OVERVIEW: What every practitioner needs to know

Are you sure your patient has homocystinuria? What are the typical findings for this disease?

Homocystinuria, due to deficiency of cystathionine beta-synthase (CBS), demonstrates variable manifestations observed in the ophthalmologic, skeletal, cardiovascular, and CNS systems. CBS deficiency causes elevations of methionine, homocysteine, and other metabolites including S-adenosyl homocysteine (SAH) and S-adenosyl methionine (SAM) and deficiencies of tissue and circulating levels of the sulfur metabolites, cystathionine and cysteine.

Ophthalmologic complications including severe myopia progressing to ectopic lentis (dislocation of the optic lens) and iridodonesis (a quivering of the iris with movements of the globe) are often the first noted findings leading to laboratory evaluation for this diagnosis. Often this presentation is in the context of a skeletal appearance suggesting increased length of limbs, also including joint hyperflexibiltiy, genu valgum, pes planus, decreased upper segment to lower segment ratio, pectus excavatum and/or carinatum, and osteoporosis.

Relative if not overt hypopigmentation of the skin and hair after several years of age is common.

Developmental delay may manifest as mental retardation after the first 2 years of life, but other neurologic manifestations, including seizures, psychiatric disorders, and/or focal neurologic deficits, may be present, especially at older ages. The CNS manifestations often reflect subclinical cerebrovascular accidents, and thromboembolic complications may occur even during the first years of life, another reason for early laboratory evaluation.

The disorder is increasingly being identified prior to overt clinical symptoms through generalized newborn blood screening. Similarly, generalized laboratory screenings for etiologies of "isolated" mental retardation/developmental delay may identify this condition prior to other overt manifestations.

What other disease/condition shares some of these symptoms?

Because the patients have a "marfinoid" skeletal appearance, Marfan syndrome, also associated with ectopic lentis and similar skeletal manifestations, is often at the top of the differential list. Of note is that homocystinuria is associated with childhood/teenage osteoporosis while Marfan syndrome is not. Similarly, many genetic conditions associated with connective tissue disorders, such as the Ehler Danlos syndromes, may be confused with the skeletal appearance of homocystinuria.

Homocystinuria should be on the differential list of any pediatric cerebrovascular accident or thromboembolic phenomenon, of which there are numerous etiologies. It is among the disorders to be investigated when determining an etiology of apparent "isolated" mental retardation.

Because of the growing number of individuals being identified by newborn blood screening for elevated levels of methionine, three other inborn errors of metabolism resulting in hypermethioninemia usually need to be considered. Two of these include those affecting methionine transmethylation (methionine adenosyltransferase (MATI/III) deficiency and glycine N-methyltransferase (GNMT) deficiency). Neither of these share clinical signs/symptoms with homocystinuria (CBS deficiency) except for rare neurologic involvement. S-adenosyl homocystine hydrolase (SAHH) deficiency similarly does not have much of an overlap phenotype except for delayed psychomotor development. All three of these disorders have elevated methionine but not homocystine.

Many patients with overt liver disease of any etiology may have elevated methionine but similarly without elevated homocystine. Other causes of laboratory identified homocystinuria, usually without elevated methionine, are discussed below in the laboratory section and are not usually confused clinically with homocystinuria due to CBS deficiency. These usually demonstrate megaloblastic anemia in the absence of folate or cobalamin (B12) deficiency.

What caused this disease to develop at this time?

Classic homocystinuria (CBS deficiency) is a relatively rare autosomal recessive disorder with variable clinical expression. Cystathionine beta-synthase (CBS) is an enzyme involving the methionine degradation/transsulfuration metabolic pathway, which converts methionine ultimately to cysteine by way of the intermediate cystathionine. One part of the explanation for the variability in severity of signs/symptoms is due to two categories of patients, one with little to no residual enzymatic activity and another with residual activity that responds to cofactor (pyridoxine (B6)) stimulation. Many of the latter group of patients are felt to be underrepresented in studies of the epidemiology of this disorder and missed by newborn screening for elevated methionine levels.

CBS deficiency is felt to have a generalized population incidence of 1/100,000-300,000 but at best this is an approximation and likely reflects only the more severely affected clinical group.

