Neuropsychiatric Disturbances in Presumed Late-Onset Cobalamin C Disease

OBSERVATION Neuropsychiatric Disturbances in Presumed Late-Onset Cobalamin C Disease

Emmanuel Roze, MD; David Gervais, MD; Sophie Demeret, MD; He´le`ne Ogier de Baulny, MD, PhD; Jacqueline Zittoun, MD, PhD; Jean-Franc¸ois Benoist, PharmD; Ge´rard Said, MD; Charles Pierrot-Deseilligny, MD, PhD; Francis Bolgert, MD

Background: Combined methylmalonic aciduria and ho- tilatory support and her 24-year-old sister had a 2-year mocystinuria cobalamin C type (cobalamin C disease) is disease course of subacute combined degeneration of the an inborn metabolic disorder consisting of an impaired in- spinal cord. A metabolic workup displayed increased tracellular synthesis of the 2 active forms of vitamin B12 methylmalonic acid levels, severe hyperhomocystein- (cobalamin), namely, adenosylcobalamin and methylco- emia, and low plasma methionine levels. The diagnosis balamin, that results in increased levels of methylmalo- was then confirmed by demonstration of impaired syn- nic acid and homocysteine in the blood and urine. Most thesis of adenosylcobalamin and methylcobalamin in cul- patients present in the first year of life with systemic, he- tured skin fibroblasts and Epstein-Barr virus–infected lym- matological, and neurological abnormalities. Late-onset phocytes. Under specific treatment the younger sister’s forms are rare and had not been comprehensively char- condition dramatically improved. acterized. They could be easily misdiagnosed. Conclusions: Although complementation studies have Objective: To describe clinical and biochemical fea- not been conducted, it is most likely these patients had tures of the disease in 2 siblings affected with presumed cobalamin C disease. This study emphasizes the possi- late-onset cobalamin C disease. bility of late-onset disease with purely neurological manifestations. Left untreated, this treatable condition can lead Design: Case report and review of the literature. to death or irreversible damage to the nervous system. Screening for intracellular vitamin B12 dysmetabolism Setting: Neurological intensive care unit of a univer- should, therefore, be considered in the investigation of sity hospital. adults with unexplained neurological disease, particu- larly when they are initially seen with a clinical picture Observation: We describe 2 patients with neurologi- suggestive of vitamin B12 deficiency. cal deterioration due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe progressive neuropathy requiring mechanical ven- Arch Neurol. 2003;60:1457-1462

ISSUE VITAMIN B12 defi- cumulation of methylmalonic acid (MMA) ciency can be due to inad- and/or homocysteine in the blood and urine From Service de Neurologie 1, 3 equate intake (as seen in (Figure 1). Tissue vitamin B12 defi- Groupe Hospitalier vegans), acquired malab- ciency is associated with a variable level of Pitie´-Salpeˆtrie`re, Paris, France (Drs Roze, Gervais, Demeret, sorption (as seen in perni- serum vitamin B12. It is always low in veg- Pierrot-Deseilligny, and ciousT anemia), or various inborn errors of ans or in those who have malabsorption and Bolgert), Service de Neurologie cobalamin (Cbl) metabolism. Depending on is usually normal in those with TCII defi- Pe´diatrique et Maladies the level of the metabolic block, the in- ciency or intracellular defects of AdoCbl or Me´taboliques (Dr Ogier de born errors may include congenital mal- MetCbl synthesis. Baulny), Service de Biochimie absorption due to intrinsic factor defi- Patients with congenital malabsorp- Hormonologie (Dr Benoist), ciency or defective transport by enterocytes tion develop megaloblastic anemia and fail- Hoˆpital Robert Debre´, Paris; (Imerslund-Grasbeck disease), defective cell ure to thrive in the first years of life and Service d’He´matologie delivery due to transcobalamin II (TCII) de- may later develop a myelopathy.2,3 In the Biologique, Hoˆpital Henri ficiency, and failure of cellular adenosyl- first months of life, most patients with TCII Mondor, Cre´teil, France (Dr Zittoun); and Service de cobalamin (AdoCbl) and/or methylcobala- deficiency present with severe megalo- Neurologie, Hoˆpital de Biceˆtre, min (MetCbl) synthesis, which are the 2 blastic anemia, failure to thrive, and diar- 1,2 Le Kremlin-Biceˆtre (Dr Said); active coenzyme forms of Cbl. These con- rhea, but neurological involvement is not Assistance Publique Hoˆpitaux genital diseases are typically characterized present at diagnosis.2,3 On the basis of de Paris, Paris. by a megaloblastic anemia and variable ac- complementation studies performed in

