Dermatologic Manifestations of Homocystinuria

Updated: May 17, 2022
Author: Janette Baloghova, MD, PhD; Chief Editor: Dirk M Elston, MD 


Practice Essentials

Homocystinuria is an inherited autosomal recessive defect in methionine metabolism that is caused by a deficiency in cystathionine synthase.[1]  This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine. Note the figure below.

Simplified picture showing homocysteine involvemen Simplified picture showing homocysteine involvement in different metabolic pathways, as well as the role of vitamins B-6, B-12, and folate as a co-factors in this pathway.

In 1960, the first case of homocystinuria was reported from Northern Ireland. The patient was initially described as having an unusual case of Marfan syndrome with renal abnormalities at age 7 years. He had recovered from acute glomerulonephritis at age 6 years and was found to be hypertensive the following year. The patient was mentally slow and thin and had fair hair, pale skin, and flushed cheeks. He had arachnodactyly, dolichostenomelia, pes cavus, a high arched palate, and bilaterally dislocated lenses. At age 10 years, the patient's urine was found to contain a large quantity of homocysteine; urinalysis results for the nitroprusside cyanide test were positive. The boy's left eye was enucleated because of a staphylococcal infection that occurred after acute pupillary-block glaucoma developed. His right lens became dislocated into the anterior chamber and had to be removed.

The patient's blood pressure readings normalized after his left kidney was removed when he was aged 13 years. Thick-walled internal arteries were noted at histologic examination. When pyridoxine supplementation was initiated at age 18 years, the patient's plasma homocysteine levels decreased below the reference range. Daily folic acid supplementation was added 1 year later because his plasma folate level was low. At age 20 years, the patient had a perforated duodenal ulcer. Chest pain occurred at age 27 years and recurred at age 34 years. The chest pain was considered to be angina and was successfully treated. At age 50 years, the patient's plasma homocysteine levels still remained low. The patient developed acute gout, which responded to indomethacin therapy.


The life expectancy of patients with homocystinuria is reduced. Almost one fourth of patients die as a result of thrombotic complications (eg, heart attack) before they are aged 30 years. The prognosis is favorable if patients use adequate diet alimentation.

Imaging studies

With conventional MRI, the brain abnormalities are detected in cobalamin C/D defect and include unusual basal ganglia lesions, hydrocephalus, and supratentorial white matter abnormalities.[2]

Histologic findings

DL-homocysteine inhibits the production of tyrosinase, which is the major pigment enzyme. Increased concentrations of the methionine metabolite are toxic to the nervous system. Histologic analysis of brain tissue specimens from patients with homocystinuria reveals local foci of gliosis and necrosis.

Also see Workup.

Surgical care

Surgical treatment should be considered, especially in patients with pupillary-block glaucoma or in those with recurrent lens dislocation into the anterior chamber. Other ophthalmologic or orthopedic disorders should be corrected.

Also see Medical Care and Long-Term Monitoring.


An ophthalmologist should be consulted for the treatment of repeated lens dislocation, acute pupillary-block glaucoma, and other ophthalmologic disorders.

An orthopedist should be consulted to correct orthopedic disorders.


Patients must maintain a diet with limited amounts of protein (1 g/kg) and amino acid mixtures. The diet must be free of protein hydrolysate.

Patients in whom the disease does not respond to pyridoxine supplements must be treated with dietary reductions in methionine and with cysteine supplementation.


Homocysteine is metabolized by means of 2 pathways: remethylation and transsulfuration.

The remethylation pathway comprises 2 intersecting biochemical pathways and results in the transfer of a methyl group (CH3) to homocysteine from methylcobalamin, which receives its methyl group from S-adenosylmethionine (SAM), from 5-methyltetrahydrofolate (an active form of folic acid), or from betaine (trimethylglycine). Methionine can then be used to produce SAM, the body's universal methyl donor, which participates in several other key metabolic pathways, including the methylation of DNA and myelin.

The transsulfuration pathway of methionine/homocysteine degradation produces the amino acids cysteine and taurine. This pathway is dependent on adequate intake of vitamin B-6 and the hepatic conversion of vitamin B-6 into its active form, pyridoxal-5'-phosphate (P5P). The amino acid serine, which is a downstream metabolite generated from betaine via the homocysteine remethylation pathway is another necessary step.

Folate and vitamin B-12 are required for the remethylation of homocysteine to methionine. Findings from experimental studies have indicated that thyroid hormones affect folate metabolism. The observation that methylenetetrahydrofolate reductase is increased in hyperthyroidism and decreased in hypothyroidism may be relevant to the relationship between plasma homocysteine levels and thyroid status.

Women tend to have lower basal levels of homocysteine than do men, and neither contraceptives nor hormone replacement therapy seems to significantly alter the levels. Homocysteine concentrations are higher in postmenopausal women than in premenopausal women.

On the basis of the type of homocystinuria, the following 3 nosologic units are distinguished:

  • Homocystinuria can be caused by the deficiency of cystathionine synthase. This is the classic form. The gene for this deficiency is located on band 21q22.3. This unit includes the following forms: vitamin B-6 sensitivity (1.5% enzymatic activity), vitamin B-6 resistance (0% enzymatic activity), an intermediate variant, and a benign variant.

