive encephalopathy, characterized by abnormal muscle tone (opisthotonus, spastic quadriplegia, pyramidal signs), progressive microcephaly, and profound intellectual disability [3.].

Lens subluxation or dislocation may appear after the newborn period. Most affected infants die within the first few months of life [3.].

Late-onset sulfite oxidase deficiency appears between six and 18 months of age, presenting with developmental delay or regression, movement disorders (dystonia, choreoathetosis), ataxia, and occasionally acute hemiplegia due to metabolic stroke [3.].

The clinical course may be progressive or episodic, with intermittent encephalopathy, dystonia, choreoathetosis, and ataxia [3.].

Diagnosis involves detecting elevated urinary thiosulfate and S-sulfocysteine, low urinary organic sulfate, and significantly reduced plasma total homocysteine. Confirmation is through identifying biallelic pathogenic variants in the SUOX gene via molecular genetic testing [3., 6.].

There is no cure for sulfite oxidase deficiency. 

Management focuses on symptomatic treatment, including anti-seizure medications, spasticity reduction, and early gastrostomy tube placement to manage feeding difficulties, ensure adequate nutrition, and reduce aspiration risk [3.].

Regular chest physiotherapy and management of vomiting, gastroesophageal reflux, and aspiration pneumonia are also necessary [3.].

Molybdenum Cofactor Deficiency [1., 4.]

Molybdenum Cofactor Deficiency (MoCD) is a severe and devastating autosomal recessive neonatal disorder requiring rapid diagnosis and intervention. 

The role of S-sulfocysteine (SSC) in MoCD highlights the importance of understanding its neurotoxic mechanisms and exploring therapeutic strategies.

MoCD is characterized by neonatal onset with intractable seizures, feeding difficulties, severe developmental delay, microcephaly, and coarse facial features. This rare condition has an incidence of 1 in 100,000 to 200,000 live births, with over 100 cases reported globally. 

Biochemically, MoCD results in the deficiency of molybdenum cofactor-dependent enzymes: sulfite oxidase, xanthine dehydrogenase, aldehyde oxidase, and mitochondrial amidoxime reducing component. 

This deficiency leads to the accumulation of sulfite, taurine, S-sulfocysteine, and thiosulfate, contributing to severe neurological impairment.

Clinically, infants with MoCD appear normal at birth but develop symptoms within hours to weeks. These symptoms include intractable seizures, encephalopathy, hyperekplexia, and poor feeding, leading to severe developmental delay. 

Affected infants typically do not achieve milestones such as sitting or speaking, and microcephaly is often observed in the neonatal period. 

Diagnosis of MoCD involves identifying specific biochemical markers: decreased serum and urine uric acid, and elevated urinary sulfite, S-sulfocysteine, xanthine, and hypoxanthine. 

Genetic analysis reveals that MoCD is caused by biallelic pathogenic variants in the genes MOCS1, MOCS2, or GPHN, with MOCS1 mutations responsible for MoCD Type A. Over 60 pathogenic variants have been identified in MOCS1 and MOCS2.

Lab Testing for Sulfocysteine

Test Information, Sample Collection and Preparation

Urine is generally used to test sulfocysteine levels. It is important to consult with the ordering provider prior to sample collection to understand if special preparation is required.

Interpreting Sulfocysteine Test Results

Optimal Levels of Sulfocysteine

Optimal levels of sulfocysteine test results are age-dependent.  

One lab company reports the following reference ranges for sulfocysteine: [8.]

0-3 years: < or =11 mmol/mol creatinine

4-6 years: < or =5 mmol/mol creatinine

7-12 years: < or =5 mmol/mol creatinine

13-18 years: < or =5 mmol/mol creatinine

Above 18 years: < or =5 mmol/mol creatinine