CFD syndrome is a newly described condition characterized by low levels of 5-methyltetrahydrofolate (the biologically active form of folates) in the cerebrospinal fluid and normal folate levels in the plasma and red blood cells. In infancy the onset of symptoms is around 4 to 6 months of age, with initially normal development followed by delayed development, deceleration of head growth, hypotonia, ataxia, and in one-third of children, dyskinesias, spasticity, speech difficulties, and epilepsy. Autistic features may be present. Visual disturbances and sensorineural hearing loss may develop around the age of 6 years. In some patients fronto-temporal atrophy with signs of periventricular and subcortical demyelination can become apparent from the age of 18 months.
This bears more than a passing resemblance with the temporal course of classic Rett syndrome. The latter condition is characterized by apparently normal psychomotor development during the first six to 18 months of life, with head growth deceleration as early as age three months followed by a period of developmental stagnation and regression in language and motor skills. Other features include autistic symptoms, episodic apnea and/or hyperpnea, gait ataxia and apraxia and tremors. Neurologic manifestations become relatively stable, although patients will likely develop dystonia and foot and hand deformities later. Seizures are reported in up to 90% of Rett syndrome cases. The hallmark of classic Rett syndrome is the loss of purposeful hand use and its replacement with repetitive stereotyped hand movements.
Both conditions have in common normal early development, regression at 4-6 months, deceleration of head growth, neurologic and autistic phenomena, and seizures. There are differences in the natural history of the two conditions. Classic Rett hand stereotypies are not generally seen in CFD. There is no gender predilection for the latter. Still, in a very young new patient below the age of 3 or 4 years with no family history, the two conditions can appear indistinguishable. Note that Cerebral folate deficiency is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid with normal folate levels in the plasma and red blood cells. The low level of 5-methyltetrahydrofolate in the CSF can result from decreased transport across the blood–brain barrier, which is most probably because of the blocking of folate transport into the CSF by the binding of folate receptor antibodies to the folate receptors in the choroid plexus. Note that this condition is different from folinic-acid responsive seizure disorder and pyridoxine-dependent epilepsy, two treatable causes of neonatal epileptic encephalopathy. The former is diagnosed by characteristic peaks on cerebrospinal fluid (CSF) monoamine metabolite analysis; its genetic basis has remained elusive. The latter is due to alpha-aminoadipic semialdehyde (alpha-AASA) dehydrogenase deficiency, associated with pathogenic mutations in the ALDH7A1 (antiquitin) gene. Treatment of CFD with folinic acid for prolonged periods can result in significant improvement of clinical symptoms and a return of 5-methyltetrahydrofolate levels in the CSF to normal. There is no treatment for classic Rett syndrome. The true incidence of CFD is unknown; in view of the response to treatment in CFD and allied conditions, however, it probably merits consideration in the differential diagnosis of a patient with regression, infantile seizures, microcephaly and autistic phenomena.