  • Homocystinuria can be caused by insufficient vitamin B-12 synthesis resulting from a defect in the remethylation of homocysteine to methionine; methylmalonic aciduria is present.

  • Homocystinuria can be caused by a deficiency in methylenetetrahydrofolate reductase.[3] The methionine level is in the reference range.

Urine methionine and homocysteine levels are elevated because of deficient levels of cystathionine beta-synthase. In addition to this, at least 7 causes of homocystinuria are known: (1) defect in vitamin B-12 metabolism, (2) deficiency in N -5,10-methylenetetrahydrofolate reductase, (3) selective intestinal malabsorption of vitamin B-12, (4) homocystinuria responsive to vitamin B-12 (cobalamin [cbl] type E), (5) methylcobalamin deficiency with cbl type G, (6) type 2 vitamin B-12 metabolic defect, and (7) transcobalamin II deficiency.

The basis of the disease is a defect of the gene coding for L-serine dehydratase cystathionine synthase, which converts homocysteine and serine into cystathionine. Deficient activity of this enzyme has been demonstrated in liver extracts, in brain tissue, and in cultured skin fibroblasts and lymphocytes. The deficiency leads to an accumulation of homocysteine and methionine and to its conversion into homocysteine, which is excreted in the urine (Legal test results are positive). Alternatively, methionine is reformed and detectable in appreciable amounts in the urine and serum. The accumulation of homocysteine leads to damage of the collagen and elastic fibers. The binding of homocysteine to lysine residues results in the formation of thiazine bonds.

DL-homocysteine inhibits the production of tyrosinase, which is the major pigment enzyme. Increased concentrations of the methionine metabolite are toxic to the nervous system. Histologic analysis of brain tissue specimens from patients with homocystinuria reveals local foci of gliosis and necrosis.

In 1985, Mudd et al studied hybrid cells of human fibroblasts with normal cystathionine beta-synthase activity and hamster cells without enzyme activity and found that enzyme activity was co-segregated with chromosome 21.[4] Two other enzymes involved in sulfur amino acid metabolism have been mapped: 5-methyltetrahydrofolate and L-homocysteine S-methyltransferase are mapped to chromosome 1, and cystathionase is mapped to chromosome 16.[5]

In cases of genetic deletion and partial trisomy, the levels of activity are consistent with the locus of cystathionine beta-synthase (CBS) between bands 21q22.1 and 21q21. As reported in the study of fibroblasts, 3 types of cystathionine synthetase deficiency exist; these include types with reduced activity and normal affinity for P5P and types with reduced activity and reduced affinity for the cofactor.

The human CBS gene spans more than 30 kilobases and contains 19 exons. Three different 5' untranslated regions exist in the gene.

Molecular analysis of the methionine synthase reductase (MTRR) gene in one patient reveals compound heterozygosity for a transition c.1459G>A (G487R) and a 2–base pair (bp) insertion (c.1623-1624insTA). Another patient was homozygous for a 140-bp insertion (c.903-904ins140). The insertion is caused by a T>C transition within intron 6 of the MTRR gene, which presumably leads to activation of an exon splicing enhancer. These findings support the concept that this disorder is caused by mutations in the MTRR gene.

Four different mutations were identified in patients in the United Kingdom (c.374G>A, R125Q; c.430G>A, E144K; c.833T>C, I278T; c.919G>A, G307S) and 8 mutations were identified in patients from the United States (c.341C>T, A114V; c.374G>A, R125Q; c.785C>T, T262M; c.797G>A, R266K; c.833T>C, I278T; c.919G>A, G307S; g.13217A>C (del ex 12); c.1330G>A, D444N).[6] The I278T was the predominant mutation in both populations. The spectrum of mutations observed in patients from the United Kingdom and the United States is closer to that observed in Northern Europe and bears less resemblance to that observed in Ireland.

Severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine can be another cause of hypermethioninemia.[7]

To date, 130 pathogenic mutations have been recognized in the CBS gene. In 2004, Orendae examined 10 independent alleles in Polish patients with cystathionine beta-synthase deficiency.[8] They detected 4 already described mutations (c.1224-2A>C, c.684C>A, c.833T>C, and c.442G>A) and 2 novel mutations (c.429C>G and c.1039+1G>T). The pathogenicity of the novel mutations was demonstrated by expression in Escherichia coli. This is the first published communication on mutations leading to cystathionine beta-synthase deficiency in Poland.

Fibrillin-1 is a 350-kd calcium-binding protein that assembles to form 10- to 12-nm microfibrils in the extracellular matrix. The structure of fibrillin-1 is dominated by 2 types of disulfide-rich motifs, the calcium-binding epidermal growth factorlike and transforming growth factor beta binding proteinlike domains. Disruption of fibrillin-1 domain structure and function contributes to the pathogenic mechanisms of homocystinuria.[9]

Methylmalonic aciduria and homocystinuria, combined methylmalonic aciduria and homocystinuria (cblC) type, is the most frequent inborn error of vitamin B-12 metabolism.[10] The gene responsible for cblC, MMACHC, has been identified. Several observations on ethnic origins were noted: the c.331C>T mutation is seen in Cajun and French-Canadian patients and the c.394C>T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations. The recognition of phenotype-genotype correlations and the association of mutations with specific ethnicities will be useful for identification of disease-causing mutations in cblC patients, for carrier detection, and for prenatal diagnosis in families in which mutations are known.[11, 12, 13]

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 X 10-3), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 X 10-3), implying clinical underascertainment.

