Reversal of Respiratory Failure in Both Neonatal and Late Onset Isolated Remethylation Disorders

Abstract

Respiratory failure is a well-documented potential presentation of inherited isolated remethylation disorders (IRDs). It appears to be a combination of both central and peripheral neuropathy and has previously often been considered to herald an irreversible neurological decline. We present three patients, one with methionine synthase (cblG) and two with methyltetrahydrofolate reductase deficiency (MTHFR). One patient with MTHFR presented in infancy, and other patients in later childhood. All three patients required intubation for respiratory failure but in all three, this was totally reversed by the initiation of medical therapy. This consisted of betaine and folinic acid supplementation in all three, methionine in two and cobalamin supplementation in two. The rate of respiratory improvement was variable, though two of the cases were successful extubated within a week of commencement of medical therapy. We document their subsequent clinical, biochemical and electrophysiological progress and review the potential pathological mechanisms underlying respiratory failure in these disorders.

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

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“…Neonates and young infants often manifest with feeding difficulties, decreased consciousness, hydrocephalus and muscular hypotonia. Apnoea is a frequent complication (Broomfield et al 2014; Diekman et al 2014; Huemer et al 2016; Schiff et al 2011; Strauss et al 2007). …”

“…There are just a few reports of older children and adults with megaloblastic anaemia in association with long-standing neurological manifestations (Broomfield et al 2014; Schiff et al 2011). …”

Antiepileptic drug-induced psychosis associated with MTHFR C677T: a case report

“…Neonates and young infants with severe MTHFR deficiency often present with respiratory complications such as apnea and phrenic nerve palsy [2, 25]. Although the precise mechanism of these respiratory complications remains poorly understood, it has been presumed to result from central and peripheral neurological impairment; this can be attributed to SAM deficiency, which is involved in dysmyelination [4, 26]. To our knowledge, no clinical studies have documented MTHFR C677T-related respiratory symptoms.…”

“…Several vitamins, such as riboflavin (vitamin B 2 ), pyridoxal (vitamin B 6 ), and cobalamin (vitamin B 12 ), play important roles as cofactors in the metabolism of homocysteine. The remethylation of homocysteine is a pivotal reaction, because adequate concentrations of methionine are required for S -adenosylmethionine (SAM) to act as a methyl donor for the methylation of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and other small molecules [3, 4].

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