CBS deficiency causes elevations of methionine, homocysteine and other metabolites including S-adenosyl homocysteine (SAH) and S-adenosyl methionine (SAM) and deficiencies of tissue and circulating levels of the sulfur metabolites, cystathionine and cysteine. It is unclear what combination of the metabolite abnormalities produces tissue pathology, but ongoing progressive accumulation of homocysteine is associated with both connective tissue and endothelial damage, interference with coagulation and platelet function, and increased oxidative stress. This is likely due to homocysteine interfering with disulfide bonds that promote normal protein secondary structure in tissues, especially that of collagen and elastin.

Accumulated damage due to the repetitive "subclinical" cerebrovascular accidents may be the etiology of the mental retardation observed.

Optic lens dislocation is best explained by the deficiency of cysteine/cystine leading to disruption of cystine-rich fibers in the zonular attaching the lens to the ciliary body. This would affect both lens position (ectopic lens) as well as shape (myopia) and fluid dynamics (glaucoma).

Interference by homocysteine with collagen cross-linking in connective tissues would explain the myriad and variability of skeletal abnormalities. It is theorized that homocysteine may also affect neurotransmission and perhaps activate N methyl-D-aspartate (NMDA) receptors in the brain, leading to death of neurons.

The inherent variability in accumulations and deficiencies in the metabolites and the damage due to induced protein instabilities therefore makes the timing of overt clinical symptomatology difficult to predict. Infants with ectopic lens and/or strokes have been reported, although the majority of patients present at 2-5 years of age when developmental delay and ophthalmologic findings (usually myopia but the majority of patients will demonstrate ectopia lentis by 10 years of age) are recognized. The skeletal appearance and problems associated with osteoporosis help identify additional young adults for evaluation of this disorder, especially among the milder pyridoxine responsive group.

Because of its variability, it is felt that there are likely other genetic and environmental factors that contribute to the clinical consequences of homocystinuria but these remain to be identified. Since dietary restriction of methionine is clearly a therapeutic option, dietary habits in a few patients may play a role. Similarly, routine daily multivitamin usage may affect clinical sequelae in some mild pyridoxine responsive patients.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Following a positve newborn screen demonstrating elevated methionine levels, plasma should be evaluated for elevations in methionine, total homocysteine, S-adenosylhomocysteine and S-adenosylmethionine and decreases in cystine. Total plasma homocysteine is important to request specifically because homocysteine has many disulfide bound forms in the blood, including bound proteins (i.e., albumin) and amino acids (i.e., cysteine-homocysteine disulfide), that may not be indicated in routine amino acid studies. Therefore, following positive newborn screen, obtain plasma amino acids (PAA), total plasma homocysteine, and urine organic acids (UOA). If these suggest homocystinuria, confirm that the above metabolites are present in the plasma, that there is no succinylacetone in urine organic acids, and total plasma homocysteine is elevated. One can proceed then to evaluate for B6 responsiveness and/or do mutation analysis.

Elevated urinary homocystine should be easily demonstrated. Urine screening tests using cyanide nitroprusside have low sensitivity, can be falsely negative and should not be considered diagnostic. Instead, a quantitative analysis of urine for amino acids should be performed. Urine organic acids may be needed as well to screen for other disorders which may lead to elevations in homocystine (i.e., cobalamin disorders).

A similar set of studies is sent for patients identified outside of the newborn period who present with clinical symptoms suggestive of the disorder. Note that the milder pyridoxine responsive group of patients may not have sufficiently appreciable increases in the plasma methionine to be identified by newborn screening. Mutation analysis of the gene CBS is available but note that most individuals are compound heterozygotes with private mutations. There are known relatively common mutations for both pyridoxine responsive and nonresponsive types of mutations that may be first directly examined prior to full sequencing of the gene. Measurement of CBS enzyme activity in culture fibroblasts is also available.

Elevated levels of homocysteine in blood and urine may also be caused by disorders of either folate or cobalamin (cbl) metabolism that influence the conversion of homocysteine back to methionine by methionine synthase. Elevations in homocysteine without elevated methionine or the other metabolites listed above are observed in disorders of MTHFR (methylene tetrahydrofolate reductase), cbl G (MTR, methionine synthase), and cblE (MTRR, methionine synthase reductase) which encode enzymes involved in the remethylation pathway of homocysteine back to methionine. Megaloblastic anemia is usually present in the absence of reduced serum cobalamin and folate levels.