The cblD gene is localized to 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region. Transfection of wild-type MMADHC rescued the cellular phenotype, and the functional importance of mutant alleles was shown by means of transfection with mutant constructs. The predicted MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin-binding motif and a putative mitochondrial targeting sequence. Mutations in a gene designated MMADHC are responsible for the cblD defect in vitamin B-12 metabolism. Various mutations are associated with each of the 3 biochemical phenotypes of the disorder.[14]

Using data from 7038 Hordaland Homocysteine Study participants, tCys concentrations show a strong positive association with body mass index, mediated through fat mass. The link between cysteine and lipid metabolism deserves further investigation.[15]

The common polymorphism of the MTHFR gene, c.677C>T, a known risk factor for elevated plasma homocysteine levels, occurs frequently in the white persons. The sequence alteration c.677C>T combined with severe MTHFR mutations in a compound heterozygous state may lead to moderate biochemical and clinical abnormalities, exceeding those attributed to the c.677TT genotype, and might require, in addition to folate substitution, further therapy to normalize homocysteine levels.[16, 17]

Jakubowski et al showed that plasma N -Hcy-protein levels are significantly elevated in CBS - and MTHFR -deficient patients and that CBS -deficient patients have significantly elevated plasma levels of prothrombotic N -Hcy-fibrinogen.[18] These results provide a possible explanation for the increased atherothrombosis observed in CBS -deficient patients.

Homocysteine is readily oxidized in plasma to form homocystine- and homocysteine-mixed disulfides. This oxidation has been correlated with reactive oxygen species generation. Homocysteine can stimulate reactive oxygen species formation in a number of different cell types, such as splenic B lymphocytes, mesangial cells, monocytes, and vascular smooth muscle cells. The oxidative stress might participate, at least in part, in the pathophysiology of homocystinuria. Homocysteine has been found to induce neurological dysfunction via oxidative stress. The cytotoxicity of homocysteine has been reported to be mitigated by antioxidants like N -acetyl cysteine, vitamin E, or vitamin C. The cells from homocystinuria patients with defects in the remethylation pathway showed high reactive oxygen species and apoptosis levels.[19]

Chang et al have described a Taiwanese infant boy with early-onset cblC disease, heterozygous for c.609G–>A and c.567dupT, who was presymptomatic at newborn screening but later showed life-threatening manifestations. He was the first Asian and was the second case with c.567dupT mutation in the literature. Moreover, all reported cblC patients with the c.609G–>A mutation have been East Asians so far; thus, authors suggest that c.609G–>A should be included in the initial mutation screening tests for a cblC patient in East Asian populations.[20]



Homocystinuria rarely occurs. The prevalence of patients with clinically ascertained CBS deficiency is only 1 in 330,000 worldwide. The molecular epidemiological studies suggest an incidence of around 1 in 10,000 in several European populations. Expanded newborn screening in the Madrid region proved fruitful.[21]

In Ireland, the frequency is higher, specifically 1 case per 65,000 population based on newborn screening and clinically detected cases. A surprisingly high prevalence of the CBS 833T-C mutation was detected among newborns who did not carry the 844ins68 variant, which is known to neutralize the 833T-CV mutation. This finding led some authors to suggest that the incidence of homocystinuria due to homozygosity for the mutation may be at least 1 case per 20,500 live births in Denmark.

The 0.5% frequency of c.1105 C>T alleles in a predominantly Slavic population of the Czech Republic is similar to the 0.8% frequency in Norwegian newborns or 0.5% shown for 200 North American adult control subjects. Although data from other European populations are lacking, similar frequencies in unrelated Norwegians, Czechs, and North Americans suggest that this variant allele may be of ancient origin and that it may be common in populations of European descent. This high population frequency of mutant CBS alleles may have important consequences for newborn screening. The expected frequency of homocystinuria because of 6 mutations in Norway and 11 mutations in the Czech Republic are similarly high, being 1 in 6,400 and 1 in 15, 500, respectively.[22]

Hypermethioninemia was reported in Korea in 2 compound heterozygous siblings with deficient activity of methionine adenosyltransferase (MAT) in their livers (MAT I/III deficiency). Molecular genetic studies demonstrate that each patient is a compound heterozygote for 2 mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III. These mutations include a previously known inactivating G378S point mutation and a novel W387X truncating mutation. W387X mutant protein, expressed in E coli and purified, has about 75% of wild-type activity.

Lu et al found an inordinately high prevalence of homocystinuria in the Taiwanese-Austronesian aboriginal tribe of Orchid Island. The prevalence of homocystinuria in the Tao tribe, estimated at approximately 1 in 240 islanders, is the highest known worldwide. All patients were homozygous for the p.D47E mutation. This mutation identified in this population suggests that it interferes with the function and stability of the CBS enzyme.[23, 24]

Sex and age

The disease is more common in males than in females, and the condition is congenital.




Neurologic features

An infant with homocystinuria is usually healthy, although thromboembolic complications of the CNS and psychomotor delay may occur during the first year of life.

