/
/

LCHAD deficiency

This is part of Rare diseases.

Diagnosis: LCHAD deficiency

Synonyms: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency


Date of publication: 2011-03-16
Version: 1.4

ICD 10 code

E71.3

The disease

LCHAD deficiency is an inherited metabolic disease caused by the impaired functionality of a particular enzyme (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase, LCHAD). This enzyme deficiency makes it harder for the body to break down fatty acids, which are important for the body’s energy supply. Fasting, infections and physical or mental stress can cause low blood sugar levels in people with LCHAD deficiency. Fat can accumulate in the liver, heart, musculature and kidneys and interfere with their functions.

The disease was first described in the 1980s and the defective enzyme was identified by the Dutch paediatrician Ronald Wanders in 1989.

Occurrence

Every year, one or two children with LCHAD deficiency are born in Sweden. It is estimated that there are approximately 15 children with the disease in the country.

Cause

Fats (triglycerides) are the body’s most important energy source. When food has been consumed the body stores fat as a source of energy. Between meals, and above all during the long hours of the night when we do not eat, fat is broken down to provide energy. When muscles are working for short periods of time they use glycogen as their energy source, while for longer periods of activity they use fat. The brain usually uses glucose as its source of energy. During periods of fast, glucose comes mainly from glycogen and aminoacids.

When the body fails to break down fat normally it cannot produce glucose sufficiently quickly for the brain, which suffers energy deficiency. Without a speedy supply of glucose, unconsciousness and brain damage can result. Fat accumulates in the liver, heart, musculature and kidneys and their functions deteriorate.

Fat is broken down with the help of approximately twenty enzymes, which are proteins acting as catalysts in this process. (A catalyst facilitates a particular chemical reaction without being affected itself.) LCHAD is an enzyme which acts as a catalyst in one of the chemical reactions involved in the breaking down of fatty acids. In this process fatty acids are first released from triglycerides and then broken down (a process called beta oxidation) with the help of enzymes in the energy-producing parts of the cell (mitochondria). LCHAD (long-chain 3-hydroxyacyl-coenzyme A dehydrogenase) is an enzyme specialising in long chain fatty acids, a major component of body fat.

Fatty acids can also be broken down in other parts of the cell, although not as quickly. Therefore, if there is impaired functionality in one of the enzyme steps, LCHAD for example, there are alternatives. This means that functionality is usually adequate. However, when there is an increased need for fats to be broken down (e.g. in cases of fasting, fever, demanding physical activity or stress) symptoms may manifest as fat cannot be broken down sufficiently quickly.

This enzyme deficiency is caused by a genetic mutation. The LCHAD enzyme is built up of 8 proteins (sub-units), 4 α sub-units and 4 β sub-units. Two genes code for the proteins, one gene for the α and one for the β sub-units. In LCHAD deficiency the HADHA gene, the gene for sub-unit α ,has mutated. Several different mutations occur, but one (c.1528G>C) dominates.

Heredity

The inheritance pattern of LCHAD deficiency is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

The first symptoms of LCHAD deficiency can manifest at any time from the neonatal period to around the age of five. Usually the child becomes ill during the first year of life. Most children with LCHAD deficiency become acutely ill when their blood sugar level drops dramatically (hypoglycemia). This can lead to unconsciousness, with the risk of the child becoming comatose. As the fat is not broken down it accumulates in the liver, muscles and heart and in the acute phase there is an increased risk of dysrhythmia and cardiac arrest. If the attack is not treated quickly the condition will become life-threatening.

Even after the diagnosis LCHAD deficiency has been made, the general condition of those with the disease is subject to change. In cases of infection, mental or physical stress and in periods when nutrition is insufficient, symptoms may manifest as the body needs to mobilise extra amounts of energy. The child can develop hypoglycemia if treatment is not commenced early enough. Muscles become weak (muscular hypotonia), tender and painful to the touch. Sometimes muscles are so severely affected in an attack that myoglobin is released into the blood, is filtered out in the kidneys, and colours the urine red (myoglobinuria). The liver is affected, although this can be reversed with treatment.

Fat accumulates in the liver and heart of children who have undiagnosed LCHAD deficiency, causing these organs to become enlarged. Their condition can be normalised with treatment. It is believed that the accumulation of fat is the reason for poor liquid absorption in the gut, causing diarrhoea in infants with the syndrome.

Some children develop the disease more slowly, symptoms manifesting in the liver, muscles and heart.

The disease is serious, sometimes life-threatening, and requires treatment. Even with good treatment, there is still a risk of long-term complications. The eyes and vision are often affected. Children may experience problems with increased light sensitivity and deteriorating night vision. Colour vision may be impaired and children can also develop visual field defects.

When the disease starts to develop there are often characteristic changes in the pigment of the retina. In eye examinations these often look like grains of black pepper. At this stage, sight is often good, but in the longer term children with LCHAD deficiency risk serious retinal damage. Parts of the retina change and/or regress, which can lead to reduced vision and sometimes to severe visual impairment or blindness. Feeling in the peripheral nerves of the hands and feet are sometimes affected.

