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Homocystinuria without Methylmalonic Aciduria Type cblG

Methylcobalamin Deficiency

Homocystinuria without methylmalonic aciduria is a rare metabolic disorder. There are three types of the disease, all of which are inherited in an autosomal recessive manner and caused by a functional deficiency of methionine synthase. Homocystinuria without methylmalonic aciduria type cblG is the result of quantitative methionine synthase deficiency, whereby this enzyme is required for the metabolization of homocysteine. Individuals suffering from methionine synthase deficiency have megaloblastic anemia, which is why the disease is also referred to as homocystinuria with megaloblastic anemia type cblG (HMAG). Patients also present diffuse encephalopathy and developmental delays.


Presentation

HMAG 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 adulthood in isolated cases [1]. Furthermore, HMAG may follow a mild, non-progressive course during childhood and adolescence, but induce a neurological deterioration in adulthood [2].

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 [3] [4]. Psychiatric conditions and behavioral disorders are not usually observed in HMAG patients but are frequently described in those suffering from related disorders [4]. HMAG patients may experience seizures, though. Visual impairment due to optic atrophy or retinopathy may be detected in ophthalmological examinations. Nystagmus has also been described [5] [6]. Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties [3] [4].

Renal involvement resulting in thrombotic microangiopathy and hemolytic uremic syndrome has been reported in two cases only [7] [8]. Cardiovascular complications are frequently observed in patients suffering from remethylation disorders and have also been described in HMAG patients. Indeed, one of those patients who developed hemolytic uremic syndrome also suffered from progressive pulmonary hypertension [7].

Movement Disorder
  • [symptoma.com] 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]
Feeding Difficulties
  • Owing to extensive neurological disease, parents often describe feeding difficulties.[symptoma.com]
Failure to Thrive
  • Most of them are soon presented to the pediatrician, showing failure to thrive, developmental delays , and neurological symptoms.[symptoma.com]
Long Arm
  • [symptoma.com] Musculoskeletal Long Arm This gene is located on the long arm of chromosome 1 and encodes for methionine synthase, a cobalamine-dependent enzyme catalyzing the conversion of homocysteine to methionine.[symptoma.com]
Visual Impairment
  • Seizures and visual impairment are also common. If left untreated, these diseases follow a slowly progressive course and may lead to severe disability or death.[symptoma.com]
Behavior Disorder
  • Psychiatric conditions and behavioral disorders are not usually observed in HMAG patients but are frequently described in those suffering from related disorders. HMAG patients may experience seizures, though.[symptoma.com]
Suggestibility
Peripheral Neuropathy
  • Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties.[symptoma.com]
Nystagmus
  • [symptoma.com] Nystagmus Nystagmus has also been described. Peripheral neuropathies may be identified. Owing to extensive neurological disease, parents often describe feeding difficulties.[symptoma.com]

Workup

Neurological symptoms are due to diffuse encephalopathy and cerebral atrophy, which are conditions that may be verified by means of diagnostic imaging [4]. HMAG may also be associated with hydrocephalus [6]. Rarely, affected individuals are microcephalic [9]. All 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 and thrombocytopenia or pancytopenia are to be expected. Despite megaloblastic anemia being a hematological hallmark of HMAG, it is not a constant feature: Patients have been described to present macrocytic anemia without megaloblastic cells, or to show macrocytosis without anemia [2] [10]. While megaloblastic changes are usually identified in bone marrow samples, this finding should neither be considered an exclusion criterion [10].
  • Hyperhomocysteinemia, hypomethioninemia, and homocystinuria are common findings in blood chemistry and urine analysis and point at a remethylation disorder. Concentrations of methylmalonic acid are within physiological ranges [3]. Although hyperhomocysteinemia, hypomethioninemia, and normal levels of methylmalonic acid constitute the classic symptom triad of HMAG, patients may not present all of these symptoms [11] [12].

These results don't allow for a reliable diagnosis of HMAG 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 [4]. While serum levels of vitamin B12 and folic acid can be assessed easily, the differential diagnosis of remethylation disorders and other inherited conditions requires genetic studies. Enzyme activity measurements in fibroblasts or lymphocytes constitute an alternative approach to HMAG diagnosis, but are more cumbersome and don't provide any information as to the specific mutation in the MTR gene. Still, such assays have to be carried out if mutations cannot be identified despite strong suspicion [4]. Concerning the results of enzyme activity assessments, the following may be expected:

