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Miscellaneous Organic/Aminoacidopathies
Anna Illner, MD; Anne G. Osborn, MD, FACR
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KEY FACTS

  • Terminology

    • Imaging

      • Clinical Issues

        TERMINOLOGY

        • Abbreviations

          • Phenylketonuria (PKU)
          • Hyperhomocysteinemia (HHcy)
          • Cystathionine β-synthase deficiency (CBSD)
          • 5,10 methylenetetrahydrofolate reductase deficiency (MTHFRD)
          • Methionine adenosyltransferase deficiency (MAT I/IIID)
          • Cobalamin C (Cbl-C), disorder vitamin B12 metabolism
        • Definitions

          • PKU: Most common inborn error of amino acid metabolism resulting in ↑ phenylalanine (Phe)
          • Hyperhomocysteinemia: Multiple disorders resulting in ↑ plasma homocysteine (Hcy) > 12 μmol/L
            • ↑ risk arteriosclerotic disease > venous thrombosis
            • Caused by inborn errors of Hcy, folate, or vitamin B12 metabolism; ↓ vitamin B12/folate intake; renal failure
            • 4 most recognized metabolic disorders: CBSD, MTHFRD, Cbl-C, MAT I/IIID
            • Variable phenotype among & within each disorder

        IMAGING

        • General Features

          • CT Findings

            • MR Findings

              • Imaging Recommendations

                DIFFERENTIAL DIAGNOSIS

                  PATHOLOGY

                  • General Features

                    • Microscopic Features

                      CLINICAL ISSUES

                      • Presentation

                        • Demographics

                          • Natural History & Prognosis

                            • Treatment

                              Selected References

                              1. Kölker S et al: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. ePub, 2015
                              2. Kölker S et al: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. ePub, 2015
                              3. Krishna SH et al: Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders. Semin Ultrasound CT MR. 35(2):160-91, 2014
                              4. Makrides V et al: Transport of amino acids in the kidney. Compr Physiol. 4(1):367-403, 2014
                              5. Barbagallo M et al: Two siblings with a homozygous MTHFR C677T (G80A-RFC1) mutation and stroke. Childs Nerv Syst. 25(3):361-5, 2009
                              6. Del Balzo F et al: MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family. Pediatr Neurol. 40(1):63-7, 2009
                              7. Gorgone G et al: Hyperhomocysteinemia in patients with epilepsy: does it play a role in the pathogenesis of brain atrophy? A preliminary report. Epilepsia. 50 Suppl 1:33-6, 2009
                              8. Bishop L et al: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria. J Child Neurol. 23(7):823-8, 2008
                              9. Ding XQ et al: MRI abnormalities in normal-appearing brain tissue of treated adult PKU patients. J Magn Reson Imaging. 27(5):998-1004, 2008
                              10. Indolfi G et al: Cryptogenic stroke in a boy with atrial septal defect and hyperhomocysteinemia. J Child Neurol. 23(9):1070-1, 2008
                              11. Shyambabu C et al: Serum vitamin B12 deficiency and hyperhomocystinemia: a reversible cause of acute chorea, cerebellar ataxia in an adult with cerebral ischemia. J Neurol Sci. 273(1-2):152-4, 2008
                              12. Thauvin-Robinet C et al: The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry. 79(6):725-8, 2008
                              13. van Spronsen FJ et al: The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis. 31(6):673-9, 2008
                              14. Vatanavicharn N et al: Reversible leukoencephalopathy with acute neurological deterioration and permanent residua in classical homocystinuria: A case report. J Inherit Metab Dis. Epub ahead of print, 2008
                              15. Anderson PJ et al: Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol. 32(2):645-68, 2007
                              16. Giovannini M et al: Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis. 30(2):145-52, 2007
                              17. Leuzzi V et al: The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. J Inherit Metab Dis. 30(2):209-16, 2007
                              18. Matthews RG et al: Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias. Clin Chem Lab Med. 45(12):1700-3, 2007
                              19. Obeid R et al: The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med. 45(12):1590-606, 2007
                              20. Vermathen P et al: Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging. Magn Reson Med. 58(6):1145-56, 2007
                              21. Castro R et al: Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis. 29(1):3-20, 2006
                              22. Cattaneo M: Hyperhomocysteinemia and venous thromboembolism. Semin Thromb Hemost. 32(7):716-23, 2006
                              23. Franco LP et al: Proton MR spectroscopy in hyperhomocysteinemia with elevated blood methionine levels. J Magn Reson Imaging. 23(3):404-7, 2006
                              24. Pérez-Dueñas B et al: Global and regional volume changes in the brains of patients with phenylketonuria. Neurology. 66(7):1074-8, 2006
                              25. Sinclair AJ et al: Recurrent dystonia in homocystinuria: a metabolic pathogenesis. Mov Disord. 21(10):1780-2, 2006
                              26. Wong A et al: Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease. J Neurol. 253(4):441-7, 2006
                              27. Boxer AL et al: Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology. 64(8):1431-4, 2005
