MTHFR Deficiency: A Potentially Treatable Cause of Adult-Onset Hereditary Spastic Paraparesis.

Dear Editor,

A 27-year-old man born out of nonconsanguineous parentage [Figure 1: Pedigree chart] with normal developmental history presented with history of insidious onset, slowly progressive spastic paraparesis for the past 3 years. At the onset, he noticed difficulty in getting up from squatting position, which was associated with stiffness of lower limbs. One year into the illness, he noticed difficulty in walking especially on uneven surfaces with history of slippage of footwear with awareness. There was no associated sensory, upper limb, bowel, bladder, or cranial nerve involvement or cognitive decline. There was no history of similar symptoms in the family. Physical examination revealed grade 1+ spasticity and exaggerated deep tendon reflexes involving both lower limbs.

Figure 1

Pedigree Chart

Magnetic resonance imaging (MRI) brain revealed symmetric T2/FLAIR hyperintensity involving periventricular and deep white matter of bilateral posterior parietal region [Figure 2]. MRI cervicodorsal spine was normal. Possibilities of infective, noninfective inflammatory metabolic myelopathies, genetic and degenerative leukoencephalopathies were considered. Nerve conduction studies and visual evoked potentials were normal. Routine hematological and biochemical blood tests were normal, as were levels of serum cortisol, vitamin B12, and folate. VDRL and HIV were nonreactive. ANA and ENA profile were negative. Fasting plasma homocysteine levels were significantly elevated (136.25 μmol/L; normal 3.3–11.3) with normal methionine levels (5.917 μmol/L; normal 5 to 75). Urine for gas chromatography and blood liquid chromatography and mass spectrometry were normal. Next generation sequencing was ordered with suspicion of Hereditary Spastic Paraparesis (HSP)/Leukodystrophy which showed mutations of MTHFR gene on exome 11 (c.1671_1672dupTG) and exome 3 (c.459C>G), clinching the diagnosis of Homocystinemia due to MTHFR deficiency. Genetic testing in the parents revealed the former mutation in the mother and the latter in the father. The patient was started on oral vitamin B12 1500 mcg/day, folate and pyridoxine supplementation, with some symptomatic improvement.

Figure 2

Sagittal T2-WI (a) shows normal thickness and signal intensity of corpus callosum. Axial T2-WI (b) and coronal FLAIR image (c) shows bilateral symmetrical periventricular white matter hyperintensities (arrows). No enhancement is seen in post-gadolinium axial T1-WI (d)

5,10-Methylenetetrhydrofolate reductase (MTHFR) deficiency is a rare, autosomal recessive, potentially treatable metabolic disorder that usually manifests in the childhood,[1] but can present in adulthood very rarely.[23456789] Hypomethioninemia may decrease global methylation reactions in the central nervous system, hence possibly affecting myelin, as attested by white matter abnormalities often found in cerebral MRIs of these patients.[1] In a case series of 24 patients with adolescent/adult-onset MTHFR deficient patients, the mean age of onset was 22.4 ± 12.1 years.[7] At presentation, gait disturbances (46%) were the most common symptom followed by epilepsy (29%), cognitive decline (21%), psychosis (12%), encephalopathy, and stroke (4% each). The mean homocysteine was 177.3 ± 49.5 micromol/L. Although severe hyperhomocystenemia, often associated with hypomethyoninemia, helps in suspicion of this disease, confirmation of the disease requires genetic analysis. However, there is usually a significant delay from onset to diagnosis (mean 5.75 years).[7] Although radiology might help in early diagnosis, they aren’t specific for any particular disease. The most common radiology finding was white matter abnormalities seen in 70% of patients in this case series.[7] Usually, early diagnosis and treatment by betaine (9000 mg/day), folinic acid (45 mg/day), vitamins B12 (1000 mg/week), and B6 supplementation (300 mg/day) are truly beneficial as reported in the literature.[110]

In a case series, there was a significant improvement in 83% of patients, whereas stabilization was noted in 17% of patients following treatment. However, only a few patients had complete disappearance of their symptoms due to the irreversible neurological damage that accumulates over time. This highlights the need for early diagnosis in MTHFR deficiency.

This case shows the importance of measuring plasma homocysteine levels in patients with presumed HSP because this may lead to the detection of MTHFR mutations and initiation of treatment. Although rare, adolescence/adult-onset MTHFR deficiency is potentially treatable. Hence, homocystenemia should be tested in unexplained spastic paraparesis, epilepsy, or any neuro-psychiatric syndrome, as waiting for a complete clinical picture may render irreversible neurological damage.

Learning points

A potentially treatable genetic condition like MTHFR mutation should be considered in cases of spastic paraparesis

Serum homocysteine is a useful screening tool for suspected MTHFR mutation in patients with noncompressive spastic paraparesis.

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Conflicts of interest

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