The Pathogenesis of Hydrocephalus in Inborn Errors of the Single Carbon Transfer Pathway

Sir,

We read with interest the paper “Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency” by Baethmann et al [[1]]. The authors describe two patients with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency who presented with hydrocephalus and signs of raised intracranial pressure soon after birth. They found that the pathophysiological mechanism of hydrocephalus remained obscure, as no signs of infection or haemorrhage resulting in a mechanical obstruction to CSF flow were present in their patients. However, they also speculated that the effects of elevated homocysteine levels on the vascular intima could contribute to impaired CSF resorption [[1]]. We would like to provide support and a tenable explanation to this hypothesis on the basis of our observations in a cohort of patients with a similar condition, that is combined methylmalonic aciduria and homocystinuria (MMA-HC) due to cobalamine deficiency [[3]].

MMA-HC is caused by the cblC, cblD, and cblF mutations, and is characterised by impaired hepatic conversion of dietary cobalamine to methylcobalamine and adenosylcobalamine, resulting in functionally decreased activity of methylmalonyl-CoA mutase and methionine synthase and, biochemically, in methylmalonic acidaemia and aciduria, hyperhomocysteinaemia, homocystinuria, and hypomethioninaemia. As such, MMA-HC is a close relative to MTHFR deficiency in that both diseases belong to single-carbon transfer pathway errors, a group of disorders of folate and cobalamine metabolism which may be complicated by demyelination as a result of S-adenosylmethionine deficiency, and both result in a biochemical derangement which prominently includes hyperhomocysteinaemia.

We recently described a series of 16 children with MMA-HC [[3]], 3 of whom presented within age 6 months with tetraventricular hydrocephalus that required shunting. We too found it difficult to explain the occurrence of hydrocephalus taking into consideration only the traditional theories of CSF production, circulation, and absorption. Recently, however, Greitz and Greitz proposed a new theory of CSF dynamics and the development of hydrocephalus [[2]]. According to this theory, CSF is produced by the choroid plexuses, flows in bulk through the aqueduct, and exits the ventricles through the fourth ventricular foramina; however, in the subarachnoid space CSF is mixed and dispersed evenly by pulsation of the intracranial extracerebral arteries and is subsequently absorbed throughout the brain and spinal cord via their capillaries, rather than through the arachnoid villi as was previously believed. Additionally, rhythmic pulsation of the intracranial extracerebral arteries occurring at each heartbeat result in the arterial pulse being damped, so that the intra-arterial pressure transmitted downstream to the brain is reduced. The normally damped intracranial arterial pressure that is propagated downstream produces an intracerebral pulse pressure and a pulsatile transcerebral mantle pressure gradient, which is responsible for maintaining the ventricles patent and of normal size. According to these authors, communicating hydrocephalus may be produced by whatever disorder results in increased arterial stiffness, and may therefore be termed “reduced arterial pulsation hydrocephalus”. In fact, pathologic processes such as arteriopathy or leptomeningitis that result in increased stiffness of the intracranial extracerebral arteries cause the arterial pulse pressure to be propagated downstream undamped, elevating the intracerebral pressure and the transcerebral mantle pressure gradient, thus leading to ventricular dilatation and higher intraventricular pulse pressure. In our paper, we proposed that the toxic effect of homocysteine to the arterial wall could slightly reduce the compliance of extracerebral intracranial arteries, thereby producing reduced arterial pulsation hydrocephalus through the mechanisms explained above [[3]].

Although further experimental studies are awaited to support this hypothesis, we believe this is a tenable explanation for the occurrence of hydrocephalus in this group of disorders. Awareness of the fact that tetraventricular hydrocephalus may be caused by metabolic disorders is especially important as these causes are often overlooked in favour of more common aetiologies such as infection, haemorrhage, tumour, or congenital malformations. Therefore, we agree with Baethmann et al in that plasma amino acid determinations including homocysteine should be implemented in the aetiological work-up of infants with tetraventricular hydrocephalus of unknown origin.

References

• 1 Baethmann M, Wendel U, Hoffmann G F. et al . Hydrocephalus internus in two patients with 5, 10-methylenetetrahydrofolate reductase deficiency.  Neuropediatrics. 2000;  31 314-317
• 2 Greitz D, Greitz T. The pathogenesis and hemodynamics of hydrocephalus. Proposal for a new understanding.  Int J Neuroradiol. 1997;  3 367-375
• 3 Rossi A, Cerone R, Biancheri R. et al . Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings.  AJNR Am J Neuroradiol. 2001;  22 554-563