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  Disease summary:

  
  
  
  
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    Homocysteine (Hcy) is a sulfur-containing amino acid whose metabolism stands at an intersection of two biochemical pathways. A remethylation pathway converts Hcy to methionine, and requires the presence of folate and vitamin B₁₂, while a trans-sulfuration pathway converts Hcy to cystathionine and cysteine in a reaction requiring vitamin B₆.

    
    
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    Important monogenic forms of hyperhomocysteinemia (HHcy) include the following:

    
    
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    Cystathionine beta-synthase (CBS) deficiency, also known as classic homocystinuria, is associated with a skeletal and ocular phenotype similar to Marfan syndrome, as well as variable developmental delay and a strong predisposition to thromboembolism; around 50% of cases respond to supplementation with vitamin B₆.

    
    
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    Disorders of B₁₂ metabolism: several disorders of intermediary cobalamin metabolism (CblC, CblD, CblE, CblF, and CblG diseases) as well as transcobalamin deficiency can cause moderate-to-severe HHcy; treatment is centered around daily hydroxocobalamin.

    
    
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    Mutations and common polymorphisms of methylenetetrahydrofolate reductase (MTHFR) cause HHcy of variable severity in both the homo- and heterozygous states.

    
    
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    Multifactorial HHcy is also associated with a range of common adult diseases including thrombophilia, coronary artery disease, stroke, neuropsychiatric disease, and osteoporosis.

  
  
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  Hereditary basis:

  
  
  
  
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    CBS deficiency, most cobalamin disorders and MTHFR deficiency follow autosomal recessive inheritance. Milder forms of HHcy follow complex or multifactorial patterns of inheritance.

  
  
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  Twin studies:

  
  
  
  
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    In a large Danish twin study, the impact of the MTHFR locus was estimated to explain 53% of the total phenotypic variation in Hcy concentrations in persons 18 to 39 years old, and 24% in persons 40 to 65 years old, that is, almost all additive genetic variance. Hcy concentrations have a high heritability that decreases with age.

  
  
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  Genome-wide association studies (GWAS):

  
  
  
  
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    Significant genome-wide associations have been found between total homocysteine (tHcy) and single-nucleotide polymorphisms (SNPs) located near GPR51 (9q22) and MTHFR (1p36). A GWAS looking at the coronary artery disease phenotype noted an association with MTHFD1L, which is important in methionine-homocysteine metabolism.

  
  
  
  
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  Pharmacogenomics:

  
  
  
  
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    Common MTHFR polymorphisms (677C>T and 1298A>C) confer increased sensitivity to fluoropyrimidines (eg, 5-FU) and antifolates (eg, methotrexate).

Definitions and Epidemiology

Severe HHcy is generally restricted to individuals with inherited disorders of Hcy metabolism, is defined as tHcy greater than 100 mmol/L. The most recognized etiology of severe HHcy is CBS deficiency, causing classic homocystinuria. In 1975, the first description of CBS deficiency and its association with thrombophilia leading to early stroke and heart attack in untreated patients led the medical community to suspect milder elevations of Hcy as a contributing factor to atherosclerosis pathogenesis. In the general population, this suspicion has been corroborated through large epidemiologic trials, although Hcy is not currently viewed as an important risk factor.

Mild HHcy is variably defined as tHcy of 12 to 30 mmol/L, and in some literature as 15 to 30 mmol/L while moderate HHcy is defined as tHcy 30 to 100 mmol/L. Mild-to-moderate HHcy of multifactorial etiology appears to be highly prevalent in the general population. The prevalence has been estimated at 5% to 10%, but may be significantly higher (30%-40%) among elderly individuals. HHcy is more common among males and persons with increased muscle mass. HHcy has been observed in the context of disruption of function affecting enzymes of folate metabolism (MTHFR, methionine synthase [MS], methionine synthase reductase [MSR]). Of these, MTHFR is the most significant from a population-wide perspective. Severe HHcy from homozygosity for mutations in MTHFR are rare, although the common 677C>T polymorphism is known to cause increased thermolability of the enzyme which may lead to mild HHcy, particularly in the folate-depleted state.

Factors that may influence plasma tHcy include MTHFR genotype, acquired folate, B₆, or B₁₂ deficiencies (dietary inadequacy or malabsorption), medications (insulin, anticonvulsants, lipid-lowering agents, metformin, vitamin B₆ antagonists, penicillamine, nitrous oxide), and lifestyle factors including exercise, tobacco consumption, caffeine intake, and alcohol use.

