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Homocystinuria

CBS Deficiency

Homocystinuria is an autosomal recessive metabolic disease characterized by elevated levels of homocysteine. The most common genetic mutation involved in the disease targets cystathionine beta-synthase, an enzyme that catalyzes the conversion of methionine into cysteine.

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Presentation

Patients with homocystinuria can present with a range of findings. Given the genetic nature of the condition, they usually have a positive family history [2]. Signs and symptoms include mental retardation, thromboembolic events that can eventually lead to aphasia, hemiplegia, pseudobulbar palsy or ataxia, features of Marfan's syndrome, ectopia lentis (dislocation of the lens in the downward direction) and abnormalities in thorax and knee anatomy (pectus excavatum and carinatum, genu valgum) [3].

Classic homocystinuria presents initially with ectopia lentis, mental retardation, seizures and marfanoid features. Other forms of the disorder that involve methylcobalamin synthesis have, in addition, severe methylmalonic acidemia.

Certain factors may aggravate the risk for strokes and these include diabetes, smoking and hypertension. Furthermore, according to one Swedish report, abnormalities in oral health may be prominent. The scientists hypothesized that a diet low in protein, which is generally part of the treatment, may be substituted with diets rich in sugar and carbohydrates, leading to dental decay. Thus, it is recommended for homocystinuria patients to undergo regular dental follow ups and make sure they are performing the necessary preventive measures. The report also found that patients tend to have shortened dental roots, especially roots of the maxillary incisors [4].

A Spanish study attempted to classify the nature and severity of the symptoms depending on the type of homocystinuria. They found that remethylation defects are associated with the severest symptoms. The majority of cases, however, were characterized by transsulfuration defects. The most common symptoms in the overall population of patients were cognitive impairments and problems with the lens of the eye. Up to half of the patients presented with neurological disorders, with greater involvement of the circulatory system in patients with CBS deficiency.

Other prominent symptoms include fine and brittle hair, decreased pigmentation of the skin, crowding of the teeth, decreased joint mobility, kyphoscoliosis, a high arched palate, myopia, glaucoma and psychiatric disorders. The average IQ of patients with homocystinuria is 80, although 30% of all patients have a normal IQ [5] [6].