                              28. Braverman NE et al: Characteristic MR imaging changes in severe hypermethioninemic states. AJNR Am J Neuroradiol. 26(10):2705-6, 2005
                              29. Duncan IC et al: Spontaneous isolated posterior communicating artery dissection in a young adult with hyperhomocysteinemia. AJNR Am J Neuroradiol. 26(8):2030-2, 2005
                              30. Fowler B: Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Semin Vasc Med. 5(2):77-86, 2005
                              31. Herrmann M et al: Homocysteine--a newly recognised risk factor for osteoporosis. Clin Chem Lab Med. 43(10):1111-7, 2005
                              32. Kono K et al: Diffusion-weighted MR imaging in patients with phenylketonuria: relationship between serum phenylalanine levels and ADC values in cerebral white matter. Radiology. 236(2):630-6, 2005
                              33. Linnebank M et al: Methionine adenosyltransferase (MAT) I/III deficiency with concurrent hyperhomocysteinaemia: two novel cases. J Inherit Metab Dis. 28(6):1167-8, 2005
                              34. Longo D et al: MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics. 36(6):366-72, 2005
                              35. Pfaendner NH et al: MR imaging-based volumetry in patients with early-treated phenylketonuria. AJNR Am J Neuroradiol. 26(7):1681-5, 2005
                              36. Ricci D et al: Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics. 36(3):181-5, 2005
                              37. Tallur KK et al: Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings. Dev Med Child Neurol. 47(1):53-6, 2005
                              38. Anderson PJ et al: Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol. 46(4):230-8, 2004
                              39. Ekinci B et al: Two siblings with homocystinuria presenting with dystonia and parkinsonism. Mov Disord. 19(8):962-4, 2004
                              40. Sijens PE et al: 1H MR chemical shift imaging detection of phenylalanine in patients suffering from phenylketonuria (PKU). Eur Radiol. 14(10):1895-900, 2004
                              41. Tada H et al: Reversible white matter lesion in methionine adenosyltransferase I/III deficiency. AJNR Am J Neuroradiol. 25(10):1843-5, 2004
                              42. Gizewska M et al: Different presentations of late-detected phenylketonuria in two brothers with the same R408W/R111X genotype in the PAH gene. J Intellect Disabil Res. 47(Pt 2):146-52, 2003
                              43. Harvey Mudd S et al: Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap. Mol Genet Metab. 79(1):6-16, 2003
                              44. Kahler SG et al: Metabolic disorders and mental retardation. Am J Med Genet C Semin Med Genet. 117C(1):31-41, 2003
                              45. Kirkham FJ: Is there a genetic basis for pediatric stroke? Curr Opin Pediatr. 15(6):547-58, 2003
                              46. Kohara K et al: MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study. Stroke. 34(5):1130-5, 2003
                              47. Moats RA et al: Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics. 112(6 Pt 2):1575-9, 2003
                              48. Sener RN: Diffusion MRI findings in phenylketonuria. Eur Radiol. 13 Suppl 6:L226-9, 2003
                              49. Sener RN: Phenylketonuria: diffusion magnetic resonance imaging and proton magnetic resonance spectroscopy. J Comput Assist Tomogr. 27(4):541-3, 2003
                              50. Biancheri R et al: Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia. 43(6):616-22, 2002
                              51. Koch R et al: Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 25(5):333-46, 2002
                              52. Stabler SP et al: Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Metabolism. 51(8):981-8, 2002
                              53. Akar N et al: Common mutations at the homocysteine metabolism pathway and pediatric stroke. Thromb Res. 102(2):115-20, 2001
                              54. Biancheri R et al: Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics. 32(1):14-22, 2001
                              55. Dezortová M et al: MR in phenylketonuria-related brain lesions. Acta Radiol. 42(5):459-66, 2001
                              56. Phillips MD et al: Diffusion-weighted imaging of white matter abnormalities in patients with phenylketonuria. AJNR Am J Neuroradiol. 22(8):1583-6, 2001
                              57. Powers JM et al: Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol. 49(3):396-400, 2001
                              58. Rossi A et al: Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol. 22(3):554-63, 2001
                              59. Weglage J et al: Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 49(4):532-6, 2001
                              60. Baethmann M et al: Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency. Neuropediatrics. 31(6):314-7, 2000
                              61. Brenton DP et al: Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr. 159 Suppl 2:S114-20, 2000
                              62. Dyer CA: Comments on the neuropathology of phenylketonuria. Eur J Pediatr. 159 Suppl 2:S107-8, 2000
                              63. Huttenlocher PR: The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr. 159 Suppl 2:S102-6, 2000
                              64. Koch R et al: Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics. 106(5):1093-6, 2000
                              65. Leuzzi V et al: Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J Inherit Metab Dis. 23(6):563-70, 2000
                              Related Anatomy
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                              Related Differential Diagnoses
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                              References
                              Tables

