Case 1: A 9-year-old female child was admitted to the hospital because she was found to be walking unsteadily with intermittent aggravation of both lower limbs for 6 years. The child was born at full term, with a birth weight of 3.5 kg; she could roll over at 6 months, sit steadily at 8 months, crawl at 10 months, walk and say children’s songs at 2 years old, and recognize pictures and objects at 3 years old; her walking ability progressed slowly, and she was prone to fall, and could not run so far. The walking ability of both lower extremities regressed after the fever and cold, manifested as weakness of both lower extremities and difficulty in walking, which could gradually recover after one week of rest. The movement of both upper limbs was flexible. He had been treated with “Lysine Inositol B12 Oral Solution” for half a year in an outside hospital and had a history of increasing the strength of both lower limbs. Family history: parents were physically fit, non-consanguineous marriage, and no patients with similar diseases in the family. Physical examination after admission: clear consciousness, natural expression, relaxed facial muscles, slow speech, clear voice; height 3500px, weight 42 kg; no abnormalities on cardiopulmonary and abdominal examination. Neurological examination: automatic posture, flexible movements of both upper limbs, normal muscle strength and tone, normal biceps and triceps tendon reflexes; mild straddling gait of both lower limbs, slow walking, slender toes, inward drooping. The proximal muscle strength of the lower limbs was normal, the distal muscle strength was grade IV, the knee tendon and Achilles tendon reflexes were hyperactive, the ankle clonus was positive, the bilateral baroreflex sign was positive, the meningeal stimulation sign was negative, and the ataxic movement was accurate. Case 2: The child was a 9-year-old female admitted to the hospital with the main reason of “intermittent inability to walk for 3 years, poor sleepiness and drowsiness for 1 month”. The child was born at full term, with a birth weight of 2.9 kg. She had the same mental-motor development as a normal child of the same age and was able to walk steadily at 1 year and 3 months. Three years ago, the child developed a cold and low fever, which lasted for 2 days, and then developed weakness in both lower limbs and did not like to stand up. Two months later, the child again developed a generalized allergic rash after a cold infusion of penicillin and was unable to stand on both lower limbs. The child’s intellectual development was good. Occasionally, due to a cold, the child experienced weakness of the lower limbs and unstable walking, which gradually recovered after resting for several days. More than 1 month ago, the child underwent allogeneic bone marrow hematopoietic stem cell transplantation (details unknown) in an outside hospital. After the operation, the child gradually developed weak mental response, drowsiness and poor appetite, which lasted for about 1 month, and repeated generalized tonic-clonic convulsions, and was transferred to our hospital urgently. Family history: The parents were physically fit, non-consanguineous, and there was no history of hereditary disease in the family. He had a brother who died of severe diarrhea at 2 months of age. On admission, physical examination: T37.0℃, H82 times/min, R16 times/min, BP110/60mmHg, height 3575px, weight 45kg, lethargic, obese body type, no abnormalities on cardiopulmonary and abdominal examination. Neurological system: hypotonia of the extremities, muscle strength grade V in both upper extremities, muscle strength grade II in both lower extremities, normal biceps and triceps tendon reflexes; knee tendon and Achilles tendon reflexes in both lower extremities were not elicited, positive bilateral Bartholin’s sign, negative meningeal stimulation sign. The clinical and auxiliary examination results were similar in the two cases, with normal blood glucose, renal function, electrolytes, muscle enzymes, mild metabolic acidosis, normal urine and stool routine, normal blood sedimentation, normal blood routine, normal erythrocyte morphology and size, normal cranial MRI indicating mild diffuse brain atrophy, normal electrocardiogram, normal liver function in case 1, and EEG indicating whole conductor diffuse low amplitude slow waves. Case 1 had normal liver function, EEG showed diffuse low wave amplitude slow wave; based on the history of recurrent lower extremity weakness under infection or stress, congenital metabolic defects were highly suspected, urine MMA was 35 times elevated, blood C3/C0 and C3/C2 were elevated, serum homocysteine (Hcy) was 75ummol/L. Case 2 had ALT 170umol/L, AST 105ummol/L, Hcy 360umol/L, blood metabolic disease screening The cranial MRI also showed acute demyelination of the white matter of the brain and a small amount of subdural fluid (see Figure 1), and the