Recessive spastic paraparesis associated with complex I deficiency due to<i>MTHFR</i>mutations

Bathgate, Deborah; Yu‐Wai‐Man, Patrick; Webb, Brian; Taylor, Robert W.; Fowler, Brian; Chinnery, Patrick F.

doi:10.1136/jnnp.2010.218586

Cited by 9 publications

(11 citation statements)

References 5 publications

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“…In total, 65 different mutations, 42 of which are novel, were identified in our patient cohort. Of the 23 previously published mutations that we reported in this study, seven have been found only in our cohort [Forges et al, 2010;Urreizti et al, 2010;Tsuji et al, 2011;Bathgate et al, 2012;Crushell et al, 2012]. Only 19 mutations were detected in more than one cell line, indicating that most patients carry private mutations.…”

Section: Mutation Identificationmentioning

confidence: 57%

“…Details of cell lines 1–25 and control fibroblasts, as well as cell culture conditions, have already been described [Suormala et al., ]. Enzyme activities and mutations, but not extended enzymatic characterization have been previously reported for cell lines 16, 49, and 56 [Urreizti et al., ; termed patients 2, 4, and 5, respectively]; 33 [Bathgate et al., ]; 55 [Forges et al., ; younger sibling]; 60 [Tsuji et al., ]; and 71 [Crushell et al. ].…”

Section: Methodsmentioning

confidence: 99%

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Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

et al. 2015

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5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%-42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide-responsiveness, and 24 abnormal kinetics of S-adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N-terminal catalytic domain, whereas missense mutations in the C-terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S-adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.

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Section: Mutation Identificationmentioning

confidence: 57%

Section: Methodsmentioning

confidence: 99%

Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

et al. 2015

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“…Furthermore, the more appropriate parameter to predict disease severity and age at onset may be the degree of residual MTHFR enzymatic activity with marked reduced activity (<1.5%) in patients with severe presentations (early onset and/or death before 2 years), moderately reduced activity (1.7‐11%) in patients with moderate to severe diseases, and mild or even no clearly reduced enzymatic activity (19%‐42%) in patients with mild symptoms 3 . Intermediate to high residual activities were found in most 7,10,11,13,14,17 but not all 9,12,15,16,19 of the previously published patients with late‐onset MTHFR deficiency. All the late‐onset patients of this series for whom we measured MTHFR activity showed a high residual activity (from 17% to 58%, compared with controls), confirming the hypothesis of a correlation with disease severity.…”

Section: Discussionmentioning

confidence: 93%

“…Apnoea is a frequent complication 2,4‐6 . However, few late‐onset (ie, after the age of 1 year) 2 and adult‐onset forms of the disease have been reported, mainly as case reports 7‐22 . Hence, the natural history of late‐onset MTHFR deficiency is largely unknown (eg, pre‐existing mild developmental delay, precipitating factors, and response to treatment).…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular characterization of adult patients with late‐onset MTHFR deficiency

Marelli

Lavigne

Stępień

et al. 2020

J of Inher Metab Disea

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5,10‐Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late‐onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult‐onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11‐54). At onset (median age: 20 years; range 9‐38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69‐266, to 90 μmol/L, range 20‐142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C‐terminal regulatory domain of the protein were over‐represented compared to early‐onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%‐58%). This series of patients with late‐onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

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“…Treatment with betaine produced a rapid decline in Hcy in all patients and improved symptomatology in three patients. Bathgate et al also described two young-adult siblings with a spastic paraparesis who developed cognitive decline and behavioural disturbance, in relation with a severe hyperhomocysteinemia 10…”

Section: Discussionmentioning

confidence: 99%

Adult-onset methylenetetrahydrofolate reductase deficiency

et al. 2020

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Severe hyperhomocysteinemia (>100 µmol/L) is often associated with inborn errors of homocysteine metabolism. It manifests typically in neonatal period with developmental delay, hypotonia, feeding problems or failure to thrive. Adult-onset forms are rare and include less severe manifestations. Early diagnosis is crucial because effective treatment is available. A 23-year-old man presented with a 3-week history of speech and gait impairment, and numbness in lower limbs. Neurological examination revealed dysarthria, decreased vibratory sensation in both legs and appendicular and gait ataxia. Brain MRI revealed T2-hyperintense symmetric white matter lesions and cortical atrophy. He had folate and vitamin B12 deficiency, a markedly elevated serum homocysteine and low methionine. Despite vitamin supplementation homocysteine levels remained elevated. Molecular studies of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene revealed a new pathogenic mutation (c.1003C>T (p.Arg335Cys)) and a polymorphism (C677T (p.Ala222Val)) associated with hyperhomocysteinemia, both in homozygosity. The patient started betaine with clinical and biochemical improvement.

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Recessive spastic paraparesis associated with complex I deficiency due toMTHFRmutations

Cited by 9 publications

References 5 publications

Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

Clinical and molecular characterization of adult patients with late‐onset MTHFR deficiency

Adult-onset methylenetetrahydrofolate reductase deficiency

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