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Adolescent/adult-onset homocysteine remethylation disorders characterized by gait disturbance with/without psychiatric symptoms and cognitive decline: a series of seven cases

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Abstract

Homocysteine remethylation disorders are rare inherited disorders caused by a deficient activity of the enzymes involved in the remethylation of homocysteine to methionine. The adolescent/adult-onset remethylation disorders are rarely reported. We analyzed the clinical and genetic characteristics of seven cases with adolescent/adult remethylation disorders, including 5 cases of the cobalamin C disease (cblC) and 2 cases of the methylenetetrahydrofolate reductase deficiency. The average onset age was 21.1 (range 14 to 40) years. All patients complained of gait disturbances. Other common symptoms included psychiatric symptoms (5/7) and cognitive decline (4/7). Acute encephalopathy, dysarthria, anorexia, vomiting, ketoacidosis, anemia, cataract, and hand tremor were also observed. The mean total homocysteine in serum when the patients were diagnosed was 94.6 (range 53.1–154.5) mol/L. Electrophysiological studies revealed neuropathy in the lower limbs (6/7). The brain MRI showed reversible altered signal from the dorsal portions of the cerebellar hemispheres (1/7), periventricular hyperintensity (2/7), and delayed/impaired myelination (2/7). The sural nerve biopsy performed in one case showed a modest loss of myelinated fibers. Five patients showed heterozygous mutations of the MMACHC gene, including c.482G>A (5/5), c.609G>A (2/5), and c.658-660delAAG (3/5). Two patients showed heterozygous mutations of the MTHFR gene, including c.698C>A (2/2), c.698C>G (1/2), and c.236+1G>A (1/2). The patients responded well to the treatments with significant improvements. Adolescent/adult-onset remethylation disorders are easily misdiagnosed. We recommend testing the serum homocysteine concentrations in young/adult patients with unexplained neuro-psychotic symptoms. Furthermore, individuals with significantly elevated serum homocysteine concentrations should be further tested by organic acid screening and genetic analysis.

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Acknowledgments

We wish to thank all patients for their cooperation in this study and Dr. Jian Wu from MyGenostics Inc. for his excellent technical assistance.

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Authors and Affiliations

  1. Department of Neuromuscular Disorders, The Third Hospital of Hebei Medical University, No 139 Road Ziqiang, Shijiazhuang, 050051, People’s Republic of China

    Kai-Jie Chang, Zhe Zhao, Hong-Rui Shen, Qi Bing, Nan Li, Xuan Guo & Jing Hu

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  1. Kai-Jie Chang
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Contributions

KC designed the study, performed neurological examinations, collected the clinical data, performed the molecular genetic test and analysis, searched the literature, and wrote the manuscript. ZZ performed neurological examinations. HS performed nerve biopsy and muscle biopsy. QB performed electrophysiological procedures. NL and XG revised the manuscript. JH designed the study and undertook the critical revision of the manuscript.

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Correspondence to Jing Hu.

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This study was approved by the Ethical Committee of the Third Hospital of Hebei Medical University and was conducted in accordance with the Declaration of Helsinki.

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Chang, KJ., Zhao, Z., Shen, HR. et al. Adolescent/adult-onset homocysteine remethylation disorders characterized by gait disturbance with/without psychiatric symptoms and cognitive decline: a series of seven cases. Neurol Sci 42, 1987–1993 (2021). https://doi.org/10.1007/s10072-020-04756-0

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