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Charles P. Venditti - One of the best experts on this subject based on the ideXlab platform.
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in vivo genome editing at the albumin locus to treat Methylmalonic Acidemia
Molecular therapy. Methods & clinical development, 2021Co-Authors: Jessica L. Schneller, Randy J. Chandler, Leah E Venturoni, Ciaran M Lee, Sangho Myung, Thomas J Cradick, Ayrea Hurley, William R Lagor, Gang Bao, Charles P. VendittiAbstract:ABSTRACT Methylmalonic Acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression, and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb, and tested various CRISPR/Cas9 genome editing vectors in newly developed knock-in mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5’ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
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central nervous system targeted adeno associated virus gene therapy in Methylmalonic Acidemia
Molecular therapy. Methods & clinical development, 2021Co-Authors: Randy J. Chandler, Francis J May, Pamelasara E Head, Leah E Venturoni, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe metabolic disorder most commonly caused by a mutation in the methylmalonyl-CoA mutase (MMUT) gene. Patients with MMA experience multisystemic disease manifestations and remain at risk for neurological disease progression, even after liver transplantation. Therefore, delivery of MMUT to the central nervous system (CNS) may provide patients with neuroprotection and, perhaps, therapeutic benefits. To specifically target the brain, we developed a neurotropic PHP.eB vector that used a CaMKII neuro-specific promoter to restrict the expression of the MMUT transgene in the neuraxis and delivered the adeno-associated virus (AAV) to mice with MMA. The PHP.eB vector transduced cells in multiple brain regions, including the striatum, and enabled high levels of expression of MMUT in the basal ganglia. Following the CNS-specific correction of MMUT expression, disease-related metabolites Methylmalonic acid and 2-methylcitrate were significantly (p
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Central nervous system-targeted adeno-associated virus gene therapy in Methylmalonic Acidemia
'Elsevier BV', 2021Co-Authors: Francis J May, Randy J. Chandler, Pamelasara E Head, Leah E Venturoni, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe metabolic disorder most commonly caused by a mutation in the methylmalonyl-CoA mutase (MMUT) gene. Patients with MMA experience multisystemic disease manifestations and remain at risk for neurological disease progression, even after liver transplantation. Therefore, delivery of MMUT to the central nervous system (CNS) may provide patients with neuroprotection and, perhaps, therapeutic benefits. To specifically target the brain, we developed a neurotropic PHP.eB vector that used a CaMKII neuro-specific promoter to restrict the expression of the MMUT transgene in the neuraxis and delivered the adeno-associated virus (AAV) to mice with MMA. The PHP.eB vector transduced cells in multiple brain regions, including the striatum, and enabled high levels of expression of MMUT in the basal ganglia. Following the CNS-specific correction of MMUT expression, disease-related metabolites Methylmalonic acid and 2-methylcitrate were significantly (p < 0.02) decreased in serum of treated MMA mice. Our results show that targeting MMUT expression to the CNS using a neurotropic capsid can decrease the circulating metabolite load in MMA and further highlight the benefit of extrahepatic correction for disorders of organic acid metabolism
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Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future.
Human gene therapy, 2019Co-Authors: Randy J. Chandler, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe, and sometimes lethal, monogenic metabolic disorder in need of improved treatments. A number of new genomic therapies, which include canonical adeno-associated virus gene addition, genome editing, and systemic mRNA therapy, have shown great promise in murine models of MMA. Each approach has unique advantages and disadvantages for treating genetic disorders like MMA. This article reviews traditional viral gene therapy experiments that have provided enabling proof of concept studies in animal models, and newer approaches that may emerge as effective treatments for MMA and related disorders of organic acid metabolism.