Other disorders of cobalamin metabolism also may adversely affect the cobalamin cofactor required to convert homocysteine to methionine via methionine synthase, but other pathways are affected as well, resulting in differentiating laboratory results. Cbl C, cbl D, and cblF demonstrate elevated homocysteine with low or normal methionine levels and in addition, elevated methylmalonic acid, in both blood and urine. Similarly, disorders in absorption and transport of cobalamin, including hereditary intrinsic factor deficiency and transcobalamin deficiency, may provide similar laboratory patterns, ie, megaloblastic anemia with elevations in homocysteine and methylmalonic acid but low methionine. Low serum cobalamin due to any reason (i.e., chronic diseases, drugs, pregnancy, idiopathic, diet, etc) may produce similar results.

In contrast, deficiencies in the methionine transsulfuration pathway enzymes prior to CBS and homocysteine (MAT, GNMT, SAHH) would produce elevated methionine without significant elevations in homocystine/total homocysteine. Therefore, complete evaluation of elevated homocystine in blood and/or urine should initially include not only plasma amino acids but urine amino and organic acids, plasma total homocysteine, and complete blood count with differential.

Would imaging studies be helpful? If so, which ones?

Osteoporosis should be assessed, and it may be detected in initial screening radiographs used to determine the basis of atypical clinical appearance of extremities and/or body habitus (e.g., decreased upper body segment to lower segment ratio, genu valgum). However, especially in consideration of the diagnosis of homocystinuria, DEXA (dual energy X-ray absorptiometry) scanning is probably indicated to confirm osteoporosis, because of its increased sensitivity and lower total body irradiation than typical skeletal radiographs.

Skeletal X-rays may demonstrate tubular appearance of bones, especially elongation and thinning of long bones, with widening of the epiphyses and metaphyses. In addition, scoliosis and vertebral abnormalities are usually present. Screening lateral X-ray views of the lumbar spine will typically show platyspondyly with biconcave vertebrae and clear signs of osteoporosis by the end of the second decade of life. Wrist and hand films may demonstrate epiphyseal and metaphyseal abnormalities, abnormal bone age and/or enlarged carpal bones but short fourth metacarpal (less frequent finding).

Ongoing ultrasound studies to reveal extent of thromboembolism affecting blood vessels is usually part of the monitoring of patients with homocystinuria.

Confirming the diagnosis

  • The currently established newborn screening algorithm (American Collge of Medical Genetics ACT guidelines for newborn screening followup) of elevated methionine, often the first consideration for homocystinuria, is as follows:

    • Obtain quantitative amino acid, total plasma homocysteine, and plasma methylmalonic acid (MMA). If methionine and total homocysteine are elevated and there is no MMA, homocystinuria is likely due to CBS deficiency. Some regional centers also suggest including urine for organic acids to ensure succinylacetone, a marker for tyrosinemia type I, is absent.

    • The diagnosis may then be confirmed by genetic testing of CBS gene (many prefer this nowadays) and/or measurement of CBS enzyme activity in cultured fibroblasts.

    • Increased methionine with normal or slightly increased total homocysteine suggests further evaluation for MAT I/III, GNMT, and SAHH deficiencies.

    • Increased total homocysteine with decreased methionine is evaluated for CblE, CblG, or MTHFR deficencies if normal MMA versus CblC, CblD, or CblF deficiencies if MMA is elevated.

In patients presenting clinically with possible homocystinuria due to CBS deficiency, first line testing includes plasma amino acids and total plasma homocysteine, both of which will be clearly elevated; and cysteine levels, which will be lowered in CBS deficiency. Usually, if total homocysteine is slightly elevated but still <30 micromolar, plasma SAM and SAH levels may be necessary to distinguish disorders of the initial enzymes of methionine transsulfuration from less severe CBS deficiency.

The absence of megaloblastic anemia, determined from differential analysis of the complete blood count, will distinguish CBS deficiency homocystinuria (with high methionine) from the group of cobalamin related conditions (disorders of cobalamin absorption and/or transport, as well as cblE and cblG deficiencies) of hyperhomocysteinemia with megaloblastic anemia. Gene sequence analysis will confirm the diagnosis, as will enzyme assay of cultured skin fibroblasts or stimulated lymphocytes.

