Rapidly Progressive Spastic Paraplegia Due to Hyperhomocysteinemia in Child with MTHFR Gene Mutation and Mitochondrial Complex I Deficiency: A Rare Association.

MTHFR enzyme deficiency is an autosomal-recessive inborn error of folate metabolism. The deficiency cause defect in the remethylation of homocysteine to methionine leading to increased blood levels of homocysteine. Hyperhomocysteinemia in infants cause seizures, hypotonia, apnoea, microcephaly, progressing to coma and death if untreated whereas in childhood onset it causes developmental delay, seizures, psychiatric disturbances, spastic gait, and ataxia. We report a 10-year-old girl with rapidly progressive spastic paraplegia requiring wheelchair ambulation within 3 months of symptom onset with behavioral disturbances. Plasma homocysteine and plasma lactate were high with normal vitamin B12 levels. Clinical exome sequencing showed homozygous missense mutation in MTHFR gene which was likely pathogenic variant. Respiratory chain complex assay from muscle sample showed reduced complex 1 deficiency (<20%). Copyright:

INTRODUCTION

MTHFR enzyme deficiency is an autosomal-recessive inborn error of folate metabolism. The symptoms can manifest over a wide range of age from neonates to the adulthood. Infants presents with seizures, hypotonia, apnea, microcephaly, progressing to coma and death if untreated due to severely reduced residual enzyme activity.[1] Developmental delay and seizures including progressive myoclonic epilepsy, psychiatric disturbances, spastic gait, and ataxia occur in childhood and adolescent onset. In adult onset enzyme deficiency, spastic paraparesis mimicking hereditary spastic paraplegia, psychotic episodes, cognitive disorder, stroke, peripheral neuropathy, and relapsing encephalopathy are the clinical manifestations.[2] Hereby, we report a 10-year-old girl with rapidly progressive spastic paraplegia requiring wheelchair ambulation within 3 months of symptom onset with behavioral disturbances. Plasma homocysteine was high with normal vitamin B12 levels. Clinical exome sequencing showed homozygous missense variation in the exon 3 of MTHFR gene (c.584C>T) causing amino acid substitution of valine for alanine at the codon 195 (p.Ala195Val). Respiratory chain complex assay from muscle sample showed reduced complex 1 deficiency (<20%). MTHFR gene mutation causing hyperhomocystenemia has to be considered in child presenting with rapidly progressive spastic paraplegia and behavioral disturbance.

CASE REPORT

A 10-year-old girl born out of consanguineous parentage with normal perinatal history, motor and language milestones presented with complaints of behavioral disturbances in the form of temper tantrums, physical assault on siblings of 3 months duration, walking difficulty in the form of dragging of both lower limbs of 2 months duration and requiring two person support to walk within 1 month of onset. She had urge incontinence of urine. She had poor scholastic performance since early childhood. There was no seizures, myoclonus, vomiting, and visual or auditory disturbances. She was slow in understanding conversation with excessive daytime sleepiness. There were no similar complaints in other siblings. Her vaccination was complete. Systemic examination was unremarkable. There was no neurocutaneous markers and normal head circumference. Fundus examination was normal. There was mild slurring of speech. Eye movements were normal. There was no other cranial nerve involvement. Motor examination showed spasticity of both lower limbs and upper limbs. Deep tendon reflexes were brisk with sustained ankle clonus. Sensory examination was normal. Plantar responses were extensor. She needed two persons support to stand and walk. Complete hemogram, renal liver and thyroid function tests, and serum electrolytes were normal. Serum homocysteine levels were elevated (223 µmol/L). Serum folate and vitamin B12 levels were normal. Urine homocysteine was present. Blood methionine levels were normal. Plasma lactate was raised (61 mg/dL). Nerve conduction and evoked potential studies were normal. Brain magnetic resonance imaging (MRI) showed mild cerebral and cerebellar atrophy [Figure 1]. MRI spine was normal. Cerebrospinal fluid analysis was normal. Autoimmune profile was negative. Quadriceps muscle biopsy did not show mitochondrial pathology. However, respiratory chain complex assay from muscle sample showed reduced complex 1 deficiency (<20%). Clinical exome sequencing showed homozygous missense variation in the exon 3 of MTHFR gene (c.584C>T) causing amino acid substitution of valine for alanine at the codon 195 (p.Ala195Val). The p.Ala195Val variant is a likely pathogenic variant and has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.003% in the ExAC database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT, and MutationTaster2. She was treated with baclofen, levocarnitine, biotin, pyridoxine, folate, and betaine. There was mild improvement at 2 months follow-up as she can stand with one person support.

