Most HMMAC patients appear normal at birth but small gestational age has been reported [1]. About 90% of patients are presented in the neonatal period or infancy with failure to thrive, developmental delays, and neurological symptoms [2]. Occasionally though, children may remain asymptomatic for prolonged periods of time and don't develop any symptoms until childhood, adolescence, or even adulthood. If symptom onset occurs beyond the age of 4, the patient is diagnosed with late-onset HMMAC [3]. Some authors consider a threshold of one year only for the distinction between early and late-onset HMMAC [4].

The spectrum of neurological deficits is broad and ranges from cognitive impairment to ataxia and other movement disorders, anomalies of muscle tone, apnea, and decreased consciousness [1] [5]. HMMAC patients may experience seizures and develop psychiatric conditions and behavioral disorders, with the latter being somewhat more common in late-onset disease [4]. Affected individuals may be microcephalic. Visual impairment due to optic atrophy or retinopathy may be detected in ophthalmological examinations [6]. Nystagmus has also been described. Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties [1] [5].

With regard to extraneural manifestations, HMMAC patients are at high risks of glomerulopathy, tubulointerstitial nephropathy, thrombotic microangiopathy leading to hemolytic uremic syndrome, and are predisposed to cardiac malformation, cardiomyopathy, and thromboembolism. Gastrointestinal and dermatological symptoms have been described in isolated cases [1] [7].

• Anemia

  Disease definition cblC type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure [orpha.net]

  […] congenital intrinsic factor deficiency Homocystinuria, Pyridoxine-Responsive Homocystinuria-Megaloblastic Anemia due to Defect in Cobalamin Metabolism, CblE Complementation Type Imerslund-Grasbeck Syndrome Methylenetetrahydrofolate Reductase Deficiency [rgd.mcw.edu]

  However, sometimes patients can be diagnosed with HUS even without the presence of hemolytic anemia,[4] based on nonimmune hemolytic anemia combined with renal biopsy. [journals.lww.com]

  Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull's eye maculopathy, was negative. [ncbi.nlm.nih.gov]

  Patients may present with severe early-onset disease that includes megaloblastic and macrocytic anemia, failure to thrive, microcephaly, lethargy, and feeding difficulties. [genedx.com]

• Poor Feeding

  The age of initial presentation of cblC ranges from (1) newborns who can be small for gestational age with unusually small head size; to (2) infants who can have poor feeding, failure to thrive, and neurologic/developmental abnormalities; to (3) toddlers [myriadwomenshealth.com]

  The age ofinitial presentation of cblC ranges from (1) newborns who can be small forgestational age (SGA)and have microcephaly; to (2) infants who can have poor feeding, failure tothrive, pallor, and neurologic signs, and occasionally hemolytic uremicsyndrome [egl-eurofins.com]

  Primary Care Management Upon Notification of the + Screen Contact the family and evaluate the infant for poor feeding, lethargy, vomiting, tachnypnea, or ketonuria. [medicalhomeportal.org]

  […] difficulties Feeding problems Poor feeding [ more ] 0011968 Global developmental delay 0001263 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ] 0001249 Lethargy 0001254 Megaloblastic [rarediseases.info.nih.gov]

• Fatigue

  […] frequent and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, retinopathy, signs of megaloblastic anemia (pallor, fatigue [cblc.it]

  Clinical description The disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia [orpha.net]

  Late-onset cases may present with megaloblastic anemia and/or psychiatric disturbance, anorexia, irritability, fatigue, myelopathy, nephropathy, thromboembolic events, or dementia. [genedx.com]

• Pallor

  […] more frequent and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, retinopathy, signs of megaloblastic anemia (pallor [cblc.it]

  Clinical description The disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia [orpha.net]

  Results: The cblA patient demonstrated a relatively mild ocular phenotype with late-onset and slowly progressing temporal disc pallor and peripapillary atrophy in the second decade of life. [ohsu.pure.elsevier.com]

• Anorexia

  Furthermore, anorexia has not been previously described in these patients. [pediatrics.aappublications.org]

