Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev
Case report
Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency Tatiana Munoz a, Jinesh Patel a, Ramses Badilla-Porras a, Jonathan Kronick a, Saadet Mercimek-Mahmutoglu a,b,⇑ a
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada b Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Canada Received 5 January 2014; received in revised form 16 March 2014; accepted 19 March 2014
Abstract Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range > 9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs*24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations. Crown copyright Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.
Keywords: Severe methylenetetrahydrofolate reductase deficiency; Scoliosis; Hypotonia; Failure to thrive; Homocysteine
1. Introduction Methylenetetrahydrofolate reductase (MTHFR) (EC 1.5.1.20) deficiency (MTHFR-D) (OMIM: 236250) is an autosomal recessively inherited disorder of folate metab-
⇑ Corresponding author. Address: The Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, 555 University Avenue, Suite 935, 9th Floor, Toronto, ON, M5G 1X8, Canada. Tel.: +1 416 813 6390; fax: +1 416 813 5345. E-mail address: [email protected] (S. MercimekMahmutoglu).
olism and caused by MTHFR enzyme deficiency, encoded by the MTHFR gene [1]. Severe MTHFR-D presents with failure to thrive (FTT), hypotonia, global developmental delay (GDD), microcephaly and seizures in infancy. Ataxia, thrombotic events and psychiatric manifestations are seen in adults [1]. The biochemical features are markedly elevated homocysteine without significant elevation of methylmalonic acid (MMA). We report a new patient with severe MTHFR-D, who presented with severe hypotonia and scoliosis, severe FFT, GDD and microcephaly within the first year of life.
http://dx.doi.org/10.1016/j.braindev.2014.03.003 0387-7604/Crown copyright Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
2
T. Munoz et al. / Brain & Development xxx (2014) xxx–xxx
2. Case report and results This 23-month-old girl was born at term by cesareansection to non-consanguineous Caucasian parents. She was discharged home at age 2 days. She developed scoliosis at age 3 months and significant FTT, vomiting, GDD and central hypotonia within the first 6–12 months of life. Nasogastric tube feeding was started at age 11 months. At age 10 months, her spine X-ray revealed thoracic levoscoliosis (Cobb angle of 44 degrees) (Fig. 1a). Her estimated developmental age was 4–6 months at 13 months chronological age (supported sitting, grasping objects and cooing). She had microcephaly (9) in the cultured skin fibroblasts confirming the diagnosis of severe MTHFR-D. She had compound heterozygous mutations in the MTHFR gene: a known disease causing c.1304T > C; p.Phe435Ser (paternal) [2] and a novel c.1539dup; p.Glu514Argfs*24 (predicting a truncated protein, considered pathogenic). The mother was not available for genetic testing. Between 16–20 months of age on treatment, she improved in her developmental milestones including: head control at age 17 months, sitting without support at age 18 months, holding and transferring objects at age 19 months, fed herself by bottle at age 19 months, babbling at age 20 months and cruising at age 20 months. She was maintained on phenobarbital with no further seizures. Her central and peripheral hypotonia improved significantly. Spine X-ray revealed increased Cobb angle of 68 degrees at age 18 months (2 months of therapy) (Fig. 1b). A repeat spine X-ray revealed Cobb angle of 50 degrees at age 20 months (4 months of therapy) (Fig. 1c). Following confirmation of MTHFR-D, hydroxycobalamin was switched to oral cyanocobalamin 1 mg/day and folate was increased to 20 mg/day. She was started on pyridoxine 100 mg/day. Despite all these supplements, homocysteine levels remained elevated between 75–85 lmol/L.
Fig. 1. The anterior-posterior supine X-ray of spine shows thoracic levoscoliosis. Cobb angle measuring from the lower border of T4 to the lower border of L1: (1a) At 44 degrees at age 10 months. (1b) At 68 degrees at age 18 months (2 months of therapy). (1c) At 50 degrees at age 20 months (4 months of therapy).
