Methylmalonic acidemia with homocystinuria

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Methylmalonic acidemia with homocystinuria is a disorder in which the body is unable to correctly process certain protein building blocks (amino acids), fat building blocks (fatty acids), and cholesterol. The body is also unable to convert the amino acid homocysteine to another amino acid, methionine. Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. There are several forms of this combined condition, and the different forms have different genetic causes and signs and symptoms. The most common and best understood form, called cblC type (or cobalamin C disease), occurs in about 80 percent of affected individuals.

The signs and symptoms of methylmalonic acidemia with homocystinuria usually develop in infancy, although they can begin at any age. When the condition begins early in life, affected individuals typically grow more slowly than expected. This sign is sometimes iedentified before the baby is born. These infants can also have difficulty feeding and have an abnormally pale appearance (pallor). Eye abnormalities and neurological problems, including weak muscle tone (hypotonia) and seizures, are also common in people with methylmalonic acidemia with homocystinuria. Many infants and children with this condition have delayed development and intellectual disability, and some have an unusually small head size (microcephaly).

Some people with methylmalonic acidemia with homocystinuria develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The signs and symptoms of early-onset methylmalonic acidemia with homocystinuria worsen over time, and the condition can be life-threatening if it is not treated.

When methylmalonic acidemia with homocystinuria begins in adolescence or adulthood, it may change an affected person's behavior and personality; the person may become less social and may experience hallucinations, delirium, and psychosis. In addition, these individuals can begin to lose previously acquired mental and physical abilities, resulting in a decline in school or work performance, difficulty controlling movements, memory problems, speech difficulties, a decline in intellectual function (dementia), or an extreme lack of energy (lethargy). Some people with methylmalonic acidemia with homocystinuria whose signs and symptoms begin later in life develop a condition called subacute combined degeneration of the spinal cord, which leads to numbness and weakness in the lower limbs, difficulty walking, and frequent falls.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Methylmalonic acidemia with homocystinuria can be caused by variants (also known as mutations) in one of several genes, including MMACHC, MMADHC, LMBRD1, and ABCD4. Variants in these genes account for the different types of the disorder: cblC, cblD, cblF, and cblJ, respectively. Another type, called epi-cblC, is caused by variants in the PRDX1 gene, usually in combination with an MMACHC gene variant.

MMACHC, MMADHC, LMBRD1, and ABCD4 are all involved in processing vitamin B12, also known as cobalamin or Cbl. The PRDX1 gene is not directly involved in processing amino acids, lipids, or cholesterol, but it is located near the MMACHC gene, and certain genetic alterations to PRDX1 can affect MMACHC gene activity.

During processing, vitamin B12 is converted to one of two molecules: adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl is required for the normal function of an enzyme that helps break down certain amino acids, lipids, and cholesterol. AdoCbl is called a cofactor because it helps the enzyme carry out its function.

MeCbl is also a cofactor, but for another enzyme that converts homocysteine to methionine. The body uses methionine to make proteins and other important compounds.

Variants in the MMACHC, MMADHC, LMBRD1, ABCD4, or PRDX1 gene affect the early steps of vitamin B12 processing, resulting in a shortage of both AdoCbl and MeCbl. Without AdoCbl, proteins and lipids are not broken down properly. As a result, potentially toxic compounds build up in the body's organs and tissues, causing methylmalonic acidemia.

Without MeCbl, homocysteine is not converted to methionine. As a result, homocysteine builds up in the bloodstream and methionine is depleted. Some of the excess homocysteine is excreted in urine (homocystinuria).

Variants in the HCFC1 gene are the most common cause of a condition called methylmalonic acidemia with homocystinuria, cblX type. This gene provides instructions for making a protein that helps regulate the activity of other genes, including the MMACHC gene. Variants in the HCFC1 gene (and, less commonly, other related genes) likely disrupt the normal activity of the MMACHC gene, impairing vitamin B12 processing and leading to methylmalonic acidemia or homocystinuria. However, variants in the HCFC1 gene likely also disrupt the normal activity of other genes, resulting in additional signs and symptoms that are more serious. Many researchers consider cblX a separate disorder from methylmalonic acidemia with homocystinuria.

Variants in other genes involved in vitamin B12 processing can cause related conditions. Variants that impair only AdoCbl production lead to methylmalonic acidemia, and variants that impair only MeCbl production cause homocystinuria.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Methylmalonic acidemia with homocystinuria is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

The condition caused by variants in the HCFC1 gene is inherited in an X-linked recessive pattern, because this gene is located on the X chromosome, one of the two sex chromosomes.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The most common form of the condition, methylmalonic acidemia with homocystinuria, cblC type, is estimated to affect 1 in 200,000 newborns worldwide. This form of the condition may be even more common in certain populations; some studies estimate that it occurs in 1 in 100,000 people in New York and 1 in 60,000 people in California.

Other types of methylmalonic acidemia with homocystinuria are much less common. Fewer than 20 cases of each of the other types have been reported in the medical literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Amblyopia · Very frequent (99-80%)

Reduced visual acuity that is uncorrectable by lenses in the absence of detectable anatomic defects in the eye or visual pathways.

Failure to thrive · Very frequent (99-80%)

Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.

Fatigue · Very frequent (99-80%)

A subjective feeling of tiredness characterized by a lack of energy and motivation.

Feeding difficulties · Very frequent (99-80%)

Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.

Global developmental delay · Very frequent (99-80%)

A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.

Hypotonia · Very frequent (99-80%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Intellectual disability · Very frequent (99-80%)

The term intellectual disability or intellectual developmental disorder is used to describe significantly sub-average intellectual and adaptive functioning based on clinical assessment and as measured by individually administered, appropriately normed, standardized and validated tests of intellectual functioning and adaptive behavior, with onset during the developmental period from infancy through adolescence.

Lethargy · Very frequent (99-80%)

A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.

Other findings in the same source

From: Orphanet

Additional reported features include Megaloblastic bone marrow (Very frequent (99-80%)); Microcephaly (Very frequent (99-80%)); Retinopathy (Very frequent (99-80%)); Seizure (Very frequent (99-80%)); Abnormal cardiovascular system morphology (Frequent (79-30%)); Abnormality of movement (Frequent (79-30%)); Atypical behavior (Frequent (79-30%)); Gait disturbance (Frequent (79-30%)); Hydrocephalus (Frequent (79-30%)); Skin rash (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Methylmalonic acidemia with homocystinuria is Metabolic Medicine, with a metabolic specialist / clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with metabolic specialist / clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Is a biochemical or molecular result needed to clarify the diagnosis?
• Does this condition require an individual plan for illness or reduced food intake?
• Should nutrition advice come from a specialist metabolic dietitian?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.