  […] and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, retinopathy, signs of megaloblastic anemia (pallor, fatigue, anorexia [cblc.it]

  Clinical description The disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia [orpha.net]

  Late-onset cases may present with megaloblastic anemia and/or psychiatric disturbance, anorexia, irritability, fatigue, myelopathy, nephropathy, thromboembolic events, or dementia. [genedx.com]

• Failure to Thrive

  Clinical description The disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia [orpha.net]

  […] who can have failure to thrive, poor head growth, developmental delay, low muscle tone, and seizures; and to (4) young adults/adults who may develop confusion, mental illness, cognitive decline, and anemia. [myriadwomenshealth.com]

  Early onset with acute metabolic decompensation is more frequent and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly [cblc.it]

• Abdominal Pain

  Isolated Methylmalonic Acidemia - GeneReviews® - NCBI Bookshelf Pancreatitis may be under-recognized because it can manifest nonspecifically with vomiting and abdominal pain. Growth failure is frequent and aciduria metilmalonica. [hablandoencristiano.info]

  pain and swelling Back pain Blood in the urine Swelling of the veins around a testicle (varicocele) Flank pain Weight loss Fever Liver dysfunction Elevated erythrocyte sedimentation rate (ESR) Excessive hair growth in females Pale skin Vision problems [pennstatehershey.adam.com]

  pain (recurrent attacks) ( Table 66-17 ) Cardiac disorders (acute cardiac failure, heartbeat disorders) ( Table 66-18 ) Bone crisis ( Table 66-19 ) Progressive Neurologic Symptoms Progressive neurologic and mental deterioration Part 1: early in infancy [ommbid.mhmedical.com]

  An intermittent episode of abdominal pain prompted suspicion of porphyria and indeed, urine and blood tests revealed mild elevation of porphobilinogen and delta-aminolevulinic acid. [ojrd.biomedcentral.com]

  Pancreatitis may be under-recognized because it can manifest nonspecifically with vomiting and abdominal pain. Growth failure. Growth failure is frequent and multifactorial. [ncbi.nlm.nih.gov]

• Loss of Appetite

  […] and loss of appetite, or a systemic disease involving more than one organ system. [ojrd.biomedcentral.com]

  In order to prevent problems, call your doctor right away when your child has any of the following: loss of appetite vomiting diarrhea infection or illness fever When ill, your child needs extra fluids and carbohydrates to prevent more serious health [newbornscreening.info]

• Muscle Hypotonia

  hypotonia, hepatomegaly and coma. [malacards.org]

• Seizure

  Seizures are treated using standard protocols. Medications have proven effective in some cases. During the first year of life, infants may need to be evaluated once or twice a month. [myriadwomenshealth.com]

  […] homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures [orpha.net]

  The girl had slightly retarded intellectual development since birth, and had episodic seizures since 3 years of age. These seizures were controlled with antiepileptic treatment. [onlinelibrary.wiley.com]

• Lethargy

  Disease definition cblC type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure [orpha.net]

  Early onset with acute metabolic decompensation is more frequent and can arise as multi-systemic disease with myocardiopathy, acidosis, hypotonia, failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly [cblc.it]

  Patients may present with severe early-onset disease that includes megaloblastic and macrocytic anemia, failure to thrive, microcephaly, lethargy, and feeding difficulties. [genedx.com]

  In some cases, abilities are lost, resulting in a decline of performance, memory and speech problems, dementia and lethargy.[12470 Methylmalonic acidemia with homocystinuria can be caused by genetic changes in one of several genes: MMACHC, MMADHC, LMBRD1 [rarediseases.info.nih.gov]

• Convulsions

  Cerebral convulsions occurred in 11 (48%); six were also hypertensive and their median plasma sodium concentration was 132 mmol/l (range 119–144), which was slightly lower than in those without convulsions (median 135 mmol/l, not statistically significant [adc.bmj.com]

  In addition, he experienced various convulsive episodes, with encephalopathic findings in the electro-encephalogram. He died 20 days after admission with severe kidney failure (creatinine 1.3mg/dl, urea 193mg/dl, potassium 6.6mEq/l). [revistanefrologia.com]

