Homocystinuria with methylmalonic aciduria 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 aciduria type cblD (HMMAD) is the result of mutations in the MMADHC gene. They interfere with the synthesis of cobalamin-derived cofactors methylcobalamin and adenosylcobalamin. Individuals suffering from HMMAD present with infantile to juvenile-onset developmental delays and neurological symptoms, and they often have megaloblastic anemia.
Most HMMAD patients appear normal at birth but are soon presented to the pediatrician with failure to thrive, developmental delays, and neurological symptoms . Occasionally though, children may remain asymptomatic for prolonged periods of time and don't develop any symptoms until adolescence . The spectrum of neurological deficits is broad and ranges from cognitive impairment to ataxia and other movement disorders and anomalies of muscle tone  . Nystagmus has been described . Apnea and decreased consciousness are not usually observed in HMMAD patients but are frequently described in those suffering from related disorders. HMMAD patients may experience seizures, though. Owing to extensive neurological disease, parents often describe feeding difficulties  .
Disorders of cobalamin metabolism are frequently associated with visual impairment due to optic atrophy or retinopathy, and peripheral neuropathies, but they are uncommon in individuals affected by HMMAD. Similarly, cardiovascular complications have not been described in HMMAD patients but have been observed in patients suffering from related disorders. They may eventually occur .
Kidney damage resulting in hemolytic uremic syndrome has been reported in HMMAD 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:
These results don't allow for a reliable diagnosis of HMMAD 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 . While serum levels of vitamin B12 and folic acid can be assessed easily, the differential diagnosis of inborn errors of cobalamin metabolism requires 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 HMMAD, and it also provides the necessary information for a familial workup and prenatal diagnosis. It should be noted, though, that MMADHC mutations are also characteristic of homocystinuria without methylmalonic aciduria type cblD-variant 1 and methylmalonic aciduria type cblD-variant 2 . The differentiation of these entities is based on laboratory findings as described above but may also be achieved by means of somatic cell complementation. Cells from patients with homocystinuria without methylmalonic aciduria type cblD-variant 1 complement reference cell lines for homocystinuria without methylmalonic aciduria types cblE and cblG; cells from patients affected by methylmalonic aciduria type cblD-variant 2 complement those for methylmalonic aciduria types cblA and cblB . In the future, it may become possible to infer the biochemical phenotype from an individual patient's genotype if the boundaries of gene segments implicated in methylcobalamin and adenosylcobalamin synthesis can be clearly defined .
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. Still, 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 HMMAD and other forms of homocystinuria with methylmalonic aciduria  .
Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAD 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 HMMAD complications and pre-existing complications may not respond to treatment. In sum, data regarding the long-term outcome of HMMAD patients is scarce but it can be assumed that most of them will experience some degree of disability over the course of their life.
HMMAD is caused by mutations in the MMADHC gene . This gene is located on the long arm of chromosome 2 and encodes for a protein involved in early cobalamin metabolism. Although the precise function of this protein remains poorly understood, we know that its dysfunction may interfere with the synthesis of methylcobalamin and adenosylcobalamin . The nature and location of MMADHC defects determine whether both are disturbed (and patients develop HMMAD), or whether one of them is preserved (and patients develop isolated homocystinuria or isolated methylmalonic aciduria). In this context, Stucki and colleagues proposed the following :
These genotype-phenotype correlations have been confirmed in a later study conducted by the same research group but it remains to be seen whether they can be confirmed in future cases .
HMMAD is a rare disease. Less than two dozen patients have been described to date    . Both males and females may be affected by HMMAD. The patients' age at symptom onset varies. While the first patients described to be affected by HMMAD presented in adolescence with neurological symptoms and megaloblastic anemia , neonatal and infantile onset has been reported later  .
HMMAD 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 HMMAD and related disorders.
The prenatal diagnosis of HMMAD is feasible. Mutations in the MMADHC 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 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 aciduria 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 aciduria type cblC and may be considered if HMMAD is diagnosed .
There are four types of homocystinuria with methylmalonic aciduria, 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 cbID or HMMAD, this form of homocystinuria with methylmalonic aciduria is the result of mutations in the MMADHC 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 aciduria" 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 aciduria 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 aciduria type cblD carry mutations in a gene named MMADHC. 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 MMADHC 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 aciduria type cblD follows a slowly progressive course and may lead to severe disability.