Alehan et al reports a case of a previously healthy girl, age 3 years 9 months, who presented with right-sided hemiparesis and seizures. Ischemic infarction was confirmed through MRI and magnetic resonance angiography. Based on the clinical and laboratory results, a diagnosis of homocystinuria was made. Homocystinuria is an inherited disorder that affects the metabolism of the amino acid methionine. Although homocystinuria is usually associated with ischemic strokes, the sudden onset of stroke as the initial clinical presentation of homocystinuria is very rare in early childhood. Based on this case, however, metabolic screening for hyperhomocystinemia is recommended in any child presenting with a stroke.[25]

A developmental delay is noted when patients are aged 2-3 years.

Pyramidal symptoms, including muscle weakness due to an insult to the innervation of the pyramidal motor tract neurons, are occasionally observed in areas such as the leg.

Homocystinuria should be included in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay.

Skeletal and muscular features

The characteristic long thin extremities and arachnodactyly may not appear until late in childhood or during adolescence. In contrast, osteoporosis, especially that of the spine, may have already been present for some time.

Ophthalmologic features

Severe myopia is the first sign of ectopia lentis and may precede lens dislocation by several months to a year or even longer. Once established, ectopia lentis progresses, even when good biochemical control is maintained.

Vascular features

Thromboembolic events, such as cerebrovascular occlusions or pulmonary emboli, usually do not occur until adulthood but are reported in childhood and infancy.

Homocystinuria can be a cause of cerebral sinovenous thrombosis in early childhood or it can be recognized later in adolescence as a cause of cerebral venous thrombosis.[26, 27]

Vascular occlusive disease is an important and serious feature.

Other features

Psychiatric symptoms are also described in approximately half the patients with homocystinuria. The most common are psychiatric disturbances such as depression, behavioral disorders, personality disorders, obsessive-compulsive disorder, and, less commonly, bipolar disorder and psychosis.[28]

Capgras syndrome (delusional misidentification syndrome [DMS]) was reported in a 42 year-old woman with homocystinuria. It is assumed that neuronal dysfunction mediated by the N-methyl-D-aspartate (NMDA) receptor may be involved in DMS.[29]

Acute psychosis was described in a 17-year-old girl affected by cystathionine beta-synthase (CBS) deficiency presenting as an acute onset of visual hallucinations, behavioral perseverance, psychomotor hyperactivity, and affective inappropriateness. Ectopia lentis, diagnosed several years before, was  not considered as possible sign of a metabolic disorder. Psychotic symptoms were unresponsive to the conventional antipsychotic drugs and were only relieved after pyridoxine and folic acid treatment.[30]

Physical Examination

Marfan syndrome is the primary differential diagnosis. Clinical features of homocystinuria, such as ectopia lentis, dolichocephalia, and chest and spinal deformities, are similar to the features found in patients with Marfan syndrome, although the cerebral symptoms, the changes in the hair, and the disorders of mental development are absent in patients with Marfan syndrome. Generalized osteoporosis, arterial and venous thrombosis, and mental retardation, which are features of homocystinuria, do not occur in patients with Marfan syndrome. In addition, homocysteine is not detectable in the urine of patients with Marfan syndrome.

Skin findings

Buccal skin shows red macules in children, adolescents, and adults, especially those living in warm environments.

Large pores are evident on the facial skin.

A livedolike pattern of blood vessels and atrophic, small, cigarette paper–like scars may be observed on the arms and hands.

Angiomata may develop in some patients.

DL-homocysteine inhibits tyrosinase, the major pigment enzyme. Hypopigmentation may be reversible in patients with pyridoxine-responsive homocystinuria.

Pigmentary dilution is observed in patients with homocystinuria. Therefore, an increase of local homocysteine may interfere with normal melanogenesis and may play a role in the pathogenesis of vitiligo. Vitamin B-12 and folic acid, levels of which are decreased in persons with vitiligo, are important cofactors in the metabolism of homocysteine. Shaker and El-Tahlawi found out that an elevated homocysteine level was higher in male patients than in female patients and higher in patients with progressive disease.[31] No significant difference in homocysteine levels was found between either untreated vitiligo patients or patients receiving UV therapy. An elevated homocysteine level may be a precipitating factor for vitiligo in predisposed individuals.

Goswami et al describe a case report of a 6-year-old boy with homocystinuria and cerebral sinovenous thrombosis (CSVT) who had hyperpigmentation over the dorsa of the fingers, axilla, and groin.[27]

Thin, dry, fine, light hair is characteristic. Hair stained with acridine orange produces orange-red fluorescence, whereas healthy hair produces green fluorescence.

Other cutaneous findings include livedo reticularis, hyperhidrosis, or dry pale skin, as well as possible acrocyanosis. Skin can be translucent with a tendency to develop eczema.

Neurologic findings

Patients may behave aggressively.

Intelligence is slightly diminished, but in approximately one third of patients, intelligence is in the normal range.

Patients' mental capabilities have been reported to be higher in conditions that respond to pyridoxine supplementation than others.

Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency may manifest with variable neurologic manifestations. Radiologic features include white matter changes (leukoencephalopathy).[32]

Muscular hypotonia is characteristic.

