Most HMMAF patients appear normal at birth but small gestational age has been reported [1]. Within their first year of life, they are presented to the pediatrician with failure to thrive, developmental delays, and neurological symptoms. The spectrum of neurological deficits is broad and ranges from cognitive impairment to movement disorders and anomalies of muscle tone. Ataxia, apnea, and decreased consciousness as well as psychiatric conditions and behavioral disorders are not usually observed in HMMAF patients. They are, however, frequently described in those suffering from related disorders. Similarly, visual impairment and peripheral neuropathy, common features in other combined disorders of cobalamin metabolism, are yet to be reported in individuals affected by HMMAF. HMMAF patients may experience seizures. Owing to extensive neurological disease, parents often describe feeding difficulties [2] [3].

With regard to extraneural manifestations, HMMAF seems to be associated with an increased risk of cardiac malformations [2] [3]. Recurrent stomatitis and skin rash have been described in isolated cases, and it may be speculated that HMMAF patients could develop other gastrointestinal and dermatological symptoms [4]. They are uncommon complications of cobalamin-related disorders such as homocystinuria with methylmalonic acidemia type cblC, but they are not unheard of. By contrast, there are no case reports on renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome in HMMAF patients.

• Fatigue

  […] description cblF type methylmalonic acidemia with homocystinuria has a variable age of onset (from birth to 11 years of age) and manifestations also vary and can include development delay, feeding difficulties, signs of megaloblastic anemia (pallor, fatigue [orpha.net]

  […] 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]

• Poor Feeding

  Clinical presentation is variable, but includes being small for gestational age, poor feeding, failure to thrive, developmental delay, and persistent stomatitis (Gailus et al. 2010; Rutsch et al. 2009). [preventiongenetics.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]

  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]

  feeding, anorexia, hypotonia) ( Table 66-54 ) Hepatomegaly and hepatosplenomegaly ( Table 66-55 ) Liver failure, ascites, edema ( Table 66-56 ) Cardiomyopathy ( Table 66-57 ) Interstitial pulmonary infiltrates ( Table 66-58 ) Tubulopathy (renal Fanconi [ommbid.mhmedical.com]

  […] 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]

• Failure to Thrive

  […] to thrive, developmental delay, intellectual deficit and seizures. [orpha.net]

  Affiliated tissues include skin, bone and bone marrow, and related phenotypes are seizures and failure to thrive Disease Ontology : 12 A methylmalonic acidemia that is characterized by the accumulation of cobalamin in lysosomes which is then unable to [malacards.org]

  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]

  Within their first year of life, they are presented to the pediatrician with failure to thrive, developmental delays, and neurological symptoms. [symptoma.com]

• Periodontitis

  […] microorganisms and in light… Expand Abnormal neurodevelopment has been widely reported in combined methylmalonic aciduria (MMA) and homocystinuria, cblC type (cblC… Expand Porphyromonas gingivalis is a major etiological agent in chronic and aggressive forms of periodontal [semanticscholar.org]

• Eczema

  […] distention Hypersexuality Intestinal obstruction Posterior subcapsular cataract Poor coordination Peripheral visual field loss Uveitis Subcapsular cataract Colitis Hypermelanotic macule Purpura Sepsis Recurrent pneumonia Long eyelashes Optic disc pallor Eczema [mendelian.co]

• Long Arm

  The HCFC1 gene, located on the long arm (q) of the X chromosome (Xq28), encoding the HCF-1 protein, which helps to regulate the activity of other genes. [ivami.com]

  This gene is located on long arm of chromosome 6 and encodes a lysosomal membrane protein presumably involved in the release of cobalamin from the lysosome to the cytosol. [symptoma.com]

  The gene for cystathionine beta-synthase is located on the long arm of chromosome 21 band 22.3. Sixty-four mutations affecting this gene have been described (7); the most frequent are 1278T (24%) and G3075 (31%). [ncbi.nlm.nih.gov]

• Muscle Hypotonia

  hypotonia, hepatomegaly and coma. [malacards.org]

• Joint Swelling

  […] disease involving both the axial and peripheral joints (ochronotic arthropathy). [mendelian.co]

Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging. 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. However, normomethioninemia does not rule out HMMAF [Carrillo]. Concentrations of methylmalonic acid are elevated in serum and urine samples.

Still, these results don't allow for a reliable diagnosis of HMMAF 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 [3]. Serum levels of vitamin B12 and folic acid can be assessed easily, and they are not usually altered [5]. However, decreased serum concentrations of vitamin B12 have been reported in isolated cases of HMMAF [1] [4] [6]. In any case, the confirmation and differential diagnosis of HMMAF require genetic and possibly complementation studies [1] [7]. In this context, the identification of the underlying mutation is the most reliable way to confirm a tentative diagnosis of HMMAF, 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 [8]. 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 HMMAF.