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Isolated Methylmalonic Acidemia
2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Charles P. VendittiAbstract:Clinical characteristics Isolated Methylmalonic Acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated Methylmalonic Acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult Methylmalonic Acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of Methylmalonic Acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis/testing Diagnosis of isolated Methylmalonic Acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of Methylmalonic Acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MMUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated Methylmalonic Acidemia – with confirmation of carrier status in the parents – can establish the diagnosis. Management Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert® bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Genetic counseling Isolated Methylmalonic Acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).
Randy J. Chandler - One of the best experts on this subject based on the ideXlab platform.
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in vivo genome editing at the albumin locus to treat Methylmalonic Acidemia
Molecular therapy. Methods & clinical development, 2021Co-Authors: Jessica L. Schneller, Randy J. Chandler, Leah E Venturoni, Ciaran M Lee, Sangho Myung, Thomas J Cradick, Ayrea Hurley, William R Lagor, Gang Bao, Charles P. VendittiAbstract:ABSTRACT Methylmalonic Acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression, and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized MMUT transgene from Alb, and tested various CRISPR/Cas9 genome editing vectors in newly developed knock-in mouse models of MMA. For one target site in intron 1 of Alb, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5’ homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
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central nervous system targeted adeno associated virus gene therapy in Methylmalonic Acidemia
Molecular therapy. Methods & clinical development, 2021Co-Authors: Randy J. Chandler, Francis J May, Pamelasara E Head, Leah E Venturoni, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe metabolic disorder most commonly caused by a mutation in the methylmalonyl-CoA mutase (MMUT) gene. Patients with MMA experience multisystemic disease manifestations and remain at risk for neurological disease progression, even after liver transplantation. Therefore, delivery of MMUT to the central nervous system (CNS) may provide patients with neuroprotection and, perhaps, therapeutic benefits. To specifically target the brain, we developed a neurotropic PHP.eB vector that used a CaMKII neuro-specific promoter to restrict the expression of the MMUT transgene in the neuraxis and delivered the adeno-associated virus (AAV) to mice with MMA. The PHP.eB vector transduced cells in multiple brain regions, including the striatum, and enabled high levels of expression of MMUT in the basal ganglia. Following the CNS-specific correction of MMUT expression, disease-related metabolites Methylmalonic acid and 2-methylcitrate were significantly (p
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Central nervous system-targeted adeno-associated virus gene therapy in Methylmalonic Acidemia
'Elsevier BV', 2021Co-Authors: Francis J May, Randy J. Chandler, Pamelasara E Head, Leah E Venturoni, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe metabolic disorder most commonly caused by a mutation in the methylmalonyl-CoA mutase (MMUT) gene. Patients with MMA experience multisystemic disease manifestations and remain at risk for neurological disease progression, even after liver transplantation. Therefore, delivery of MMUT to the central nervous system (CNS) may provide patients with neuroprotection and, perhaps, therapeutic benefits. To specifically target the brain, we developed a neurotropic PHP.eB vector that used a CaMKII neuro-specific promoter to restrict the expression of the MMUT transgene in the neuraxis and delivered the adeno-associated virus (AAV) to mice with MMA. The PHP.eB vector transduced cells in multiple brain regions, including the striatum, and enabled high levels of expression of MMUT in the basal ganglia. Following the CNS-specific correction of MMUT expression, disease-related metabolites Methylmalonic acid and 2-methylcitrate were significantly (p < 0.02) decreased in serum of treated MMA mice. Our results show that targeting MMUT expression to the CNS using a neurotropic capsid can decrease the circulating metabolite load in MMA and further highlight the benefit of extrahepatic correction for disorders of organic acid metabolism
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Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future.
Human gene therapy, 2019Co-Authors: Randy J. Chandler, Charles P. VendittiAbstract:Methylmalonic Acidemia (MMA) is a severe, and sometimes lethal, monogenic metabolic disorder in need of improved treatments. A number of new genomic therapies, which include canonical adeno-associated virus gene addition, genome editing, and systemic mRNA therapy, have shown great promise in murine models of MMA. Each approach has unique advantages and disadvantages for treating genetic disorders like MMA. This article reviews traditional viral gene therapy experiments that have provided enabling proof of concept studies in animal models, and newer approaches that may emerge as effective treatments for MMA and related disorders of organic acid metabolism.