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 impaired proprioception of the lower limbs, with a posi- Digestive Blood Cell Tract tive bilateral Babinski sign. Serologic test results for hu- S-Adenosyl Homocysteine S-Adenosylmethionine man immunodeficiency virus and human T-cell lym- photrophic virus 1 were negative as were those from tests Cbl for syphilis. Magnetic resonance imaging of the brain and Homocysteine Methionine Stomach IF the spinal cord showed no abnormalities, and fundos- Methionine Synthase copy findings and visual evoked responses were nor- Methyl THF Methyl Cbl mal. Routine laboratory investigation findings were nor-

Cbl C, D, E THF mal including hematological indices (hemoglobin, 11.9 ϫ 9 Cbl, E, G g/dL; white blood cell count, 5.7 10 /L; platelet count, Ileum IF - Cbl TCII - Cbl Cbl 281 ϫ109/L; and mean corpuscular volume, 89.5 µm3). Serum vitamin B12 levels (490 pg/mL; reference range, Cbl, A, B, H Adenosyl Cbl Ͼ200 pg/mL) and cerebrospinal fluid examination re- Mutase sults were normal. Nine months after onset, corticoste- Succinyl-CoA L-Methylmalonyl-CoA roids were administered without benefit. During the following 18 months, her condition remained stable. When her sister (case 2) was diagnosed as having Cbl C dis- Figure 1. Cbl indicates cobalamin; CoA, coenzyme A; THF, thymic humor factor; TCII, transcobalamin II; and IF, intrinsic factor. ease, we performed an analysis of urinary organic acid levels and measured plasma homocysteine levels. The findings—a high urinary MMA level (3330 µmol/mmol of cre- cultured skin fibroblasts, failure in the synthesis of cel- atinine; reference range, Ͻ50 µmol/mmol of creatinine) lular AdoCbl and/or MetCbl has been divided into dis- and a raised homocysteine level level (reference range, ease groups, Cbl A to Cbl H.1,4 Isolated increased levels 125 µmol/L; Ͻ15 µmol/L)—suggested that she had the of MMA in the blood and urine characterizes Cbl A, Cbl same disease as her sister. Defective synthesis of AdoCbl B, and Cbl H diseases. Most of these patients present in and MetCbl was confirmed in cultured Epstein-Barr vi- infancy with recurrent episodes of ketoacidosis without rus (EBV)–infected lymphocytes (Table 1). A com- megaloblastic anemia. Hyperhomocysteinemia and hy- bined daily treatment with intramuscular hydroxoco- pomethioninemia without methylmalonic aciduria char- balamin (1 mg), oral betaine (9 g), L-carnitine (3 g), and acterize Cbl E and Cbl G diseases. Most patients who have folinic acid (10 mg) was started. After 3 months there these 2 diseases present in the first months of life with was a marked decrease in urinary MMA and plasma ho- megaloblastic anemia, poor feeding, and, if their disease mocysteine levels (Table 2), but the clinical examina- is not promptly diagnosed, with various neurological defi- tion findings were unchanged. However, the patient de- cits such as tonus abnormalities or seizures. Cobalamin scribed a mild improvement in walking and a decreased C, Cbl D, and Cbl F diseases are due to defective syn- frequency of falls. thesis of both MetCbl (resulting in hyperhomocysteinemia and hypomethioninemia) and AdoCbl (resulting in CASE 2 methylmalonic aciduria). Most of these patients present in the neonatal period with feeding difficulties, failure Two years after the onset of symptoms in the patient in to thrive, neurological deterioration, and megaloblastic case 1, her 16-year-old sister was initially seen with a anemia. In addition, they may have renal and liver fail- 3-month history of dissociative symptoms and delu- ure, cardiomyopathy, pneumonia, and retinopathy.3,5 sions of persecution with visual and auditory hallucina- Late-onset forms are rare and difficult to diagnose tions. One month prior to hospital admission, she had because they are usually restricted to the nervous sys- also developed an unsteady gait and urinary inconti- tem, thus lacking the indicative hematological signs.5,6 nence. She was previously healthy and had been an av- Given the few reported cases and their possible genetic erage student. Physical examination on admission showed heterogeneity, the clinical spectrum of late-onset Cbl C an areflexic paraparesis with an extensor plantar re- disease needs to be clarified. We report 2 cases in a sib- sponse on the right side and impaired vibration and po- ship with presumed Cbl C disease. The suspected patho- sition sense in the lower limbs. Fundoscopy findings were physiology of neurological and psychiatric disturbances normal. Neurophysiological studies showed intermedi- is also discussed. ate conduction velocity with reduction of amplitude and denervation. A sural nerve biopsy specimen displayed de- REPORT OF CASES myelination and wallerian degeneration (Figure 2). Rou- tine laboratory examination findings were normal in- CASE 1 cluding hematological indices (hemoglobin, 12.0 g/dL; white blood cell count, 6.0 ϫ109/L; platelet count, 375 A 24-year-old woman was admitted because of a pro- ϫ109/L; and mean corpuscular volume, 81 µm3). Tests gressive gait disorder. Her medical history was unre- for common causes of peripheral neuropathy, including markable. She was born to nonconsanguineous parents values for serum vitamin B12 (417 pmol/L; reference range, and was 1 of 4 siblings. She reported frequent falls, in- Ͼ200 pmol/L) and urine porphyrin, and cerebrospinal ability to run, and difficulty in ascending and descend- fluid examination findings were normal. Electroencepha- ing stairs. Findings on neurological examination were bi- lography showed diffuse slow waves. Magnetic reso- lateral proximal weakness, hyperreflexia, spasticity, and nance imaging brain study showed mild cortical atro-