If you are able to confirm that the patient has homocystinuria, what treatment should be initiated?

Treatment of classic homocystinuria is based on ameliorating and/or preventing the sequelae of chronic metabolite abnormalites manifested by elevated total homocysteine. To this end, patients should first be therapeutically challenged with pyridoxine (B6) to distinguish the likely milder pyridoxine responsive versus nonresponsive patients. This challenge must be performed in the presence of normal folate and vitamin B12 levels. Positive response, indicated by declines in total homocysteine and methionine levels, should be evident following doses of 100-200 mg three times daily (50 mg three times daily in neonates). No side effects have been reported, but neurologic precautionary followup is advised, especially if higher doses are used.

Patients who do not respond adequately, or at all, are placed on methionine restricted diets. These are usually some combination of methionine free amino acid mixtures and added natural protein which is restricted based on serial analyses of amino acid and homocysteine levels. Close monitoring by a metabolic nutritionist or equivalent will be necessary.

These restricted diets are not often easily tolerated, especially if started outside the infant age groups. For patients with inadequate responses, whether due to dietary noncompliance or severe deficiency of CBS activity, pharmacologic therapy with betaine (N,N,N-trimethylglycine) is indicated. Betaine is a potent methyl donor and can serve in the remethylation pathway of homocysteine to methionine. The side effect of increasing the level of methionine appears to be well tolerated and the benefits of lowering plasma homocysteine and total homocysteine levels are evident in both pyridoxine responsive and nonresponsive patients.

Of note, although betaine may limit the need for dietary restriction in some patients, cysteine remains a required essential amino acid that will need to be supplemented in some form. Similarly, folate and vitamin B12 supplementation may be needed to optimize their levels, considering their roles in methionine synthesis.

What are the adverse effects associated with each treatment option?

Pyridoxine therapy appears to thus far be without adverse effects. Cautionary monitoring for neurologic symptoms, however, is recommended.

Betaine thus far appears to be a relatively well tolerated drug. There may be a rare association of betaine usage with cerebral edema in patients with excessively elevated blood levels of methionine, both of which are reversed with elimination of betaine dosage. In contrast, several patients have complained about a sulfurous body odor associated with use of the drug, which may limit its compliance.

The methionine restricted diet, with cysteine supplementation, may not be easily tolerated in some patients.

What are the possible outcomes of homocystinuria?

As stated above, classic homocystinuria due to CBS defiiciency results in some combination of ophthalmologic, neurologic, skeletal, and cardiovascular complications.

Severe progressive myopia leading to ectopic lentis may be present in approximately 70% of patients by age 10. Accompanying this complication may be acute pupillary block glaucoma due to anterior dislocation of the lens. This progression of ophthalmologic complications occurs in both B6 responsive and nonresponsive types, although the timing for B6 responsive patients is variably prolonged by several years.

Osteoporosis is detected in at least 50% of all patients by the end of their second decade of life, again with a few years difference between B6 responder and nonresponders.

Thromoboembolic events with vascular occlusions can occur at any age. Untreated B6 responsive patients appear to not demonstrate this risk until age 12 years, with a risk progressing to at least 25% probability by age 20 years. In contrast, non B6 responders have a cumulative risk of 25% by about 15 years of age. Even in the absence of symptoms of ischemia, ultrasonographic studies can demonstrate many patients to have signs of early vascular disease. Clinical states associated with increased risk of thromboembolism, such as pregnancy and postpartum periods, are even greater risks.

Anecdotal reports of unexplained pediatric pulmonary hypertension, bronchiectasis, spontaneous pneumothoraces, and any CNS (seizures, behavioral, psychiatric) or ocular manifestations abound in the literature suggesting the variable consequences of such thromboembolic events. It has been suggested that any pediatric patient with a deep venous thrombosis or stroke be considered for evaluation for homocystinuria.

Most studies indicate developmental delay as the most likely presenting sign, usually by 2 years of age. Median IQ scores of 64 were found in one international study but with widely varying individual IQ scores. Median IQ scores in B6-nonresponsive patients were 56 compared to B6 responsive patients demonstrating 78, and further studies have continued to demonstrate more severe involvement in B6 nonresponsive patients.

