Homocystinuria with methylmalonic acidemia is a rare metabolic disorder. There are four types of the disease, all of which are inherited in an autosomal recessive manner and caused by functional deficiencies of methionine synthase and methylmalonyl-CoA mutase. Homocystinuria with methylmalonic acidemia type cblF (HMMAF) is the result of mutations in the LMBRD1 gene. They interfere with the intracellular transport of cobalamin and thus with the synthesis of cobalamin-derived cofactors methylcobalamin and adenosylcobalamin. Individuals suffering from HMMAF present with infantile-onset developmental delays and neurological symptoms, and they often have megaloblastic anemia.
Most HMMAF patients appear normal at birth but small gestational age has been reported . 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  .
With regard to extraneural manifestations, HMMAF seems to be associated with an increased risk of cardiac malformations  . 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 . 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.
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:
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 . Serum levels of vitamin B12 and folic acid can be assessed easily, and they are not usually altered . However, decreased serum concentrations of vitamin B12 have been reported in isolated cases of HMMAF   . In any case, the confirmation and differential diagnosis of HMMAF 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 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 . 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.
Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAF have recently been published . In general, treatment aims at improving clinical features and normalizing hematological and metabolic values:
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  . 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 .
HMMAF is caused by mutations in the LMBRD1 gene . 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 .
Genotype-phenotype correlations have not yet been established for HMMAF  .
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  . Both males and females may be affected by HMMAF. Due to a founder effect, HMMAF seems to mainly affect people of European descent . All patients reported to date developed HMMAF-associated symptoms within their first year of life .
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 . Thus, there are two pathophysiological cascades implicated in neurodegeneration and extraneural disease progression:
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 .
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 .
There are four types of homocystinuria with methylmalonic acidemia , namely cblC, cblD, cblF, and cblJ . 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  .
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.