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Total Cyanocobalamin Labeled With Cobalt 57 Uptake and Adenosylcobalamin and Methylcobalamin Synthesis Performed in Cultured Skin Fibroblasts (SF) and EBV-Infected Lymphocytes (EL)

Case No. Cultured Medium [57Co] Cyanocobalamin Uptake Adenosylcobalamin Methylcobalamin 1 EL 0.03 pmol/107 cells (N: 0.09-0.17) 9.5% (N: 23-29) 6.2% (N: 28-42) 2 SF 0.17 pmol/107 cells (N: 0.6-1.46) 12% (N: 14-40) 14.5% (N: 27-58) EL 0.045 pmol/107 cells (N: 0.09-0.17) 12% (N: 23-29) 6% (N: 28-42)

Abbreviation: EBV, Epstein-Barr virus.

Table 2. Biological Course of the Disease Under Treatment A of Patients With Presumed Late-Onset Cobalamin C Disease

Before After Case No./Source Treatment Treatment 1/Shinnar and Singer7, 1984 HC, µmol 46 2 MMA, µmol/mmol of creatinine ++ 0 MET, µmol 0 25 2/Gold et al,8 1996 HC, µmol 174 NA MMA, µmol/mmol of creatinine 2900 NA MET, µmol 7 NA 3/Agoustides-Savvopoulou et al,9 1999 225 58 MMA, µmol/mmol of creatinine 558 26 B MET, µmol 4 17 4/Powers et al,10 2001 (patient 1) HC, µmol NA NA MMA, µmol/mmol of creatinine NA NA Figure 2. A sural nerve biopsy specimen displayed (A) demyelination and MET, µmol NA NA (B) wallerian degeneration. 5/Powers et al,10 2001 (patient 2) HC, µmol NA NA MMA, µmol/mmol of creatinine NA NA MET, µmol NA NA 6/Bodamer et al,11 2001 HC, µmol 27.9 15.3 MMA, µmol/mmol of creatinine 1722 12 MET, µmol NA NA 7/Present report, 2002 (case 1) HC, µmol 125 48 MMA, µmol/mmol of creatinine 3300 80 MET, µmol 10 35 8/Present report, 2002 (case 2) HC, µmol 205 14 MMA, µmol/mmol of creatinine 3890 250 MET, µmol 7 41