Other CNS involvement includes psychiatric abnormalities of all types, perhaps being as high as 50% of patients, seizures or EEG abnormalities alone occurring in about 20-25% of patients, and some patients having focal neurologic findings that include extrapyramidal symptoms suggesting prior cerebrovasculcar accidents.

Early death and, less commonly, ischemic heart disease, may be a complication of the arteriovenous thromboemboli.

Several clinical studies have demonstrated the efficacy of pyridoxine in both types of patients in preventing initial clinically detected thromboembolic events, frequency of lens dislocation and improvement in behavior and IQ. In response to patients identified by newborn screening followup, pyridoxine should demonstrate at least a partial biochemical response in B6-responsive patients within 4-6 days, although the majority of patients identified by newborn screening are likely to be the B6 nonresponsive types. These would be placed on methionine restricted diets and prospective and retrospective studies have demonstrated fewer and less severe problems related to thromboembolic events, osteoporosis, and ectopic lentis.

Many of these patients identified in the newborn period and fed methionine-restricted diets have age appropriate intellectual testing scores at higher rates than predicted for untreated patients. Limited data on the few B6 responsive individuals detected by newborn screening suggest that, in association with methionine restriction, most attain normal or near normal intelligence. In patients detected after the newborn period, similar but less dramatic results are observed.

The use of betaine has been associated with the absence of vascular events in even B6 nonresponsive patients in some studies but with variable improvements in behavior complications and little change in already evident osteoporosis. Its effect on the development of progressive myopic damage and ectopic lentis remains to be studied.

What causes this disease and how frequent is it?

Homocystinuria is due to disruption of the normal metabolic degradation pathway producing homocysteine from methionine. The classical form of the disease is an autosomal recessive disorder due to mutations in the CBS gene, encoding the enzyme cystathionine beta-synthase (CBS), which degrades homocysteine to cystathionine.

The prevalence of the disorder has been reported to be 1/200,000 to 1/335,000 worldwide, but with some local regional variation. The milder clinical forms of B6 responsive CBS deficiency have often not been recognized and historically likely resulted in underestimation of the prevalence.

Using molecular techniques to detect all forms of CBS deficiency in populations and results from newborn screening, several areas are now known to have much higher prevalence rates. These include extremely high rates in Qatar (1/1800) and perhaps Norway (estimated 1/6400). In contrast, slightly more modest rates are noted in Germany (1/17,800) and Ireland (1/65,000). Certain alleles are associated with either B6 responsiveness or B6 nonresponsiveness but the majority of the mutations noted are patient/family specific.

Heterozygote carriers of single mutations in the CBS gene are clinically asymptomatic. Rarer metabolic causes of elevations of homocysteine are due to disruption of the normal metabolic pathway converting homocysteine back to methionine. These usually involve steps in producing the cobalamin (B12) cofactor for the enzyme methionine synthase (MTR). These disorders are similarly autosomal recessive due to mutations in the associated genes involved in the sequential steps affecting cobalalmin metabolism (MMACHC, MTRR, and MTR for cblC, cblE, and cblG respectively) and an interacting step involving methyl group transfer to cobalalmin, MTHFR, a folate containing enzyme.

How do these pathogens/genes/exposures cause the disease?

The enzymatic deficiencies in either degrading homocysteine into cystathionine (CBS mutations) or converting homocysteine back to methionine (cbl C-G disorders, MTHFR) produce abnormally elevated levels of homocysteine. Homocysteine contains an active sulfhydryl group which readily produces disulfide bonds with itself (homocystine) and the amino acid cysteine (homocysteine-cysteine mixed disulfide) to produce elevation of these compounds in body fluids.

In a similar way, the sulfhydryl group in the elevated homocysteine (and related compounds) is thought to disrupt secondary structure in a number of proteins through interaction with their sulfur containing amino acids. In this way, protein structure and function is affected in the vascular endothelium, platelets and connective tissue, including bone.

Since CBS deficiency causes a decrease in the production of cysteine from homocysteine through its block in formation of the required intermediate cystathionine, the structure of the cysteine rich region of the zonular fibers of the lens is additionally affected. The accumulated damage from subclinical and overt strokes from vascular thromboses contribute to this progressive, multiorgan disorder. This most likely explains the prevalent but variable mental retardation associated with homocystinuria.