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neutralizing antibodies against adeno associated viral capsids in patients with mut Methylmalonic Acidemia
Human Gene Therapy, 2016Co-Authors: Elizabeth Harrington, Randy J. Chandler, Jennifer L. Sloan, Irini Manoli, Mark E Schneider, Peter J Mcguire, Roberto Calcedo, James M Wilson, Charles P. VendittiAbstract:Isolated Methylmalonic Acidemia (MMA), a group of autosomal recessive inborn errors of metabolism, is most commonly caused by complete (mut0) or partial (mut−) deficiency of the enzyme methylmalonyl-CoA mutase (MUT). The severe metabolic instability and increased mortality experienced by many affected individuals, especially those with mut0 MMA, has led centers to use elective liver transplantation as a treatment for these patients. We have previously demonstrated the efficacy of systemic adeno-associated viral (AAV) gene delivery as a treatment for MMA in a murine model and therefore sought to survey AAV antibody titers against serotypes 2, 8, and 9 in a group of well-characterized MMA patients, accrued via a dedicated natural history study (clinicaltrials.gov ID: NCT00078078). Plasma samples provided by 42 patients (8 mut− and 34 mut0; 10 had received organ transplantation), who ranged in age between 2 and 31 years, were analyzed to examine AAV2 (n = 35), AAV8 (n = 41), and AAV9 (n = 42) antibody titers...
Jennifer L. Sloan - One of the best experts on this subject based on the ideXlab platform.
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fgf21 underlies a hormetic response to metabolic stress in Methylmalonic Acidemia
JCI insight, 2018Co-Authors: Irini Manoli, Jennifer L. Sloan, Justin R Sysol, Madeline W Epping, Cindy Wang, Alexandra Pass, Jack Gagne, Yiouli P Ktena, Niraj S Trivedi, Bazoumana OuattaraAbstract:Methylmalonic Acidemia (MMA), an organic Acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
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Isolated Methylmalonic Acidemia
2016Co-Authors: Irini Manoli, Jennifer L. Sloan, Charles P. VendittiAbstract:Clinical characteristics Isolated Methylmalonic Acidemia/aciduria, the topic of this GeneReview, is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Onset of the manifestations of isolated Methylmalonic Acidemia/aciduria ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. In the neonatal period the disease can present with lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia and can result in death within the first four weeks of life. In the infantile/non-B12-responsive phenotype, infants are normal at birth, but develop lethargy, vomiting, dehydration, failure to thrive, hepatomegaly, hypotonia, and encephalopathy within a few weeks to months of age. An intermediate B12-responsive phenotype can occasionally be observed in neonates, but is usually observed in the first months or years of life; affected children exhibit anorexia, failure to thrive, hypotonia, and developmental delay, and sometimes have protein aversion and/or vomiting and lethargy after protein intake. Atypical and "benign"/adult Methylmalonic Acidemia phenotypes are associated with increased, albeit mild, urinary excretion of methylmalonate. Major secondary complications of Methylmalonic Acidemia include: intellectual impairment (variable); tubulointerstitial nephritis with progressive renal failure; "metabolic stroke" (acute and chronic basal ganglia injury) causing a disabling movement disorder with choreoathetosis, dystonia, and para/quadriparesis; pancreatitis; growth failure; functional immune impairment; and optic nerve atrophy. Diagnosis/testing Diagnosis of isolated Methylmalonic Acidemia relies on analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry. Establishing the specific subtype of Methylmalonic Acidemia requires cellular biochemical studies (including 14C propionate incorporation and B12 responsiveness, complementation analysis, and cobalamin distribution assays) and molecular genetic testing. The finding of biallelic pathogenic variants in one of the five genes (MMUT, MMAA, MMAB, MCEE, and MMADHC) associated with isolated Methylmalonic Acidemia – with confirmation of carrier status in the parents – can establish the diagnosis. Management Treatment of manifestations: Critically ill individuals are stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output. Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections. Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation; and antioxidants for the treatment of optic nerve atrophy. Prevention of primary manifestations: In some cases, newborn screening allows for presymptomatic detection of affected newborns and early treatment. Agents/circumstances to avoid: Fasting and increased dietary protein. Other: Medic Alert® bracelets and up-to-date, easily accessed, detailed emergency treatment protocols facilitate care. Genetic counseling Isolated Methylmalonic Acidemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible using molecular genetic techniques if the pathogenic variants in the family are known. In some circumstances, prenatal diagnosis for pregnancies at increased risk is possible by enzyme analysis and metabolite measurements on cultured fetal cells (obtained by chorionic villus sampling or amniocentesis).