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
T. Munoz et al. / Brain & Development xxx (2014) xxx–xxx
3. Discussion We report on a new patient with severe MTHFR-D who presented with early onset severe scoliosis associated with severe hypotonia at age 4 months, severe FTT, GDD and microcephaly 6–12 months of age and afebrile seizures at age 16 months. Due to stereotypical hand movements and microcephaly, she was investigated for Rett and atypical Rett syndromes. New onset afebrile seizures warranted a metabolic consultation and led the diagnosis of MTHFR-D. One patient with kyphoscoliosis and MTHFR-D has been reported previously who had mild speech delay, attention deficit and hyperactivity at age 2 years. She had moderate delays, mild hyperlaxity of small joints. There was no detailed information regarding onset and severity of kyphoscoliosis at age 11.5 years [3]. Hyperhomocysteinemia and defective folate metabolism are the hallmark of severe MTHFR deficiency [1]. It is likely that both of these metabolic abnormalities disturb collagen cross-linking in bones, cause bone resorption and destruction of bone architecture predisposing bone disease and scoliosis in patients with severe MTHFR-D as a potential mechanisms [4]. To the best of our knowledge, this is the first patient with severe infantile onset scoliosis and MTHFR-D. We therefore suggest that plasma homocysteine measurement should be included as part of initial work-up in the investigations of severe global developmental delay, hypotonia and early onset scoliosis prior to organizing any genetic investigations. So far less than 100 patients have been reported [5–7]. The most common signs and symptoms were GDD (46%), hypotonia (35%), seizures (33%), FTT (17%), thromboembolic events (16%), microcephaly (15%), ataxia (9%) and peripheral neuropathy (7%) (Excel database is available upon request). The seizure phenotype varied from myoclonic, generalized tonic to infantile spasms, evolving to atonic, myoclonic, atypical absences as well as complex partial seizures [5]. Onset of thromboembolic events has been reported from the newborn period to adulthood including superior sagittal sinus thrombosis, pulmonary thromboembolism, stroke and deep venous thrombosis attributed to elevated homocysteine levels [7,8]. Betaine, folic acid, folinic acid, pyridoxine, vitamin B12, methionine, methyltetrahydrofolate have been used in patients [9,10]. A recent systematic review regarding betaine treatment reported normal developmental outcome in five patients with early treatment, however, none of the patients achieved normal development with late treatment [6]. The authors emphasized importance of newborn screening for MTHFR-D [6]. Despite late treatment, our patient showed favorable short-term improvements in development and scoliosis.
3
In summary, we report a new patient with severe MTHFR-D caused by novel compound heterozygous pathogenic mutations in the MTHFR gene. Our patient presented with early onset severe hypotonia and scoliosis. Favorable short-term treatment outcome support the inclusion of homocysteine measurement in the diagnostic work-up of patients with severe hypotonia and global developmental delay. Acknowledgements We would like to thank to Dr. Salomons for performing molecular genetic studies on the clinical basis, Dr. Rosenblatt performing MTHFR enzyme activity in the cultured skin fibroblasts on the clinical basis. We would like to thank to Pediatric Residents, Nurses and Staff Physicians at The Hospital for Sick Children for their excellent care. We would like to thank to our patient’s family for consenting to share their child’s history and investigations. References [1] Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 2012;35:665–70. ´ ngeles A, Cozar M, [2] Urreizti R, Moya-Garcı´a AA, Pino-A Langkilde A, Fanhoe U, et al. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet 2010;78:441–8. [3] Tonetti C, Amiel J, Munnich A, Zittoun J. Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study. J Inherit Metab Dis 2001;24:833–42. [4] Swart KM, van Schoor NM, Lips P. Vitamin B12, folic acid, and bone. Curr Osteoporos Rep 2013;11:213–8. [5] Prasad AN, Rupar CA, Prasad C. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev 2011;33:758–69. [6] Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol 2014;71:188–94. [7] Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, et al. Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 2007;91:165–75. [8] Cizmeci MN, Kanburoglu MK, Akelma AZ, Donmez A, Sonmez FM, Polat A, et al. Cerebral sinovenous thrombosis associated with MTHFR A1298C mutation in the newborn: a case report. J Thromb Thrombolysis 2013;35:279–81. [9] Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H. Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 2011;34:137–45. [10] Abeling NG, van Gennip AH, Blom H, Wevers RA, Vreken P, van Tinteren HLG, et al. Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene tetrahydrofolate reductase deficiency. J Inherit Metab Dis 1999;22:240–2.
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
Case report
Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency Tatiana Munoz a, Jinesh Patel a, Ramses Badilla-Porras a, Jonathan Kronick a, Saadet Mercimek-Mahmutoglu a,b,⇑ a
Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Canada b Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Canada Received 5 January 2014; received in revised form 16 March 2014; accepted 19 March 2014
Abstract Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessively inherited inborn error of folate metabolism. We report a new patient with severe MTHFR deficiency who presented at age 4 months with early onset severe scoliosis associated with severe hypotonia. Markedly decreased MTHFR enzyme activity (0.3 nmoles CHO/mg protein/h; reference range > 9) and compound heterozygous mutations (c. 1304T>C; p.Phe435Ser and c.1539dup; p.Glu514Argfs*24) in the MTHFR gene confirmed the diagnosis. She was treated with vitamin B12, folic acid and betaine supplementation and showed improvements in her developmental milestones and hypotonia. To the best of our knowledge, this is the first patient with MTHFR deficiency reported with severe early onset scoliosis. Despite the late diagnosis and treatment initiation, she showed favorable short-term neurodevelopmental outcome. This case suggests that homocysteine measurement should be included in the investigations of patients with developmental delay, hypotonia and scoliosis within first year of life prior to organizing genetic investigations. Crown copyright Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.