Increased homocysteine levels have been detected in persons with neurological disorders such as Alzheimer disease, idiopathic Parkinson disease, Huntington disease, primary dystonia, and neural tube defects.

Skeletal and muscular findings

Signs of Marfan syndrome, such as thin and long extremities, arachnodactylia, kyphoscoliosis, and deformations of the thorax, may be present.

Homocystinuria is associated with low bone mineral density, which can lead to osteoporosis.[33]

Genua valga, pectus carinatum (excavatum), and deformed teeth can be present.

The homocysteine concentration is an important risk factor for hip fractures in Parkinson disease patients receiving levodopa.[34]

Inguinal and umbilical hernias are observed.

Muscular hypotonia is characteristic.

Spasms may occur.

Ophthalmologic findings

Ophthalmologic findings are similar to those in patients with Marfan syndrome.

Ectopia lentis is an almost universal feature in patients older than 10 years, and it can even be present in newborns.

Other findings include myopia, iridopathy, cataracts, secondary glaucoma, and degeneratio (amotio) retinae.

Atrophy of the optic nerve, strabismus, nystagmus, or diminished convergence can occur in some patients.

Dislocation of the ocular lenses usually occurs in patients aged 4-10 years.

The lens is usually displaced either inferiorly or inferonasally. Superonasal displacement is rare. Comparing other inheritable disorders that can be associated with ectopia lentis (Marfan syndrome, Ehlers-Danlos syndrome, Weil-Marchesani syndrome, Treacher Collins syndrome) in homocystinuria, the lenses are significantly more mobile and tend to dislocate frequently.[35]

Ocular phenotype in patients with cblC is variable.[36] Ocular involvement seems to be correlated with age at onset. Patients with early-onset cblC developed generally progressive retinal disease ranging from subtle retinal nerve fiber layer loss to advanced macular and optic atrophy with bone-spicule pigmentation. Patients with late-onset disease showed no definite evidence of retinal degeneration.

Retinal dysfunction in cblC disease may be more common than previously thought and can involve cones only or both rods and cones. Gaillard et al recommend a formal ocular examination with full-field electroretinography in patients with Cblc disease.[37]

Montalvo et al report a case of a male infant affected by a familial exudative vitreoretinopathy (FEVR)‒like presentation of homocystinuria that resolved with treatment of the homocystinuria. A complete ocular examination on patients with homocystinuria should be performed to rule out or diagnose retinal abnormalities. Angiography, including wide-field angiography, can be considered to evaluate retinal abnormalities with a vascular component.[38]

Vascular findings

Vascular changes mainly affect the lower extremities. Fatal arterial and venous thromboses may occur.

Hyperhomocysteinemia is an independent risk factor for atherosclerotic heart disease and pulmonary embolism. One third of patients have a thrombotic event, typically before age 30 years.[39]

Patients with homocystinuria resulting from a deficiency of cystathionine beta-synthase have an increased risk of thrombosis when they also have the Leiden mutation for factor V.

Homocysteine induces tissue factor procoagulant activity in cultured human endothelial cells.

Reduced survival and abnormally rapid turnover of platelets, fibrinogen, and plasminogen have been noted in patients with homocystinuria.

Goswami et al present a case report of a 6-year-old boy with homocystinuria and CSVT. The most common sites of CSVT are the transverse, superior sagittal, sigmoid, and straight sinuses. This child had involvement of the right transverse and superior sagittal sinuses.[40]

Oral and craniofacial findings

D’Alessandro et al reports a case of an 11-year-old patient with methylmalonic aciduria and homocystinuria, which developed during the neonatal period.[41]

The patient showed some facial features previously reported in the literature (high forehead, large floppy, low-set ears, flat philtrum, hypotonia of perioral and masticatory muscles), but no dolichocephalic skull nor long face.

The patient also showed signs that had not been previously described: epicanthal folds, broad nasal bridge, long and flat philtrum, amimic expression and, particularly, a postural alteration (the head is rotated and bent towards the left shoulder, which is lower than the right one).

Such alteration can be attributed to visual impairment and is responsible for breaking muscular and skeletal balance in the frontal plane, thus causing the horizontal planes of both maxillary bones to converge towards the right.

Other findings

A slightly foul odor of the urine is typical.

Spontaneous pneumothorax is reported in some adolescents with homocystinuria.

Pancreatitis is described as a complication of homocystinuria.

Increased homocysteine levels are implicated in a variety of other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, diabetic microangiopathy, and premenstrual syndrome.

Children with autism might have lower baseline plasma concentrations of methionine, SAM, homocysteine, cystathionine, cysteine, and total glutathione and significantly higher concentrations of S-adenosylhomocysteine (SAH), adenosine, and oxidized glutathione. This metabolic profile is consistent with impaired capacity for methylation (significantly lower ratio of SAM to SAH) and increased oxidative stress (significantly lower redox ratio of reduced glutathione to oxidized glutathione) in children with autism. An increased vulnerability to oxidative stress and a decreased capacity for methylation may contribute to the development and clinical manifestation of autism.[42]

Cystathionine beta-synthase is encoded on chromosome 21, and deficiency in its activity causes homocystinuria. The most common genetic cause of mental retardation is trisomy 21 or Down syndrome. The levels of cystathionine beta-synthase in the brains of persons with Down syndrome are approximately three times greater than those in healthy individuals.[43] The over-expression of cystathionine beta-synthase may cause the developmental abnormality in cognition in Down syndrome children and that may lead to Alzheimer-type disease in Down syndrome adults.