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neutralizing antibodies against adeno associated viral capsids in patients with mut Methylmalonic Acidemia
Human Gene Therapy, 2016Co-Authors: Elizabeth Harrington, Randy J. Chandler, Jennifer L. Sloan, Irini Manoli, Mark E Schneider, Peter J Mcguire, Roberto Calcedo, James M Wilson, Charles P. VendittiAbstract:Isolated Methylmalonic Acidemia (MMA), a group of autosomal recessive inborn errors of metabolism, is most commonly caused by complete (mut0) or partial (mut−) deficiency of the enzyme methylmalonyl-CoA mutase (MUT). The severe metabolic instability and increased mortality experienced by many affected individuals, especially those with mut0 MMA, has led centers to use elective liver transplantation as a treatment for these patients. We have previously demonstrated the efficacy of systemic adeno-associated viral (AAV) gene delivery as a treatment for MMA in a murine model and therefore sought to survey AAV antibody titers against serotypes 2, 8, and 9 in a group of well-characterized MMA patients, accrued via a dedicated natural history study (clinicaltrials.gov ID: NCT00078078). Plasma samples provided by 42 patients (8 mut− and 34 mut0; 10 had received organ transplantation), who ranged in age between 2 and 31 years, were analyzed to examine AAV2 (n = 35), AAV8 (n = 41), and AAV9 (n = 42) antibody titers...
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propofol administration in patients with Methylmalonic Acidemia and intracellular cobalamin metabolism disorders a review of theoretical concerns and clinical experiences in 28 patients
Journal of Inherited Metabolic Disease, 2015Co-Authors: Yiouli P Ktena, Jennifer L. Sloan, Irini Manoli, Eva H. Baker, Trygg Ramstad, Andrew J Mannes, Charles P. VendittiAbstract:Background Methylmalonic Acidemia and intracellular cobalamin metabolism disorders represent a heterogeneous group of inborn errors of metabolism. Most patients will require diagnostic and/or therapeutic procedures frequently requiring sedation or anesthetic management due to neurological and neurocognitive impairments. It has been stated that propofol is contraindicated in this population. We report our experience with propofol administration in a large series of patients.