Clinical Characteristics of Monogenic Disorders Resulting in Hyperhomocysteinemia

(Table 90-1):

CBS Deficiency

This is a rare disease causing severe HHcy with an incidence of 1 in approximately 340,000 live births, though is much common in certain regions (incidence 1:3000 in indigenous Qatari population; 1:65,000 in Ireland and parts of New South Wales, Australia). The enzyme, CBS, is active in several tissues (liver, brain, pancreas, cultured fibroblasts). When CBS is nonfunctional, accumulating Hcy molecules readily form dimeric complexes with methionine, cysteine, and other Hcy molecules, including proteins comprising sulfide-containing amino acids.

Infants with CBS deficiency are typically normal at birth. The spectrum of clinical findings in the untreated individual is wide and affects a variety of organ systems, outlined below:

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  Vascular: Arterial and venous thromboembolism are common in CBS deficiency, and account for the majority of morbidity and mortality. Thrombophlebitis and pulmonary embolism are the most common vascular complications. Thrombosis of medium and large arteries is a frequent cause of death. When CBS deficiency is compounded by the presence of alleles at other loci linked to increased risk of vascular disease (677C>T mutation of MTHFR gene; R506Q mutation of factor V Leiden gene), tendency toward thromboembolism increases further.

  
  
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  Ocular: Ectopia lentis, myopia, and glaucoma are frequent manifestations, with cataracts, retinal detachment, and optic atrophy occurring as later complications. Ectopia lentis, which is usually inferolateral in orientation (differentiating it from the type observed in Marfan syndrome), is detectable by 5 to 10 years of age and serves as a useful diagnostic clue. After dislocation has occurred, iridodonesis (tremulous movements of the iris with eye or head movement) may be observed.

  
  
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  Osseous: Osteoporosis is invariably detectable after puberty, and often earlier. Affected individuals may develop scoliosis and vertebral collapse. CBS deficiency is associated with tall stature with thinning and elongation of long bones and enlarged epiphyses and metaphyses, often most evident at the knees. Many patients have pes cavus, genu valgum or pectus carinatum/excavatum. Joint mobility is typically restricted. Body habitus is often described as marfanoid. Radiologic findings include flattened intervertebral discs, growth arrest lines in the distal tibia, enlarged carpal bones, and short fourth metacarpals.

  
  
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  Neurodevelopmental: About 60% of untreated patients have variable degrees of mental retardation and developmental delay. Seizures, subclinical EEG abnormalities and psychiatric symptoms are all common in untreated patients. Neurocognitive morbidity is greatly reduced when treatment is initiated early. Cerebrovascular disease is significantly more prevalent than in the general population.

  
  
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  CBS deficiency in pregnancy: One study of 15 pregnancies in 11 women with CBS deficiency (six pyridoxine responsive, five pyridoxine nonresponsive) reported the birth of 10 healthy infants. One infant had multiple anomalies at birth and another was later diagnosed with Beckwith-Wiedemann syndrome (BWS). Two women suffered pre-eclampsia and another suffered from superficial venous thrombosis. Two pregnancies ended in spontaneous first trimester miscarriage. No relationship was established between biochemical derangements observed during pregnancy and pregnancy outcomes.

Disorders of Vitamin B12 (Cobalamin) Metabolism

Vitamin B₁₂ is an essential cofactor for the enzyme methionine synthase, which catalyzes the conversion of Hcy to methionine. Several inherited disorders of vitamin B₁₂ metabolism result in hyperhomocysteinemia with or without methylmalonic acidemia (MMA). CblC (homocystinuria with methylmalonic acidemia) is the commonest of this group, and has been ascribed to mutations in the MMACHC gene, located at 1p34.1, causing impaired production of methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). CblC, D, and F diseases are characterized biochemically by HHcy, hypomethioninemia, and MMA. CblE and CblG diseases cause HHcy without MMA. Although variable, clinical manifestations of CblC are unlike those of either isolated homocystinuria or isolated MMA. The commonest presentation is in early infancy, manifesting as a progressive neurologic syndrome with hematologic, ophthalmologic, and cardiac features. More rarely, symptomatic onset of CblC occurs later in childhood or in adulthood with neuropsychiatric disturbance or dementia. Adult-onset patients may also have megaloblastic anemia, glomerulopathy, and myelopathy. Brain magnetic resonance imaging (MRI) may reveal leukodystrophy. In CblC, tHcy is typically elevated into the 30 to 100 mmol/L range when well and on treatment, but may be greater than 100 mmol/L when ill.

Severe MTHFR Deficiency

When present in the homozygous state, severe mutations of MTHFR (such as 1129C>T) cause severe HHcy, infantile-onset neurologic deterioration with seizures, mental retardation, and developmental delay.

Polymorphisms in MTHFR

The C677T variant of MTHFR has been associated with a decreased activity of MTHFR, an increased level of Hcy and altered distribution of folate. The 1298A>C polymorphism has been related to reduced MTHFR activity, but its effects are considered to be less potent than those of the 677C>T variant.