Marfanoid Habitus
  • The authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit[ncbi.nlm.nih.gov]
  • Gene CBS (AR) Diagnostic Test Plasma Total Homocysteine, Urine Organic Acids Neurological Psychosis/depression, behavioral disturbances, stroke, dystonia Non-Neurological Marfanoid habitus, ectopia lentis, osteoporosis, thromboembolic Treatment Methionine[treatable-id.org]
  • This will cause the complications of thromboembolism etc only (not those marfanoid habitus etc stuff).[forums.studentdoctor.net]
  • Without treatment , symptoms vary widely and may present at different ages, ranging from lens dislocation, poor vision, developmental delays, marfanoid habitus, and acute thromboembolism.[medicalhomeportal.org]
  • Nutrition/Growth/Bone Orthopedic issues include osteoporosis, marfanoid habitus, scoliosis, pectus carinatum, and pectus excavatum or pes cavus.[medicalhomeportal.org]
Arachnodactyly
  • The girl presented at the age of 13 years with macrocytic anaemia, cognitive regression and Marfanoid features such as increased arm-span, arachnodactyly, joint hyperlaxity and scoliosis.[ncbi.nlm.nih.gov]
  • Clinical features include a tall slender habitus, SCOLIOSIS, arachnodactyly, MUSCLE WEAKNESS, genu varus, thin blond hair, malar flush, lens dislocations, an increased incidence of MENTAL RETARDATION, and a tendency to develop fibrosis of arteries, frequently[fpnotebook.com]
  • Clinical features include a tall slender habitus, scoliosis, arachnodactyly, muscle weakness, genu varus, thin blond hair, malar flush, lens dislocations, an increased incidence of mental retardation, and a tendency to develop fibrosis of arteries, frequently[icd10data.com]
  • Arachnodactyly (long, spidery fingers) Seizures Cerebrovascular events Psychiatric disorders Osteoporosis Infant failure to thrive Increased chance of blood clot formation and for deep vein thrombosis Cutaneous signs of homocystinuria include: Hypopigmentation[dermnetnz.org]
  • Other symptoms include: Chest deformities ( pectus carinatum , pectus excavatum ) Flush across the cheeks High arches of the feet Intellectual disability Knock knees Long limbs Mental disorders Nearsightedness Spidery fingers ( arachnodactyly ) Tall,[huronregional.org]
Pallor
  • Two patients had definitive optic nerve pallor. All patients had retinal findings ranging from peripheral pigmentary retinal changes to central macular atrophy with Bull's eye lesions.[ncbi.nlm.nih.gov]
  • Patients with methylmalonic acidemia with homocystinuria of all types can present with developmental delay, signs of megaloblastic anemia (pallor, fatigue, and anorexia), lethargy and seizures.[orpha.net]
  • 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.[clinicaladvisor.com]
High Arched Palate
  • Long, thin fingers, tall stature, and a high arched palate are seen in some individuals and the hair is often lightly pigmented. Patients with homocystinuria have a considerable risk for blood clots that can lead to heart attacks and strokes.[disorders.eyes.arizona.edu]
  • , arched palate with crowding of the teeth Kyphoscoliosis Ectopic lentis (dislocation of the lens) Myopia Glaucoma Mental retardation (with an average IQ of 80, although approximately 30% of patients with homocystinuria have IQs in the normal range).[dermnetnz.org]
  • Presentation Skeletal features: Marfanoid habitus with normal to tall stature (occasionally failure to thrive in infancy), fine, brittle hair, hypopigmentation, high arched palate, crowded teeth, arachnodactyly, limited joint mobility, pectus excavatum[patient.info]
  • Other prominent symptoms include fine and brittle hair, decreased pigmentation of the skin, crowding of the teeth, decreased joint mobility, kyphoscoliosis, a high arched palate, myopia, glaucoma and psychiatric disorders.[symptoma.com]
  • Later in life, the abnormalities listed below may be seen: General Tall thin habitus with long fingers and toes Growth Parameters Tall for family height Skin Areas of hypopigmentation, malar flush, livedo reticularis Mouth/Teeth High-arched palate Chest[medicalhomeportal.org]
Low Set Ears
  • The patient shows some of the facial features that were already reported in the literature (high forehead, large floppy, low-set ears, flat philtrum and hypotonia of perioral and masticatory muscles) but no dolichocephalic skull nor long face.[ncbi.nlm.nih.gov]
Ectopia Lentis
  • Ectopia lentis and homocystinuria appear to have a strong correlation in Pakistani population.[ncbi.nlm.nih.gov]
  • Ectopia lentis, diagnosed several years before, didn't have been considered as possible sign of a metabolic disorder.[ncbi.nlm.nih.gov]
  • Homocystinuria usually presents with ectopia lentis, mental retardation, thromboembolic complications, and skeletal abnormalities.[ncbi.nlm.nih.gov]
  • The authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit[ncbi.nlm.nih.gov]
