Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12

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Abstract

Subacute combined degeneration (SCD) of the spinal cord is a characteristic complication of vitamin B12 deficiency, but it has never been neuropathologically demonstrated in a B12-inborn error of metabolism. In this report SCD is documented in a 15-year-old boy with early-onset cobalamin C (cblC) disorder. The neuropathologic findings included multifocal demyelination and vacuolation with predilection for the dorsal and lateral columns at the mid-thoracic level of the spinal cord, confirming the similarity of SCD in cblC disorder to the classic adult SCD due to vitamin B12 deficiency. SCD developed in this boy despite treatment for cblC disorder that began at 3 months of age. There is clinical and experimental evidence to suggest that a deficiency in remethylation with concomitant reduction in brain methionine may be the cause of SCD. In this patient plasma methionine levels were low without betaine and/or l-methionine supplementation and in the normal range for only a 2-year period during compliance with therapy. In cblC disorder, a consistent increase in blood methionine to high normal or above normal levels by the use of betaine and l-methionine supplementation may be helpful in preventing SCD. This is especially important now that the presymptomatic detection of cblC disorder is possible through the expansion of newborn screening.

Introduction

Cobalamin C (cblC) disorder is an inborn error of metabolism in which formation of the two coenzymatically active derivatives of vitamin B12, deoxyadenosylcobalamin and methylcobalamin, is impaired. Deficiencies of these two coenzymes result in reduced activity of methionine synthase (Fig. 1) and methylmalonyl-CoA mutase, producing metabolic derangements that most strikingly feature homocystinuria with methylmalonic aciduria [1], [2].

The biochemical phenotype of cblC disorder has been consistent and includes increased plasma concentrations of homocystine, total homocysteine, and cystathionine, reduced concentration of methionine (Fig. 1), and the presence of homocystine and methylmalonic acid in urine. The clinical expression, however, has been variable. The majority of patients present, within the first year of life, with severe manifestations including mirocephaly, developmental delay/mental retardation, hypotonia, retinal degeneration, and seizures. The later onset presentation is less common, beginning in childhood or early adolescence with neurologic dysfunction that includes extrapyramidal signs, declining cognitive performance, confusion, and psychotic symptoms. Megaloblastic anemia has been found in both early and late-onset cblC patients [3]. Treatment primarily consists of large amounts of vitamin B12, preferably in the form of hydroxocobalamin, the precursor of the coenzymes. Additional therapies include betaine, the remethylation enhancer of methionine (Fig. 1), carnitine, folinic acid, dietary protein restriction [3], [4], and, on occasion, methionine supplementation [5].

Despite therapy, clinical outcome in the early-onset cases has been poor. The course of the retinal degeneration that eventually leads to blindness is unaltered. Many of these children develop severe neurological impairment and a number die [3]. Although most of the late onset cases have shown improvement on B12 therapy, some dramatically so, neurological recovery in them has not been consistent [3], [6], [7].

Both methylcobalamin and adenosylcobalamin are reduced in cblC patients [8]. Thus, it has been presumed that the cellular metabolic defect in cblC disorder must be located before B12 diverges to synthesize the two cofactors. Accordingly, the molecular defect in cblC disorder was recently identified in a gene named MMACHC [8]. The MMACHC gene product is not yet known, although it seems to encode a protein that is involved in energy transduction for B12 transport or cobalamin reduction. Since B12 therapy, primarily hydroxocobalamin supplementation, partially corrects the metabolic abnormalities and the megaloblastic anemia, this defect may not be complete. Nevertheless, the lack of clinical benefit of B12 administration, especially in the early-onset patients, raises the question of the relationship between the metabolic and clinical abnormalities.

We followed the first reported case of cblC disorder diagnosed by newborn screening from early infancy until his death at 15 years of age [9], [10]. Despite the patient’s receiving large amounts of B12, including hydroxocobalamin and, at times, methylcobalamin, his clinical course progressed and eventually included a severe peripheral neuropathy with neuropathological findings of subacute combined degeneration (SCD) of the spinal cord characteristic of B12 deficiency. The complete clinical course and neuropathology at autopsy, reported here, have important implications for pathogenesis and treatment in cblC disorder.

Section snippets

Case report

The patient was the first child of non-consanguinous parents of Italian heritage. He was born full term to a G1P0 29-year-old mother via spontaneous vaginal delivery after an uncomplicated pregnancy. Birth weight was 2.2 kg (<3rd percentile), birth length 48.2 cm (25th percentile), and head circumference at birth 31 cm (<3rd percentile). Methylmalonic aciduria was identified at 1 month of age by routine newborn urine screening [11]. CblC disorder was diagnosed by subsequent plasma amino acid

Systemic pathology

At autopsy, the patient was cachectic with height and weight below the 5th percentile, and severe, global skeletal muscle wasting. The immediate cause of death was multi-system infection. There was acute aspiration pneumonia with postmortem lung cultures positive for Candida albicans and Streptococcus viridans, and early sepsis, with blood cultures positive for rare Candida albicans. In addition, the patient had a urinary tract infection with urine cultures positive for Escherichia coli, and an

Discussion

The relationship between vitamin B12 (cobalamin) deficiency and SCD of the spinal cord has been known for over a century, since the first full clinical and neuropathological description of SCD published by Russell and colleagues in 1900 [12]. This case description is the first neuropathologically confirmed SCD in an inborn error of metabolism resulting from cblC disorder. Based on our patient’s clinical course, it is apparent that SCD developed later despite early initiation of cobalamin

Acknowledgments

S.E.S. was supported by NIH training Grant T32 GM07748 to the Harvard Medical School Training Program in Medical Genetics. H.C.K. was supported by grant P30 HD18655 for the Mental Retardation Research Center (MRRC) at Children’s Hospital Boston. H.L.L. is supported by grants R01-HG02085 from the NIH and 1U22MC03959 from the Health Resources and Services Administration (HRSA).

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