Keywords: Severe methylenetetrahydrofolate reductase deficiency; Scoliosis; Hypotonia; Failure to thrive; Homocysteine
1. Introduction Methylenetetrahydrofolate reductase (MTHFR) (EC 1.5.1.20) deficiency (MTHFR-D) (OMIM: 236250) is an autosomal recessively inherited disorder of folate metab-
⇑ Corresponding author. Address: The Hospital for Sick Children, Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, 555 University Avenue, Suite 935, 9th Floor, Toronto, ON, M5G 1X8, Canada. Tel.: +1 416 813 6390; fax: +1 416 813 5345. E-mail address: [email protected] (S. MercimekMahmutoglu).
olism and caused by MTHFR enzyme deficiency, encoded by the MTHFR gene [1]. Severe MTHFR-D presents with failure to thrive (FTT), hypotonia, global developmental delay (GDD), microcephaly and seizures in infancy. Ataxia, thrombotic events and psychiatric manifestations are seen in adults [1]. The biochemical features are markedly elevated homocysteine without significant elevation of methylmalonic acid (MMA). We report a new patient with severe MTHFR-D, who presented with severe hypotonia and scoliosis, severe FFT, GDD and microcephaly within the first year of life.
http://dx.doi.org/10.1016/j.braindev.2014.03.003 0387-7604/Crown copyright Ó 2014 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
2
T. Munoz et al. / Brain & Development xxx (2014) xxx–xxx
2. Case report and results This 23-month-old girl was born at term by cesareansection to non-consanguineous Caucasian parents. She was discharged home at age 2 days. She developed scoliosis at age 3 months and significant FTT, vomiting, GDD and central hypotonia within the first 6–12 months of life. Nasogastric tube feeding was started at age 11 months. At age 10 months, her spine X-ray revealed thoracic levoscoliosis (Cobb angle of 44 degrees) (Fig. 1a). Her estimated developmental age was 4–6 months at 13 months chronological age (supported sitting, grasping objects and cooing). She had microcephaly (9) in the cultured skin fibroblasts confirming the diagnosis of severe MTHFR-D. She had compound heterozygous mutations in the MTHFR gene: a known disease causing c.1304T > C; p.Phe435Ser (paternal) [2] and a novel c.1539dup; p.Glu514Argfs*24 (predicting a truncated protein, considered pathogenic). The mother was not available for genetic testing. Between 16–20 months of age on treatment, she improved in her developmental milestones including: head control at age 17 months, sitting without support at age 18 months, holding and transferring objects at age 19 months, fed herself by bottle at age 19 months, babbling at age 20 months and cruising at age 20 months. She was maintained on phenobarbital with no further seizures. Her central and peripheral hypotonia improved significantly. Spine X-ray revealed increased Cobb angle of 68 degrees at age 18 months (2 months of therapy) (Fig. 1b). A repeat spine X-ray revealed Cobb angle of 50 degrees at age 20 months (4 months of therapy) (Fig. 1c). Following confirmation of MTHFR-D, hydroxycobalamin was switched to oral cyanocobalamin 1 mg/day and folate was increased to 20 mg/day. She was started on pyridoxine 100 mg/day. Despite all these supplements, homocysteine levels remained elevated between 75–85 lmol/L.
Fig. 1. The anterior-posterior supine X-ray of spine shows thoracic levoscoliosis. Cobb angle measuring from the lower border of T4 to the lower border of L1: (1a) At 44 degrees at age 10 months. (1b) At 68 degrees at age 18 months (2 months of therapy). (1c) At 50 degrees at age 20 months (4 months of therapy).