Vascular disease is associated with increased plasma asymmetric dimethylarginine and homocysteine, and levels of both are increased in persons with renal failure. The relationship between hyperhomocysteinemia and increased plasma asymmetric dimethylarginine may not be direct, but could be secondary do reduced renal function.[44]

Snyderman reports a case of a homocystinuric patient with development of paraparesis and increasing liver failure.[45] A liver transplantation was successful in achieving metabolic control without the need for any dietary restrictions.

Muacevic-Katanec et al present a case of a 47-year-old man, with deep venous thrombosis and spontaneous small bowel perforation. Since all possible known causes of small bowel perforation in this patient were excluded, a possible association with classic homocystinuria was considered. Homocysteine permanently degrades cysteine and lysine amino acid residues in proteins and, by this mechanism, may cause the connective-tissue weakness resulting in spontaneous pneumothorax or small bowel perforation. It could be hypothesized that connective-tissue weakness in homocystinuria is a result of homocysteine interference with recombinant human fibrillin-1 fragments or cross-linking of collagen through permanent degradation of disulfide bridges and lysine amino acid residues in proteins. DNA analysis showed three detectable mutations in the cystathionine beta-synthetase gene, 1278T:c.833T>C, and 2 new mutations, V372G:c.ll33T>G, and D520G:c.l558A>G in the alternatively spliced exon 15.[46]


Homocystinuria can cause pancreatitis.

Homocystinuria may result in thromboembolic complications.

Some authors speculate that inappropriate treatment might enhance CNS lesions of MAT I/III deficiency by causing a reversible vacuolating myelinopathy. Clinical symptoms (eg, mildly decreased appetite, sleepiness) and MRI findings (eg, abnormal T1 and T2 prolongations and reduced diffusion in the cerebral white matter) improved after discontinuation of therapy.[47]

Spontaneous pneumothorax can occur as a complication of pyridoxine-responsive homocystinuria.[48]

Legg-Calvé-Perthes disease, a previously unknown complication in homocystinuria, was seen in one of patients with the novel p.Trp323X mutation in Saudi Arabia. Some evidence suggests further support to the hypothesis of clotting abnormalities with vascular thrombosis. This may explain the occurrence of Legg-Calvé-Perthes disease in homocystinuria as a vascular thromboembolic consequence of the persistently elevated homocysteine, leading to vascular necrosis of the femoral head in this patient.[49]





Laboratory Studies

The diagnosis is based on the clinical picture and the results of laboratory analysis.

The cyanide nitroprusside reaction in the urine is used as the Brand reaction. In patients with positive screening test results, the diagnosis can be confirmed by analyzing methionine, homocysteine, and cystathionine levels by using paper chromatography, high-performance liquid chromatography (HPLC) with fluorescence detection, high-voltage electrophoresis, and amino acid tests. The reference range methionine level is less than 1 mg/dL (30 µM). Homocysteine levels of up to 0.2 µmol/mL and methionine levels of up to 2 µmol/mL characterize cystathionine synthetase deficiency.

Levels of homocysteine excreted in the urine are more than 200 mg, and the fraction of mixed bisulfite homocysteine and cysteine is established.

In the liver, the enzymatic activity of cystathionine synthase is deficient. This reduced activity can be demonstrated in a liver biopsy specimen.

Cultured fibroblasts derived from healthy skin, as well as from cells in the amniotic fluid, demonstrate cystathionine synthase activity, although the enzyme is not detectable in intact healthy skin. Fibroblasts grown from the skin of patients with homocystinuria are deficient in the enzyme.

Heterozygous patients with homocystinuria have a dominant negative effect. The cblE type of homocystinuria is a rare autosomal recessive disorder, which manifests with megaloblastic anemia.[50]

The most widely used method for newborn screening for homocystinuria is a semiquantitative bacterial inhibition assay for measuring methionine concentration in dried blood spots (DBS).

Because this method has resulted in a number of missed cases due to many factors, in 2004 Febriani developed an HPLC method with fluorescence detection to measure total homocysteine (tHcy) in DBS, which might be useful for newborn screening for homocystinuria.[51] One disk of DBS, 3 mm in diameter, was sonicated in 10 minutes. The extract was reduced with dithioerythritol and was derivatized with 4-aminosulfonyl-7fluoro-2,1,3-benzoxadiazole before injection into HPLC. This method showed good linearity (r = 0.996), precision (coefficient of variation range 2.7-5%), and excellent correlation coefficient between DBS and serum tHcy, both in control (r = 0.932) and patient samples (r = 0.952). By this method, the mean tHcy concentration in DBS of preterm newborns, full-term newborns, and adults was 1.4 ± 1.0, 2.5 ± 1.6, and 4.9 ± 1.5 µmol/L, respectively. The mean tHcy DBS concentrations in two cases of cystathionine beta-synthase (CBS) deficiency and one case of 5,10-methylenetetrahydrofolate reductase deficiency were 22.7 ± 2.88, 29.3 ± 1.90, and 41.3 µmol/L, respectively. This method, which is rapid, user friendly, and reliable, appears applicable to newborn screening of homocystinuria in place of methionine measurement.