The way sight and nerves are affected in the longer term is unknown as the first patient in the world to receive treatment from an early age (five months) is now only twenty-one years old. It appears that children who receive a diagnosis and treatment early do not develop such severe retinal damage or impairment of peripheral nerve functions.

Women expecting a child with LCHAD deficiency are more likely than average to suffer from severe pre-eclampsia during their last trimester. They can develop HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), a very serious condition affecting the liver. Parents with a child with LCHAD deficiency who plan to have more children should be aware that there is a risk of this complication arising.

Diagnosis

Early diagnosis is important. An unexpected and dramatic deterioration in an infant’s general condition when suffering from a simple infection, fever or diarrhoea may indicate the disease. Symptoms of LCHAD deficiency may be difficult to recognise. LCHAD deficiency may be suspected if the child’s liver is affected and he/she also has both muscle weakness and hypertrophic cardiomyopathy (a condition in which the heart muscle becomes thick). Another suspicious factor is abnormal pigmentation of the retina.

The diagnosis is strengthened if the child has elevated levels of certain enzymes, including transaminases (ASAT, ALAT) and creatine kinase (CK).

A blood plasma test for elevated levels of acylcarnitines will confirm the diagnosis. In the acute phase, the presence of specific by-products will be found in a test of organic acids in the urine.

When the diagnosis is made, the eyes of children with LCHAD deficiency should be examined, preferably by a paediatric ophthalmologist or an ophthalmologist with knowledge of metabolic diseases. Subsequently, testing should be once a year. The appearance of the retina does not indicate how well or badly it functions so for this reason an electroretinography (ERG) should be carried out. In small children ERGs are usually carried out under anaesthetic and the benefits of the investigation must be weighed against the risk of precipitating a physical crisis.

The diagnosis is confirmed by a DNA-based analysis. If the mutation is known in the family pre-natal diagnosis, and often pre-implantation embryo diagnosis, are possible.

Treatment/interventions

The disease is very serious but seldom life-threatening when the diagnosis has been confirmed and treatment started.

In the acute phase glucose is administered intravenously. It has two functions. It raises glucose concentrations in the blood so that the brain’s energy needs are met, and it also releases insulin into the blood. Insulin stops the breaking down of fat so that fat accumulation in different organs slows down. During the first year of life the supply of liquids and medicine can be facilitated by a port-A-cath unit. In a surgical procedure, the unit is fitted under the skin and is connected by a tube to a large blood vessel. Medicines and liquids are injected into the unit and then flow into the blood vessel.

Continued treatment after the acute phase consists of a special low-fat diet, most of which are MCT fats (medium chain triglycerides). These medium chain fatty acids are broken down by enzymes, though not by LCHAD. Children receive vitamin supplements, minerals and some essential fatty acids otherwise found in food. The diet should be drawn up in consultation with a dietician with a thorough knowledge of metabolic diseases in children. The dietician plays an important role in treatment and is able to give information and practical advice to make everyday life easier.

If treatment is started early it can delay the impairment of vision and the onset of neurological symptoms. The diet is demanding but effective. Fat accumulations in the liver and heart disappear and muscles regain their strength. The gap between meals should not exceed four hours as it is important to avoid long periods of fasting. To prevent large amounts of fat being broken down during the night and the risk of blood sugar levels sinking, the child should be provided either with an extra night meal or a continuous supply of special nutrients. Almost all those with LCHAD deficiency receive nutritional supplements via a percutaneous endoscopic gastrostomy (PEG). In PEG, a surgical procedure creates a direct connection between the abdominal wall and the stomach. To provide special nutrients during the night a pump can be attached to the feeding tube.

In the case of infection causing an elevated body temperature, or another kind of stress associated with an increased need for energy, the person should be provided with extra glucose so low blood sugar, cramps and unconsciousness are avoided. There are many lengthy hospital visits during the first years of life for a child with LCHAD deficiency.

As the child grows, becoming more mobile and active, the parents and other adults who know the child should be aware of the the importance of the balance between play and energy intake.

Individuals with impaired vision or low visual acuity require contact with a low vision centre or similar for visual habilitation. The habilitation team includes experts from different fields with special knowledge of disabilities. Measures focus on existing needs, may vary over time and occur in collaboration with individuals close to the child. An over-sensitivity to light or reduced night vision are the most common problems.

Children and young people with the disease, with their families, may require psychological and social support. Contact with others in similar situations is valuable.

Practical advice

Sunglasses/protective goggles and/or a cap are useful in cases of over-sensitivity to light.

National and regional resources in Sweden

In collaboration with their local hospital, all children who have been diagnosed with LCHAD deficiency in Sweden receive regular treatment from a team of doctors, dieticians, nurses and psychologists who have special expertise in inherited metabolic diseases.

Specialised diagnostics

The testing of organic acids in urine and acylcarnitines in plasma is carried out at the Centre for Inherited Metabolic Diseases, CMMS, Karolinska University Hospital, Solna and the Clinical Chemistry Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.

The most common mutation (c.1528G>C) can be identified by both laboratories above. The sequencing of the whole HADHA gene is carried out at CMMS, Karolinska University Hospital.