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
T. Munoz et al. / Brain & Development xxx (2014) xxx–xxx
3. Discussion We report on a new patient with severe MTHFR-D who presented with early onset severe scoliosis associated with severe hypotonia at age 4 months, severe FTT, GDD and microcephaly 6–12 months of age and afebrile seizures at age 16 months. Due to stereotypical hand movements and microcephaly, she was investigated for Rett and atypical Rett syndromes. New onset afebrile seizures warranted a metabolic consultation and led the diagnosis of MTHFR-D. One patient with kyphoscoliosis and MTHFR-D has been reported previously who had mild speech delay, attention deficit and hyperactivity at age 2 years. She had moderate delays, mild hyperlaxity of small joints. There was no detailed information regarding onset and severity of kyphoscoliosis at age 11.5 years [3]. Hyperhomocysteinemia and defective folate metabolism are the hallmark of severe MTHFR deficiency [1]. It is likely that both of these metabolic abnormalities disturb collagen cross-linking in bones, cause bone resorption and destruction of bone architecture predisposing bone disease and scoliosis in patients with severe MTHFR-D as a potential mechanisms [4]. To the best of our knowledge, this is the first patient with severe infantile onset scoliosis and MTHFR-D. We therefore suggest that plasma homocysteine measurement should be included as part of initial work-up in the investigations of severe global developmental delay, hypotonia and early onset scoliosis prior to organizing any genetic investigations. So far less than 100 patients have been reported [5–7]. The most common signs and symptoms were GDD (46%), hypotonia (35%), seizures (33%), FTT (17%), thromboembolic events (16%), microcephaly (15%), ataxia (9%) and peripheral neuropathy (7%) (Excel database is available upon request). The seizure phenotype varied from myoclonic, generalized tonic to infantile spasms, evolving to atonic, myoclonic, atypical absences as well as complex partial seizures [5]. Onset of thromboembolic events has been reported from the newborn period to adulthood including superior sagittal sinus thrombosis, pulmonary thromboembolism, stroke and deep venous thrombosis attributed to elevated homocysteine levels [7,8]. Betaine, folic acid, folinic acid, pyridoxine, vitamin B12, methionine, methyltetrahydrofolate have been used in patients [9,10]. A recent systematic review regarding betaine treatment reported normal developmental outcome in five patients with early treatment, however, none of the patients achieved normal development with late treatment [6]. The authors emphasized importance of newborn screening for MTHFR-D [6]. Despite late treatment, our patient showed favorable short-term improvements in development and scoliosis.
3
In summary, we report a new patient with severe MTHFR-D caused by novel compound heterozygous pathogenic mutations in the MTHFR gene. Our patient presented with early onset severe hypotonia and scoliosis. Favorable short-term treatment outcome support the inclusion of homocysteine measurement in the diagnostic work-up of patients with severe hypotonia and global developmental delay. Acknowledgements We would like to thank to Dr. Salomons for performing molecular genetic studies on the clinical basis, Dr. Rosenblatt performing MTHFR enzyme activity in the cultured skin fibroblasts on the clinical basis. We would like to thank to Pediatric Residents, Nurses and Staff Physicians at The Hospital for Sick Children for their excellent care. We would like to thank to our patient’s family for consenting to share their child’s history and investigations. References [1] Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 2012;35:665–70. ´ ngeles A, Cozar M, [2] Urreizti R, Moya-Garcı´a AA, Pino-A Langkilde A, Fanhoe U, et al. Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency. Clin Genet 2010;78:441–8. [3] Tonetti C, Amiel J, Munnich A, Zittoun J. Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study. J Inherit Metab Dis 2001;24:833–42. [4] Swart KM, van Schoor NM, Lips P. Vitamin B12, folic acid, and bone. Curr Osteoporos Rep 2013;11:213–8. [5] Prasad AN, Rupar CA, Prasad C. Methylenetetrahydrofolate reductase (MTHFR) deficiency and infantile epilepsy. Brain Dev 2011;33:758–69. [6] Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM. Survival and psychomotor development with early betaine treatment in patients with severe methylenetetrahydrofolate reductase deficiency. JAMA Neurol 2014;71:188–94. [7] Strauss KA, Morton DH, Puffenberger EG, Hendrickson C, Robinson DL, Wagner C, et al. Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 2007;91:165–75. [8] Cizmeci MN, Kanburoglu MK, Akelma AZ, Donmez A, Sonmez FM, Polat A, et al. Cerebral sinovenous thrombosis associated with MTHFR A1298C mutation in the newborn: a case report. J Thromb Thrombolysis 2013;35:279–81. [9] Schiff M, Benoist JF, Tilea B, Royer N, Giraudier S, Ogier de Baulny H. Isolated remethylation disorders: do our treatments benefit patients? J Inherit Metab Dis 2011;34:137–45. [10] Abeling NG, van Gennip AH, Blom H, Wevers RA, Vreken P, van Tinteren HLG, et al. Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene tetrahydrofolate reductase deficiency. J Inherit Metab Dis 1999;22:240–2.
Please cite this article in press as: Munoz T et al. Severe scoliosis in a patient with severe methylenetetrahydrofolate reductase deficiency. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.03.003