spinal MRI showed atrophy and thinning of the entire spinal cord, but no other abnormalities were observed. The diagnosis of methylmalonic acid combined with hyperhomocysteinemia was confirmed. Treatment: low protein, high carbohydrate diet was given to reduce the accumulation of toxic metabolites; ①Vitamin B12: 1mg/time intramuscularly at the beginning of hospitalization, once every other day, after the condition stabilized, it was changed to 2 times/week; ②L-carnitine: 50mg/kg/d intravenous infusion at the beginning of the disease, after 1 week, it was changed to long-term oral administration. Betaine: 2000~3000mg/d orally. ④Folic acid: 10mg/d orally, 5mg/d after stabilization. ⑤Vitamin B6: 100~200mg/d intravenous infusion at the beginning of the disease, changed to 40~60mg/d orally after 1 week. The children recovered significantly: the first case was hospitalized for 10 days and discharged with the ability to walk fast and alone, with the tip of the foot still drooping and the gait crossing, and was able to run and ride a bicycle after six months of follow-up. The second child was found to have increased Hcy on the second day of admission, and after 2 days of active treatment, he became conscious, his convulsions disappeared, and his cognitive ability recovered after 5 days; he was given active limb function training, and after 1 week, Hcy decreased to 79ummol/L, and both upper limbs could eat on their own, and tendon reflexes of both lower limbs could be elicited, but his motor ability recovered slowly, and he could stand on his feet after 3 weeks, and after 1 month, he could walk with slow swaying, with both toes drooping and straddling gait. After 6 months of discharge, the patient was able to walk alone more stably, and the toes were still weak, and he was able to ride a bicycle to school one year after discharge. 3, case analysis Methylmalonic acid is a metabolite of methylmalonyl coenzyme A. Under normal circumstances, it is converted into succinic acid under the action of methylmalonyl coenzyme A metatase (mutaseapoenzyme, mut) and vitamin B12, and participates in the tricarboxylic acid cycle (see Figure 2). Methylmalonicacidemia (MMA) is the most common of the congenital abnormalities of organic acid metabolism and is a general term for the accumulation of methylmalonic acid in the body due to various causes, first reported in 1967. Inherited methylmalonic acidemia has multiple biochemical defects, including complete mutase deficiency (mut0) and partial deficiency (mut-) arising from mut defects; defects in the synthesis of the coenzyme adenosine cobalamin (vitamin B12), classified as mitochondrial cobalamin reductase deficiency ( mitochondrial cobamide reductase (cblA) and mitochondrial cobalamin adenosyltransferase (cblB); and three defects in adenosylcobalamin and methylcobalamin synthesis due to abnormal cytoplasmic and lysosomal cobalamin metabolism (cblA). cobalamin synthesis defects (cblC, cblD, cblF) due to abnormal cytoplasmic and lysosomal cobalamin metabolism. The genetic defects mut0, mut-, cblA, and cblB have only methylmalonic acidemia with similar clinical manifestations; the defects cblC, cblD, and cblF are combined with homocysteine (Hcy); all are autosomal recessive. The pathogenesis is a mut defect or vitamin B12 metabolism disorder leading to abnormal accumulation of metabolites such as methylmalonic acid, propionic acid, and methylcitrate, decreased succinate dehydrogenase activity, and impaired mitochondrial energy synthesis, causing multiple organ damage such as nerve, liver, kidney, and bone marrow. Depending on the patient’s response to vitamin B12 treatment, patients can be clinically classified into vitamin B12-responsive and non-responsive types. Vitamin B12-responsive patients are mostly defective in coenzyme synthesis, and Cb1A, CblC, CblD, and CblF types are mostly vitamin B12-responsive. Patients with mut0 type have the earliest onset of disease, with 80% developing within a few hours to 1 week after birth, and have symptoms similar to acute encephalopathy, such as: refusal of breast milk, vomiting, dehydration, coma, convulsions, acidosis, ketonuria, hypoglycemia, with extremely high early mortality and poor prognosis. mut- and Cb1A and Cb1B type patients mostly develop after 1 month after birth, with mental and motor backwardness and hypotonia in infancy; cblC deficient individuals have a more variable clinical presentation, but all are dominated by neurological symptoms. In early-onset cases, symptoms appear two months after birth and are characterized by poor growth, feeding difficulties, or lethargy. Late-onset cases may show symptoms from 4 to 14 years of age and may have lethargy, delirium and convulsions, mental retardation, and motor deficits. Most cases have hematologic abnormalities such as macrocytic and megaloblastic anemia, polymorphonuclear leukocyte nuclear hyperfoliation, and