  • Eye anomalies include ectopia lentis (85% of the cases), with high myopia. Skeletal changes include genu valgum and pes cavus, followed by dolichostenomelia, pectus excavatum or carinatum and kyphosis, or scoliosis and osteoporosis.[orpha.net]
Strabismus
  • Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]).[ncbi.nlm.nih.gov]
  • Optical Pathway Choroid Congenital Syndromes, Malformations and Abnomalities Conjunctiva Cornea Glaucomas, Ocular Hypertension Hypertensive Retinopathy Iris and Ciliary Body Lacrimal System Lens Lids Neuro-Ophthalmology Optic Nerve Orbit Retina Sclera Strabismus[atlasophthalmology.net]
Epicanthal Folds
  • The patient also shows 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[ncbi.nlm.nih.gov]
Osteoporosis
  • Most homocystinuria patients diagnosed in adulthood have severe osteoporosis, and homocystinuria is frequently mentioned as a cause of osteoporosis. Good control of plasma homocysteine may prevent or delay some of these complications.[ncbi.nlm.nih.gov]
  • The authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit[ncbi.nlm.nih.gov]
  • HCU has been associated with increased risk for osteoporosis in some studies, but the natural history of HCU-related bone disease is poorly understood.[ncbi.nlm.nih.gov]
  • . • Homocystinuria frequently present with ectopia lentis, myopia, cognitive impairment, Marfan-like phenotype, osteoporosis, cerebrovascular, or cardiac thrombosis. • Acute psychosis has rarely been reported as a presenting symptom of the disease. •[ncbi.nlm.nih.gov]
  • The most common forms of this disorder may involve the following symptoms: dislocation of the lenses in the eyes nearsightedness abnormal blood clots osteoporosis, or weakening of the bones learning disabilities developmental problems chest deformities[healthline.com]
Genu Valgum
  • Skeletal changes include genu valgum and pes cavus, followed by dolichostenomelia, pectus excavatum or carinatum and kyphosis, or scoliosis and osteoporosis.[orpha.net]
  • valgum, thromboembolism, fatty liver; most die before age 30 of arterial and venous occlusive disease; lesser of homocysteine is seen in heterozygotes, in those with folic acid, vitamin B 12 , in renal failure and after heart transplants Lab homocysteine[medical-dictionary.thefreedictionary.com]
  • valgum), vascular system (premature atherosclerosis and thromboembolism), and central nervous system (developmental delay/mental retardation, seizures, psychiatric problems).[genedx.com]
  • valgum, pes cavus Osteoporosis Malar flush Decreased hair, skin, iris pigmentation Seizures Vascular disease and stroke Psychiatric abnormalities Mental retardation Follow-up Testing after Positive Screen Quantitative plasma amino acid analysis, total[medicalhomeportal.org]
Chest Deformity
  • Additionally, their doctor may search for signs such as chest deformities, a curvature of the spine, and dislocated lenses in the eyes.[healthline.com]
  • Other symptoms include: Chest deformities ( pectus carinatum , pectus excavatum ) Flush across the cheeks High arches of the feet Intellectual disability Knock knees Long limbs Mental disorders Nearsightedness Spidery fingers ( arachnodactyly ) Tall,[huronregional.org]
Muscle Hypotonia
  • Ehlers-Danlos syndrome type 6A (kyphoscoliotic type) is a generalized connective tissue disorder characterized by friable, hyperextensible skin, thin scars, and easy bruising; generalized joint laxity; severe muscle hypotonia at birth; progressive scoliosis[medicalhomeportal.org]
Muscle Spasm
  • The child responded well to this therapy and the muscle spasms as well as skin manifestations such as cutis marmorata subsided. The treatment is being continued; the case is reported here because of its rarity.[ncbi.nlm.nih.gov]
Blonde Hair
  • Systemic signs are blond hair, intellectual impairment and some of the features of Marfan's syndrome (e.g. tall, thin build). ho·mo·cys·ti·nu·ri·a ( hō'mō-sis'ti-nyū'rē-ă ) [MIM*236200] Metabolic disorder characterized by sparse blond hair, long limbs[medical-dictionary.thefreedictionary.com]
  • Clinical features include a tall slender habitus, SCOLIOSIS, arachnodactyly, MUSCLE WEAKNESS, genu varus, thin blond hair, malar flush, lens dislocations, an increased incidence of MENTAL RETARDATION, and a tendency to develop fibrosis of arteries, frequently[fpnotebook.com]
  • Clinical features include a tall slender habitus, scoliosis, arachnodactyly, muscle weakness, genu varus, thin blond hair, malar flush, lens dislocations, an increased incidence of mental retardation, and a tendency to develop fibrosis of arteries, frequently[icd10data.com]
  • Discussion All patients with dislocated lenses and mental retardation are suspect of having homocystinuria, especially if blue-eyed, blond-haired and rosy cheeked.[healio.com]
Eczema