  Clinical features include developmental delay, stomatitis, glossitis, convulsions and sensitive aciduria methylmalonic B12. [ivami.com]

  […] with the medium age of onset 12 years old(10 days~26 years old). 12 late onset patients(70.6%)presented with poor academic performance, memory loss, poor expression, and decreased exercise capacity, while 5 early onset patients(29.4%)presented with convulsion [qikan.cqvip.com]

  Organic acidurias have long been known to cause neurological problems, such as convulsions, stupor, coma, and psychomotor and mental retardation. Download PDF Download. 1 Março das doenças raras: Datos bibliográficos Por. Slide 3: 3 orpha. [vugovigiq.tk]

• Hematuria

  Hematuria (35.38/HP) and proteinuria (3+) were present in the urine, and the urinary red blood cell morphology suggested it to be glomerular hematuria. [journals.lww.com]

  […] progressive encephalopathy, subacute degeneration of the spinal cord, hemolytic uremic syndrome, pulmonary hypertension, and thromboembolic events.5 These patients may previously be asymptomatic or have a history of learning or emotional difficulties, hematuria [onlinelibrary.wiley.com]

  Clinical hallmarks: hematuria and flank pain. 1/3 are discovered incidentally. Males:females = 3:1 Peak incidence – after 50 years of age. Risk factor – tobacco smoking. [posterng.netkey.at]

  The patient was admitted to the previous hospital 59 days after birth for the treatment of anemia, hematuria, and proteinuria. The next day, he developed dyspnea, renal failure, and progressive anemia despite red cell transfusion. [pediatr-neonatol.com]

  Only 10% of patients present with the classic triad of flank pain, hematuria, and flank mass. [emedicine.medscape.com]

Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging. HMMAC may also be associated with hydrocephalus [1]. These findings are non-specific, though. Analyses of blood and urine samples have to be carried out and provide essential information as to the underlying metabolic disorder:

• With regard to blood counts, megaloblastic anemia is the most common finding but leukopenia and thrombocytopenia have also been observed.
• Hyperhomocysteinemia, hypomethioninemia, and homocystinuria are common findings in blood chemistry and urine analysis and point at a remethylation disorder. Additionally, concentrations of methylmalonic acid are elevated in serum and urine samples.

Still, these results don't allow for a reliable diagnosis of HMMAC since similar findings may be obtained in patients suffering from much more common disorders like vitamin B12 deficiency and folic acid deficiency, and in those with other hereditary diseases [1]. While serum levels of vitamin B12 and folic acid can be assessed easily, the confirmation and differential diagnosis of HMMAC require genetic and possibly complementation studies. In this context, the identification of the underlying mutation is the most reliable way to confirm a tentative diagnosis of HMMAC, and it also provides the necessary information for a familial workup and prenatal diagnosis.

Enzyme activity measurements in fibroblasts or lymphocytes constitute an alternative approach to the diagnosis of combined disorders of cobalamin metabolism, but are more cumbersome than genetic studies and don't provide any information as to the specific mutation. Nevertheless, such assays have to be carried out if the aforementioned analyses don't yield conclusive results despite strong suspicion, or if they are not available. Both methionine synthase and methylmalonyl-CoA mutase activities are decreased in case of HMMAC.

• Neutropenia

  43, 66-44, 66-45, 66-46 ) Angiokeratoma ( Table 66-47 ) Alopecia ( Table 66-48 ) Hematologic Symptoms Nonregenerative anemias (macrocytic) ( Table 66-49 ) Nonmacrocytic anemias (due to hemolysis or combined mechanisms) ( Table 66-50 ) Pancytopenia, neutropenia [ommbid.mhmedical.com]

  Initial signs and symptoms may include: Poor feeding Hypotonia followed by spasticity Failure to thrive Vomiting Dehydration Lethargy Lab findings: Metabolic acidosis Anemia Elevated ammonia levels in the blood Elevated ketone levels in the urine Neutropenia [medicalhomeportal.org]

