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Methylmalonic Acidemia with Homocystinuria

Homocystinuria with methylmalonic acidemia (HMMA) 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. In detail, complementation groups cblC, cblD, cblF, and cblJ correspond to inborn errors of cobalamin metabolism associated with hyperhomocysteinemia/homocystinuria and excess urinary excretion of methylmalonic acid.


Presentation

Most HMMA patients appear normal at birth but may develop clinical disease within hours after birth. In other cases, children remain asymptomatic for prolonged periods of time or clinical disease doesn't become apparent until adulthood. Although a formal distinction between early and late-onset disease has only been proposed for HMMA type cblC, asymptomatic long-term survival has also been observed in other variants of the disease [1].

Failure to thrive, developmental delays, and neurological symptoms are the most common presenting symptoms. 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. HMMA patients may experience seizures and develop psychiatric conditions and behavioral disorders, with the latter being somewhat more common in late-onset disease. Affected individuals may be microcephalic. Visual impairment due to optic atrophy or retinopathy may be detected in ophthalmological examinations. Nystagmus has also been described. Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties [2] [3].

With regard to extraneural manifestations, HMMA patients are at high risks of thrombotic microangiopathy and hemolytic uremic syndrome [4], and are predisposed to cardiac malformation, cardiomyopathy, and thromboembolism. Gastrointestinal and dermatological symptoms have been described in isolated cases [3].

Pallor
  • 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]
Fatigue
  • 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]
Anorexia
  • 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]
Movement Disorder
  • 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.[symptoma.com]
Asymptomatic
  • In other cases, children remain asymptomatic for prolonged periods of time or clinical disease doesn't become apparent until adulthood.[symptoma.com]
Visual Impairment
  • Still, even adequate therapy cannot entirely prevent the development of HMMA complications and pre-existing complications like visual impairment may not respond to treatment.[symptoma.com]
Suggestibility
  • Diagnostic methods Measurement of organic acids and amino acids, in particular evidence of increased total plasma homocysteine (tHcy), is suggestive of the disease.[orpha.net]
  • Although the precise function of the ATP-binding cassette transporter encoded by the ABCD4 gene remains unknown, its colocalization with the LMBD1 protein, which is dysfunctional in HMMA type cblF patients, suggests a pathogenetic mechanism akin to that[symptoma.com]
Ataxia
  • Onset of the disorder can be early (infantile) or late (juvenile or adult), with the late-onset form characterized by ataxia, dementia and psychosis.[orpha.net]
  • 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.[symptoma.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]
Language Delays
  • Good metabolic control and correction of hematologic problems can sometimes be achieved with this treatment but most patients continue to have signs of motor and language delay, intellectual deficit and abnormal ophthalmologic findings.[orpha.net]
Behavior Problem
  • Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations[orpha.net]
Learning Difficulties
  • Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations[orpha.net]

Workup

Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging. HMMA may also be associated with hydrocephalus [3]. 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 HMMA 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]. While serum levels of vitamin B12 and folic acid can be assessed easily, the confirmation and differential diagnosis of HMMA 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 HMMA, 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. 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 HMMA.

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

Treatment

Guidelines for the diagnosis and management of cobalamin-related disorders including HMMA 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, HMMA 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 repeatedly been reported to improve disease control and is thus recommended as an additional therapeutic measure [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.

Prognosis

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 [6]. Still, even adequate therapy cannot entirely prevent the development of HMMA complications and pre-existing complications like visual impairment may not respond to treatment. In sum, data regarding the long-term outcome of HMMA patients is scarce but it can be assumed that most of them will experience some degree of disability over the course of their life [7] [8].

Etiology

The term HMMA refers to a genetically heterogeneous group of inherited disorders of cobalamin metabolism. They are all inherited in an autosomal recessive pattern. In detail, the following mutations have been related to HMMA subtypes:

  • HMMA type cblC has been related to mutations in the MMACHC gene [9]. This gene encodes for a protein presumably involved in the binding and intracellular trafficking of cobalamin. Sequencing of the MMACHC gene has subsequently been done to confirm the diagnosis of HMMA type cblC both pre- and postnatally [10]. Only recently, HMMA type cblC has been diagnosed in members of an affected family who were heterozygous for MMACHC mutations and mutations in the adjacent, reverse-oriented PRDX1 gene [11]. 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.
  • Similarly, HMMA type cblD is caused by a dysfunctional protein whose precise function has not yet been clarified. This protein is encoded by the MMACHD gene [12]. Of note, variants of this gene may give rise to homocystinuria without methylmalonic aciduria type cblD-variant 1 and methylmalonic aciduria type cblD-variant 2, rare disorders that don't fulfill the biochemical criteria of HMMA [13].
  • Mutations in the LMBRD1 gene account for HMMA type cblF [1]. This gene encodes for a lysosomal membrane protein presumably facilitating cobalamin export to the cytoplasm.
  • Finally, HMMA type cblJ is caused by mutations in a gene named ABCD4 or PXMP1L [14]. It encodes for an ATP-binding cassette transporter initially thought to locate to peroxisomal membrane, but more recently shown to colocalize with lysosomal proteins LAMP1 and LMBD1.

Genotype-phenotype correlations have been described for HMMA types cblC and cblD only [3]. With regard to the former, MMACHC mutations c.271dupA and c.331C>T, which account for almost half of all cases, trigger early-onset disease. By contrast, MMACHC mutation c.394C>T, to be found in about 20% of all patients, results in late-onset disease [15]. Concerning HMMA type cblD, missense mutations in a conserved C-terminal region and N-terminal mutations may give rise to incomplete phenotypes characterized by isolated homocystinuria and isolated methylmalonic aciduria, respectively. Patients suffering from both homocystinuria and methylmalonic aciduria and thus HMMA type cblD are likely to carry deleterious null mutations across the C-terminus [13].