  • […] thrive Increased chance of blood clot formation and for deep vein thrombosis Cutaneous signs of homocystinuria include: Hypopigmentation due to inhibition of tyrosinase Fair and thin hair Thin, translucent skin Hyperhidrosis Dry skin with tendency to eczema[dermnetnz.org]
  • […] reported Treatment: Pyridoxine Sulfite oxidase deficiency (606887) Sulfite oxidase SUOX (12q13)* Biochemical profile: Elevated urine sulfite, thiosulfate, and S-sulfocysteine; decreased sulfate Clinical features: Developmental delay, ectopia lentis, eczema[merckmanuals.com]
Sparse Hair
  • Symptoms of homocystinuria include mental retardation; displacement of the lenses of the eyes; shuffling gait; fine, sparse hair; skeletal deformations; and sometimes fatal episodic obstruction of blood vessels with clots.[britannica.com]
Hyperhidrosis
  • […] disorders Osteoporosis Infant failure to thrive Increased chance of blood clot formation and for deep vein thrombosis Cutaneous signs of homocystinuria include: Hypopigmentation due to inhibition of tyrosinase Fair and thin hair Thin, translucent skin Hyperhidrosis[dermnetnz.org]
Broad Nasal Bridge
  • The patient also shows 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[ncbi.nlm.nih.gov]
Broad Nasal Bridge
  • The patient also shows 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[ncbi.nlm.nih.gov]
Visual Hallucination
  • We describe a previously well 17-year-old adolescent with an acute psychosis characterized by auditory and visual hallucinations and marked paranoia who was found to have pyridoxine-responsive homocystinuria.[ncbi.nlm.nih.gov]
  • Here, we describe a 17-year-old girl affected by CBS deficiency presenting acute onset of visual hallucinations, behavioral perseverance, psychomotor hyperactivity, and affective inappropriateness.[ncbi.nlm.nih.gov]
Psychiatric Symptoms
  • CNS and psychomotor delay may occur during the first year of life, developmental delay (in patients aged 2-3 years), psychiatric symptoms, pyramidal symptoms including muscle weakness may occur.[apicareonline.com]
Seizure
  • Reported is an association of atypical benign childhood epilepsy with centrotemporal spikes (BECTS) and homocystinuria in three apparently healthy children with borderline intelligence, two of whom had difficult-to-control seizures.[ncbi.nlm.nih.gov]
  • A previously healthy girl, age 3 years 9 months, presented with right-sided hemiparesis and seizures. Ischemic infarction was confirmed through magnetic resonance imaging and magnetic resonance angiography.[ncbi.nlm.nih.gov]
  • There was no significant past history of mental retardation, failure to thrive, or seizure disorder as reported in classic cases of cblC.[ncbi.nlm.nih.gov]
  • The authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit[ncbi.nlm.nih.gov]
  • At most recent follow-up (mean age 50 months, range 9-84 months), of twelve children with early-onset cblC, three (25%) had a history of clinical seizures and two (17%) meet criteria for microcephaly.[ncbi.nlm.nih.gov]
Stroke
  • 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.[ncbi.nlm.nih.gov]
  • The differential diagnosis includes the following: Other problems to be considered include carotid disease and stroke.[emedicine.medscape.com]
  • Furthermore, homocystinuria is rarely revealed by cerebral sinovenous thrombosis at the onset of the disease and should systematically be ruled out in pediatric stroke.[ncbi.nlm.nih.gov]
  • Nervous system involvement can lead to strokes, seizures and psychiatric disorder. Diagnosis is established with extensive metabolic testing.[symptoma.com]
  • […] developmental delays History / PE : Marfan features (tall stature, joint hyperlaxity, long extremities) PLUS mental retardation, thromboembolic events, downward dislocation of the lens Treatment : High doses of vitamin B6 Complications : Thromboembolic events (strokes[medlibes.com]
Nystagmus
  • Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]).[ncbi.nlm.nih.gov]
  • Case 2 involves an 8-year-old girl with nystagmus and developmental delay in whom megaloblastic anaemia was detected at 11 weeks of age.[ncbi.nlm.nih.gov]
  • A majority of children had hypotonia and nystagmus.[ncbi.nlm.nih.gov]
Hyperactivity
  • […] authors report a 15-year-old Thai male who presented with generalized tonic-clonic seizures from superior sagittal sinus thrombosis, bilateral downward subluxation of ocular lenses (ectopia lentis), Marfanoid habitus, osteoporosis, attention deficit and hyperactivity[ncbi.nlm.nih.gov]
  • Here, we describe a 17-year-old girl affected by CBS deficiency presenting acute onset of visual hallucinations, behavioral perseverance, psychomotor hyperactivity, and affective inappropriateness.[ncbi.nlm.nih.gov]
Aphasia
  • Signs and symptoms include mental retardation, thromboembolic events that can eventually lead to aphasia, hemiplegia, pseudobulbar palsy or ataxia, features of Marfan's syndrome, ectopia lentis (dislocation of the lens in the downward direction) and abnormalities[symptoma.com]