Abbreviations: HC, homocysteine; MET, methionine; MMA, methylmalonic acid; NA, not available. *Cobalamin C disease is a combination of methylmalonic aciduria and homocystinuria cobalamin C type.

phy and bilateral hyperintensity in the periventricular white matter on T2-weighted and flair images (Figure 3). Over the following 6 months, the motor deficit pro- gressed to respiratory failure requiring mechanical ven- Figure 3. The magnetic resonance imaging brain study showed mild cortical tilatory support. She also developed a deep venous throm- atrophy and bilateral hyperintensity in the periventricular white matter on bosis in the left femoral and pelvic veins, which was treated T2-weighted and fluid-attenuated inversion recovery images. with antivitamin K. At this stage, she had persistent psychotic features, lethargy, and a complete tetraplegia characterized by spasticity of the upper limbs and flaccidity atinine; reference range, Ͻ50 µmol/mmol of creati- of the lower limbs. She was fully dependent on mechani- nine), an elevated plasma total homocysteine level (205 cal ventilatory support. A metabolic workup displayed a µmol/L; reference range, Ͻ15 µmol/L), and hypomethio- cellular vitamin B12 deficiency with a high degree of meth- ninemia (methionine levels, 7 µmol/L; reference range, ylmalonic aciduria (MMA level, 3890 µmol/mmol of cre- Ͼ20 µmol/L]) with normal serum TCII levels. Measure-

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Case No./ Source Age at Onset, y/Sex Disease Manifestations Response to Therapy Shinnar and Singer,7 1984 1/14/F Dementia; subacute myelopathy Full recovery of mental function; residual walking difficulties Gold et al,8 1996 2/12/F Relapsing-remitting myelopathy; peripheral Partial recovery; residual paraplegia neuropathy requiring wheelchair use Agoustides-Savvopoulou et al,9 1999 3/10/F Dementia; behavioral disturbances Full recovery Powers et al,10 2001 (patient 1) 4/32/M Subacute myelopathy Not treated; death from multiple infections Powers et al,10 2001 (patient 2) 5/44/M Dementia; behavioral disturbances; deep Not treated; death from pulmonary venous thrombosis embolism Bodamer et al,11 2001 6/19/M Progressive encephalopathy; subacute Full recovery of the mental and upper myelopathy; motor neuron disease; deep extremity function; residual paraplegia venous thrombosis and bladder dysfunction Present report 2002 (case 1) 7/22/F Subacute myelopathy Partial recovery; residual walking difficulties Present report 2002 (case 2) 8/16/F Psychosis subacute myelopathy; peripheral Full recovery of the mental and upper neuropathy; deep venous thrombosis extremity function; residual paraplegia requiring wheelchair use

*Cobalamin C disease is a combination of methylmalonic aciduria and homocystinuria cobalamin C type.