  • In case of HMAG, methionine synthase activity is decreased under all assay conditions.
  • In case of homocystinuria without methylmalonic aciduria type cblE, methionine synthase activity is within reference ranges when assayed under standard conditions including exogenous reducing agent [13].
  • Fibroblasts derived from patients with homocystinuria without methylmalonic aciduria type cblD-variant 1 behave similar to those derived from HMAG patients but may be recognized by somatic cell complementation or genetic studies [4] [14] [15].
Macrocytosis
  • Serum Macrocytosis Despite megaloblastic anemia being a hematological hallmark of HMAG, it is not a constant feature: Patients have been described to present macrocytic anemia without megaloblastic cells, or to show macrocytosis without anemia.[symptoma.com]
Macrocytic Anemia
  • Despite megaloblastic anemia being a hematological hallmark of HMAG, it is not a constant feature: Patients have been described to present macrocytic anemia without megaloblastic cells, or to show macrocytosis without anemia [2] [10].[symptoma.com]
Diffuse Encephalopathy
  • [symptoma.com] Other Pathologies Diffuse Encephalopathy Patients also present diffuse encephalopathy and developmental delays. HMAG patients appear normal at birth.[symptoma.com]

Treatment

Guidelines for the diagnosis and management of cobalamin-related remethylation disorders including HMAG have recently been published [4]. 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, HMAG 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 [4].
  • The administration of folate and betaine has repeatedly been reported to improve disease control and is thus recommended as an additional therapeutic measure [2] [16]. 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, motor function, and alertness, 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. Still, even adequate therapy cannot entirely prevent the development of HMAG complications. Ophthalmological complications of HMAG don't usually respond to treatment and progressive visual impairment is common despite compliance with therapeutic regimens [4]. Treatment failure seems to be more common in HMAG patients than in those suffering from homocystinuria without methylmalonic aciduria type cblE although this fact could not yet be explained [16].

Etiology

HMAG is related to mutations in the MTR gene. This gene is located on the long arm of chromosome 1 and encodes for methionine synthase, a cobalamine-dependent enzyme catalyzing the conversion of homocysteine to methionine. Despite the rarity of the disease, more than a dozen MTR mutations have been reported to date, the most common one being missense mutation c.3518C>T. This mutation may account for more than half of all cases [1]. Still, genotype-phenotype correlations have neither been established for missense mutation c.3518C>T nor for other, generally private MTR mutations [5].

Epidemiology

HMAG is a rare disease. About two dozen patients have been described to date [3] [4]. Both males and females may be affected by HMAG. First symptoms usually manifest in infancy, but may be observed as early as the neonatal period or be delayed until adulthood [1].

Sex distribution
Age distribution

Pathophysiology

Under physiological conditions, methionine synthase catalyzes the conversion of homocysteine to methionine. 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 HMAG 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 [4].

It could not yet be clarified whether methionine synthase fulfills non-enzymatic functions. If this was the case, the dysregulation of the respective processes would constitute another pathogenetic mechanism in HMAG and related disorders.

Prevention

The prenatal diagnosis of HMAG is feasible. Mutations in the MTR 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 MTR 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. While an increased concentration of homocysteine in amniotic fluid may indicate a number of remethylation and transsulfuration disorders, decreased activity of methionine synthase reductase in cultured amniotic cells specifically suggests HMAG [4].

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 HMAG is diagnosed [17].

Summary

There are three types of homocystinuria without methylmalonic aciduria, namely cblD-variant 1, cblE, and cblG [15] [18]. All of them are induced by functional methionine synthase deficiency and resemble each other in their clinical presentation, but they differ in how methionine synthase deficiency is caused. With regard to type cbIG or HMAG, this form of homocystinuria without methylmalonic aciduria is the result of mutations in the MTR gene. The MTR gene encodes for methionine synthase, an enzyme required for the remethylation of homocysteine to methionine. Thus, HMAG-related functional methionine synthase deficiency results from quantitative methionine synthase deficiency.

Because cobalamin functions as a cofactor for methionine synthase, HMAG may also be classified as an inherited disorder of cobalamin metabolism. The abbreviation cbl stands for cobalamin.

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" 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 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. If left untreated, these diseases follow a slowly progressive course and may lead to severe disability or death.

Individuals affected by homocystinuria without methylmalonic aciduria type cblG carry mutations in a gene named MTR. 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 MTR mutations. Children will develop the disease if they inherit pathogenic alleles from their mother and their father. Their prognosis largely depends on their age at the time of diagnosis and the 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.

References

Article

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  2. Carmel R, Watkins D, Goodman SI, Rosenblatt DS. Hereditary defect of cobalamin metabolism (cblG mutation) presenting as a neurologic disorder in adulthood. N Engl J Med. 1988; 318(26):1738-1741.
  3. 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.
  4. 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.
  5. Huemer M, Burer C, Jesina P, et al. Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis. 2015; 38(5):957-967.
  6. Poloschek CM, Fowler B, Unsold R, Lorenz B. Disturbed visual system function in methionine synthase deficiency. Graefes Arch Clin Exp Ophthalmol. 2005; 243(5):497-500.
  7. Labrune P, Zittoun J, Duvaltier I, et al. Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr. 1999; 158(9):734-739.
  8. Vaisbich MH, Braga A, Gabrielle M, Bueno C, Piazzon F, Kok F. Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls. Pediatr Nephrol. 2017; 32(6):1089-1092.
  9. Wilson A, Leclerc D, Saberi F, et al. Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Am J Hum Genet. 1998; 63(2):409-414.
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Last updated: 2019-07-11 19:53