Resource personnel

Associate professor Jan Alm, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: jan.alm@karolinska.se.

Associate professor Ulrika von Döbeln, Centre for Inherited Metabolic Diseases (CMMS), Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, email: ulrika.vondobeln@karolinska.se.

Senior physician Maria Halldin, Uppsala University Children’s Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: maria.halldin@kbh.uu.se.

Senior physician, Anna Nordenström, Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00, email: anna.nordenström@karolinska.se.

Senior physician Annika Reims, Centre for Inherited Metabolic Disorders, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00, email: annika.reims@vgregion.se.

Associate professor Kristina Teär-Fahnehjelm, Children’s Eye Clinic, St Erik Eye Hospital, Polhemsgatan 50, SE-112 82 Stockholm, Sweden. Tel: +46 8 672 30 00, email: kristina.tear-fahnehjelm@sankterik.se.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year some adults with rare diseases also visit Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

National Association for Patients with Liver Disease, Box 2918, SE-187 29 Täby, Sweden. Email: kansli@rfl-lever.se, www.rfl-lever.se.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development (R&D)

LCHAD deficiency research is under way in many parts of the world. A team in Amsterdam under the leadership of Ronald Wanders is studying the chemical and genetic aspects of LCHAD deficiency.

At Karolinska University Hospital a project is under way into energy expenditure in children with LCHAD deficiency both before and after meals and during physical exertion, and how the process is affected by diet. The research team includes a paediatrician, dietician, psychologist, ophthalmologist, clinical pathologist, chemist and physiologist. Contact Anna Nordenström. See under “Resource Personnel.”

At St Erik Eye Hospital, the paediatric eye clinic at Karolinska University Hospital, a follow-up study of eye complications in children with LCHAD deficiency is being carried out. Contact Associate professor Kristina Teär-Fahnehjelm. See under “Resource Personnel.”

Information material

An information leaflet on LCHAD deficiency summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-6-24). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Newsletter from Ågrenska on LCHAD deficiency, nr 234 (2004). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They can be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. The newsletter is also available on www.agrenska.se.

Literature

Fahnehjelm KT, Holmström G, Ying L, Haglind CB, Nordeström A, Halldin M et al. Ocular characteristics in 10 children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a cross-sectional study with long-term follow-up. Acta Ophthalmol Scand 2008; 86: 329-337.

Gillingham MB, Weleber RG, Neuringer M, Connor WE, Mills M, van Calcar S et al. Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase and trifunctional protein deficiency. Mol Genet Metab 2005; 86: 124-133.

Hagenfeldt L, von Döbeln U. MCAD-brist och LCHAD-brist - våra vanligaste betaoxidationsdefekter. Metaboliten 2001; 1: 6-14.

Hagenfeldt L, von Döbeln U, Holme E, Alm J, Brandberg G, Enocksson E et al. 3-Hydroxydicarboxylic aciduria - a fatty acid oxidation defect with severe prognosis. J Pediatr 1990; 116: 387-392.

Halldin MU, Forslund A, von Döbeln U, Eklund C, Gustafsson J. Increased lipolysis in LCHAD deficiency. J Inherit Metab Dis 2007; 30: 39-46.

Lund AM, Skovby F, Vestergaard H, Christensen M, Chrisensen E. Clinical and biochemical monitoring of patients with fatty acid oxidation disorders. J Inherit Dis 2010 Jan 12. Epub ahead of print.

Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H et al. Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. J Inherit Metab Dis 2009; 32: 488-497.

Steinmann D, Knab J, Priebe HJ. Perioperative management of a child with 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Paediatr Anaesth 2010; 20: 371-373.

Tyni T, Kivelä T, Lappi M, Summanen P, Nikoskelainen E, Pihko H. Ophtalmologic findings in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation: a new type of hereditary metabolic chorioretinopathy. Ophtalmology 1998a; 105: 810-824.

Tyni T, Paetau A, Strauss AW, Middleton B, Kivelä T. Mitochondrial fatty acid beta-oxidation in the human eye and brain: implications for the retinopathy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Res 2004; 56: 744-750.

Tyni T, Pihko H, Kivelä T. Ophthalmic pathology in long-chain 3-hydroxyacyl-CoA dehydrogenase defiency caused by the G1528C mutation. Curr Eye Res 1998b; 17: 551-559.

Walter JH. Tolerance to fast rational and practical evaluation in children with hypoketonemia. J Inherit Metab Dis 2009; 32: 214-217.

Wanders RJ, IJlst L, van Gennip AH, Jakobs C, de Jager JP, Dorland L et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 1990; 13: 311-314.

Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal 3-hydroxyacyl Coenzyme A dehydrogenase deficiency. Lancet 1993; 13: 407-408.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate professor Ulrika von Döbeln, Karolinska University Hospital, Solna, Stockholm,Sweden.

Associate Professor Kristina Teär-Fahnehjelm, St Erik Eye hospital, Stockholm, has also contributed to the production of this material.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2011-03-16
Version: 1.4
Publication date of the Swedish version: 2010-09-17

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.