Another mechanism thought to contribute to the diverse clinical phenotype includes the production of excess reactive species of oxygen from homocysteine, resulting in oxidative damage to tissues.

Other clinical manifestations that might help with diagnosis and management

Despite similar skeletal appearance and eye findings, differentiation of patients with homocystinuria from Marfan syndrome may be evident by the lack of protrusion of the thumb beyond the edge of the folded hand when placed against the palm (Thumb sign of Marfan syndrome) and generally less hyperdistensibility of joints. More frequently (but not always) the dislocated lens is displaced inferiorly compared to the superior displacement observed in Marfan syndrome.

Patients with homocystinuria often demonstrate hypopigmentation of the skin and hair. The skin may react in an exaggerated way in response to either heat or cold, with pallor, erythema, or bluish discoloration, as well as cutis marmorata. The hair may be quite coarse.

Psychiatric disorders including depression, personality disorders, obsessive-compulsive and other behavioral disorders, as well as schizophrenia may be present. Many, if not all, patients have some type of hepatic involvement which may produce mild hepatomegaly with imaging characteristics and/or biopsied pathology of fatty infiltration. There may be mild increases in serum transaminases. It is unclear whether this reflects damage producing a true hepatocellular dysfunction versus simply inflammation in most cases. Hypertension due to renal artery thrombosis may be present. Vascular thromboses may affect any organ and produce clinical findings.

What complications might you expect from the disease or treatment of the disease?

Discussed above.

Are additional laboratory studies available; even some that are not widely available?

Discussed above.

How can homocystinuria be prevented?

As an autosomal recessive disorder, homocystinuria will statistically be the result of 25% of the offspring of carriers of mutations in the CBS gene. Once a proband is identified with homocystinuria, molecular testing of the CBS gene should be performed to both confirm the diagnosis and provide the ability to test other family members for carrier status and/or presymptomatic state.

Prenatal testing is available by both biochemical and molecular genetic testing. The latter may be performed on cultured amniocytes and chorionic villi sampled cells if both disease-causing alleles of an affected family member have been identified. Measurement of CBS enzyme activity may be performed on amniotic fluid cell cultures (but not CVS samples). Measurement of total homocysteine in cell-free amniotic fluid is also available. This can provide data for reproductive choices and/or earliest newborn identification for treatment.

Similarly, newborn screening may identify presymptomatic individuals whose clinical course can be positively affected by early treatment approaches using pyridoxine (B6) supplementation, dietary restriction of methionine, sometimes requiring cysteine supplementation, and betaine therapy.

What is the evidence?

Picker, JD, Levy, HL, Pagon, RA, Bird, TD, Dolan, CR. "University of Washington". Seattle. 2011.

(An excellent review, especially of diagnostic and genetic testing and clinical differential approaches to patients.)

Mudd, SH, Levy, HL, Kraus, JP, Valle, D, Beaudet, A. "Chapter 88: Disorders of Transsulfuration in Scriver’s OMMBID The Online Metabolic and Molecular Bases of Inherited Disease". The McGraw-Hill Companies. pp. 1-110.

(A comprehensive and updated review of all of the disorders associated with the metabolic pathways. Excellent comprehensive listings of mutations and reviews of outcome of previous and ongoing therapeutic studies.)

Fowler, B, Sarafoglou, K, Hoffman, GF, Roth, KS. "Pediatric Endcrinology and Inborn Errors of Metabolism (2009)". McGraw Hill Medical. pp. 185-193.

(An excellent clinically oriented review of the subject.)

Mudd, SH. "Hypermethioninemias of genetic and non-genetic origin:a review". Am J Med Genet Par C Semin Med Genet. vol. 157. 2011. pp. 3-32.

(A comprehensive review of the six genetic conditions leading to abnormal methionine elevations. Excellent section on CBS deficiency, pp 10-16, with excellent review of mutations and clinical consequences with insights into pathophysiology.)

Lawson-Yuen, A, Levy, HL, Theone, JG. "Betaine treatment for the homocystinurias". Small Molecule Therapy for Genetic Disease. Cambridge University Press. 2010. pp. 173-181.

(A comprehensive review of the results to date of this directed therapy of homocystinuria.)

Ongoing controversies regarding etiology, diagnosis, treatment

Discussed above.

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