ment of AdoCbl and MetCbl synthesis in cultured clearly affected with a neurological form of vitamin B12 de- skin fibroblasts and in cultured EBV-infected lympho- ficiency only diagnosed by the demonstration of homo- cytes confirmed the defective synthesis of MetCbl and cystinuria and methylmalonic aciduria. Patient 1 exhib- AdoCbl (Table 1). A combined daily treatment with in- ited a subacute combined degeneration of the spinal cord, travenous hydroxocobalamin (2 mg), oral betaine (9 g), which is highly suggestive of a vitamin B12 deficiency. Nev- L-carnitine (3 g), and folinic acid (10 mg) was started. ertheless, the diagnosis of functional vitamin B12 defi- After 6 weeks, clinical improvement was dramatic with ciency had been long delayed because of normal serum the recovery of arm function and the disappearance of vitamin B12 levels although a metabolic investigation of the psychotic features and lethargy. She also regained enough cellular vitamin B12 status had not been performed. axial strength to allow her to sit but remained wheel- The metabolic disorder of these sisters can prob- chair bound. She was weaned off mechanical ventila- ably be included in the Cbl C group, although no comple- tory support on day 45. Concurrently, biochemical ab- mentation studies were done with fibroblasts from pa- normalities markedly improved (Table 2). tients identified with Cbl D or Cbl F. First, Cbl C is the Screening of her 2 healthy brothers showed nor- most common of these diseases; to our knowledge, only mal results for the presence of homocystinemia and meth- 2 cases in a sibship have been reported as Cbl D disease ylmalonic aciduria and they were considered free of the and fewer than 10 cases as Cbl F disease.6 Second, in con- disease. trast to fibroblasts from patients with Cbl F, which ac- cumulate excess unmetabolized cyanocobalamin, fibro- METHODS blasts from our patient had a low incorporation of Synthesis and measurement of AdoCbl and MetCbl were done cyanocobalamin (in accordance with our findings in other on fibroblasts, EBV-infected lymphocytes, or both, as previ- patients with Cbl C disease) compared with healthy con- ously described.12,13 In case 1, fibroblast culture failed despite the trol subjects. Similar therapeutic approaches are pro- addition of both methionine (15 mg/L) and 30% fetal calf se- posed for these 3 groups of Cbl disease and aim to nor- rum, an occurrence that we have previously seen in some other malize all metabolite values including methionine levels. cases of Cbl C disease. Briefly, cells undergoing exponential Most patients who have Cbl C disease have an early growth were transferred to RPMI medium deprived of vitamin clinical onset, in the neonatal period or in early infancy. B12, supplemented with glutamine and 10% AB serum labeled The neonates usually display feeding difficulties and rap- with cobalt 57–labeled cyanocobalamin, and then incubated for idly progressive neurological deterioration that pro- 72 hours in a carbon dioxide incubator. Subsequently, cells were washed and centrifuged. The radioactivity was evaluated on a ceeds to coma. They often are initially seen with mega- part of the pellet corresponding to the total intracellular up- loblastic anemia and thrombocytopenia. They may also take; the remainder was purified and fractionated by thin-layer develop hemolytic uremic syndrome due to thrombotic chromatography. Distribution of the different forms of Cbl was microangiopathy. Most of them follow a downhill course then measured. with liver, cardiac, and pulmonary involvement. Survi- vors have mental retardation and a peculiar retinopathy 5,6 COMMENT with nystagmus. Late-onset Cbl C disease occurs more rarely as only 6 cases of patients with symptoms begin- Our patients presented no evidence of having defective vi- ning after the age of 10 years have been reported in the 7-11 tamin B12 supplies, malabsorption, or transport since they literature. Table 3 summarizes the main manifesta- had normal vitamin B12 and TCII levels in their serum. De- tions of the disease in this age group. Late-onset Cbl C spite the absence of megaloblastic anemia and the pres- disease can manifest with various neurological or psy- ence of normal vitamin B12 serum levels, they were both chiatric disturbances, but all 8 patients (including the 3