Epidemiology

In general, HMMA is a rare disease. HMMA type cblC is the most common inborn error of cobalamin metabolism, with more than 250 cases reported to date [9]. Its incidence has been estimated to 1-5 in 200,000 life births [2]. By contrast, less than two dozen patients suffering from HMMA type cblD and clbF have been described in the literature [16] [17]. According to current knowledge, HMMA type cblJ has the lowest incidence of all types of HMMA and accounts for <1% of all cases [2]. Both males and females may be affected by HMMA. First symptoms usually manifest in infancy, but may be observed as early as the neonatal period or be delayed until adulthood [2] [3].

Sex distribution
Age distribution

Pathophysiology

Cobalamin-derived methylcobalamin and adenosylcobalamin function as cofactors of methionine synthase and methylmalonyl-CoA mutase. In case of HMMA, the synthesis of methylcobalamin and adenosylcobalamin is disturbed in what could be called an early common pathway [18]:

  • Cobalamin is an essential nutrient. It is absorbed in the gastrointestinal tract and is initially transported to the liver via the portal system. Cobalamin uptake in hepatocytes (and virtually all other cell types) occurs via receptor-mediated endocytosis and involves transcobalamin.
  • Lysosomal cobalamin release may be followed by cobalamin reduction and reductive methylation, thereby yielding methylcobalamin, the cofactor of methionine synthase.
  • Alternatively, reduced cob(I)alamin may be transported to the mitochondria and be attached an adenosyl group. The mitochondrial generation of adenosylcobalamin is required for methylmalonyl-CoA mutase activity.

The early common pathway mentioned above involves all reactions from cellular cobalamin uptake to the reduction of cob(III)alamin to cob(I)alamin.

  • In patients suffering from HMMA type cblF, lysosomal cobalamin release is disturbed [1].
  • Similarly, cobalamin transport seems to be impaired in those affected by HMMA type cblJ. Although the precise function of the ATP-binding cassette transporter encoded by the ABCD4 gene remains unknown, its colocalization with the LMBD1 protein, which is dysfunctional in HMMA type cblF patients, suggests a pathogenetic mechanism akin to that described for this disease [14].
  • Both HMMA types cblC and cblD may be associated with insufficient cytosolic cobalamin reduction.

In sum, genetic defects underlying HMMA interfere with early cobalamin metabolism and lead to two pathophysiological cascades implicated in neurodegeneration and extraneuronal disease progression, namely the one triggered by functional methionine synthase deficiency and the one induced by lack of methylmalonyl-CoA mutase activity. The former has been investigated more in detail; it has been hypothesized that methionine synthase deficiency results in the accumulation of neurotoxic metabolites and an overall decreased methylation capacity [3]. Little is known about the contribution of functional methylmalonyl-CoA mutase deficiency to the biochemical and clinical presentation of HMMA, but it has been speculated that methylmalonyl-CoA mutase deficiency may render HMMA patients susceptible to metabolic decompensation [2].

Prevention

The prenatal diagnosis of HMMA is feasible. Mutations in the respective genes 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 gene 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 HMMA 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 HMMA type cblC and may be considered if other forms of HMMA are diagnosed [19].

Summary

There are four types of HMMA, 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:

  • HMMA type cblC is the most common combined disorder of cobalamin metabolism and is caused by mutations in the MMACHC gene.
  • HMMA type cblD is the result of mutations in the MMADHC gene. Similar to MMACHC, this 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.
  • HMMA type cblF is caused by mutations in the LMBRD1 gene, which interfere with intracellular cobalamin transport.
  • HMMA type cblJ has been related to mutations in the ABCD4 gene, which may have consequences similar to LMBRD1 mutations.

Genetic and/or complementation studies have to be carried out to distinguish these disorders.

Patient Information

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" (HMMA) is differentiated from "homocystinuria without methylmalonic aciduria". HMMA itself is a general term referring to at least four diseases caused by distinct gene defects. However, these aren't reflected in the clinical presentation. Most patients suffering from HMMA 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, anomalies of muscle tone, apnea, and decreased consciousness. Seizures and visual impairment are also common. Occasionally, symptom onset is delayed until adolescence or adulthood.

As has been indicated above, individuals affected by HMMA carry mutations in determined genes. 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 such 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, HMMA follows a slowly progressive course and may lead to severe disability or death.

References

Article

  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. Morath MA, Hörster F, Sauer SW. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol. 2013; 28(2):227-235.
  5. 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.
  6. 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.
  7. 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.
  8. Andersson HC, Marble M, Shapira E. Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med. 1999; 1(4):146-150.
  9. 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.
  10. 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.
  11. 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.
  12. Coelho D, Suormala T, Stucki M, et al. Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med. 2008; 358(14):1454-1464.
  13. Stucki M, Coelho D, Suormala T, Burda P, Fowler B, Baumgartner MR. Molecular mechanisms leading to three different phenotypes in the cblD defect of intracellular cobalamin metabolism. Hum Mol Genet. 2012; 21(6):1410-1418.
  14. Coelho D, Kim JC, Miousse IR, et al. Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. Nat Genet. 2012; 44(10):1152-1155.
  15. 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.
  16. 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.
  17. Miousse IR, Watkins D, Coelho D, et al. Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism. J Pediatr. 2009; 154(4):551-556.
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  19. 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.

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Last updated: 2019-07-11 19:56