BASICS

DESCRIPTION

• Homocystinuria compromises a group of inborn errors of methionine metabolism that result in elevated levels of homocysteine in the urine (homocystinuria) and blood (homocysteinemia).

• Cystathione β-synthetase deficiency (classic homocystinuria) is the most common cause and is discussed here.

• Other defects leading to elevated levels of plasma and urine homocysteine include defects in methylcobalamin formation and methylenetetrahydrofolate reductase deficiency.

• Signs and symptoms of classic homocystinuria are systemic, primarily involving the ocular, nervous, cutaneous, skeletal, and hematologic systems.

• Ocular involvement is marked by progressive myopia (nearsightedness) and ectopia lentis (dislocation of the native lens).

EPIDEMIOLOGY

Incidence

• Varies by region; the highest incidence in the world, a ratio of about 1:3000 live births, is found in Qatar. Other nations with high incidence include Norway (1:6400), Germany (1:17,800), and Ireland (1:65,000).

• General incidence is estimated to be 1:200,000 to 1:300,000 live births.

RISK FACTORS

Genetics

• Classic homocystinuria is autosomal recessive.

• The gene for cystathionine β-synthetase is located on chromosome 21q22.3.

• Patients typically harbor 2 different mutations in the gene for cystathionine β-synthetase (i.e., compound heterozygotes).

• Varying disease manifestations are felt to be related to the particular mutations inherited.

GENERAL PREVENTION

• Newborn screening

– Not available in all states

– Tests for methionine levels

High false-negative rates secondary to normal neonatal levels during the first few days of life

• Genetic counseling

PATHOPHYSIOLOGY

• Progressive lenticular myopia and eventual ectopia lentis

• Acute glaucoma secondary to pupillary block

• Thromboembolism secondary to increased vascular endothelial adhesiveness and platelet activation

ETIOLOGY

• Incompetence and disruption of the zonular fibers

• Ischemia to brain and vital organs

COMMONLY ASSOCIATED CONDITIONS

• Developmental delay (common)

• Thromboembolic disease (common)

DIAGNOSIS

HISTORY

• Birth history

– Neonatal screening performed?

• Development

– Speech delay

– Mental retardation

– Behavioral/psychiatric disturbances

• Family history

– Consanguinity

– Thromboembolic death at an early age

• Ocular history

– Poor vision

– Profound nearsightedness (reading material held very close to face)

– Eye pain

PHYSICAL EXAM

• General

– Poor speech/interaction for age

– Marfanoid habitus

– Scoliosis

– Pectus excavatum or carinatum

– Genu valgum

– Pes cavus

– High arched palate

– Dental crowding

– Malar flush

– Generalized osteoporosis

• Ocular

– Thick glasses/progressive and severe myopia

– Increased intraocular pressure

– Red eye

– Ectopia lentis with disrupted zonular fibers

– Usually after age 2

– Cataract

– Retinal detachment

– Optic atrophy

– Staphyloma

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Classic homocystinuria is a clinical diagnosis affirmed by laboratory and genetic testing.

• Laboratory testing reveals elevated levels of plasma methionine and plasma homocysteine.

• Urinary levels of homocysteine are elevated. This should be a freshly voided specimen as the compound is unstable.

• Pyridoxine (B₆) challenge differentiates B₆ responders from nonresponders and dictates treatment.

– 100 mg pyridoxine PO × 1.

– Plasma amino acids measured in 24 hours.

– A reduction of 30% or more in plasma homocystine and/or plasma methionine concentration suggests B₆ responsiveness.

– If no significant change occurs, 200 mg pyridoxine PO × 1, then reassess as above.

– If still no change has occurred, 500 mg of pyridoxine is given in a child or adult.

– If plasma homocystine and methionine concentrations are not significantly decreased after the last dose of pyridoxine, it is concluded that the individual is B₆-nonresponsive.

Note: Infants should not receive more than 300 mg of pyridoxine. This can lead to ventilator-dependent respiratory failure.

Imaging

• MRI with stroke protocol if any suggestion of focal CNS lesion on examination.

• DEXA scan for osteoporosis monitoring.

Diagnostic Procedures/Other

• Prenatal diagnosis possible with amniocentesis.

• Molecular genetic testing is available to isolate the genetic mutations.

• Liver biopsy can be used to assay for cystathionine β-synthetase.

Pathological Findings

• Disrupted zonular fibers (as opposed to Marfan syndrome where fibers tend to be stretched).

• Ectopia lentis in homocystinuria can occur in any direction (contrary to classical teaching).

DIFFERENTIAL DIAGNOSIS

• Trauma

• Isolated ocular disease

– Buphthalmos

– Aniridia

– Ectopia lentis et pupillae

– Familial ectopia lentis

– Persistent hyperplasia of the primary vitreous/persistent fetal vasculature

– Coloboma

• Infectious

– Syphilis

• Metabolic/syndromic

– Marfan syndrome

– Weill–Marchesani syndrome

– Sulfite oxidase deficiency

– Xanthine oxidase deficiency

– Molybdenum cofactor deficiency

– Hyperlysinemia

– Methylenetetrahydrofolate reductase deficiency

TREATMENT

MEDICATION

• B₆/pyridoxine

– 200–1000 mg/24 hr B₆

– 1–5 mg/24 hr pyridoxine

Drives methionine metabolism forward

Patients with some residual enzyme activity (40% of affected) will respond.

• B₁₂ supplementation

• Betaine (1)[C]

– 200–250 mg/kg/day

– Remethylates homocysteine to methionine

ADDITIONAL TREATMENT

General Measures

• Address refractive error with glasses or contact lens.

• Treat amblyopia, which can result from anisometropia.

• Hydration to prevent thromboembolism.

SURGERY/OTHER PROCEDURES

• Patients are at extremely high risk of intraoperative stroke and thrombosis.

• Urgent lens extraction for acute glaucoma caused by ectopia lentis

• Elective lens extraction for extreme myopia or to prevent acute glaucoma

– Accomplished via pars plana lensectomy with successful long-term outcome (2)[C].

• Thrombolysis for acute stroke

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Pediatric ophthalmologist

• Contact lens specialist (if aphakic)

• Pediatric metabolic disease specialist

• Hematology evaluation

Patient Monitoring

• Special intraoperative antithrombotic measures are indicated if patients require a surgical procedure (3)[C].

• See “Follow-up” section.

DIET

Methionine-restricted diet.

PATIENT EDUCATION

• Genetics Home Reference: Homocystinuria (http://ghr.nlm.nih.gov/condition=homocystinuria)

PROGNOSIS

• Usually limited lifespan (thromboembolism) and intelligence.

• If B₆ therapy instituted at an early age in a responsive patient, developmental delay and ectopia lentis can be prevented (4)[C].

COMPLICATIONS

• Visual loss

• Death (thromboembolism)

• Fractures (osteoporosis)

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