Figure 1

Brain magnetic resonance imaging (A) axial fluid-attenuated inversion recovery image and (B) axial T2 image shows cerebral atrophy (red arrow)

DISCUSSION

The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme catalyses the reduction of 5,10-methylene tetrahydrofolate to 5-methyl tetrahydrofolate which is irreversible and NADPH dependent. 5-Methyl tetrahydrofolate acts as a methyl donor for the remethylation of homocysteine to methionine by the enzyme methionine synthase. Deficiency of MTHFR enzyme causes deficiency of 5-methyl tetrahydrofolate and defect in the remethylation of homocysteine to methionine. This leads to increase in the blood levels of homocysteine with low or low-normal plasma methionine levels and low folate levels.[2] The remethylation of homocysteine to methionine is also done by the enzyme betaine homocysteine methyl transferase using betaine as co-factor. Methionine is required in deoxy ribonucleic acid and protein methylation, neurotransmitter, and phospholipid synthesis. Deficiency of methionine and folate cause cerebral demyelination and excess homocysteine cause endothelial dysfunction and increased oxidative stress. The MTHFR enzyme deficiency is an autosomal-recessive inborn error of folate metabolism. The symptoms can manifest over a wide range of age from neonates to the adulthood. Infants presents with seizures, hypotonia, apnea, microcephaly, progressing to coma, and death if untreated due to severely reduced residual enzyme activity.[3] Developmental delay, seizures including progressive myoclonic epilepsy, psychiatric disturbances, spastic gait, and ataxia occur in childhood and adolescent onset.[4] In adult onset enzyme deficiency, spastic paraparesis mimicking hereditary spastic paraplegia, psychotic episodes, cognitive disorder, stroke, peripheral neuropathy, and relapsing encephalopathy are the clinical manifestations.[56]

Bathgate et al.[7] reported MTHFR deficiency in two adult siblings with slowly progressive spastic paraparesis with change in behavior and encephalopathy. First sibling had spastic paraparesis followed by change in behavior and encephalopathy and other sibling had change in behavior, cognitive deficits, and spastic paraparesis within 6 months of onset. Plasma homocysteine was high with normal methionine levels. Sequencing of fibroblast cDNA identified a novel homozygous missense mutation in the MTHFR gene (c596C>T, pA195V). Respiratory chain complex assays showed a significant defect of complex I (25%). It is postulated that the MTHFR enzyme deficiency cause secondary abnormalities of mitochondrial DNA. The authors postulated that the neurological features seen in MTHFR deficiency are mediated though a mitochondrial mechanism.[7]

Our patient presented with rapidly progressive spastic paraplegia with behavioral disturbance of 3 months duration. Serum homocysteine was high. We also found a homozygous missense variation in the exon 3 of MTHFR gene (c.584C>T) causing amino acid substitution of valine for alanine at the codon 195 (p.Ala195Val). We have not done the estimation of MTHFR activity in cultured skin fibroblasts. We also found deficiency of complex 1 in skeletal muscle biopsy. Whether this mutation is associated with secondary mitochondrial respiratory chain complex defect has to be investigated.

CONCLUSION

In children presenting with rapidly progressive spastic paraplegia, behavioral disturbance should be evaluated with homocysteine levels. MTHFR deficiency should be considered in patients with secondary respiratory chain complexes deficiency. MTHFR deficiency is one of the treatable causes of spastic paraplegia in children.

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