  Complete blood cell (CBC) counts may reveal neutropenia, anemia, and thrombocytopenia, the result of the downregulation of hematopoietic growth, which may also be present during acute episodes of infection or metabolic decompensation. [emedicine.medscape.com]

  This includes feeding difficulties, failure to thrive, developmental delay, hypotonia, seizures, anemia, thrombocytopenia, neutropenia, and microangiopathy.4x4Sharma, A.P., Greenberg, C.R., Prasad, A.N., and Prasad, C. [aaojournal.org]

  Severe neutropenia in an infant with methylmalonic acidemia. Bol Asoc Med P R. 2003; 95 :17–20. [ PubMed : 12898746 ] Harting I, Seitz A, Geb S, Zwickler T, Porto L, Lindner M, Kölker S, Hörster F. [ncbi.nlm.nih.gov]

Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAC have recently been published [1]. In general, treatment aims at improving clinical features and normalizing hematological and metabolic values:

• Cobalamin supplementation is the mainstay of therapy. In order to maintain methionine synthase activity, HMMAC patients should receive regular intramuscular injections of hydroxycobalamin. While the drug may also be administered via the subcutaneous or intravenous route, the efficacy of subcutaneous applications seems to be limited and long-term intravenous treatment is inconvenient. Initially, 0.33 mg of hydroxycobalamin should be administered per kg body weight and day. Over the course of the disease, single doses and injection frequencies may be lowered if clinical and laboratory parameters remain stable. In order to prevent irreversible damage to the nervous system, hydroxycobalamin should be administered to all patients presenting symptoms consistent with a remethylation disorder and those who tested positive for hyperhomocysteinemia [1].
• The administration of folate and betaine has repeatedly been reported to improve disease control and is thus recommended as an additional therapeutic measure [8]. Both folate and betaine enhance the conversion of homocysteine to methionine and thus contribute to the reduction of hyperhomocysteinemia. Beyond that, carnitine and methionine supplementation may be considered but data regarding the efficacy of this measure are scarce.
• Patients should be recommended to avoid protein restriction and circumstances that may induce a catabolic state. Nitrous oxide shouldn't be utilized in these patients either.

Although cobalamin supplementation is likely to improve neurological parameters like cognitive performance and motor function, central nervous system damage is largely irreversible. Substantial improvements in cerebral atrophy and white matter changes are not to be expected. Therefore, patients who are diagnosed and treated early have a much better prognosis than those who are diagnosed after the manifestation of clinical symptoms. In an ideal scenario, affected individuals are diagnosed before birth or identified by means of newborn screening [9]. Still, even adequate therapy cannot entirely prevent the development of HMMAC complications and pre-existing complications like visual impairment may not respond to treatment [6] [10]. In sum, available data suggest that most patients will experience some degree of disability over the course of their life [11].

HMMAC is caused by mutations in the MMACHC gene [12]. This gene is located on the short arm of chromosome 1 and encodes for a protein presumably involved in the binding and intracellular trafficking of cobalamin. Although the precise function of the protein remains poorly understood, we know that its dysfunction interferes with the synthesis of methylcobalamin and adenosylcobalamin. It may possibly catalyze the decyanation of cyanocobalamin, thereby providing cob(II)alamin, a substrate required for the generation of the aforementioned cofactors [13].

Interestingly, pathogenic mutations in the MMACHC gene may be induced by defects in the adjacent, reverse-oriented PRDX1 gene [14]: Only recently, HMMAC has been diagnosed in members of an affected family who were heterozygous for MMACHC mutations and mutations in the PRDX1 gene. The respective PRDX1 mutation has been shown to cause an epimutation in the MMACHC gene that has been passed on through at least three generations.

Genotype-phenotype correlations have been described for some of the more common mutations in the MMACHC gene [1]. MMACHC mutations c.271dupA and c.331C>T, which account for 42 and %% all cases, respectively, trigger early-onset disease. By contrast, MMACHC mutations c.394C>T, to be found in about 20% of all patients, and c.482G>A results in late-onset disease [3]. Of note, these genotype-phenotype correlations may not apply to individuals who are compound heterozygous for pathogenic MMACHC mutations.