• Diffuse Encephalopathy

  Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging. These findings are non-specific, though. [symptoma.com]

Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAF have recently been published [3]. 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, HMMAF 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 [3].
• The administration of folate and betaine has been reported to improve disease control in patients affected by related disorders and is thus recommended as an additional therapeutic measure [2] [3] [5]. 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 [8] [9]. Still, even adequate therapy cannot entirely prevent the development of HMMAF complications and pre-existing complications may not respond to treatment. In sum, data regarding the long-term outcome of HMMAF patients is scarce but it can be assumed that most of them will experience some degree of disability over the course of their life [4].

HMMAF is caused by mutations in the LMBRD1 gene [1]. This gene is located on long arm of chromosome 6 and encodes a lysosomal membrane protein presumably involved in the release of cobalamin from the lysosome to the cytosol. Thus, LMBRD1 mutations may impede cobalamin export to the cytoplasm and lead to a decrease in the substrates available for the synthesis of methylcobalamin and adenosylcobalamin [10].

Genotype-phenotype correlations have not yet been established for HMMAF [1] [2].

Inborn errors of cobalamin metabolism are rare diseases, with HMMAF being one of the least common ones. Less than two dozen patients have been described to date [2] [4]. Both males and females may be affected by HMMAF. Due to a founder effect, HMMAF seems to mainly affect people of European descent [1]. All patients reported to date developed HMMAF-associated symptoms within their first year of life [4].

HMMAF 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 [2]. 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 HMMAF 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 [3].
• Little is known about the contribution of functional methylmalonyl-CoA mutase deficiency to the biochemical and clinical presentation of HMMAF. 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, HMMAF 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 HMMAF patients susceptible to metabolic decompensation [2].

It could not yet be clarified 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 HMMAF and related disorders.

The prenatal diagnosis of HMMAF is feasible. Mutations in the LMBRD1 gene can be identified in nucleic acids isolated from chorionic villi or amniotic fluid samples. Targeted genetic analyses require strong suspicion based on the carrier state of both parents. Most reliable results are obtained if the specific LMBRD1 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 [3].

Of note, prenatal therapy via maternal treatment with hydroxycobalamin has yielded promising results in a child affected by homocystinuria with methylmalonic acidemia type cblC and may be considered if HMMAF is diagnosed [11].

There are four types of homocystinuria with methylmalonic acidemia , namely cblC, cblD, cblF, and cblJ [2]. 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 cblF or HMMAF, this form of homocystinuria with methylmalonic acidemia is the result of mutations in the LMBRD1 gene. The LMBRD1 gene encodes a lysosomal membrane protein presumably facilitating cobalamin export to the cytoplasm, where it is required for the synthesis of methylcobalamin and adenosylcobalamin, which function as cofactors for methionine synthase and methylmalonyl-CoA mutase [1] [10].

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.

Individuals affected by homocystinuria with methylmalonic acidemia type cblF carry mutations in a gene named LMBRD1. 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 LMBRD1 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 cblF follows a slowly progressive course and may lead to severe disability or death.

1. Rutsch F, Gailus S, Miousse IR, et al. Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat Genet. 2009; 41(2):234-239.
2. 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.
3. 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.
4. Alfadhel M, Lillquist YP, Davis C, Junker AK, Stockler-Ipsiroglu S. Eighteen-year follow-up of a patient with cobalamin F disease (cblF): report and review. Am J Med Genet A. 2011; 155a(10):2571-2577.
5. Wilcken B. Leukoencephalopathies associated with disorders of cobalamin and folate metabolism. Semin Neurol. 2012; 32(1):68-74.
6. Oladipo O, Rosenblatt DS, Watkins D, et al. Cobalamin F disease detected by newborn screening and follow-up on a 14-year-old patient. Pediatrics. 2011; 128(6):e1636-1640.
7. Watkins D, Rosenblatt DS. Failure of lysosomal release of vitamin B12: a new complementation group causing methylmalonic aciduria (cblF). Am J Hum Genet. 1986; 39(3):404-408.
8. Armour CM, Brebner A, Watkins D, Geraghty MT, Chan A, Rosenblatt DS. A patient with an inborn error of vitamin B12 metabolism (cblF) detected by newborn screening. Pediatrics. 2013; 132(1):e257-261.
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. Gailus S, Höhne W, Gasnier B, Nürnberg P, Fowler B, Rutsch F. Insights into lysosomal cobalamin trafficking: lessons learned from cblF disease. J Mol Med (Berl). 2010; 88(5):459-466.
11. 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.