                              Tables

                              KEY FACTS

                              • Terminology

                                • Imaging

                                  • Clinical Issues

                                    TERMINOLOGY

                                    • Abbreviations

                                      • Phenylketonuria (PKU)
                                      • Hyperhomocysteinemia (HHcy)
                                      • Cystathionine β-synthase deficiency (CBSD)
                                      • 5,10 methylenetetrahydrofolate reductase deficiency (MTHFRD)
                                      • Methionine adenosyltransferase deficiency (MAT I/IIID)
                                      • Cobalamin C (Cbl-C), disorder vitamin B12 metabolism
                                    • Definitions

                                      • PKU: Most common inborn error of amino acid metabolism resulting in ↑ phenylalanine (Phe)
                                      • Hyperhomocysteinemia: Multiple disorders resulting in ↑ plasma homocysteine (Hcy) > 12 μmol/L
                                        • ↑ risk arteriosclerotic disease > venous thrombosis
                                        • Caused by inborn errors of Hcy, folate, or vitamin B12 metabolism; ↓ vitamin B12/folate intake; renal failure
                                        • 4 most recognized metabolic disorders: CBSD, MTHFRD, Cbl-C, MAT I/IIID
                                        • Variable phenotype among & within each disorder

                                    IMAGING

                                    • General Features

                                      • CT Findings

                                        • MR Findings

                                          • Imaging Recommendations

                                            DIFFERENTIAL DIAGNOSIS

                                              PATHOLOGY

                                              • General Features

                                                • Microscopic Features

                                                  CLINICAL ISSUES

                                                  • Presentation

                                                    • Demographics

                                                      • Natural History & Prognosis

                                                        • Treatment

                                                          Selected References

                                                          1. Kölker S et al: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. ePub, 2015
                                                          2. Kölker S et al: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. ePub, 2015
                                                          3. Krishna SH et al: Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders. Semin Ultrasound CT MR. 35(2):160-91, 2014
                                                          4. Makrides V et al: Transport of amino acids in the kidney. Compr Physiol. 4(1):367-403, 2014
                                                          5. Barbagallo M et al: Two siblings with a homozygous MTHFR C677T (G80A-RFC1) mutation and stroke. Childs Nerv Syst. 25(3):361-5, 2009
                                                          6. Del Balzo F et al: MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family. Pediatr Neurol. 40(1):63-7, 2009
                                                          7. Gorgone G et al: Hyperhomocysteinemia in patients with epilepsy: does it play a role in the pathogenesis of brain atrophy? A preliminary report. Epilepsia. 50 Suppl 1:33-6, 2009
                                                          8. Bishop L et al: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria. J Child Neurol. 23(7):823-8, 2008
                                                          9. Ding XQ et al: MRI abnormalities in normal-appearing brain tissue of treated adult PKU patients. J Magn Reson Imaging. 27(5):998-1004, 2008
                                                          10. Indolfi G et al: Cryptogenic stroke in a boy with atrial septal defect and hyperhomocysteinemia. J Child Neurol. 23(9):1070-1, 2008
                                                          11. Shyambabu C et al: Serum vitamin B12 deficiency and hyperhomocystinemia: a reversible cause of acute chorea, cerebellar ataxia in an adult with cerebral ischemia. J Neurol Sci. 273(1-2):152-4, 2008
                                                          12. Thauvin-Robinet C et al: The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry. 79(6):725-8, 2008
