Homocystinuria (HCU): A treatable metabolic disorder

HCU is a rare metabolic disorder which can affect the eye, skeleton, nervous and vascular systems. A metabolic disorder occurs when the way our bodies utilise food to create energy is not working correctly.

Proteins are large, complex molecules that are critical for the normal functioning of the human body. They are essential for the structure, function and regulation of the body’s tissues and organs. Proteins are made up of hundreds of smaller units called amino acids that are attached to one another by peptide bonds, forming a long chain. A way of visualising protein is as a string of beads where each bead is an amino acid. The role of amino acids goes beyond building blocks – they are essential for the synthesis of proteins, enzymes, hormones, neurotransmitters, metabolic pathways, mental stabilisation and most functions in the human body. Amino acids have been classified into essential and non-essential groups – essential amino acids must be found in food sources as they cannot be made in the body, whereas non-essential amino acids can be made within the body via biochemical pathways and so are not essential to the human diet.


What is homocystinuria?

One essential amino acids is methionine that is found in meat, fish and dairy products, which can be converted within the body to another amino acid known as cysteine (non-essential), during this process of conversion homocysteine is temporarily created. If the conversion pathway is not functioning, there is a build-up of homocysteine in the body and this accumulation leads to a range of dangerous symptoms as it is toxic to the body at high levels. The B vitamins namely Vitamin B6 and B12 along with folic acid normally operate within this pathway to help maintain low levels of homocysteine.

The most common form of build-up of high levels of homocysteine is known as Classical Homocystinuria (HCU). In this case the build-up occurs due to the deficient activity of an enzyme cystathionine beta-synthase. There are other very rare forms of homocystinuria which are caused by specific genetic faults affecting the same conversion pathway.

What do methionine and cysteine do in the body?

Both methionine and cysteine play key roles in protecting and promoting the health of your connective tissue, joints, skin, hair and nails. Methionine is the main precursor of the amino acid cysteine, which is essential to make the body’s ‘master antioxidant’ glutathione, this plays a crucial role in the detoxification and antioxidant systems of the body. Glutathione has been used to treat acute liver poisoning and orally for non-alcoholic fatty liver disease (1).

Homocysteine can be recycled back into methionine using Vitamin B12-related enzymes. Cysteine affects the way proteins within cells are folded, maintains their shape and links them to each other. Vitamin B6, Vitamin B12 and folic acid are key components of this pathway and therefore deficiencies in any of them can have a detrimental effect with related increases in levels of homocysteine.

The complexity of this pathway and the importance of the vitamins involved have been the focus of many studies. In a study of 1041 elderly people low levels of B12 increased homocysteine in the blood and this has been indicated with a greater risk of coronary heart disease(2). Also, cigarette smoking has been connected to increased homocysteine levels (3) along with chronic renal failure. Folic acid supplementation has been shown to lower the homocysteine concentration and reduce the risk of blood clots and atherosclerosis (4,5). The higher the homocysteine level the more severe the symptoms may become. Another view is that this is not the direct cause of damage and that homocysteine merely inhibits the methyl flow which leads to impaired DNA methylation with corresponding major negative impacts on the body (6). There are many very rare inherited enzymopathies and since most GPs do not have experience with methylation disorders they are largely underdiagnosed (7).

methionine–cysteine pathway

What are the symptoms of HCU? (8)

There is an excellent infographic showing Living with HCU (facts, figures and the importance of getting screened at birth).

HCU affects the eye, skeleton, nervous system and vascular system. It is specifically characterised by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (blood clots/thromboembolism) and central nervous system (developmental delay/intellectual disability). Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. All four ‒ or only one ‒ of the systems can be involved; expressivity is variable with corresponding different and severity of symptoms. It is not unusual for a person with no previous history or apparent symptoms to have a stroke (thromboembolic event) in their adult years. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant (9).

Prevalence and Screening

Up to 5–7% of the population will have elevations in plasma homosysteine levels (10,11). Mounting evidence suggests that even moderately raised levels can be an independent risk factor for vascular disease and recurrent venous thromboembolism.