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©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 described herein) had normal vitamin B12 levels; none had group essential for methionine synthesis and, thus, for megaloblastic anemia. Although a rapidly progressive dis- SAM synthesis (Figure 1).18 Methylenetetrahydrofolate ease is usual, a relapsing-remitting course may occur.8 reductase deficiency and Cbl G disease thus share the re- As exemplified by the findings in our patients, disease methylation defect with Cbl C disease. expression is variable, even in a sibship. At present, nei- In addition, to neuropsychiatric disturbances, 1 of the ther this variability nor the existence of later-onset forms 2 sisters described herein also developed a deep venous can be explained. thrombosis of the femoral and pelvic veins, as previously The subacute myelopathy with demyelination and described in 2 other cases of late-onset Cbl C disease (Table peripheral neuropathy observed in these patients are simi- 3). Although the peripheral neuropathy (in 2 of these 3 lar to those observed in acquired forms of vitamin B12 de- patients noted in Table 3)—and the subsequent loss of mo- ficiency, such as pernicious anemia. The clinical neuro- bility—could have favored the thrombotic complication, myelopathy related to vitamin B12 deficiency has been it is more likely to be related to the extreme hyperhomo- described for more than a century, but the link between cysteinemia present in these patients. Patients initially seen these neurological signs and the vitamin deficiency was with inborn errors of metabolism resulting in hyperho- not discovered until later.14 This neuromyelopathy is due mocysteinemia and homocystinuria are known to have in- to demyelination, as evidenced in our patient 2 in find- creased susceptibility to premature occlusive vascular dis- ings on both sural nerve biopsy and magnetic resonance ease and, in some cases, autopsy has revealed multiple imaging examination of the brain. A reduced supply of thrombi involving both arteries and veins.29,30 the methyl group has previously been implicated as a cause Most patients with Cbl C disease respond biochemi- of central nervous system demyelination.15,16 In fact, meth- cally and clinically when treated with high-dose sys- ylation of homocysteine to form methionine is im- temic hydroxocobalamin.7-11 As with pernicious ane- paired. This leads to a deficiency of S-adenosylmethio- mia, myelopathy and peripheral neuropathy improved nine (SAM), which is a key intermediary in methylation more slowly and less completely than cortical signs (Table reactions.17 In inborn errors of the methyltransfer path- 3). Because this treatable condition can lead to death or way, demyelination has been shown to be associated with irreversible neurological damage, it requires prompt di- low SAM levels in the cerebrospinal fluid whereas nor- agnosis and treatment. This article emphasizes the need, malization of SAM levels has been associated with evi- at any age, for extensive investigation of the vitamin B12 dence of remyelination.18 Myelin basic protein, which is status in patients with neurological symptoms whose clini- a major component of the myelin sheath, is methylated cal picture is consistent with vitamin B12 deficiency and by a specific methyltransferase requiring SAM as the in whom the serum vitamin B12 level is normal. methyl donor.19 It has, therefore, been hypothesized that demyelination may be due to decreased methylation of Accepted for publication December 30, 2002. myelin basic protein, causing conformational changes in Author contributions: Study concept and design (Drs the protein and subsequent splitting of the myelin sheath.16 Roze, Gervais, Demeret, Ogier de Baulny, Zittoun, and Among 8 late-onset cases of patients with Cbl C dis- Bolgert); acquisition of data (Drs Roze, Zittoun, Benoist, ease (Table 3), 4 exhibited signs of psychosis or demen- Said, and Bolgert); analysis and interpretation of data (Drs tia, isolated or in association with myeloneuropathy, but Roze, Demeret, Ogier de Baulny, Zittoun, Pierrot Deseil- without any hematological abnormalities. In adults, vi- ligny, and Bolgert); drafting of the manuscript (Drs Roze tamin B12 deficiency has been described in neuropsychi- and Zittoun); critical revision of the manuscript for im- atric disorders in the absence of anemia and/or macro- portant intellectual content (Drs Roze, Gervais, Demeret, cytosis, but in association with increased levels of Ogier de Baulny, Zittoun, Benoist, Said, Pierrot Deseil- homocysteine and urinary MMA.20-22 Metabolic evi- ligny, and Bolgert); obtained funding (Dr Roze); admin- dence for vitamin B12 deficiency has also been found more istrative, technical, and material support (Drs Benoist, Pier- frequently in elderly patients with Alzheimer-type de- rot Deseilligny, and Bolgert); study supervision (Drs mentia than in controls.23 Whatever its cause (congeni- Gervais, Demeret, Ogier de Baulny, Zittoun, Pierrot De- tal or acquired), hyperhomocystinemia and methylma- seilligny, and Bolgert). lonic aciduria are the metabolic hallmarks of vitamin B12 We thank Nicole Baumann and Katia Youssov for help deficiency and measurements of their degree of severity with the clinical care of the patients. We also thank Thi- seem (by measuring homocysteine and methionine lev- erry Maisonobe who performed the neurophysiological stud- els) to be the most sensitive and accurate markers of in- ies and Kristin Roze for support. 24,25 tracellular vitamin B12 status. Dementia and psycho- Corresponding author: Francis Bolgert, MD, Service de sis in patients with Cbl C disease are similar to those Neurologie 1, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Unite´de observed in adults intially seen with acquired vitamin B12 Re´animation Neurologique, 47-83 Boulevard de l’hoˆpital, 75651 deficiency. These psychiatric signs are most likely re- Paris CEDEX 13, France (e-mail: sophie.demeret@psl lated to defective methylation. This hypothesis is sus- .ap-hop-paris.fr). tained by the description of similar signs of myeloneuropathy variously associated with schizophrenia in REFERENCES patients affected with either a Cbl G disease or a methylenetetrahydrofolate reductase deficiency.26-28 Indeed, 1. 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