Inborn errors of cobalamin metabolism are rare diseases, with HMMAC being the most common one. More than 250 cases have been reported to date and the incidence of HMMAC has been estimated to 1-5 in 200,000 life births [5] [12] [15]. Both males and females may be affected by HMMAC. First symptoms usually manifest in the neonatal period or infancy, but symptom onset may be delayed until childhood, adolescence, or even adulthood. In patients carrying either of the common MMACHC mutations c.271dupA and c.331C>T, symptom onset generally occurs within 18 months after birth. With regard to patients carrying MMACHC mutation c.394C>T, their age at symptom onset ranged from <1 to 14 years [3]. Adult-onset HMMAC has repeatedly been described [4].

HMMAC is a combined disorder of cobalamin metabolism, i.e., the underlying mutation interferes with the synthesis of methylcobalamin and adenosylcobalamin, cofactors of methionine synthase and methylmalonyl-CoA mutase [5]. Thus, there are two pathophysiological cascades implicated in neurodegeneration and extraneural disease progression:

• Under physiological conditions, methionine synthase catalyzes the conversion of homocysteine to methionine. Functional methionine synthase deficiency is thus associated with increased serum and tissue levels of homocysteine. Homocysteine and its metabolic product homocysteic acid possibly exert neurotoxic effects and cause neurological deficits in HMMAC patients. At the same time, methionine concentrations are reduced. Shortage of this essential amino acid may interfere with a variety of biological processes, e.g., the function of rapidly proliferating tissues such as bone marrow or epithelia. Methionine is converted to S-adenosylmethionine, which acts as a methyl group donor. Therefore, deficiencies of methionine result in a lack of S-adenosylmethionine and a decreased methylation capacity [1].
• Little is known about the contribution of functional methylmalonyl-CoA mutase deficiency to the biochemical and clinical presentation of HMMAC. The enzyme is required for the isomerization of methylmalonyl-CoA to succinyl-CoA, which is an intermediate in the tricarboxylic acid cycle. Methylmalonyl-CoA is synthesized from propionyl-CoA. Accordingly, HMMAC is associated with increased levels of propionyl-CoA and methylmalonyl-CoA, and decreased levels of succinyl-CoA. These conditions may affect a myriad of metabolic processes. Possibly, methylmalonyl-CoA mutase deficiency renders HMMAC patients susceptible to metabolic decompensation [5].

Enhanced oxidative stress due to impaired glutathione metabolism has been proposed as an additional factor in HMMAC pathogenesis [10]. The underlying molecular mechanisms have not yet been clarified, though. It also remains unknown whether methionine synthase or methylmalonyl-CoA mutase fulfill non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in HMMAC and related disorders.

The prenatal diagnosis of HMMAC is feasible. Mutations in the MMACHC gene can be identified in nucleic acids isolated from chorionic villi or amniotic fluid samples [16]. Targeted genetic analyses require strong suspicion based on the carrier state of both parents. Most reliable results are obtained if the specific MMADHC mutations of a child's mother and father are known. If genetic studies cannot be realized or yield inconclusive results, biochemical assays and enzyme activity measurements may be carried out. In this context, increased concentrations of homocysteine and methylmalonic acid in cell-free amniotic fluid indicate the possibility of homocystinuria with methylmalonic acidemia but don't allow for the identification of its type [1].

Of note, prenatal therapy via maternal treatment with hydroxycobalamin has yielded promising results in a child affected by HMMAC and may be considered if this disease is prenatally diagnosed [17].

There are four types of homocystinuria with methylmalonic acidemia, namely cblC, cblD, cblF, and cblJ [5]. All of them are induced by functional deficiencies of methionine synthase and methylmalonyl-CoA mutase, and they resemble each other in their clinical presentation. However, they differ in how enzyme deficiencies are caused. With regard to type cblC or HMMAC, this form of homocystinuria with methylmalonic acidemia is the result of mutations in the MMACHC gene. The MMADHC gene encodes for an as-of-yet unknown protein required for the synthesis of methylcobalamin and adenosylcobalamin, which function as cofactors for methionine synthase and methylmalonyl-CoA mutase.

