General description

Homocystinuria is an inherited metabolic disorder characterized by elevated levels of homocysteine in blood and urine, primarily caused by cystathionine β-synthase (CBS) deficiency. Homocystinuria is most commonly caused by autosomal recessive mutations in the CBS gene, leading to deficient activity of cystathionine β-synthase, an enzyme critical in the transsulfuration pathway. This pathway converts homocysteine to cystathionine, which is further metabolized to cysteine. CBS deficiency results in homocysteine accumulation and methionine overproduction due to impaired remethylation. A less frequent etiology involves defects in the remethylation pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency (see Methylenetetrahydrofolate reductase (MTHFR) deficiency), which disrupts homocysteine recycling to methionine. Both pathways culminate in hyperhomocysteinemia, the primary driver of systemic pathology.

This condition is characterized by a range of systemic abnormalities. Eye complications are particularly common, with lens dislocation often appearing during adolescence, leading to vision issues such as nearsightedness, astigmatism, or glaucoma. Over time, more severe ocular problems like retinal detachment and optic nerve damage may develop.

Skeletal and connective tissue symptoms resemble those of Marfan syndrome, including tall stature and long fingers, but with decreased joint mobility. Bone fragility is common due to early-onset osteoporosis, resulting in frequent fractures and spinal deformities such as scoliosis and kyphosis. Imaging frequently reveals low bone density.

Neurological symptoms typically begin in infancy and include developmental delays and intellectual disability in half of the patients. Additional signs such as seizures, tremors, and exaggerated reflexes suggest both cortical and subcortical involvement. Psychiatric disorders—such as obsessive-compulsive behaviors, depression, and personality changes—are also present, often worsened by poor metabolic control.

Blood clots significantly contribute to the disease burden, with both venous and arterial events occurring. These can lead to strokes, heart attacks, or other serious outcomes, sometimes beginning in adolescence. One reported case involved a brain sinus clot that caused headaches and seizures.

References

1. Li, Charles Q., et al. "Brain magnetic resonance imaging findings in poorly controlled homocystinuria." Journal of Radiology Case Reports 12.1 (2018): 1.