Workup

Homocystinuria refers to excessive excretion of the amino acid homocysteine in the urine, but is also associated with elevated plasma concentration of the same amino acid. CBS deficiency is one of many possible metabolic abnormalities that can lead to homocystinuria. A range of other abnormalities may underlie high homocysteine levels and these include problems with remethyation, deficiency in vitamin B12 (cobalamin), vitamin B9 (folate), vitamin B2 (riboflavin) and vitamin B6 (pyridoxal phosphate). Remethylation defects can be mediated by a number of abnormalities in the synthesis of methionine synthase, MTHFR or cobalamin. Given the large extent of potential causative mechanisms, a broad range of biochemical tests need to be done to narrow the differential diagnosis.

Diagnosis of CBS deficiency may be performed by measuring amino acid levels in the plasma and urine. They will usually show elevation of methionine and presence of homocysteine. These tests are also possible in the metabolic screening programs performed on neonates. Unlike CBS deficiency, other causes of homocystinuria such as MTHFR, methionine synthase deficiency or defects in cobalamin, will not show elevated methionine. Vitamin B12 deficiency and other cobalamin defects can be ruled out through quantitative analyses of methylmalonic acid [7].


Measurements of homocysteine levels directly may be difficult because of the complex binding of a large portion of the homocysteine present in the blood with other amino acids and proteins. The connection is usually mediated by disulfide bonds such as the one present in cysteine-homocysteine and homocysteine-homocysteine complexes. Although the proportions of free and bound homocysteine are variable, the concentration of total homocysteine is generally constant. Thus, total homocysteine needs to be measured to assess for the precise quantity of homocystinuria. This is done by reducing all disulfide bonds before running the analysis with HPLC and the use of a fluorescent agent for derivatization [8].

The differential diagnosis of homocystinuria is broad, but Marfan's syndrome should be particularly suspected [9]. Other potential conditions that may explain the presenting symptoms include psoriasis, a postmenopausal status, leukemia, hypothyroidism, intake of certain drugs such as methotrexate and isoniazid and old age.

Homocysteine Increased
  • When this process does not occur as it should, blood levels of homocysteine increase and blood levels of methionine decrease. This causes harmful symptoms to develop.[cystadane.com]

Treatment

Homocystinuria is generally treated with 100 to 500 mg per day of pyridoxine. Nonetheless, not all patients are sensitive to the treatment. Those who respond require, in addition to pyridoxine, folic acid and vitamin B12. The three drugs work in combination to reduce levels of homocysteine and may help in ameliorating symptoms. Patients should also undergo preventive measures for strokes and cardiovascular disease, in the form of clopidogrel, aspirin-dipyridamole or aspirin. Studies have not conclusively determined if anticoagulants or other antiplatelet drugs have better or equal efficacy. Treatment response can be followed by assessing serum levels of homocysteine.

Patients who are insensitive to pyridoxine are recommended initially to follow a diet low with methionine. Betaine supplements can also decrease serum homocysteine levels [10].

