A case of small cerebral vascular disease and moderate hyperhomocysteinemia caused by methylenetetrahydrofolate reductase gene mutation is reported.The patient was a 61-year-old man who presented with tongue stiffness and slurred speech,bilateral hand numbness and lower limb weakness.He had a history of recurrent cerebral infarction,cerebral hemorrhage,accompanied by leukoencephalopathy and cerebral microhemorrhage etc.Blood homocysteine(Hcy)66.2 μmol/L.Head magnetic resonance imaging revealed subacute cerebral infarction and white matter lesions in right parieto-occipital lobe and left pressor corpus callosum.The skin pathology showed normal density of small fibers,infiltration of perivasculitis cells in the epidermis and dermis,and swelling of endothelial cells in a wide range of small vessels in the dermis.Whole exon sequencing indicated homozygous pathogenic mutation of MTHFR gene c.665C>T(p.A222V).After 1 month of treatment,Hcy decreased to 20.5 μmol/L.This report suggests that HHcy is not only associated with leucoencephalopathy,but also can lead to skin small vessel lesions.Attention should be paid to peripheral vascular screening in this population for early intervention of potential risks.

Objective:To investigate the clinical, phenotypic and genotypic features of hereditary hyperhomocysteinemia mainly involving the nervous system.Methods:The clinical data, physical examination, imaging results, blood-urine tandem mass spectrometry analysis and genetic results of 8 patients with hyperhomocysteinemia from the Department of Neurology of the Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from September 2020 to December 2023 were collected, and the clinical, genetic features and pathogenic mechanisms of these patients were summarized and analyzed.Results:Among all the 8 patients (male∶female=5∶3), the age of onset was 7 to 74 (40.4±7.4) years. Seven had adult-onset and 1 had juvenile-onset, with various types of onset symptoms, including progressive stiffness in lower limbs and walking difficulty, limb numbness, tremor, mental and behavioral abnormalities, cerebrovascular events, etc. Moderate to severe hyperhomocysteine (38.4-190.6 μmol/L) was present in all patients at first diagnosis. Among the 5 patients with cranial imaging examinations, all had white matter lesions. The genetic testing showed 7 patients with MTHFR gene pathogenic mutations (1 case with c.416C>T, and 6 cases with c.665C>T), and 1 patient with MMACHC gene pathogenic mutation (c.482G>A). Conclusions:Hereditary hyperhomocysteinemia is a metabolic disease, with complicated manifestations, varying degrees of severity, and diverse pathogenic genes. The cases with neurological involvement are not rare, such as spastic paraplegia-like manifestations, tremor, peripheral neuropathy, mental and behavioral abnormalities, cerebrovascular events.

A case of small cerebral vascular disease and moderate hyperhomocysteinemia caused by methylenetetrahydrofolate reductase gene mutation is reported.The patient was a 61-year-old man who presented with tongue stiffness and slurred speech,bilateral hand numbness and lower limb weakness.He had a history of recurrent cerebral infarction,cerebral hemorrhage,accompanied by leukoencephalopathy and cerebral microhemorrhage etc.Blood homocysteine(Hcy)66.2 μmol/L.Head magnetic resonance imaging revealed subacute cerebral infarction and white matter lesions in right parieto-occipital lobe and left pressor corpus callosum.The skin pathology showed normal density of small fibers,infiltration of perivasculitis cells in the epidermis and dermis,and swelling of endothelial cells in a wide range of small vessels in the dermis.Whole exon sequencing indicated homozygous pathogenic mutation of MTHFR gene c.665C>T(p.A222V).After 1 month of treatment,Hcy decreased to 20.5 μmol/L.This report suggests that HHcy is not only associated with leucoencephalopathy,but also can lead to skin small vessel lesions.Attention should be paid to peripheral vascular screening in this population for early intervention of potential risks.

Objective:To investigate the clinical, phenotypic and genotypic features of hereditary hyperhomocysteinemia mainly involving the nervous system.Methods:The clinical data, physical examination, imaging results, blood-urine tandem mass spectrometry analysis and genetic results of 8 patients with hyperhomocysteinemia from the Department of Neurology of the Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from September 2020 to December 2023 were collected, and the clinical, genetic features and pathogenic mechanisms of these patients were summarized and analyzed.Results:Among all the 8 patients (male∶female=5∶3), the age of onset was 7 to 74 (40.4±7.4) years. Seven had adult-onset and 1 had juvenile-onset, with various types of onset symptoms, including progressive stiffness in lower limbs and walking difficulty, limb numbness, tremor, mental and behavioral abnormalities, cerebrovascular events, etc. Moderate to severe hyperhomocysteine (38.4-190.6 μmol/L) was present in all patients at first diagnosis. Among the 5 patients with cranial imaging examinations, all had white matter lesions. The genetic testing showed 7 patients with MTHFR gene pathogenic mutations (1 case with c.416C>T, and 6 cases with c.665C>T), and 1 patient with MMACHC gene pathogenic mutation (c.482G>A). Conclusions:Hereditary hyperhomocysteinemia is a metabolic disease, with complicated manifestations, varying degrees of severity, and diverse pathogenic genes. The cases with neurological involvement are not rare, such as spastic paraplegia-like manifestations, tremor, peripheral neuropathy, mental and behavioral abnormalities, cerebrovascular events.