Cerebral folate deficiency | |
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Other names | Cerebral folate deficiency syndrome, neurodegeneration due to cerebral folate transport deficiency, cerebral folate transport deficiency, FOLR1 deficiency [1] [2] |
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5-methyltetrahydrofolate is decreased in concentration in the human brain | |
Causes | Genetic disorder, [2] autoantibodies |
Diagnostic method | Lumbar puncture |
Medication | Folinic acid |
Frequency | FOLR1 mutation, <20 described cases [2] |
Cerebral folate deficiency is a condition in which concentrations of 5-methyltetrahydrofolate are low in the brain as measured in the cerebral spinal fluid despite being normal in the blood. [3] Symptoms typically appear at about 5 to 24 months of age. [3] [2] Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures. [3]
One cause of cerebral folate deficiency is a mutation in a gene responsible for folate transport, specifically FOLR1 . [2] [4] This is inherited in an autosomal recessive manner. [2] Other causes appear to be Kearns–Sayre syndrome [5] and autoantibodies to the folate receptor. [6] [7] [8]
For people with the FOLR1 mutation, even when the systemic deficiency is corrected by folate, the cerebral deficiency remains and must be treated with folinic acid. Success depends on early initiation of treatment and treatment for a long period of time. [9] [3] Fewer than 20 people with the FOLR1 defect have been described in the medical literature. [2]
Children with the FOLR1 mutation are born healthy. Symptoms typically appear at about 5 to 24 months of age. The symptoms get worse with time. Without treatment there may be poor muscle tone, trouble with coordination, trouble talking, and seizures. [2] [3] In addition, signs of psychomotor retardation, sleep disturbances, cerebellar ataxia, and delayed development of head growth can occur. At around age three, visual disturbances can develop, and sensorineural hearing loss can occur at around age six. [11] In children with cerebral folate deficiency, the cerebrospinal fluid shows low levels of 5MTHF, and a loss of white matter in the brain (leukodystrophy) may occur. As a result of the decreased levels of 5MTHF, the child experiences low levels of Vitamin B folate. [12] There is inability for the 5MTHF to be transported across the blood-brain barrier, resulting in symptoms of seizures, delayed cognitive and motor processing, and autistic features. [13]
One cause of cerebral folate deficiency is due to a genetic mutation in the FOLR1 gene. It is inherited in an autosomal recessive manner. [2] The mutation of the FOLR1 gene causes an inability to produce the FRA protein. [12] More commonly, CFD involves the malfunction and disruption of the folate receptor alpha (FRA). One way the FRA can be disrupted is by the attachment of the autoantibodies, causing dysfunction in the receptor. Also, a mitochondrial disease can impact the functioning of the folate receptor alpha. In order for the receptor to function properly, energy from the mitochondria is required. Folate must be actively transported into the brain, so ATP from the mitochondria is essential. If the individual has a mitochondrial disease, the FRA could be lacking adequate energy, resulting in the deficiency of folate in the brain. [12]
Other causes appear to be Kearns–Sayre syndrome [5] and autoantibodies to the folate receptor. [6] [7] [8] Furthermore, secondary cerebral folate deficiency can develop in patients with other conditions. For example, it can develop in AADC deficiency through the depletion of methyl donors, such as SAM and 5-MTHF, by O-methylation of the excessive amounts of L-dopa present in patients. [14] [15]
For people with the FOLR1 mutation, even when the systemic deficiency is corrected by folate, the cerebral deficiency remains, and must be treated with folinic acid. Folinic acid is a metabolically active form of folate that can be easily introduced into the folate cycle. A typical dose that is administered to children is 0.5–1 mg/kg daily, but the dose can be increased depending on the severity of symptoms and the age of the child. Over time, the treatment with folinic acid has shown to reduce a variety of symptoms of CFD. The treatment of folinic acid can lead to improvements in walking, speech, interpersonal skills and reduction in seizures. [16] Success depends on early initiation of treatment. [9] Starting the folinic acid treatment before the age of six is more advantageous for the child with CFD. If the treatment is started after the age of six, its results are not as effective. [16] Treatment requires taking folinic acid for a significant period of time. [3] Fewer than 20 people with the FOLR1 defect have been described in the medical literature. [2] Treatment with pharmacologic doses of folinic acid has also led to reversal of some symptoms in children diagnosed with cerebral folate deficiency and testing positive for autoantibodies to folate receptor alpha. [17]
Homocystinuria or HCU is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected. Symptoms of homocystinuria can also be caused by a deficiency of vitamins B6, B12, or folate.
Autism spectrum disorders (ASD) are neurodevelopmental disorders that begin in early childhood, persist throughout adulthood, and affect three crucial areas of development: communication, social interaction and restricted patterns of behavior. There are many conditions comorbid to autism spectrum disorders such as attention-deficit hyperactivity disorder and epilepsy.
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Menkes disease (MNK), also known as Menkes syndrome, is an X-linked recessive disorder caused by mutations in genes coding for the copper-transport protein ATP7A, leading to copper deficiency. Characteristic findings include kinky hair, growth failure, and nervous system deterioration. Like all X-linked recessive conditions, Menkes disease is more common in males than in females. The disorder was first described by John Hans Menkes in 1962.
Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax, particularly prior to diagnosis and during times of acute illness. It was described by John Menkes in the 1950s.
Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products can accumulate and cause damage to the brain, but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may occur.
Biotinidase deficiency is an autosomal recessive metabolic disorder in which biotin is not released from proteins in the diet during digestion or from normal protein turnover in the cell. This situation results in biotin deficiency.
Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.
Glycine encephalopathy is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebrospinal fluid.
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations. Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.
Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in a type of anemia in which red blood cells become abnormally large and is a late finding in folate deficiency and folate deficiency anemia is the term given for this medical condition. Signs of folate deficiency are often subtle. Symptoms may include feeling tired, heart palpitations, shortness of breath, feeling faint, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. Folate deficiency anemia during pregnancy may give rise to the birth of low weight birth premature infants and infants with neural tube defects.
GLUT1 deficiency syndrome, also known as GLUT1-DS, De Vivo disease or Glucose transporter type 1 deficiency syndrome, is an autosomal dominant genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier. Glucose Transporter Type 1 Deficiency Syndrome has an estimated birth incidence of 1 in 90,000 to 1 in 24,300. This birth incidence translates to an estimated prevalence of 3,000 to 7,000 in the U.S.
Folate receptor 1 is a protein that in humans is encoded by the FOLR1 gene.
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5,10-Methenyltetrahydrofolate synthetase deficiency is a rare neurodevelopmental disorder caused by mutations affecting the MTHFS gene, which encodes the enzyme 5,10-Methenyltetrahydrofolate synthetase.
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Dihydrofolate reductase deficiency is a rare inherited disorder of folate metabolism caused by defects in the DHFR gene. The disorder is inherited in the autosomal recessive manner and may present with megaloblastic anemia, cerebral folate deficiency and neurological symptoms of varying type and severity. The patient may have a developmental delay and develop epileptic seizures.