Prognosis

Patients with homocystinuria can expect normal life expectancy if the disease is treated. In untreated cases, patients are at greatest risk from thromboembolic events that especially target the cardiac and nervous systems.

Etiology

Proteins are valuable nutritious materials to the human organism, but need to be properly processed before they can be used. Normally, proteins are broken down to their constituent amino acids. The latter are absorbed in the small bowel and further modified in the tissue where they are used in various functions.

Homocystinuria occurs when there is a defect in an enzyme called cystathionine beta-synthase (CBS). CBS normally helps metabolizing methionine, an important amino acid in the human system. When the enzyme is not working properly either because it's defective or because not enough of it is made, there is a subsequent build up of homocysteine. The concentration of homocysteine and its metabolites rises considerably in the blood and eventually results in dysfunction in various organs.

Genetic mutations in the CBS gene represent the primary etiological factors underlying homocystinuria. The National Institutes of Health has reported up to 150 mutations in the CBS gene that can eventually lead to the development of the condition. The CBS enzyme usually requires vitamin B6 to convert homocysteine. The mutation disrupts the function of the enzyme, with a resulting build up of homocysteine and a number of toxic biochemical elements in the blood. This leads to significant dysfunction in the central and peripheral nervous systems as well as in the vascular system.

Other mutations have been also involved in the disorder particularly mutations in the MTR, MTRR, MMADHC and MTHFR genes. All of these genes function in the biochemical conversion methionine into cysteine. The mode of inheritance is autosomal recessive, meaning that two copies of the mutated gene need to be acquired to express the disorder. Normally, one copy of the gene is transmitted from the mother and the other from the father. Thus, both parents need to have at least one copy of the defective gene for transmission to occur.

Epidemiology

In the United States, studies report an incidence of 1 in 100,000 of homocystinuria. These rates vary considerably internationally, with incidence ranging from 1 in 50,000 individuals to 1 in 200,000 individuals.

Mudd et al. conducted a scientific survey to determine morbidity and mortality. They found that 18% of patients with homocystinuria pass away by the time they are 30 years old. The case series involved a total of 629 patients who are deficient in the CBS enzymes [1]. Most cases of mortality are related to cardiovascular or cerebrovascular incidents. Prompt diagnosis and treatment are critical in the prevention of many complications of the disorder, particularly mental retardation, coagulopathy and ectopia lentis.

Homocystinuria can present directly at birth or much later. Mudd et al. found that risk of thromboembolic events significantly rises after patients reach the age of 20. Patients with homocystinuria type I, manifesting with CBS deficiency, are usually normal at birth. On the other hand, abnormal syntheses of methylcobalamin or disrupted tetrahydrofolate metabolism result in a form of the condition that presents very early in infancy.

Sex distribution
Age distribution

Pathophysiology

Homocystinuria is attributed to decreased activity of the enzyme cystathionine beta synthase that normally acts to convert methionine into cysteine. With a deficient enzyme, there is a build-up of homocysteine and other byproducts. The gene responsible for the enzyme is present on locus 21q22.

The accumulation of homocysteine and methionine ultimately leads to damage in tissues by disrupting collagen fibers.

Prevention

Given the genetic nature of the disease, preventive measures are essentially limited. Any family history of homocystinuria should prompt the patient to visit a genetic counselor. This may help in estimating the likelihood of having an offspring with the disorder. Pregnant women may also undergo a genetic analysis of amniotic cells and villi to detect responsible genetic mutations in the fetus.

Summary

Homocystinuria is a genetic metabolic disorder characterized by increased serum and urine concentration of homocysteine, an amino acid involved in the metabolism of methionine. Several genetic mutations are associated with the disease, the most important of which is cystathionine beta-synthase (CBS). This enzyme catalyzes the transformation of methionine to cysteine. Absence or deficient enzyme can lead to a buildup of methionine, homocysteine and other toxic products that can subsequently damage tissue, particularly in regards to collagen cross-linking. Homocystinuria is transmitted in an autosomal recessive fashion.