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MRI Characteristics of Globus Pallidus Infarcts in Isolated Methylmalonic Acidemia
AJNR. American journal of neuroradiology, 2014Co-Authors: Eva H. Baker, Jennifer L. Sloan, Irini Manoli, N. S. Hauser, David R. Adams, Camilo Toro, Charles P. VendittiAbstract:BACKGROUND: Bilateral infarcts confined to the globus pallidus are unusual and occur in conjunction with only a few disorders, including isolated Methylmalonic Acidemia, a heterogeneous inborn error of metabolism. On the basis of neuroradiographic features of metabolic strokes observed in a large cohort of patients with Methylmalonic Acidemia, we have devised a staging system for Methylmalonic Acidemia–related globus pallidus infarcts. MATERIALS AND METHODS: Forty patients with isolated Methylmalonic Acidemia and neurologic symptoms underwent clinical brain MR imaging studies, which included 3D-T1WI. Infarcted globus pallidus segments were neuroanatomically characterized, and infarct volumes were measured. RESULTS: Globus pallidus infarcts were present in 19 patients; all were bilateral, and most were left-dominant. A neuroanatomic scoring system based on the infarct patterns was devised; this revealed a 5-stage hierarchical susceptibility to metabolic infarct, with the posterior portion of the globus pallidus externa being the most vulnerable. Globus pallidus infarct prevalence by Methylmalonic Acidemia class was the following: cblA (5/7, 71%), cblB (3/7, 43%), mut o (10/22, 45%), and mut- (1/4, 25%). Tiny lacunar infarcts in the pars reticulata of the substantia nigra, previously unrecognized in Methylmalonic Acidemia, were found in 17 patients, 13 of whom also had a globus pallidus infarct. CONCLUSIONS: The staged pattern of globus pallidus infarcts in isolated Methylmalonic Acidemia suggests a nonuniform, regionally specific cellular susceptibility to metabolic injury, even for patients having milder biochemical phenotypes. In support of this hypothesis, the delineation of lacunar infarcts in the pars reticulata of the substantia nigra, a tissue functionally and histologically identical to the globus pallidus interna, supports the concept of cell-specific pathology.
Yi Liu - One of the best experts on this subject based on the ideXlab platform.
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a study on a cohort of 301 chinese patients with isolated Methylmalonic Acidemia
Journal of Inherited Metabolic Disease, 2020Co-Authors: Lulu Kang, Jinqing Song, Hui Dong, M Shen, Y Liu, Yi Liu, Ying Jin, Yao Zhang, Xueqin Liu, Hui YanAbstract:Methylmalonic Acidemia (MMA) is the most common organic Acidemia in China. This study aimed to characterise the genotypic and phenotypic variabilities, and the molecular epidemiology of Chinese patients with isolated MMA. Patients (n = 301) with isolated MMA were diagnosed by clinical examination, biochemical assays, and genetic analysis. Fifty-eight patients (19.3%) were detected by newborn screening and 243 patients (80.7%) were clinically diagnosed after onset. Clinical onset ranged from the age of 3 days to 23 years (mean age = 1.01 ± 0.15 years). Among 234 MMA patients whose detailed clinical data were available, 170 (72.6%) had early onset disease (before the age of 1 year), and 64 (27.4%) had late-onset disease. The 234 MMA patients manifested with neuropsychiatric impairment (65.4%), haematological abnormality (31.6%), renal damage (8.5%), and metabolic crises (67.1%). Haematological abnormality was significantly more common in early-onset patients than that in late-onset patients. The incidence of metabolic crises was significantly high (P C in MMUT in our cohort was also higher than that in 151 European patients. MMUT mutations c.729_730insTT and c.914T>C are specific for the Chinese population. Our study expanded the spectrum of phenotypes and genotypes in isolated MMA.
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generation of a human ipsc line sdqlchi021 a from a patient with Methylmalonic Acidemia cblc type carrying compound heterozygous mutations in mmahc gene
Stem Cell Research, 2020Co-Authors: Jingyun Guan, Zhongtao Gai, Haiyan Zhang, Xiaomeng Yang, Rui Dong, Yi LiuAbstract:Abstract Methylmalonic Acidemia and homocystinuria, cblC type is a rare autosomal recessive inheritance disease. Its clinical phenotype involves multiple systems with varying degrees of severity. The disease is caused by the mutations in the MMACHC gene located on chromosome 1p34.1. Here we report the generation of an iPSC line from the PBMCs of a patient with compound heterozygous mutations in the MMACHC gene. This new iPSC line will allow a better understanding of the MMA disease.