thrombocytopenia. Patients with normal serum cobalamin and folic acid concentrations. cblD deficient patients have a later onset and present with behavioral abnormalities, mental retardation and neuromuscular lesions without hematologic abnormalities. A small number of patients with cblF deficiency may develop in adulthood or even for life. cblF deficient patients often develop stomatitis, hypotonia and facial dysmorphism in the first two weeks of life, and some have abnormal blood cell morphology. In this paper, two patients with cblF deficiency had approximately normal development during infancy, and gradually developed episodic bilateral lower extremity dyskinesia during school age, which could fluctuate due to stress factors such as colds, and was aggravated by the prolonged course of the disease. The main manifestation was episodic weakness of both lower extremities, and the neurological localization could be manifested as upper or lower motor neuron damage, tendon reflex hyperactivity or disappearance, distal muscle atrophy, and muscle strength loss depending on the severity of involvement, with progressive brain damage; there was no renal damage, megaloblastic anemia, or other bone marrow hematopoietic disorders. Both girls showed a more obese appearance, looser facial muscles and better intelligence. The tendon reflexes of both lower limbs were hyperactive and progressive dyskinesia, and the neural reflexes of both upper limbs were normal. This is a common manifestation of hereditary spastic paraplegia, which requires active testing of blood and urine gas phase mass spectrometry and tandem mass spectrometry, as well as serum Hcy testing to prevent misdiagnosis and loss of treatment opportunities. Fever, infection, starvation, fatigue, trauma and other stressful conditions increase the body’s energy demand, high protein diet, blood transfusion and other factors cause accumulation of methionine, threonine, isoleucine and valine, depletion of L-carnitine due to valproic acid and macrolides, and impaired excretion of methylmalonic acid, causing acute metabolic disorders, resulting in acute onset or intermittent onset of the disease course in patients with MMA. Careful history taking in clinical diagnosis and treatment can identify the characteristics of this disease as early as possible, and early detection and treatment can reduce the appearance of disability. Hcy is an intermediate metabolite of methionine, which is produced in the body by the transmethylation of methionine. There are two metabolic pathways, one is the production of cysteine catalyzed by cystathione condensase (CBS) and cystathionase, which requires the participation of vitamin B6, or homocysteine via sulfhydryl oxidation, and the re-methylation of Hcy with the aid of folic acid and vitamin B12, which requires the catalysis of methionine synthase (MS) and the presence of N5-methyltetrahydrofolate as a donor of methyl, the latter is produced by tetrahydrofolate catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR); therefore, the combination of high-dose vitamin B6, folinic acid, and betaine to provide methyl is required to reduce Hcy in severe hyperhomocysteinemia. case 2 patient with progressive disease leading to severe hyperhcythemia, on high-dose vitamin B12 and levocarnitine based on the combined application of Hcy lowering measures, the child recovered rapidly from the state of consciousness and brain damage was repaired. Methylmalonic acidemia mut0 and mut- type for liver transplantation treatment, there are successful cases abroad, vitamin B12 effective type more than not advocate liver or kidney transplantation; allogeneic bone marrow stem cell transplantation is still in the exploration stage, the specific application of case 2 patients is unknown, the reason for unsatisfactory results to be explored. With the invention and popularization of second-generation sequencing technology, it has gradually become routine to clarify the specific variants of genes related to genetic metabolic diseases. According to the clinical performance, it is presumed that the genetic type of the two children is CblC or CblD. Because of the early diagnosis, clear clinical diagnosis and obvious treatment effect of the cases, and the parents are older and have no requirement for reproduction, the relevant genetic testing was not performed for the time being. 4. Conclusion The combination of methylmalonic acidemia and hyperhomocysteinemia with episodic bilateral lower limb paralysis is a rare clinical case, which often behaves normally in the early development of children, and with the accumulation of abnormal metabolites, peripheral nerve damage in the spinal cord and both lower limbs becomes prominent. The key to nerve repair is to conduct comprehensive blood and urine metabolic disease screening and Hcy measurement to achieve early detection and treatment, and the prognosis is mostly good.