Symptoms can present early in life or later. Prominent symptoms include a marfanoid habitus, downward dislocation of the lens, pectus excavatum or carinatum, mental retardation and thromboembolic events. Thromboembolic events are responsible for most of the mortality and morbidity, especially when they target the cardiac and nervous systems. Nervous system involvement can lead to strokes, seizures and psychiatric disorder.

Diagnosis is established with extensive metabolic testing. Homocysteine levels in the serum and urine are difficult to estimate because the amino acid is usually bound to other proteins or amino acids with disulfide bonds. Bound and free levels of homocysteine can vary considerably although total homocysteine concentration is generally constant. Thus, evaluation of total homocysteine after reducing all disulfide bonds can determine any particular metabolic abnormalities involving the amino acid. CBS deficiency is also associated with elevated methionine levels. These tests can be performed on newborns for screening purposes.

Homocystinuria is treated with pyridoxine, although not all patients respond. Cobalamin and folic acid are also part of the treatment and help in ameliorating symptoms. Patients who are not sensitive to pyridoxine are started on a low methionine diet with betaine supplements. All patients require prophylaxis against thromboembolic events in the form of aspirin or clopidogrel.

Prognosis for patients with homocystinuria is good if patients are diagnosed early and treated properly, with no decrease in life expectancy.

Patient Information

Homocystinuria is a genetic metabolic disorder characterized by elevated levels of homocysteine. Homocysteine is an amino acid involved in many metabolic reactions in the body. Amino acids are the building blocks of proteins, one of the primary components of the nutritious material the body normally needs.

Homocystinuria is caused by genetic mutations to several genes and are transmitted in an autosomal recessive fashion. That means that the disease has no gender predilection and each offspring requires two copies of the mutated gene to have the disease. Normally, a child receives one copy from every gene from each parent, and generally both parents need to have a copy of the gene to transmit the disease to their child.

Patients with homocystinuria can present at birth or later in life. When not treated, they can suffer from mental retardation, psychiatric disorders, lax joints and clots in their hearts or brain. The latter is the most serious manifestation of the disease and can lead to grave consequences and possibly death.

Homocystinuria is diagnosed with biochemical tests that measure the levels of homocysteine and other biochemical compounds. Newborns can be screened for the disorder. Treatment is administered with pyridoxine, vitamin B12 and folic acid. Some patient may not respond to pyridoxine and would require a diet low in methionine and supplemented with betaine. Patients can expect a normal life expectancy if they are diagnosed early in infancy and treated appropriately.

References

Article

  1. Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985 Jan. 37(1):1-31.
  2. Maillot F, Kraus JP, Lee PJ. Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report. J Med Case Rep. 2008 Apr 20;2:113. 
  3. Kaur M, Kabra M, Das GP, Suri M, Verma IC. Clinical and biochemical studies in homocystinuria. Indian Pediatr. 1995 Oct; 32(10):1067-75. 
  4. Björksved M, Arnrup K. Homocystinuria and oral health. A report of 14 cases. Swed Dent J. 2012; 36(2):101-8.
  5. García-Jiménez MC, Baldellou A, García-Silva MT, et al. [Epidemiological study of the metabolic diseases with homocystinuria in Spain]. An Pediatr (Barc). 2012 Mar; 76(3):133-9. 
  6. Gomber S, Dewan P, Dua T. Homocystinuria: a rare cause of megaloblastic anemia. Indian Pediatr. 2004 Sep;41(9):941-3.
  7. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem. 2004 Jan;50(1):3-32.
  8. Carducci C, Birarelli M, Nola M, Antonozzi I. Automated high-performance liquid chromatographic method for the determination of homocysteine in plasma samples. J Chromatogr A. 1999 Jun 18;846(1-2):93-100.
  9. Summers KM, West JA, Peterson MM, et al. Challenges in the diagnosis of Marfan syndrome. Med J Aust. 2006 Jun 19;184(12):627-31.
  10. Schiff M, Blom HJ. Treatment of inherited homocystinurias. Neuropediatrics. 2012 Dec; 43(6):295-304.

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Last updated: 2018-06-22 11:14