Bártl et al developed a rapid screening procedure for simultaneous determination of cystathionine, methionine, and total homocysteine in DBS by liquid chromatography/tandem mass spectrometry.[52]

Serious complications of homocystinuria caused by cystathionine beta-synthase deficiency can be prevented by early intervention. In 2004, Refsum determined the prevalence of 6 specific mutations in 1133 newborn blood samples.[53] These results suggest that homocystinuria is more common than previously reported. Newborn screening for homocystinuria through mutation detection should be further considered.

In the study reported by Yamasaki-Yashiki et al, a new fluorometric microplate assay using a methionine-specific dehydrogenase and the resazurin/diaphorase system was established to determine the L-methionine concentration in an extract from dried blood spots for newborn mass screening for homocystinuria due to cystathionine b-synthase deficiency.[54]

The determination of thiodiglycolic acid levels in urine may help to characterize the metabolic imbalance of substances participating in methionine synthesis, which leads to hyperhomocystinuria. The determination of thiodiglycolic acid levels of the pretreated patient may indicate the degree of success of the treatment.[55]

CBS plays a key role in the intracellular disposal of homocysteine and is the single most common locus of mutations associated with homocystinuria. Sen et al used hydrogen-exchange mass spectrometry to map peptides, whose motions are correlated with transmission of interasteric inhibition and allosteric activation.[56] The mass spectrometric data provide an excellent correlation between kinetically and conformationally distinguishable states of the enzyme. A pathogenic regulatory domain mutant, D444N, is conformationally locked in 1 or 2 states sampled by the wild type of enzyme.

CBS deficiency is usually confirmed by assaying the enzyme activity in cultured skin fibroblasts. Another method of measuring the presence of CBS activity in human plasma or serum is using isotopically labeled substrates and LC-MS/MS instrumentation. Very low catalytic activities of enzymes originating from the liver can be measured in cell-free extracellular fluids.[57]

Smith et al present a study also with sensitive liquid chromatography mass spectrometry (LC–MS) method to assess the CBS activity in different kinds of cell extracts in order to diagnose CBS deficiency at the enzyme level and to evaluate the effects of diet or other manipulations on CBS activity in different cell types.[58] Secondly, it might be used in newborn screening for homocystinuria, since a faster and more sensitive method is required for an accurate diagnosis.

Since LC–MS methods use stabile isotope dilution, they usually offers the highest precision of the available techniques. This intra-assay variation is higher than a previously published the LC–MS method (1.4%)[57] ; however, those activities were measured in plasma and expressed as nmol/h X L. The CBS activity in cell extracts in this study is expressed per mg protein, which makes the rather inaccurate spectrophotometric protein determination (intra-assay CV 6%) the dominant factor invariation. In addition, the overall analysis time was reduced from 2 days to only 1 day for LC–MS methods. Another benefit of a LC–MS method is the possibility of up-scaling it to 96-wells plates, which enables high-throughput analyses.[58]  

For second-tier testing in newborn screening, LC–MS methods offer the possibility of measurement of CBS activity in plasma or cells exhibiting low CBS activity, like peripheral blood mononuclear cells. This would considerably lower diagnosis time and costs since cell culture would not be required.[58]

It is known that methionine in individuals affected by homocystinuria may not elevate until 7 days after birth. It is better to detect homocystinuria in newborns by quantification of the total homocysteine present. A quick and easy 96-well-plate method that requires a run time of 3 minutes per sample was developed. The method involves liquid chromatography tandem mass spectrometry and a deuterium-labeled homocystine internal standard. Authors anticipate the implementation of this method as a second-tier test to improve the screening algorithm for homocystinuria.[59]

Scherer et al showed that acute hyperhomocysteinemia (in vivo study) significantly reduced cholinesterase activity in the serum of rats of all ages tested.[60] They also observed that 500 μM homocysteine added to the incubation medium (in vitro study) significantly inhibited cholinesterase activity both in serum of rats and humans. These findings seem to reinforce the proposed associations of cholinesterase activity with hyperhomocysteinemia.

Patients with homocystinuria due to remethylation defects have an isolated brain choline deficiency, probably secondary to depletion of labile methyl groups produced by the transmethylation pathway.[61] Although biochemical studies suggest mild peripheral creatine deficiency, brain creatine is in the reference range, indicating a possible compartmentation phenomenon. Paradoxical increase of S-adenosylmethionine suggests that secondary inhibition of methylases contributes to the transmethylation defect in these conditions.

CBS carriers tend to have a higher total homocysteine level in the presence of folate deficiency than noncarriers.[24]

Sosvorová et al developed and evaluated a novelized gas chromatography method with flame ionization detection (GC-FID) tailored for the assessment of small changes in homocysteine concentrations in cerebrospinal fluid (CSF) during lumbar drainage in patients diagnosed with hydrocephalus. Lumbar drainage led to a decrease in homocysteine concentration, and decreasing levels corresponded to amelioration of the clinical state. Determination of CSF homocysteine in patients with confirmed or suspected hydrocephalus may serve as an independent marker for deciding on their further treatment strategy.[62]

Other Tests

Testing for heterozygosity may be valuable. The results can be used to guide the use of preventative measures such as reduced methionine intake and pyridoxine supplementation. Such testing is especially helpful in families of patients with homocystinuria.