                                                          13. van Spronsen FJ et al: The truth of treating patients with phenylketonuria after childhood: the need for a new guideline. J Inherit Metab Dis. 31(6):673-9, 2008
                                                          14. Vatanavicharn N et al: Reversible leukoencephalopathy with acute neurological deterioration and permanent residua in classical homocystinuria: A case report. J Inherit Metab Dis. Epub ahead of print, 2008
                                                          15. Anderson PJ et al: Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol. 32(2):645-68, 2007
                                                          16. Giovannini M et al: Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis. 30(2):145-52, 2007
                                                          17. Leuzzi V et al: The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. J Inherit Metab Dis. 30(2):209-16, 2007
                                                          18. Matthews RG et al: Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias. Clin Chem Lab Med. 45(12):1700-3, 2007
                                                          19. Obeid R et al: The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med. 45(12):1590-606, 2007
                                                          20. Vermathen P et al: Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging. Magn Reson Med. 58(6):1145-56, 2007
                                                          21. Castro R et al: Homocysteine metabolism, hyperhomocysteinaemia and vascular disease: an overview. J Inherit Metab Dis. 29(1):3-20, 2006
                                                          22. Cattaneo M: Hyperhomocysteinemia and venous thromboembolism. Semin Thromb Hemost. 32(7):716-23, 2006
                                                          23. Franco LP et al: Proton MR spectroscopy in hyperhomocysteinemia with elevated blood methionine levels. J Magn Reson Imaging. 23(3):404-7, 2006
                                                          24. Pérez-Dueñas B et al: Global and regional volume changes in the brains of patients with phenylketonuria. Neurology. 66(7):1074-8, 2006
                                                          25. Sinclair AJ et al: Recurrent dystonia in homocystinuria: a metabolic pathogenesis. Mov Disord. 21(10):1780-2, 2006
                                                          26. Wong A et al: Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease. J Neurol. 253(4):441-7, 2006
                                                          27. Boxer AL et al: Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology. 64(8):1431-4, 2005
                                                          28. Braverman NE et al: Characteristic MR imaging changes in severe hypermethioninemic states. AJNR Am J Neuroradiol. 26(10):2705-6, 2005
                                                          29. Duncan IC et al: Spontaneous isolated posterior communicating artery dissection in a young adult with hyperhomocysteinemia. AJNR Am J Neuroradiol. 26(8):2030-2, 2005
                                                          30. Fowler B: Homocysteine: overview of biochemistry, molecular biology, and role in disease processes. Semin Vasc Med. 5(2):77-86, 2005
                                                          31. Herrmann M et al: Homocysteine--a newly recognised risk factor for osteoporosis. Clin Chem Lab Med. 43(10):1111-7, 2005
                                                          32. Kono K et al: Diffusion-weighted MR imaging in patients with phenylketonuria: relationship between serum phenylalanine levels and ADC values in cerebral white matter. Radiology. 236(2):630-6, 2005
                                                          33. Linnebank M et al: Methionine adenosyltransferase (MAT) I/III deficiency with concurrent hyperhomocysteinaemia: two novel cases. J Inherit Metab Dis. 28(6):1167-8, 2005
                                                          34. Longo D et al: MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics. 36(6):366-72, 2005
                                                          35. Pfaendner NH et al: MR imaging-based volumetry in patients with early-treated phenylketonuria. AJNR Am J Neuroradiol. 26(7):1681-5, 2005
                                                          36. Ricci D et al: Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics. 36(3):181-5, 2005
                                                          37. Tallur KK et al: Folate-induced reversal of leukoencephalopathy and intellectual decline in methylene-tetrahydrofolate reductase deficiency: variable response in siblings. Dev Med Child Neurol. 47(1):53-6, 2005
