Unraveling a Treatable Cause of Adult-Onset Spastic Paraparesis

Case Presentation
QL, aged early 20 years, presented with a 1-year history of progressive stiffness and weakness of both lower limbs. The weakness involved both proximal and distal muscle groups, with no associated sensory deficits. Bowel and bladder function were normal, and no upper-limb involvement was noted. QL, the first-born child of nonconsanguineous parents, had no history of perinatal insult or developmental delays. There was no family history of similar complaints. QL had experienced cerebral venous sinus thrombosis at age 16 years, which was treated with anticoagulation therapy for 6 months. A tall stature and gynecomastia (Figure 1) were noted on examination, with tenderness and edema noted in the left lower limb. 

Figure 1. Image of an individuals with gynecomastia.

Neurologic examination revealed grade 3 spasticity in both lower limbs, 3/5 motor strength in both lower limbs, ankle and knee clonus, and bilateral extensor plantar responses. Sensory and cerebellar examinations had normal results. Gait was spastic and support was required for ambulation.

A markedly elevated serum homocysteine level (>44 µmol/L [biologic reference interval, 5–15 µmol/L]) was found. Brain MRI showed symmetric T2 and fluid-attenuated inversion recovery hyperintensities in the bilateral posterior periventricular and frontoparietal white matter, indicative of white matter disease, along with chronic hemorrhagic foci in the bilateral thalami (Figure 2). Magnetic resonance venography confirmed chronic cerebral venous thrombosis. Spinal MRI results were normal. Whole exome sequencing identified an MTHFR sequence variation with autosomal recessive inheritance (c.459C>G), leading to a diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency.

Figure 2. Fluid-attenuated inversion recovery MRI of the brain shows periventricular and frontoparietal hyperintensities.

Case Resolution
QL experienced marked clinical improvement after treatment with high-dose supplementation with pyridoxine (vitamin B6) (100 mg/d), folic acid (vitamin B9) (5 mg/d), vitamin B12, and betaine (100 mg/kg/d). Within 2 months of starting treatment, QL regained the ability to walk independently. Clinical improvement continued over an 11-month follow-up.

Discussion
MTHFR deficiency, despite being the most common genetic cause of hyperhomocysteinemia, is a rare, autosomal recessive, potentially treatable metabolic disorder that usually manifests in the neonatal period or childhood.¹

Biologic hallmarks of MTHFR deficiency are moderately low plasma folate levels, hyperhomocysteinemia, hypomethioninemia, and absence of methylmalonic aciduria, which is present in cobalamin metabolism disorders.² MTHFR deficiency presents with heterogeneous neurologic symptoms (eg, encephalopathy, psychomotor delay, gait disorder, spastic paraparesis, psychotic episodes, cognitive disorder, epilepsy), which may also be associated with thrombotic events.³ Neonatal forms are usually more severe and are related to the lowest level of residual MTHFR activity. Adolescent or adult onset MTHFR deficiency is rare.

MTHFR deficiency is caused by genetic defects in MTHFR, the rate-limiting enzyme in the methionine cycle. There are 2 common MTHFR sequence variations that lead to MTHFR deficiency. In the more significant of the 2 sequence variations, the individual is homozygous for the MTHFR 677C>T polymorphism,² which is the most common genetic cause of hyperhomocysteinemia. The other variant is caused by a homologous MTHFR 1298A>C polymorphism.²

The MTHFR sequence variation leads to an enzymatic deficiency that results in a reduction in synthesis of 5-methyl-tetrahydrofolate (5MTHF)—the biologically active form of folate—which is a cofactor necessary for the remethylation of homocysteine into methionine. Homocysteine is converted into methionine in the methionine cycle; therefore, defects in MTHFR can lead to hyperhomocysteinemia. The most common form of genetic hyperhomocysteinemia results from production of a thermolabile variant of MTHFR with reduced enzymatic activity. Elevations in plasma homocysteine levels can also result from deficiencies in folate, vitamin B6, or vitamin B12.

Metabolic therapeutic strategies aim at enhancing methionine synthesis (using vitamins B9 and B12), bypassing methionine synthase using betaine (a cofactor of another enzyme involved in homocysteine remethylation), and supplementing methionine if needed.⁴

Elevated homocysteine levels are likely to promote thrombotic events. Hypomethioninemia may decrease global methylation reactions in the central nervous system, which may affect myelin as evidenced by white matter abnormalities often found in cerebral MRI scans of individuals with MTHFR deficiency.⁵

Conclusion
This case highlights the importance of promptly diagnosing the cause of spastic paraparesis, because early identification facilitates effective treatment. The initial evaluation results suggested hereditary spastic paraparesis, a condition typically without a definitive treatment. However, considering the history of cerebral venous sinus thrombosis, homocysteine levels were checked. Elevated homocysteine levels can be indicative of MTHFR deficiency, which is treatable.

The key takeaway from this case is the recommendation to test homocysteine levels in individuals presenting with unexplained spastic paraparesis or neuropsychiatric symptoms. MTHFR deficiency—a condition that can be managed through treatment (such as folate supplementation)—might be overlooked in such cases. Early diagnosis and treatment of MTHFR deficiency could potentially improve outcomes by preventing further neurologic damage associated with elevated homocysteine levels.