Electroencephalographic abnormalities may be reflected as increased intracerebral pressure.

Cellular integrity may be affected in patients with high homocysteine levels, thus indicating that phase angle could be a valuable indicator of prognosis in classic homocystinuria. Phase angle is a measurement derived from bioelectrical impedance analysis that reflects cell membrane integrity and intracellular and extracellular water distribution. It is an independent predictor of mortality in several pathological conditions, such as cancer, amyotrophic lateral sclerosis, HIV infection, and kidney disease.[63]

In families with deceased probands, genetic diagnosis can be made by testing the parental MMACHC genes. If both of the parents have a MMACHC mutation at a heterozygous level, the proband’s genotype can be deduced. Zong et al report a study with 10 pedigrees, with the probands having clinically and biochemically confirmed combined methymalonic aciduria and homocystinuria. Nine variations in MMACHC were identified. Chorionic villi samples were collected in the first trimester of pregnancy for prenatal genetic diagnosis for three families. One fetus was found to be affected by cblC deficiency with compound heterozygous mutations of MMACHC, one fetus was determined to be a mutation carrier, while the third fetus had a normal genotype. By transabdominal chorionic villi sampling and DNA sequencing, genetic prenatal diagnose is performed and proved to be accurate and convenient.[64]

Hayıroglu et al present a case of 19-year-old boy. On electrocardiography, there was ST segment elevation in aVR derivation and ST segment depression in all other derivations. Transthoracic echocardiography revealed global hypokinesia. Merely plaques were detected ın coronary angiography.[65]



Medical Care

The diagnosis should be established as early as possible. Neonates in whom homocystinuria is diagnosed have had a benign course when they are fed on methionine-restricted cysteine-supplemented diets. Cysteine can be supplemented to a maximum of 500 mg/d.

The administration of pyridoxine in high doses (300-600 mg/d) is effective in some patients.

Other possible treatments include the use of folic acid (in pharmacologic doses), betaine (3-methylglycine decreases serum concentrations of homocysteine), or cyanocobalamin, as well as symptomatic supportive measures.

Homocysteine Reduction Formula, a special nutritional supplement created by Brimhall, can also lower homocysteine levels.

In patients with hypothyroidism, treatment with L-thyroxine can normalize homocysteine levels.

Betaine improves metabolic control in B6-nonresponsive patients with homocystinuria after optimum dietary control.[66, 67, 68]

Betaine therapy can precipitate cerebral edema, although the exact mechanism is uncertain. Betaine does raise the methionine level, and cerebral edema can occur when plasma methionine values exceed 1000 µmol/L. Methionine levels must be monitored in patients with cystathionine beta-synthase deficiency who are on betaine; consider betaine as an adjunct, not an alternative, to dietary control.[69, 70]

However, even when patients' serum betaine concentrations are increased by supplementation, serum homocysteine concentrations are often not lowered to the reference range. Following a low-methionine diet that keeps serum methionine within the reference range may be necessary when treating patients with homocystinuria due to cystathionine beta-synthase deficiency when betaine is administered.

Conventional treatment of cystathionine beta-synthase deficiency by diet and pyridoxine/betaine normalizes many, but not all, metabolic abnormalities associated with cystathionine beta-synthase deficiency.[71] The finding of low plasma serine concentrations in patients with untreated cystathionine beta-synthase deficiency may merit further exploration because supplementation with serine might be a novel and safe component of treatment of homocystinuria.

Long-Term Monitoring

There are very few reports of pregnancies in females with homocystinuria. Pregnancy in an affected female is associated with an increased risk of complications, miscarriage, a definite risk of a thromboembolic event. Liu et al report a case of a 23-year-old woman who had late-onset cblC, which presented at age 15 years. After long-term treatment she completely recovered. Protein intake was not restricted before or during pregnancy. She underwent a successful pregnancy and delivery of a healthy baby at term.[72]



Dietary supplements

Class Summary

These agents are used to correct nutritional deficiencies. In addition to the supplements listed below, cysteine is a sulfur-containing amino acid. It is generally considered an essential amino acid in infants.

Betaine anhydrous (Cystadane)

Betaine anhydrous is an antihomocystinuric that acts as a methyl-group donor in the remethylation of homocysteine to methionine, removing excess homocysteine from the body.


Class Summary

Vitamins are essential for normal DNA synthesis.

Pyridoxine (Pyri 500, Neuro-K)

Pyridoxine is a precursor to pyridoxal, which is important in the metabolism of proteins, carbohydrates, and fats. It also aids in the release of liver- and muscle-stored glycogen. It is involved in the synthesis of GABA in the CNS.

Cyanocobalamin (Pysicians EZ use B-12, B-12 Compliance injection)

Cyanocobalamin deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 is synthesized by microbes but not by humans or plants. It is a coenzyme in various metabolic functions, including carbohydrate and fat metabolism and protein synthesis, which are responsible for cell replication and hematopoiesis.

Folic acid (FA-8)

Folic acid is an important cofactor for enzymes used in nucleoprotein synthesis and maintenance of erythropoiesis. It stimulates white blood cells and platelet production in folate deficiency anemia.