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hydrocephalus in cblc type Methylmalonic Acidemia
Metabolic Brain Disease, 2019Co-Authors: Kaihui Zhang, Min Gao, Guangyu Wang, Yingying Shi, Guangye Zhang, Zhongtao Gai, Yi LiuAbstract:Methylmalonic Acidemia (MMA) is a typical type of organic Acidemia caused by defects in methylmalonyl-CoA mutase or adenosyl-cobalamin synthesis. Hydrocephalus (HC), results from an imbalance between production and absorption of cerebrospinal fluid (CSF), causeing enlarged cerebral ventricles and increased intracranial pressure, is a condition that requires urgent clinical decision-making. MMA without treatment could result in brain damage. However, HC in MMA was rarely reported. In this study, 147 MMA were identified from 9117 high risk children by gas chromatography mass spectrometry (GC/MS) for organic acidurias screening in urine samples and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for amino acids detection in blood samples. Totally 10 cases with MMA and HC were determined by brain MRI/CT, as well as gene mutation testing either by high throughput sequencing or Sanger sequencing. Besides, homocysteine was also analyzed for the 10 MMA with HC. Out of them, 9 cases carry out compound heterozygous mutations or homozygous mutation in MMACHC gene, and 1 case has MUTmutation. The mutation c.609G > A in MMACHC was the most common in the cbl type patients. Although MMA has a high incidence in Shandong province of China, especially cblC type. All of the 10 patients were not correctly diagnosed before developing HC. As a result, when a child develops progressive and refractory HC, the screening for inherited metabolic diseases should be immediately conducted.
Nuria Carrillocarrasco - One of the best experts on this subject based on the ideXlab platform.
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a critical reappraisal of dietary practices in Methylmalonic Acidemia raises concerns about the safety of medical foods part 2 cobalamin c deficiency
Genetics in Medicine, 2016Co-Authors: Jennifer G Myles, Nuria Carrillocarrasco, Eva Morava, Kevin A Strauss, Holmes MortonAbstract:Cobalamin C (cblC) deficiency impairs the biosynthesis of 5′-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in Methylmalonic Acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients. Dietary intake was correlated with biochemical, anthropometric, and body composition measurements and other disease parameters in a cohort of 28 patients with early-onset cblC deficiency. Protein-restricted diets were followed by 21% of the patients, whereas 32% received medical foods. Patients on protein-restricted diets had lower height-for-age z-score (P = 0.034), whereas patients consuming medical foods had lower head circumference Z-scores (P = 0.037), plasma methionine concentrations (P = 0.001), and predicted methionine influx through the blood–brain barrier Z-score (−1.29 vs. −0.0617; P = 0.007). The combination of age at diagnosis, a history of seizures, and the leucine-to-valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R2 = 0.945). Patients with cblC deficiency treated with medical foods designed for isolated Methylmalonic Acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development. Genet Med 18 4, 396–404.
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combined Methylmalonic Acidemia and homocystinuria cblc type ii complications pathophysiology and outcomes
Journal of Inherited Metabolic Disease, 2012Co-Authors: Nuria Carrillocarrasco, Charles P. VendittiAbstract:Combined Methylmalonic Acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials.
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liver directed recombinant adeno associated viral gene delivery rescues a lethal mouse model of Methylmalonic Acidemia and provides long term phenotypic correction
Human Gene Therapy, 2010Co-Authors: Nuria Carrillocarrasco, Randy J. Chandler, Suma Chandrasekaran, Charles P. VendittiAbstract:Methylmalonic Acidemia is an autosomal recessive metabolic disorder caused by a deficiency in the mitochondrial enzyme, methylmalonyl-CoA mutase (MUT). In this study, Carrillo-Carrasco and colleagues demonstrate that a single intrahepatic injection of AAV8 encoding the Mut gene under control of the liver-specific thyroxine-binding globulin promoter is sufficient to rescue Mut −/− mice from neonatal lethality and provides long-term phenotypic correction.