The most common form of homocystinuria (classical HCU) affects at least 1 in 200,000 to 335,000 people worldwide. The disorder appears to be more common in some countries, such as Ireland (1 in 65,000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 1,800). The rarer forms of homocystinuria each have a small number of cases reported in the scientific literature (12) In New Zealand HCU is included in the disorders screened at birth by newborn screening. However, screening does not detect all cases of homocystinuria. If not diagnosed as a neonate, delays may be on average 4.5 years from disease onset to accurate diagnosis. There are different genetic defects that cause this disease and the fact that diet impacts its severity makes diagnosis all the more difficult.

Diagnosis and testing

Diagnosis is via a blood test. The main biochemical features of homocystinuria include markedly increased concentrations of plasma total homocysteine and methionine.

The rarer forms of HCU include the inherited methylation disorders which will also raise the homocysteine levels in the body – just via a different pathway to that of classical HCU. The cause relates to the transmethylation process in the metabolic pathway between methionine and homocysteine. The strong recommendation is to measure plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or blood symptoms, spinal cord degeneration or unexplained vascular thrombosis. If diagnosis can be determined and treatment given (parenteral hydroxocobalamin) it significantly improves survival and incidence of severe complications (13).

Treatment and management: a treatable disorder

There are several different treatments available for individuals with HCU. People with a mild form of HCU often respond to large doses of vitamin B6 (pyridoxine).

People who do not respond to vitamin B6 treatment may need to be on a special diet that is low in methionine (protein). Specialised formulas or supplement drinks rich in other amino acids can help improve nutritional balance and homocysteine levels also.

Betaine, Vitamin B12 or Vitamin B9 (folate) are also sometimes added to the HCU diet as they can help promote the conversion of homocysteine back to methionine.

HCU cannot be cured so treatment must continue for the whole of the individual’s life.

What about the patient perspective?

NZORD posed some key questions to those who know the most about living with HCU: the patients themselves.

Main challenges encountered:

  • Understanding and awareness of the disease and gaining clear information on HCU for patients themselves plus clinicians and GPs
  • Having access to resources or directly with a dietitian to gain clear informative advice for new parents on low protein recipes and foods
  • Awareness and spreading the positive outlook of HCU being a manageable disorder
  • Using a social model rather than clinical one and not only focusing on the negatives

Most helpful aspects:

  • Being one of the lucky ones to be diagnosed at birth
  • Finding other metabolic organisations such as PKU and similar, rare, inherited metabolic disorders (14); they offer low protein cooking classes and educational workshops as well as new parent café (great event for those with newly diagnosed children)

Best advice for a person to have at start of HCU journey:

  • To be told it will all be OK, to be affirmed and listened to, that it will take time to understand and adapt
  • To meet others who have already faced what you are about to go through

Future wishes for HCU:

  • Increased awareness of HCU and other related metabolic disorders
  • Better support to manage medication and diet for HCU
  • Awareness of the financial impact and expense of having a disorder like HCU – including insurance, food, bills etc
  • Better transition from paediatric to adult care
  • Standard support for access to the required proper nutrition and low protein foods
  • Better focus on metabolic diseases by researchers
  • Having the health professionals or a central body being aware of the support networks for HCU and ensuring that they inform patients of these support groups

What support is available?

NZORD offer general support for anyone in New Zealand when looking for advice or links to support groups, and their database lists HCU Network Australia who offer fantastic resources and support which New Zealanders are welcome to access. There is no designated HCU NZ support group that NZORD are aware of.

There is no formal adult service for metabolic disease, this gap has been filled by the paediatric metabolic service at Auckland hospital. Dr Callum Wilson, metabolic paediatrician at Starship Hospital, was a speaker during NZORD’s Rare Disease Day Symposium 2018. His talk can be viewed on the symposium’s webpage. There is currently no trained adult physician for metabolic disorders although this has been repeatedly requested by Dr Wilson through the Auckland DHBs. There are 600 active patients in New Zealand and over 2000 patients on the metabolic database. NZORD sees this as a major issue for equitable healthcare access for rare disease patients.


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