Diagnostic Criteria

Guidelines for the diagnosis of homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) have been published .

Suggestive Findings

HCU-CBS deficiency should be suspected in an infant with an or a and family history. Note: (1) Individuals with untreated HCU-CBS deficiency usually develop manifestations in the first or second decade of life. (2) A symptomatic individual can have untreated HCU-CBS deficiency due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result.

Infant with Out-of-Range NBS Result

NBS for HCU-CBS deficiency is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify methionine concentration, typically by tandem mass spect...

Source: GeneReviews — "Homocystinuria due to Cystathionine Beta-Synthase Deficiency"

Differential Diagnosis

The clinical condition that most closely mimics homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) is Marfan syndrome (an autosomal dominant disorder caused by pathogenic variants in FBN1), which shares the features of long, thin body habitus, arachnodactyly, and predisposition for ectopia lentis and myopia. Although ectopia lentis can also occur early in isolated sulfite oxidase deficiency (an autosomal recessive disorder caused by pathogenic variants in SUOX), this condition is clinically distinct from homocystinuria. Individuals with sulfite oxidase deficiency and Marfan syndrome have normal concentrations of plasma homocysteine and methionine.

Source: GeneReviews — "Homocystinuria due to Cystathionine Beta-Synthase Deficiency"

Management Guidelines

Clinical practice guidelines for management of homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency (HCU-CBS deficiency) have been published .

Evaluations Following Initial Confirmatory Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HCU-CBS deficiency, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Homocystinuria due to Cystathionine Beta-Synthase Deficiency: Recommended Evaluations After Establishing a Diagnosis

System/Concern | Evaluation | Comment

Biochemical

| Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian1 | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).

• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (re diet mgmt risk of vascular event) initiate treatment following pyridoxine challenge.

• Pyridoxine (vitamin B6) challenge prior to initiation of treatment (See .)

Eyes | Ophthalmology eval | Evaluate for myopia ectopia lentis.

Orthopedic

| Clinical assessment for scoliosis, arachnodactyly, pes cavus, pectus deformity, genu valgum | Radiographs for scoliosis as needed

Neurologic

| Consultation w/neurologist | In those w/possible seizures extrapyramidal signs such as dystonia

Eval per vascular specialist | In those presenting w/vascular event

Genetic counseling

| By gene...

Source: GeneReviews — "Homocystinuria due to Cystathionine Beta-Synthase Deficiency"

Surveillance Guidelines

The evaluations summarized in are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations.

Table 10.

Homocystinuria due to Cystathionine Beta-Synthase Deficiency: Recommended Surveillance

Manifestation | Evaluation | Frequency/Comment

Metabolic/

Nutrition

| • Eval w/metabolic specialist metabolic dietitian

• Plasma total homocysteine, plasma amino acids (incl methionine), folate, vitamin B12

| Frequency per metabolic specialist based on severity of disorder, vitamin B6 responsiveness, adherence to treatment, age, history of venous thrombosis1

• CBC iron studies (ferritin, iron, total iron-binding capacity)

• Vitamin mineral testing (25-hydroxyvitamin D level, zinc)

• Prealbumin

• Additional labs as clinically indicated may include methylmalonic acid, serum calcium, phosphate, other vitamins trace minerals, essential fatty acids.2

| In those on methionine-restricted diet per metabolic specialist2

Ophthalmologic

| Ophthalmology exam to evaluate for myopia ectopia lentis | At least annually1

Skeletal complications

| Assess for long bone overgrowth deformity, genu valgum, pes cavus, pectus deformity, kyphosis/scoliosis, frequency of fractures. | At each visit

Radiographs for scoliosis | As needed

DXA scan | Every 3-5 yrs from adolescence; more frequent in those w/frequent fractures /or low vitamin D concentration

Cardiovascular/ Venous thromboembolism/ Stroke

| • Lipid profile to assess cardiovascular risk factors

Source: GeneReviews — "Homocystinuria due to Cystathionine Beta-Synthase Deficiency"