The term "homocystinuria" refers an increased excretion of homocystine in the urine. This condition may be due to distinct metabolic disorders associated with elevated serum concentrations of homocysteine, an intermediate amino acid and precursor of methionine. In patients suffering from inherited conditions that interfere with the conversion of homocysteine to methionine, blood and tissue levels of homocysteine are increased while methionine concentrations are below reference ranges.

There are different types of homocystinuria and they differ with regards to hematological and biochemical anomalies. Besides hyperhomocysteinemia and hypomethioninemia, patients may have increased serum levels of methylmalonic acids, which is why "homocystinuria with methylmalonic acidemia" is differentiated from "homocystinuria without methylmalonic aciduria". These differences originate from distinct gene defects, but they aren't reflected in the clinical presentation. Most patients suffering from homocystinuria with methylmalonic acidemia present within the neonatal period or infancy: Their parents may claim feeding difficulties and failure to thrive, and affected children show neurological deficits ranging from cognitive impairment to movement disorders and anomalies of muscle tone. Seizures are also common. Occasionally, symptom onset is delayed until adolescence.

Individuals affected by homocystinuria with methylmalonic acidemia type cblC carry mutations in a gene named MMACHC. Thus, genetic studies can be carried out to confirm the diagnosis. Genetic studies may even be realized before birth if a child's parents are known to be carriers of MMACHC mutations. Children will develop the disease if they inherit pathogenic alleles from their mother and their father. Their prognosis largely depends on the time of diagnosis and initiation of treatment. The earlier an adequate treatment is started, the better the prognosis of the individual patient. Treatment mainly consists in intramuscular injections of hydroxycobalamin and oral supplementation of betaine and folic acid. Lifelong therapy is required in all cases and despite utmost compliance with therapeutic regimens, it may not be possible to prevent all complications. If left untreated, homocystinuria with methylmalonic acidemia type cblC follows a slowly progressive course and may lead to severe disability or death.

1. Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis. 2017; 40(1):21-48.
2. Fischer S, Huemer M, Baumgartner M, et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis. 2014; 37(5):831-840.
3. Lerner-Ellis JP, Anastasio N, Liu J, et al. Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat. 2009; 30(7):1072-1081.
4. Huemer M, Scholl-Bürgi S, Hadaya K, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis. 2014; 9:161.
5. Carrillo N, Adams D, Venditti CP. Disorders of Intracellular Cobalamin Metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
6. Brooks BP, Thompson AH, Sloan JL, et al. Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency. Ophthalmology. 2016; 123(3):571-582.
7. Morath MA, Hörster F, Sauer SW. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol. 2013; 28(2):227-235.
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9. Huemer M, Kožich V, Rinaldo P, et al. Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. J Inherit Metab Dis. 2015; 38(6):1007-1019.
10. Pastore A, Martinelli D, Piemonte F, et al. Glutathione metabolism in cobalamin deficiency type C (cblC). J Inherit Metab Dis. 2014; 37(1):125-129.
11. Andersson HC, Marble M, Shapira E. Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med. 1999; 1(4):146-150.
12. Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet. 2006; 38(1):93-100.
13. Kim J, Gherasim C, Banerjee R. Decyanation of vitamin B12 by a trafficking chaperone. Proc Natl Acad Sci U S A. 2008; 105(38):14551-14554.
14. Guéant JL, Chéry C, Oussalah A, et al. APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nat Commun. 2018; 9(1):67.
15. Weisfeld-Adams JD, Morrissey MA, Kirmse BM, et al. Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab. 2010; 99(2):116-123.
16. Zong Y, Liu N, Zhao Z, Kong X. Prenatal diagnosis using genetic sequencing and identification of a novel mutation in MMACHC. BMC Med Genet. 2015; 16:48.
17. Trefz FK, Scheible D, Frauendienst-Egger G, et al. Successful intrauterine treatment of a patient with cobalamin C defect. Mol Genet Metab Rep. 2016; 6:55-59.