                                                          38. Anderson PJ et al: Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol. 46(4):230-8, 2004
                                                          39. Ekinci B et al: Two siblings with homocystinuria presenting with dystonia and parkinsonism. Mov Disord. 19(8):962-4, 2004
                                                          40. Sijens PE et al: 1H MR chemical shift imaging detection of phenylalanine in patients suffering from phenylketonuria (PKU). Eur Radiol. 14(10):1895-900, 2004
                                                          41. Tada H et al: Reversible white matter lesion in methionine adenosyltransferase I/III deficiency. AJNR Am J Neuroradiol. 25(10):1843-5, 2004
                                                          42. Gizewska M et al: Different presentations of late-detected phenylketonuria in two brothers with the same R408W/R111X genotype in the PAH gene. J Intellect Disabil Res. 47(Pt 2):146-52, 2003
                                                          43. Harvey Mudd S et al: Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap. Mol Genet Metab. 79(1):6-16, 2003
                                                          44. Kahler SG et al: Metabolic disorders and mental retardation. Am J Med Genet C Semin Med Genet. 117C(1):31-41, 2003
                                                          45. Kirkham FJ: Is there a genetic basis for pediatric stroke? Curr Opin Pediatr. 15(6):547-58, 2003
                                                          46. Kohara K et al: MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study. Stroke. 34(5):1130-5, 2003
                                                          47. Moats RA et al: Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics. 112(6 Pt 2):1575-9, 2003
                                                          48. Sener RN: Diffusion MRI findings in phenylketonuria. Eur Radiol. 13 Suppl 6:L226-9, 2003
                                                          49. Sener RN: Phenylketonuria: diffusion magnetic resonance imaging and proton magnetic resonance spectroscopy. J Comput Assist Tomogr. 27(4):541-3, 2003
                                                          50. Biancheri R et al: Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia. 43(6):616-22, 2002
                                                          51. Koch R et al: Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 25(5):333-46, 2002
                                                          52. Stabler SP et al: Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency. Metabolism. 51(8):981-8, 2002
                                                          53. Akar N et al: Common mutations at the homocysteine metabolism pathway and pediatric stroke. Thromb Res. 102(2):115-20, 2001
                                                          54. Biancheri R et al: Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics. 32(1):14-22, 2001
                                                          55. Dezortová M et al: MR in phenylketonuria-related brain lesions. Acta Radiol. 42(5):459-66, 2001
                                                          56. Phillips MD et al: Diffusion-weighted imaging of white matter abnormalities in patients with phenylketonuria. AJNR Am J Neuroradiol. 22(8):1583-6, 2001
                                                          57. Powers JM et al: Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol. 49(3):396-400, 2001
                                                          58. Rossi A et al: Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol. 22(3):554-63, 2001
                                                          59. Weglage J et al: Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 49(4):532-6, 2001
                                                          60. Baethmann M et al: Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency. Neuropediatrics. 31(6):314-7, 2000
                                                          61. Brenton DP et al: Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr. 159 Suppl 2:S114-20, 2000
                                                          62. Dyer CA: Comments on the neuropathology of phenylketonuria. Eur J Pediatr. 159 Suppl 2:S107-8, 2000
                                                          63. Huttenlocher PR: The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr. 159 Suppl 2:S102-6, 2000
                                                          64. Koch R et al: Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics. 106(5):1093-6, 2000
                                                          65. Leuzzi V et al: Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J Inherit Metab Dis. 23(6):563-70, 2000