Hydrocephalus Internus in Two Patients with 5,10-Methylenetetrahydrofolate Reductase Deficiency

Hydrocephalus internus (HCI) of all four ventricles in association with early neurological abnormalities is described as the presenting symptom in two patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. Decreased activity of MTHFR leads to reduction of 5-methyltetrahydrofolate, the main methyl donor for methionine synthesis necessary for synthesis of S-adenosyl-methionine (SAM). Demyelination in MTHFR deficiency has been attributed to low SAM levels in the brain. The biochemical hallmarks of the disorder are hyperhomocystinemia, homocystinuria and low levels of plasma methionine. Hydrocephalus internus requiring neurosurgical intervention has to our knowledge not been reported as a presenting feature of homocystinuria due to deficiency of MTHFR so far. The surprising finding of HCI of all four ventricles in MTHFR deficiency must be kept in mind when evaluating patients with hydrocephalus of unknown origin.

Hydrocephalus internus in metabolic disorders - Single carbon metabolism - Homocysteine - Methylenetetrahydrofolate

References

• 1 Afifi A K, Sato Y, Waziri M H, Bell W E. Computed tomography and magnetic resonance imaging of the brain in Hurler's disease.  J Child Neurol. 1990;  5 235-241
• 2 Allen R J, Wong P, Rothenberg S P, Di Mauro S, Headington J T. Progressive neonatal leukoencephalopathy due to absent methylenetetrahydrofolate reductase.  Ann Neurol. 1980;  8 211
• 3 Al-Moutaery K R, Choudhury A R, Hassanen M O. Cervical cord compression and severe hydrocephalus in a child with Saudi variant of Multiple Sulfatase Deficiency.  Acta Neurochir. 1994;  131 160-163
• 4 Beck M. Mukopolysaccharidosen, Nosologie - Klinik - Therapieansätze.  Monatsschrift Kinderheilkunde. 1991;  139 120-127
• 5 Burk R D, Valle D, Thomas G H, Miller C, Moser A, Moser H, Rosenbaum K N. Early manifestations of multiple sulfatase deficiency.  J Pediatr. 1984;  104 574-578
• 6 Engbersen A M, Franken D G, Boers G H, Stevens E M, Trijbels F J, Blom H J. Thermolabile 5, 10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia.  Am J Hum Genet. 1995;  56 142-150
• 7 Engelbrecht V, Rassek M, Huismann J, Wendel U. MR and proton MR spectroscopy of the brain in hyperhomocysteinemia caused by methylenetetrahydrofolate reductase deficiency.  AJNR. 1997;  18 536-539
• 8 Freeman J M, Finkelstein J D, Mudd S H. Folate responsive homocystinuria and “schizophrenia”. A defect in methylation due to deficient 5, 10-methylenetetrahydrofolate reductase activity.  NEJM. 1975;  292 491-495
• 9 Goyette P, Frosst P, Rosenblatt D S, Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency.  Am J Hum Genet. 1995;  56 1052-1059
• 10 Harpey J P, Rosenblatt D S, Cooper B A, LeMoel G, Roy C, Lafourcade J. Homocystinuria caused by 5, 10-methylenetetrahydrofolate reductase deficiency: A case in an infant responding to methionine, folinic acid, pyridoxine and vitamin B12 therapy.  J Pediatr. 1981;  98 275-278
• 11 Haworth J C, Dilling L A, Surtees R AH, Seargeant L E, Lue-Shing H, Cooper B A, Rosenblatt D S. Symptomatic and asymptomatic methylenetetrahydrofolate reductase deficiency in two adult brothers.  Am J Med Genet. 1993;  45 572-576
• 12 Hoffmann G F, Athanassopoulos S, Burlina A B. et al . Clinical course, early diagnosis, treatment and prevention of disease in glutaryl-CoA dehydrogenase deficiency.  Neuropediatrics. 1996;  27 115-123
• 13 Hyland K, Smith I, Bottiglieri T, Perry J, Wendel U, Clayton P T, Leonard J V. Demyelination and decreased S-adenosylmethionine in 5, 10-methylenetetrahydrofolate reductase deficiency.  Neurology. 1988;  38 459-462
• 14 Kanwar Y S, Manaligod J R, Wong P WK. Morphologic studies in a patient with homocystinuria due to 5, 10-methylenetetrahydrofolate reductase deficiency.  Pediat Res. 1976;  10 598-609
• 15 Kluijtmans L AJ, Wendel U, Stevens E MB, van der Heuvel L PWJ, Trijbels F, Blom H J. Identification of four novel mutations in severe methylenetetrahydrofolate reductase deficiency.  Eur J Hum Genet. 1998;  6 257-265
• 16 Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway.  Lancet. 1991;  338 1550-1554
• 17 Walk D, Kang S S, Horwitz A. Intermittent encephalopathy, reversible nerve conduction slowing and MRI evidence of cerebral white matter disease in methylenetetrahydrofolate reductase deficiency.  Neurology. 1994;  44 344-347
• 18 Wendel U, Bremer H J. Betaine in the treatment of homocystinuria due to 5, 10-methylenetetrahydrofolate reductase deficiency.  Eur J Pediatr. 1984;  142 147-150
• 19 Wong P WK, Justice P, Hruby M, Weiss E B, Diamond E. Folic acid nonresponsive homocystinuria due to methylenetetrahydrofolate reductase deficiency.  Pediatrics. 1977;  59 749-756