Methylenetetrahydrofolate reductase deficiency: therapy and outcome (with video)

The methylenetetrahydrofolate reductase (MTHFR) deficiency (OMIM 236250) is based on an inborn error of folate metabolism with a broad variability of clinical presentation. Early forms often show a progressive neurological deterioration combined with a severe epileptic encephalopathy. Indicative laboratory findings show homocysteine elevated and methionine reduced. We present the course of the disease in a girl, who was diagnosed with MTHFR-deficient at the age of 6 months (Video).

Case report: 1/1 child, 2 healthy half siblings. Sectio at term; BW: 2500 g, L: 48 cm, HC: 35 cm. Newborn screening: normal (decreased methionine).

At 3 months there was developmental delay and aggravated dystrophy.

At 6 months the girl was hospitalized with severe dystrophy and neurological deterioration.

W: 5.5 kg (1 kg < 3. P.), L: 61 cm (3 cm < 3. P.), HC: 38.5 cm (2.5 cm < 3. P.): muscular hypotonia, reflexes+, strabismus convergence on both sides, no fixation of objects, no apparent interest in surroundings or social contact, short myoclonia of trunk, atypical abscences.

EEG showed epileptic discharges in both hemispheres not synchronized.

cMRI showed enlargement of the externe cerebral fluid interspaces-signs of demyelination.

CSF: low 5-methylen tetrahydrofolate

Plasma: methionine 4µmol/L (ref > 8), homocysteine: 138µmol/L (ref < 13)

Suspicion of MTHFR-deficiency: therapy with vitamin B₆, folinate, riboflavine, betaine, hydroxycobalamin was initiated.

Under therapy methionine came to normal ranges, Homocysteine descended to 45µmol/L. Antiepileptic therapy consisted of vigabatrin and cortisone.

Enzyme activity/fibroblasts: 5 nmol/h/mg protein (20% of the norm) Confirmation of MTHFR deficiency.

Under metabolic and antiepileptic treatment the patient was showing a significant improvement in psychomotor development as well as in somatic measures.

Motoric function at the time: able to maintain a crawling position (14 LMs), improvement of the EEGs (Video).

Summary: In case of a treatment responder an early and consequent metabolic and antiepileptic treatment can delay or even stop the progress of neurological symptoms in MTHFR.