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 cblJ (HMMAJ) is the result of mutations in the ABCD4 gene. They presumably interfere with the intracellular transport of cobalamin and thus with the synthesis of cobalamin-derived cofactors methylcobalamin and adenosylcobalamin. Individuals suffering from HMMAJ present with infantile-onset developmental delays and neurological symptoms, and they often have megaloblastic anemia.
HMMAJ patients appear normal at birth. Most of them are soon presented to the pediatrician showing failure to thrive, developmental delays, and neurological symptoms  . Symptom onset may, however, be delayed until adolescence . The spectrum of neurological deficits described in HMMAJ patients is less broad than that reported for individuals suffering from other forms of homocystinuria with methylmalonic acidemia and is limited to lethargy, anomalies of muscle tone, respiratory distress and tachypnea, and seizures   . However, HMMAJ has been characterized as pathogenetically, biochemically and phenotypically similar to the cblF type  , so neurological symptoms ranging from cognitive impairment to movement disorders, apnea and decreased consciousness, and possibly psychiatric conditions and behavioral disorders may be expected in HMMAJ patients  . Visual impairment due to retinal dystrophy may be detected in ophthalmological examinations . Owing to extensive neurological disease, parents often describe feeding difficulties  .
With regard to extraneural manifestations, HMMAJ seems to be associated with an increased risk of cardiac malformations . A single patient has been reported to have experienced a transient ischemic . Beyond that, distinct cardiovascular complications have been observed in patients suffering from related disorders and may eventually occur in HMMAJ patients. Similarly, there are no case reports on renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome in HMMAJ patients even though kidney damage is a dreaded complication of related diseases . Hyperpigmentation of the skin and hypopigmentation of the hair have been observed in two HMMAJ patients and it may be speculated that affected individuals could develop other dermatological symptoms  . They are uncommon complications of cobalamin-related disorders such as homocystinuria with methylmalonic acidemia type cblC, but they are not unheard of.
It should be noted that there is only a handful of case reports on HMMAJ. Therefore, it is not possible to state whether there is a causal relationship between isolated clinical findings and ABCD4 mutations underlying HMMAJ .
Clinical findings are non-specific and little is known about the results of diagnostic imaging to be expected in HMMAJ patients. Cerebral atrophy, a common finding in those suffering from related disorders, has been reported once . 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 HMMAJ 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 in patients suffering from homocystinuria with methylmalonic acidemia  . However, decreased serum concentrations of vitamin B12 have been reported in isolated cases of HMMAJ . In any case, the confirmation and differential diagnosis of HMMAJ 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 HMMAJ, 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 HMMAJ.
Guidelines for the diagnosis and management of cobalamin-related disorders including HMMAJ 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 HMMAJ complications and pre-existing complications may not respond to treatment. In sum, data regarding the long-term outcome of HMMAJ patients is scarce but it can be assumed that most of them will experience some degree of disability over the course of their life.
HMMAJ is caused by mutations in the ABCD4 gene . This gene has also been referred to as PXMP1L, is located on long arm of chromosome 14 and encodes an ATP-binding cassette transporter initially thought to locate to the peroxisomal membrane, but more recently shown to colocalize with lysosomal proteins LAMP1 and LMBD1. Colocalization with LMBD1 is of particular interest since dysfunctional LMBD1 has been shown to trigger homocystinuria with methylmalonic acidemia type cblF  . Both proteins may actually interact with each other . In patients suffering from homocystinuria with methylmalonic acidemia type cblF, the release of cobalamin from the lysosome to the cytosol is disturbed and cobalamin is trapped inside the lysosome. It has thus been speculated that HMMAJ may be induced in a similar manner  . However, experimental evidence has not yet been provided to this end.
Available data don't suffice to establish reliable genotype-phenotype correlations  . However, ABCD4 mutation c.423C>G has been shown to give rise to a milder phenotype in two cases  .
Inborn errors of cobalamin metabolism are rare diseases, with HMMAJ being the least common one. Only a handful of patients have been described to date and ABCD4 mutations account for <1% of all cases of homocystinuria with methylmalonic acidemia     . Both males and females may be affected by HMMAJ. First symptoms usually manifest in the neonatal period or infancy, but symptom onset may be delayed until adolescence  .
HMMAJ 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 HMMAJ and related disorders.
The prenatal diagnosis of HMMAJ is feasible. Mutations in the ABCD4 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 ABCD4 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 HMMAJ 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 cblJ or HMMAJ, this form of homocystinuria with methylmalonic acidemia is the result of mutations in the ABCD4 gene. The ABCD4 gene encodes a lysosomal membrane protein and pathogenic mutations result in the accumulation of unmetabolized free cobalamin in lysosomes  . Because cobalamin export to the cytoplasm is a prerequisite for the synthesis of methylcobalamin and adenosylcobalamin, which function as cofactors for methionine synthase and methylmalonyl-CoA mutase, this condition induces functional enzyme deficiencies.
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 including, but not limited to, lethargy, anomalies of muscle tone and seizures. Occasionally, symptom onset is delayed until adolescence.
Individuals affected by homocystinuria with methylmalonic acidemia type cblJ carry mutations in a gene named ABCD4. 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 ABCD4 mutations. Children will develop the disease if they inherit pathogenic alleles from their mother and their father. Only a handful of cases have been described to date, so recommendations regarding diagnosis and treatment are mainly based on experiences with patients suffering from other forms of homocystinuria with methylmalonic acidemia. In this context, it is likely that the patients' 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 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.